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Therapy & Research
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Highlights
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2018 ALS
Update, Mayo Clinic
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Promising
Drug: Ibudilast
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Possible
Therapy: Acthar® Gel
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BIIB067: Gene
Therapy On The Cusp?
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Virus &
Retrovirus As A Cause
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Primary
Lateral Sclerosis (PLS)
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Care
Management: How to Win
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Find the Best
Clinical Trials
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Stem Cell
Frauds
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How to Fall
Asleep Without Drugs
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Acthar® Gel Trial
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A Phase 1 “pilot” study of Acthar® Gel (Repository Corticotropin Injection) has ended, and
a new Phase 2b trial
has started. Corticotropin is a
hormone produced by the anterior pituitary gland that stimulates the
adrenal cortex.
A total of 43 patients participated in the Phase 1
study. All 43 received Acthar
subcutaneous injections daily for 36 weeks
(9 months), and 21 of the 43 continued for an additional 48 weeks (12
months).
After 36 weeks (9 months) the ALSFRS-R
scores of Acthar recipients decreased by a mean 4.3 points, whereas the
scores of the control group decreased by 6.6 points.
Thus, due to the Acthar® Gel, the functional decline was 35% less than that
of controls.
At the end of the second 48-week period (that is, 84
weeks elapsed time or 21 months) there was still a reduced decline in
function loss; however, the reduction was not so great as the initial
36-week reduction.
The new Phase 2b trial NCT03068754
will enroll 213 patients and is
being held at 39 centers.
Some features of the study:
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The accepted age
range is 18-75.
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The study is randomized on a 2:1 basis. So, for every 2 patients receiving the experimental
therapy, one will not (a placebo instead).
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Like most
other agents, this one does NOT restore capabilities, but attempts to slow
the physical decline.
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It requires
daily visits to the treatment facility.
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More details here,
including the Eligibility Criteria.
The drug will probably
not disqualify the patient from future Stem Cell trials.
The study provides for a 36-week double-blind
treatment period with the primary efficacy endpoint at week 36. After week-36 participants can continue
in a 48-week, open-label extension in which all participants receive the experimental
therapy.
For details on the
completed Phase 1 trial and a copy of the Phase 2d Trial Description download
this file. And some research
details are found in this
manufacturer document.
Acthar®
Gel Trials Halted – Permanently
In July 2019 the
independent Data and Safety
Monitoring Board, created by the manufacturer, halted the Phase 2b trial after careful analysis found that
Acthar Gel® was too great a pneumonia risk for ALS patients who experience increased
pneumonia susceptibility as the disease progresses. The board, created to comply with
industry best practice, cited “other
adverse events” as well. See this
news release from manufacturer Mallinckrodt.
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ALS History & Background
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ALS Update 2018,
Mayo Clinic
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This
excellent May
2018 article offers speculation on the causes of ALS, and outlines the
prospects for current and some anticipated
therapies.
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Drugs in Development
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This
fine
2017 article describes most of the therapies under development. It is somewhat dated, and some of the
cited trials are now finished.
However it is a good article on the subject.
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The Search For A Cause
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This
comprehensive 30-page
article summarizes the findings of research on the possible causes of this disease.
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20 Years of Disappointment
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Clinical
trials must be chosen carefully and must NOT be based solely on animal
research. Nearly all human trials
fail, but they all begin with successful animal studies. This
excellent 2017 article tells the history of ALS trial failures – what
worked and what didn’t.
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ALSFRS-R, The ALS Functional Rating Scale
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This
scale is used by all neurologists to determine progress or decline, and to
determine eligibility for clinical trials.
The best score is 48 and declines from there.
The ALSFRS-R score can be
computed using the online form here,
or can be calculated from a downloadable
form.
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AMX0035 Trial
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The AMX0035 Phase 2 trial has two parts: An ongoing
randomized trial NCT03127514
(lasting 24 weeks) and an open-label extension trial NCT03488524 (lasting
12 months). They are taking place at
more than 20 sites in the US. The extension trial was added in March
2018.
AMX0035 is a combination of two older drugs, Sodium
Phenylbutyrate (NaPB) and Tauroursodeoxycholic Acid (TUDCA), whose activity
against ALS is claimed but not fully proven.
Regrettably, the new Phase 2 trials are NOT based upon a Phase 1 AMX0035 trial or
upon combined NaPB+TUDCA, but upon two independent
trials – one evaluating NaPB
and the other assessing TUDCA.
Here is what those earlier trials found:
1.
NaPB Trial. In 2009 researchers for the Phase 2 NaPB trial reported
that oral NaPB increased Histone Acetylation within the bloodstreams of its
26 ALS test subjects. Because Histone
Acetylation promotes cell survival, they speculate that ALS victims would
benefit.
There was no direct evaluation of ALS
functional decline or symptom control – no determination of whether
increased Histone Acetylation translates into ALS patient betterment – just
presumption that NaPB will do so (which is not trustworthy science).
And, the trial size was very small (n=26). So, it is unrealistic to extend the
findings with confidence to the larger ALS population.
The NaPB dose was 9 to 21g/day for a 20-week
period, although 9g/day was reported
to be “therapeutically efficient in improving
Histone Acetylation levels.”
In the current trial, without
explanation, NaPB dosage is reduced
by one-third, to 6g/day. In trial NCT03488524 AMX0035
is administered “twice daily – a combination including 3gram of [NaPB]
and 1g TUDCA” – thus a daily total of 6g NaPB plus 2g TUDCA.
Finally, it has been 9 years since this drug was used in an
ALS trial. Why is it revisited now,
when no other researcher in 9 years considered it valuable?
2.
TUDCA Trial. The TUDCA Phase 2 trial, described in this
2015 Italian report, was also very small at 29 patients. Smaller still, since only 15 patients
received the drug, administered at 2g per
day for 54 weeks.
TUDCA is a bile acid which is claimed
to have “potential
neuroprotective activity” as well as “cytoprotective [cell protection] and anti-apoptotic [anti-cell suicide] action.”
By comparing the ALSFRS-R
declines between the two groups – the 15-member test group and the 14-member
control (placebo) group – researchers
claimed “slower
[disease] progression in the TUDCA than in the
placebo group.”
The earlier TUDCA trial had the
following additional findings:
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TUDCA
patients had “A lesser decline in lung function.”
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“At the end of the 54-week treatment period,
patients in the TUDCA group had a mean ALSFRS-R score corresponding to that
of the placebo group at week 36. This suggests that a 1-year TUDCA
treatment may slow ALS deterioration
by 18 weeks.
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“TUDCA treatment was also associated with a less
pronounced deterioration in muscle strength and quality of life.
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“It is arguable that prevention of deterioration
is more achievable in the earlier stages
of ALS, when a greater number of motor neurons are still viable.” [This is
not a unique finding; other trials have reached the same conclusion.]
It is very difficult to extend these findings to the
general ALS population with any reliability, because the sample size was so
small.
And there was an anomaly: Within the TUDCA group 87% were responders. Yet 43% of subjects in the placebo group
were also responders, suggesting a problem with the sample size or the
definition of response – producing an exaggeration of the drug’s
effectiveness.
After reading this, perhaps the reader can appreciate
the value of unearthing the prior human trials which underlie the new human
trial.
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AMX0035’s 2-Part Trial NCT03127514 & NCT03488524
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The new AMX0035 trial, of which there
are two parts, has the following features among others:
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This drug
combination, NaPB+TUDCA, with its unproven synergy, has never been tried
before. This is essentially a Phase 1 trial, not a Phase
2 trial. So, we have no guidance
whatsoever based upon prior human experience. The NaPB+TUDCA combination has not been tested for efficacy even in animal studies.
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Trial NCT03127514,
lasting 24 weeks, was 2:1 randomized, so one-third
of participants did not receive the experimental drug. It was held at more than 20 sites in the USA. Enrollment was limited to 132 patients,
18-80 years of age whose ALS onset must have been within 18 months.
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Trial extension
NCT03488524 ,
lasting 30months, is open only by
invitation to the 132 participants of the initial randomized
study. All participants receive the
drug open-label. This extension is
housed only at two sites: Massachusetts
General Hospital
and University of Massachusetts Memorial Medical Center.
Review
the Trial Descriptions for information including Eligibility Criteria, here and here.
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AMX0035’s 2-Part Trial Update
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In December 2019 the Wall
Street Journal reported favorable, but partial, results from these
trials. According to drug
manufacturer Amylyx Pharmaceuticals, “The
drug slowed the rate of ALS’s progression.” Project researchers added that release of
specific performance numbers will have
to await the publication of their journal article or conference report in
2020.
The
WSJ report cited the experience of one trial participant who said that her
ability to talk had been gradually declining before the trial, but stabilized while in the study. After it ended, she lost fine motor skills
and had more trouble walking and swallowing until she began taking the drug
again under the trial extension.
In nearly all trials some participants benefit, but many (or most) do not. Some ALS specialists
are cautious about the results to date. Six months, isn’t long enough to answer
the key questions: Whether the drug would prolong lives, whether it slowed
ALS progression and whether the drug impacted specific functions,
especially breathing, questioned Raymond Roos, director of the ALS
treatment center at the University of Chicago Medical Center. Dr Roos is not a project researcher.
The manufacturer, Amylyx Pharmaceuticals
Inc, was launched in 2013 by two medical science students using $6,000 in personal savings and family donations. It had three employees in March 2019 and
seven by late 2019.
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AMX0035 Availability
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No additional trials are scheduled as yet. However, the relevant drugs, Sodium
Phenylbutyrate (NaPB) and Tauroursodeoxycholic
Acid (TUDCA), are readily available:
NaPB under prescription and TUDCA as an unregulated supplement. One must be certain that the TUDCA is
certified as pure and not China
sourced.
And, the NCT03488524 trial
description gives the desired dosages: “AMX0035 twice daily – a combination therapeutic
including 3 gram of Phenylbutyrate [NaPB] and 1g TUDCA.” That is a daily total of 6 grams NaPB
plus 2 grams of TUDCA.
Although these (or greater) dosages have been used
in past human ALS research (revealing Phenylbutyrate and TUDCA
dosages) the user must be especially
careful to assure that there are no counter-indications; that the
drugs are consumed under the correct conditions, and that the untried
combination will be tolerable.
For example, Sodium Phenylbutyrate should be used
with great care, if at all, by patients with congestive heart failure,
renal insufficiency or propensity toward sodium retention with edema. Physician
monitoring is essential.
TUDCA is relatively expensive – often $5 per
gram. However, this UK supplier
offers a price of approximately $2 per gram. If better prices are found, this section
will be updated with that information.
NaPB’s
FDA label is available
here, and additional TUDCA information is available
here.
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Arimoclomol
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Arimoclomol is currently being tested in Phase 3
trial NCT03491462,
described here.
This Phase 3 effort, which adds sporadic patients,
was created after the earlier Phase 2/3 trial failed to accrue enough SOD1
patients for the Phase 3 part of the research.
This review will evaluate two aspects of
Arimoclomol: (1) whether the agent can be expected to perform well and (2) whether Arimoclomol is suitable for BOTH
familial and sporadic forms of the
disease.
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Performance
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The
principal efficacy numbers come from the small Phase 2/3 trial of 36 SOD1
mutation patients, 17 of whom received Arimoclomol and 19 a placebo. The 2018 trial report is downloadable
here.
The functional decline in Arimoclomol-treated
patients was 2.5 ALSFRS-R points per month, versus 3.0 points per month for
the placebo group. This is a very
beneficial 0.5 point per month reduction. SOD1 patients tend to decline more
rapidly than sporadic patients.
And, the reduction in decline was more pronounced
in patients afflicted with the A4V subset
of SOD1, which progresses more rapidly.
The drop was 2.6 ALSFRS-R points per month in the Arimoclomol group,
versus 3.6 points in the placebo group – a reduction of 1.0 points per
month.
Although the numbers are favorable, the researchers
are cautious in their assessment, stating: “The study lacked the precision
to conclude, or to exclude, an important therapeutic benefit of
Arimoclomol.”
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Suitable for Sporadic ALS?
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In
familial ALS the mutant SOD1 protein becomes
toxic, leading to rapid loss of motor neurons.
Arimoclomol works by increasing the Heat Shock Protein
(HSP) response, especially the favorable HSP70 version. HSP70 can bind to faulty SOD1 and remove
it.
The relevance of HSP70 to the new Phase 3 trial is that
HSP70 enhancement (and thus Arimoclomol) may
not help sporadic ALS patients, even though sporadic patients are
being recruited.
The authors of the Phase
2 trial report, who also lead the Phase 3 trial, state:
“Arimoclomol’s mechanism of action is likely to be
relevant to all forms of ALS in which aberrant proteostasis plays an
essential role in disease pathophysiology.”
“Aberrant proteostasis” exists
when the SOD1 mutation and misfolded proteins are present. The researchers add: “Generalizability of the
preliminary efficacy results to non-SOD1
and more slowly progressive ALS is less
clear . . . ”
So, the authors suggest that
Arimoclomol is less likely to help sporadic patients. Further, the relevance of SOD1 and
Arimoclomol to sporadic patients is confused by two recent research
reports.
In 2017 University
of California research declared: “Whereas
misfolded SOD1 is readily detectable in samples from patients with SOD1
mutations, it is below detection limits for , , , patients with sporadic or
non-SOD1 inherited ALS . . . SOD1 misfolding is not a primary component of
sporadic ALS.”
However, a 2018
Canadian-Sweden report appeared to disagree: “Five different misfolded SOD1 staining patterns were found
consistently in tissue sections from sporadic ALS cases . . . ” supporting
“a possible pathological role of misfolded SOD1 in sporadic ALS.”
Perhaps, then, SOD1 misfolding is not a primary
sporadic component, but appears only in trace amounts. In either case, the sporadic patient is likely to benefit less
than the familial SOD1 patient from this Phase 3 clinical trial.
In summary, Arimoclomol boosts HSP70 which tends
to neutralize the harmful misfolded SOD1 proteins afflicting familial
patients. In contrast sporadic
patients possess few SOD1 proteins, so are less likely to obtain the indefinite
Arimoclomol benefit.
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Trial Features
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The
ongoing Phase 3 trial has the following features. More information at NCT03491462.
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Patient
enrollment is 231 at 23 study locations for a period of 19 months
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Patients 18
years and older are accepted
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Randomized
double-blind design; so, only half get the experimental agent
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No more than
18 months since first symptoms, ALSFRS-R equal > 35 and SVC% >
80%.
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BHV-0223 (Riluzole)
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Riluzole has been available for 20 years, the only
FDA-approved drug before the advent of Edaravone.
Like Edaravone, it can only slow the progression
of the disease, but most patients are non-responders, meaning that they
gain nothing from the drug.
However, to increase
its effectiveness two agents have been combined with Riluzole in
recent research: Ibudilast and
Masitinib (discussed below).
Learn about the Ibudilast
research here and the Masitinib research here.
Finally, new research from the UK (report
published in 2018) has found that Riluzole is effective during the last stage of the disease, Stage 4, but
not during Stages 2 or 3.
The recent UK
research did not determine Riluzole efficacy during Stage 1. However, if Riluzole is used during Stage
1, there could be added benefit to combining it with either Ibudilast or Masitinib
(although it could be used without them to lesser effect).
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BIIB067 (Tofersen) Trial
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Be sure to get tested for the inherited SOD1
defect, a cause of familial ALS.
Absent testing, one cannot rule out this heritable form of the
disease.
This BIIB067 trial, of which there are two parts,
is a Gene Therapy effort seeking to
moderate the SOD1 gene. BIIB067 is
injected into the spinal fluid.
BIIB067, an AntiSense Oligonucleotides (ASOs), COULD be a minor breakthrough for
hereditary SOD1 ALS patients. ASOs
seek to block the creation of SOD1 protein.
Although BIIB067 is not a cure, it might slow
neurologic decline long enough to get the SOD1 patient to the next
generation ASO.
This therapy is applicable to only 2% of all ALS
cases. SOD1 occurs in only 15% of
familial (inherited) ALS cases, and familial cases represent about 10% of
all ALS cases (15% x 10% = 1.5%).
The initial Phase 1/2 BIIB07 trial NCT02623699, now
closed, was randomized, accepted 84 patients and will last about 6
months. A Phase 1/2 long-term continuation
trial NCT03070119
accepts 48 patients, but those patients must have completed the initial
trial. The continuation study is
non-randomized and will last about 2 years.
Clues to BIIB067 performance can be
found in two completed efforts: (1) an earlier-generation ASO used in human
trial NCT01041222
and (2) a second-generation ASO used in a more
recent animal study.
The early human trial, concluded in 2012, studied
patient tolerance and safety but not efficacy. There were 21 treated patients of whom 11
received 2 separate ASO treatments over a 12-month period.
Some performance indicators for the early-ASO were
revealed in the human
trial’s 2013 report:
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The trial did
not show a reduction in SOD1 protein, a requirement for successful
performance. Further,
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“ALSFRS-R and FVC were generally
stable during the study and did not differ between placebo and [ASO] treated participants.” This means
that the early ASO formula provided NO benefit
to the 11 treated patients.
That early-ASO effort was sponsored
by Ionis Pharmaceuticals. Later,
Biogen (a Roche Laboratories subsidiary) joined Ionis for the development
of a second-generation ASO called BIIB067.
Subsequently, in late 2018
Biogen acquired from Ionis the exclusive rights to develop and
commercialize BIIB067.
BIIB067, the second-generation
ASO, was used to treat animals afflicted by the SOD1 ALS mutation. The 2018
report on that research revealed the following:
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The
BIIB067-treated mice maintained their weight 26 days longer and lived 37
days longer (22% longer) than the placebo mice.
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Treated SOD1 mice experienced improved
muscle function over the weeks following treatment.
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While both
treated and placebo mice showed increasing signs of neurological damage,
the placebo mice exhibited symptoms twice as quickly.
● ASOs may benefit an ALS population beyond strict
SOD1-mutant patients, to include “misfolded SOD1” patients. But that is mere speculation at this
time.
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Researchers
warn: “While we are . . . encouraged
by the demonstration of reversal in these studies, we recognize that these
results . . . may not . . . translate to humans.” [Most often the animal-to-human translation
does NOT occur.]
Some features of the BIIB067 trials:
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Participants
must have a diagnosis of SOD1-ALS.
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The Phase 1/2
BIIB07 trial NCT02623699,
active but closed, is randomized, using multiple ascending doses, and lasts
about 6 months. Some patients do NOT
receive the experimental agent.
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It enrolled 84
patients “18 years and older” and
is operating at 17 locations, including Johns Hopkins and Massachusetts General Hospital.
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A Phase 1/2
long-term continuation trial NCT03070119 is
non-randomized (all patients receive the agent), but assigns patients to
any of 4 BIIB067 doses.
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The
“continuation trial” will enroll 48 patients “18 Years and older.” But,
those patients must have fully completed the initial trial.
● The continuation trial will last about 2 years and
is available at 14 locations, including sites in Baltimore
and Boston.
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Results, BIIB067 (Tofersen) Phase
1/2 Trial
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In
May 2019 researchers released results for the double-blind, 3:1 randomized,
placebo-controlled trial NCT02623699, which
was conducted at 17 sites in North America and Western Europe.
The outcome is summarized in this
Biogen press release. However,
far greater detail is provided
in this poster report, which was presented at the 71st Annual Meeting of
the American Academy of Neurology. A separate copy of the 2019 Tofersen
conference poster is downloadable here.
Although the research tested both Single Ascending
Dose (SAD) AND Multiple Ascending Doses (MAD), only the repeated-dose MAD is discussed in the poster
report, specifically repetitive doses of 20, 40, 60, 80 or 100mg of
Tofersen vs placebo, each given to separate cohorts.
Over the 85-day period (approximately 3 months)
each dose was administered 5 times, at intervals of 15 to 30 days. There were approximately 10 patients (9
to 12) in each cohort.
Among
the findings are the following:
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In the Cerebrospinal Fluid
(CSF) SOD1 concentrations declined for Tofersen doses 40, 60 and 10mg. SOD1 decline is desirable. But, maximum reduction occurred in the
100mg cohort, a 37% SOD1 reduction
compared to the placebo group.
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By Day-85 the Tofersen 100mg cohort displayed a slowing of
functional decline (ALSFRS-R): -1.1 vs -5.3.
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For that cohort the
decline in respiratory function (SVC) also slowed: -6.4 vs -14.8, as did
the decline in muscle strength (HHD): -0.03 vs -0.30.
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According to the
researchers, the benefit of Tofersen, compared to placebo, “was
most apparent [pronounced] in participants with fast progressing disease.” In the ALSFRS-R
graph of Figure 4, downloadable
here, the blue and red dotted lines represent “fast
progressive” patients.
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If that
poster graph is drawn precisely, members of the 100mg cohort, on
average, began to improve during the last 30 days of the trial. And, the improvement seen on Day-85 is nearly
as good as the condition which members exhibited on Day-15.
Unfortunately, none
of these benefits can be assured for the larger SOD1 ALS population,
because the sample and cohort sizes are exceedingly
small. But, the findings are
hopeful and argue in favor of the much larger 183 participant trial now
underway, and described immediately below.
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Phase 3 Trial, Ongoing
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Trial
NCT02623699
is similar to the Phase 1/2 trial, but with a far larger enrollment of 183,
compared to the 84 in the Phase 1/2 study.
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Like the
earlier trial it has three parts.
However, Parts A and B were completed by January 2019. Part C may still be recruiting the 99
participants sought for that component.
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The
participant must have a confirmed SOD1 mutation and no past therapy via
RNA, stem cell or gene therapy. Be
sure to review the trial
description for other Eligibility Criteria.
● The trial is being conducted a 28 locations in
North America, Australia
and Europe, and participation lasts for
approximately 200 days (one half year).
This is very hopeful research,
albeit for 2% of the ALS population.
And, Biogen may eventually apply its large resources to sporadic ALS
as well.
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CK-2127107 (Reldesemtiv)Trial
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This drug MAY boost muscle function. It does
not restore muscle mass but instead increases the calcium
sensitivity of “fast skeletal muscle.”
In other words CK-2127107 gets more oomph from the remaining muscle. It does not halt overall physical decline. One should not expect improvement or even
disease stability.
CK-2127107 is a FSTA, a Fast Skeletal muscle
Troponin Activator, which has little of no effect on slow skeletal or
cardiac muscle. Tirasemtiv is an
early-version FSTA. CK-2127107 is an
advanced FSTA.
CK-2127107 is currently being tested in the Phase
2 trial NCT03160898
at more than 50 centers.
There was a Phase
1 trial (more akin to a laboratory
experiment) which was double-blind, randomized and
placebo-controlled. However, this early
trial utilized healthy adults and compared CK-2127107 to Tirasemtiv, the first FSTA studied in humans.
The Phase 1 trial report, found
here, describes the carefully-designed tests
conducted by the drug manufacturer.
Within a confining apparatus the volunteer’s leg was electrically
stimulated and the muscle force measured.
Tests began hours after consuming the drug and
ended on the same day. A 7-day drug
“washout period” was instituted between drug doses.
The key part of the trial employed 16 healthy male adults and had this
overall finding: “CK-2127107
has shown comparable effects at less than half the concentration of Tirasemtiv
and has generated more than twice the increase in peak force at electrical
stimulations.”
The ongoing Phase 2 trial NCT03160898 is based
solely on the Phase 1 laboratory experiments plus the past history of the
earlier FSTA drug, Tirasemtiv.
Interested trial participants should NOT expect to acquire true muscle restoration or even a slowing of the disease. Only some improved muscle strength from
the same muscle mass can be expected.
Some features of the Phase 2 trial:
● Enrollment is limited to 445 and 18-80 years of
age.
● The trial is double-blind and randomized (1:1:1:1)
to receive either 300, 600 or 900 mg/day or placebo. So, one-fourth of participants will not
receive the experimental drug.
● Different trial arms will receive different
dosages, either 300, 600 or 900 for 12 weeks (3 months).
● Excluded are patients who have received or are considering receiving during the course of the study any form
of stem cell or gene therapy.
●
More
information is here,
including Eligibility Criteria.
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CK-2127107 Phase 2 Trial Update
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In May 2019 at the American Academy
of Neurology Annual Meeting, Cytokinetics
reported on its Phase 2 trial NCT03160898. Graphics from that report are available
through Global
News Wire.
A total of 458 patients participated, recruited
from centers across the U.S.,
Canada, Europe, and Australia. During the 12-week trial,
the effects of three different doses of Reldesemtiv were compared to a
placebo. When each dose was compared
separately to the placebo, there was no
statistically significant difference in physical decline between
drug and placebo.
However, when all three dosage
groups were pooled together, there
was a 27% reduction (1.7 points) in
SVC decline compared to the placebo (a decline of 4.8 rather than 6.5) and
a 25% reduction (0.9 points) in ALSFRS-R decline (a decline of 2.6 rather than 3.5).
SVC (Slow Vital Capacity measures respiratory
function, and ALSFRS-R (ALS Functional Rating Scale Revised) measures the
ability to perform daily functions such as speech, swallowing, and
dressing.
Below, the graph compares
ALSFRS-R decline, Reldesemtiv group compared to
placebo group. The SVC graph
displays a very similar pattern.
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Some additional matters:
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Although
there were reductions in decline, there was continued deterioration
nevertheless. The decline reductions
were not large, and a test period
of 3 months is not great.
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The decline
reductions continued even after the drug
was halted. Note the “Off
Drug” section of the graph above.
●
The drug
raised safety questions: The
frequency of Cystatin C increases occurred as the dose increased. A Cystatin C increase indicates reduced
kidney function. In the placebo
group 2% of participants experienced a Cystatin C increase, as did 7% of
the 300 mg group, 8% of the 600 mg group and 17% of the 900 mg group.
●
Reldesemtiv
slows decline in the muscle control needed for speech. See
this report.
●
For patients
suffering slower progressing disease no significant difference between
Reldesemtiv and placebo was observed.
●
Patients on
placebo had a slower-than-anticipated decline through 12 weeks, showing an
average drop of 6.5 percentage points. Researchers had expected the decline to be
8 percentage points, based on previous studies.
The
manufacturer is preparing for a possible Phase
3 trial which might begin in 2020.
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Diet and Exercise
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Diet and Foods: Diets
and supplements are the measures least likely to control ALS. However, if a measure is based on serious
research by a prominent research center, it can do little harm to try them,
unless, of course, their time or cost detracts from other, more
reliable aids.
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High-Calorie Requirement. Generally, ALS specialists
agree that, if the ALS patient maintains or
gains body weight, there is a prospect that he will live better and
longer than he would if underweight.
According to recent research reported
in 2018, nearly half of ALS patients are hypermetabolic (unable to assimilate
calories fully), resulting in weight loss.
Thus, for hypermetabolic patients an exceedingly high-calorie
diet of carbohydrates, fats and proteins is beneficial – extending life and
wellbeing according to research
reported in 2014.
In that study successful ALS patients consumed
about 50% more calories than would
be required by healthy humans.
Research into helpful diets has
produced evolving results over time.
Some early reports, principally
based upon animal research,
cautiously favored high-fat, Ketogenic-type diets. In this
earlier 2013 article from Harvard
Medical School,
researchers cautiously favor a high-caloric, high-fat diet. And, French researchers in this 2018
article theorize that a high-fat diet MIGHT prove helpful, based on their
metabolic assumptions derived from animal studies. But, human outcomes do not always mimic
animal models.
In this
2015 journal article describing human
trials, the authors report favorable outcomes for high-caloric
diets, principally high-carbohydrate diets, compared to a “regular diet.”
That journal article relies upon this
2014 report of a Phase 2 trial which studied 24 tube-fed patients, who were
randomized to a high-carbohydrate diet, to a high-fat diet or to an
isocaloric diet (the control).
The researchers, representing 10 USA
institutions, reported the following
findings in that 2014 article:
●
“Participants in the HC [High
Carbohydrate] arm gained on average 0.39 kg/ month, consuming 1.54±0.33 times their estimated energy
requirements.
●
“Participants in the HF [High Fat]
arm lost 0.46 kg/month despite consuming on average 1.51±0.33 times their estimated energy requirements.
That adverse outcome may be due in part to Oxepa, the fat
supplement employed. Oxepa
contains Eicosapentaenoic Acid (EPA), a form of Omega3 fatty acid shown to
reduce survival for SOD1 mice.
●
“ALSFRS-R scores declined more slowly in the HC arm −1.06
points/month vs. −2.17 in the surviving controls vs. −1.59 in
the HF group . . .
●
“Participants who gained weight
overall during the study gained primarily fat mass [but] the HF diet was not associated with increased
cholesterol.
●
“Continued weight loss may have been
due to gastrointestinal malabsorption.”
The researchers warn that the “results should be interpreted with caution given the small
sample size.” It is very difficult to achieve patient-uniformity
among study groups when group sizes are 7-10 people.
Other complications noted by
researchers: “The HC group had a lower baseline
BMI, were slightly younger, had a shorter time since diagnosis, and had
fewer participants who had been prescribed BIPAP” – in other words they were thinner
but healthier.
The tube-feeding formula Jevity 1.5 was used for
the high-carbohydrate diet and Oxepa for the high-fat diet. Oxepa contains 55% of calories from fat,
compared to 29% in the Jevity product.
The proportion of calories from protein (17%) was the same across
all types of formulae.
High-Fat
Diet Reconsidered. Interest in High-Fat
diets may have been revived
by a painstaking double-blind clinical trial completed recently. Researchers studied 201 ALS patients at
12 institutions in Germany
by means of trial NCT02306590,
the equivalent of a Phase 3 study.
During that trial all patients adhered to a normal
diet but were randomized to receive additional nutrition, either a HCFD
(High Caloric Fatty Diet) or placebo.
The HCFD was Calogen,
manufactured by Nutricia, taken at a dose of 30ml three times per day,
which added an extra daily calorie intake of 405kcal.
The same dose of the placebo, formulated to have
an identical appearance, added only 8kcal per day. Kcal is a kilocalorie.
In their 2019
trial report German researchers presents the following findings:
●
Researchers
found “no
evidence for a life-prolonging effect of HCFD for the whole ALS population,
which included BOTH fast-progressing and slow-progressing patients.
●
However, they
found “a significant survival benefit for the
subgroup of fast-progressing patients.” “Survival probability was 0.62 (62%) in the HCFD group
. . . and 0.38 (38%) in the placebo group,” that is a 24%
(0.62-0.38) increased probability of surviving 28 months. Fast-progressing was defined as a loss of
more than 0.62 ALSFRS-R points per month.
Slow progression is < 0.62 point loss per month.
●
Fast-progressing
HCFD patients also lost less weight. Investigators noted that, without further
research, they “cannot determine whether
the higher calorie intake or an increased fat consumption is responsible for the treatment effect
in this subgroup.”
●
The study
dropout rate was high at 26%.
According to researchers, “patients gave a wide variety of reasons, which were
predominantly associated with the effort required by the study.” This is unexpected patient behavior,
since nearly as many placebo patients as HCFD patients dropped out.
What
Action To Take. The best human research, the 2014
Phase 2 trial and the 2019
trial, suggests several helpful actions:
●
It is clear
that ALS patients, to maintain weight and wellbeing, must consume far more calories than the
healthy, non-ALS human, perhaps as many as 50% more calories.
●
Generally,
supplemental carbohydrates are
preferred for all ALS patients (2014
trial). However, fats have proven
beneficial for fast-progressing patients
(2019
trial), although carbohydrates MAY also work well, a speculation
requiring further investigation according to researchers.
●
Vital is diet-compliance,
the patient’s willingness to maintain a sometimes objectionable menu.
When more diet research becomes available, it will
be presented here.
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Supplements
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Gamisoyo-San
(GSS). In this
2018 report on careful animal research, Korean investigators (1) maintain
that there is a link between nerve inflammation and ALS disease
progression, and (2) suggest that GSS, a common Asian remedy, can function as
an anti-inflammatory and antioxidant agent and thus inhibit ALS somewhat.
The researchers randomly assigned 12 mice to 3
groups, much like the divisions in a human trial. Two groups contained only SOD1 mice. Daily, the mice were fed 1mg GSS per gram
of body weight for six weeks. For a
170 pound man that would be 2.5 oz of GSS per day, which may be a lot.
Postmortem found that, in hSOD1 mice, GSS significantly reduced the levels of inflammation and oxidation in muscles
and “regulated
iron homeostasis.” And, in
SOD1 mice, GSS “ameliorated TLR4, CD11b and BAX.” More in this
news story.
Of course, there is no
certainty that GSS will provide any benefit to humans, since there have
been no human trials.
Omega3
Fatty Acid. Eicosapentaenoic Acid (EPA) is a form of Omega3 fatty acid, often obtained from
marine sources. Although it may
beneficial to the general healthy population, Omega3 has been shown to
reduce survival for SOD1 mice, animals suffering from ALS.
There
may be other supplements to consider. They will be addressed when the author
has time to return to this topic.
Meanwhile, this
good 2015 article reviews other alternate therapies and their potential
benefits.
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Exercise
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There is an ongoing debate over whether muscular
activity is harmful or beneficial to those with ALS. With muscles already deteriorating, the
negative argument centers on the idea that overexertion can accelerate
functional loss.
For example. The Cleveland Clinic’s website suggests that physical
therapy can help people with ALS, but they do not recommend strengthening
exercises. On the other hand, the Massachusetts General Hospital’s website references
small research studies that showed that light strengthening may be
beneficial.
This 2017
multi-center study may have the current best answer, because its human
trial was randomized, the best way to separate Truth from Falsity in
medicine.
USA researchers concluded that resistance, endurance,
stretching and range of motion programs “are all safe
to be performed with the specified regimen without any worsening of
outcomes as related to ALS function.”
Unfortunately, the study also found these exercises did not stall disease
progression.
A
Japanese study, published in 2018, reported that 10 individuals with
ALSFRS-R scores of 41 profited from exercise. The research findings: “Physical
therapy for ambulatory individuals with ALS who do not use an assistive
device could improve knee extension muscle strength but not functions such
as gait and stair climbing.”
It seems that research
into this heartbreaking disease rarely has any good news.
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Edaravone (Radicava)
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Despite it enormous price tag, $146,000 per year,
Edaravone (Radicava) offers benefit only
to a small subset of ALS patients – those suffering from EARLY stage disease, as noted in this
2017 Japanese research report.
In this Phase 3 trial 69 patients were randomly
assigned to receive Edaravone, and 68 received placebo. Treatment lasted for 24 weeks (6
months). The research found that
ALSFRS-R scores for Edaravone users decrease by 5.01 points on average, whereas the placebo recipients
declined by a mean 7.50 points. The 7.50 points may be disputed by a
later reexamination of the research, addressed below. No
patients improved.
The Edaravone benefit is limited to a slowing of
the disease and its symptoms, so no
progress is detectable to the patient.
A 2018
Polish overview of Edaravone research details the results of five
clinical trials. The report notes
that FDA approved the drug “after only one small positive clinical trail of short
duration,” which is the Japanese research cited above. None of the other four trials produced
positive results. See Table 1,
especially the Results column, which shows negative results for all 5
studies.
However, in the latest investigation Japanese
researchers reported in 2018 that Edaravone patients survived significantly longer, 61.0 vs
32.5 months, after being treated for a median 8.8 months (+6 months). This 1-institution study tracked patients
seen during the period 2010 through 2016.
However, the research had significant
shortcomings, and the 61.0 vs 32.5 months is likely misleading:
●
The study was small – a total of 57 patients,
27 treated and 30 untreated patients – so the results are difficult to
apply to the larger ALS population.
●
Although the
Edaravone-treated group appeared to live longer than the control group, the
control group contained three times
the number of bulbar-onset patients.
Bulbar patients tend
to suffer a more aggressive disease and to experience shorter
life-expectancy. There were 33% bulbar (10 of 30) patients in the
control group. So, that group tended
to deteriorate more rapidly than the Edaravone group which contained only 11% bulbar (3 of 27 patients).
●
Distribute
the bulbar patients evenly between the two groups, and Edaravone’s claimed longevity could easily disappear.
Had this been a
rigorous randomized trial, bulbar participation would have been distributed
equally between the two groups.
Instead, this retrospective effort was preordained
to favor Edaravone.
● A significant finding of the research: All
benefit appears to have occurred during the first
6 months of treatment.
According to the researchers: “ALSFRS-R scores were
not significant at 12 and 18 months between the groups.”
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Ethics Considerations, Research
Reevaluation
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Finally, a new
therapy rarely attracts an ethics evaluation. But, in this
2018 ethics essay the authors challenge the morality of prescribing
Edaravone in all cases. They warn “that [Edaravone] treatment is neither
curative nor stabilizing.” Referring to the key Phase 3 trial, the
authors emphasize that, when trial data for patients of ALL disease stages
are considered, “There was no
significant difference between the placebo and treatment groups with
regard to the rate of decline.” And yet Edaravone is approved for all ALS
stages and all ALS conditions.
Only the trial’s dpEESP2y subpopulation experienced a benefit: “Over a 24-week period, the Edaravone
group demonstrated a smaller [ALSFRS-R] decline . . . ” However, “There were no differences between the Edaravone and control groups in
FVC, grip strength or pinch strength.” FVC is Forced Vital Capacity, a
breathing test.
The ethics authors emphasize: Historically “most patients with ALS decline by about 5.6 points on the ALSFRS-R [scale] over
6 months, and [the dpEESP2y] patients . . . lost
5.1 points on the ALSFRS-R scale” – the net 0.5 point
difference (5.6 – 5.1) is not a profound reduction in decline.
In
a second
ethics article, dated October 2018, researcher John
Turnbull, MD, PhD, reevaluates the pivotal Study 19 which gained
Edaravone its FDA approval. He concludes: “Edaravone performed better than placebo, but both
placebo and Edaravone likely did worse
than no intervention.”
In other words, Edaravone is worse than no treatment.
Discovering
that, in the human trial, both Edaravone recipients AND placebo patients decline in accelerated fashion after
randomization (meaning, after therapy was started), the author seeks the
cause.
Accordingly,
he examines three possible explanations for the unwelcome
acceleration. The first, that such acceleration is the
natural course of the disease, is disproved by three independent analyses
of ALS databases. Moreover, one
analysis of research patients demonstrated that, over time, average patient
decline tended to diminish due to the drop-out of sicker patients.
A second
possibility, that accelerated
decline is a statistical aberration, is also disproved. Indeed, the author found that
acceleration was “not spurious, and that some patients in both placebo
and treatment arms experience an accelerated decline . . . some approaching
one [ALSFRS] point per WEEK
(emphasis added),” according to the
author.
Consequently,
the author concludes: “We are then
left with a third possibility, that a
factor common to both groups [Edaravone and placebo groups] has
caused a worsening in some or all patients.”
For a common
factor the author targets intravenous infusion, the Edaravone method of delivery. Thrombosis occurs in 72-73 percent of
chronic infusion patients, and the most frequent adverse event in Edaravone
treatment is “contusions
and bruising (19%), [further] thrombosis and thromboembolism would be more
prevalent in paretic limbs, more likely with repeated or prolonged IV use.”
The author,
citing animal studies, suggests that chronic infusion or recovery delays
from thrombosis could lead to decline due to the patient’s loss of
customary physical activities.
In conclusion,
the author summarizes the efficacy of the therapy profoundly: “ . . . in a highly selected population Edaravone
performed better than placebo, but that both placebo and Edaravone did worse than no intervention. As such, there is a real possibility that
Edaravone, as delivered in the trial, is both
ineffective and harmful.”
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Treatment Schedule
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Edaravone is infused daily for 14 days in a
hospital setting, followed by two weeks off, then 10 more daily
infusions. After that initial cycle,
patients are given 10 days of infusions followed by 14 days off, followed
by a repeat of that cycle.
Due to the need for a hospital setting, Edaravone
is likely covered by Medicare-Medigap.
An oral form of the drug is in
development.
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GDC-0134 Trial
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Phase I trial NCT02655614,
in an attempt at Gene Therapy, uses
the DLK inhibitor GDC-0134 to reduce brain-cell death.
Because this is a “first
in human” trial, there is no human efficacy data of any kind. There is only mouse-model data presented
in this
very thorough 2017 report.
During the animal research investigators found
that:
1.
Unwanted DLK/JNK
signaling is elevated in ALS victims;
2.
DLK influences
neurodegeration by regulating the JNK protein, and
3.
DLK-suppression
protected against neuron loss in mouse models of ALS.
Like Stem Cell Therapy, Gene Therapy
is intellectually appealing – they are fine buzzwords. But, the reality is that this attempt at Gene Therapy worked only modestly in
animal studies.
In the ALS mouse model GN-3511 (presumed to be GDC-0134)
did not halt the disease, but delayed disease progression by only 10%.
Perhaps the reader can appreciate the value of unearthing
the animal research which was used to justify the human trial.
And very little
can be guaranteed by animal studies.
In the past 20 years all human trials have failed except one (Edaravone,
brand name: Radicava), and every failed human trial (of which there was a multitude)
began as a successful animal study.
Some features of the trial:
●
Age eligibility
is “18 Years and older.”
●
The trial
will enroll 82 patients and will last 48 months.
●
Participants must be able to fast
from food for 8 hours prior to dosing and for 2 hours after dosing –
a total of 10 consecutive hours.
●
The study is randomized double-blind, so half of
patients do not receive the
experimental therapy.
However, there is an open-label
extension near the end during which all participants receive the drug.
●
Three additional drugs are used in the trial:
(1)
Rabeprazole,
a proton pump inhibitor (perhaps to overcome indigestion caused by GDC-0134);
(2)
Caffeine
(perhaps to stimulate neural activity), and
(3)
Midazolam
used to aid sleep (perhaps to overcome the Caffeine).
Problems with GDC-0134
digestion and tolerance are hinted in the prior, preparatory trial NCT03237741.
●
The trial is
available at Mayo-Jacksonville, Johns
Hopkins, Massachusetts General
Hospital and 9 other
sites.
● The trial is available at Mayo-Jacksonville. More information is here, including
Eligibility Criteria.
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Gene Therapy
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Introduction
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Genetic testing, especially for SOD1, should be considered. Although it is known that many genes are
associated with ALS, there is no clear biochemical connection between them.
And most of the mutations are
inherited.
Chapter
8 of the 2017 book Molecular and Cellular Therapies for
Motor Neuron Diseases gives an overview of Gene Therapy attempts to
date. And, this
2019 French journal article also describes the science, and summarizes
the current experimental efforts.
Described immediately
below are the two current Gene Therapy trials.
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BIIB067 (Tofersen) Trial
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A more detailed review of this Gene Therapy trial
is given in the BIIB067 section above.
About 10% of ALS is inherited, and 15% of those inherited cases are caused by mutations
of the SOD1 gene (that’s 2 SOD1
victims per 100 ALS cases).
By means of a new randomized trial NCT02623699
the first attempt to manage SOD1 in humans is now underway at 17 sites in
the US
and overseas, including Johns Hopkins and Massachusetts General.
The investigational drug, BIIB067, is an AntiSense
Oligonucleotides agent (abbreviated ASO).
In animal research the ASO BIIB067 increased
lifespan by 22% and maintained weight for a longer period than that of
untreated animals. Unfortunately,
there were no cures.
The animal research, which preceded the NCT02623699
human research, is described in this
2018 journal article. And these news
reports describe the pre-clinical research and the new human
trial. At the end of the document is
the new related clinical trial description.
Pre-clinical research is
non-human research
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GDC-0134 Trial
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Phase I trial NCT02655614,
in an attempt at Gene Therapy, uses
the DLK inhibitor GDC-0134 to reduce brain-cell death. More on the GDC-0134 trial
above.
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Ibudilast Trial
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Ibudilast plus Riluzole MAY perform as well as Edaravone or better. Ibudilast
is a product of MediciNova, which is licensed by manufacturer Kyorin Pharmaceutical to advance
Ibudilast in Western nations. Kyorin
maintains control in Asia.
ALS is driven in part by neuro inflammation. Ibudilast is an
anti-inflammatory drug, a phospho-diesterase inhibitor, used
mainly in Japan and Asia to treat bronchial asthma, stroke and
cerebrovascular disorders.
In Ibudilast’s recently-concluded Phase 2 trial NCT02238626
71 subjects were randomized either to Ibudilast (MN-166) plus Riluzole or to
placebo plus Riluzole. The trial was
initiated in September 2014. And 34
patients were later categorized as “Early
ALS,” recent ALS victims with high ALSFRS-R scores.
Trial results were presented at the AAN Annual
Meeting in April 2018 using this highly
detailed report.
An analysis of the “Early
ALS” subgroup found that 32% either remained stable or improved throughout the trial period, which was
6-months double-blind plus a 6-month open-label extension – a total of 12
months.
About half of 71 trial participants experienced no
benefit, a group called “non-responders.”
Such non-responders are typical in all human trials, and they
generally represent more than half of patients.
However, researchers reported that members of the “Early ALS” subgroup benefitted most from
Ibudilast.
But, not every “Early ALS” was a responder. So, a followup, Biomarker trial for 35
participants was initiated in March 2016.
That Phase 1/2 trial NCT02714036 is now classified
“Active, Not Recruiting”, thus closed to new participants. Trial NCT02714036 will
report its findings soon, perhaps in 2020.
A Biomarker trial examines patient and disease
characteristics (as well as efficacy), to determine what PRE-therapy clinical
features pinpoint those patients most likely to benefit from Ibudilast.
In September 2018 FDA
gave Ibudilast its go-ahead for a Phase 3 trial, which will test
Ibudilast at 100mg per day, greater than the prior 60mg per day dosage. That Phase 2b/3 trial NCT04057898 is currently
“Recruiting”. It will enroll 230
participants at 15 US and Canadian sites for an 18-month trial period. It is a Randomized, Double-Blind,
Placebo-Controlled design; so only half of the participants receive Ibudilast. The other half receives a placebo.
Early ALS patients are likely to be the favored trial
candidates. In a December
2019 conference report researchers use a new analysis of Phase 2 data
to speculate that “the efficacy of MN-166 (Ibudilast) is expected to be
more robust in patients with a short ALS history” (less than 600
days since the onset of symptoms).
MediciNova appears
so confident of the drug’s eventual success in either ALS or MS trials, that
it undertook Phase 1 trial NCT03533387, now
completed, to determine which of two 50mg Extended Release (ER) formulations
might be selected for manufacture. Its
current 10mg product is considered Intermediate Release, not Extended
Release. A 50mg product will facilitate
a 100mg daily total using two capsules per day.
The trial utilized 28
healthy volunteers to determine the bioavailability, pharmacokinetics and plasma
concentrations of the two formulations.
Now, back to the remarkable Phase 2 trial. Within a subgroup of 34 “Early Stage”
patients, 11 (32%) experienced stable disease or improvement, which is an
astonishing achievement if accurate.
Each of the 11 is represented by a red line in the graph below,
which comes from this
very detailed 2018 trial report.
After 3 elapsed months
each of the 11 patients remained either stable (the line becomes
horizontal) or improved (the line slopes upward). The remaining 22 patients (68% of the 34),
represented by blue lines, continued to decline, but some less rapidly than
others.
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Availability
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Although it has been available in Asia
for 29 years, Ibudilast is not yet FDA-approved for ALS, so insurance will
not cover its cost. However, the
drug entered FDA’s Fast Track approval
for Multiple Sclerosis in 2016 and for ALS
in 2015. If the upcoming Phase 3
trial is successful, Ibudilast will become FDA-approved.
Ibudilast can be purchased
online from Mimaki Family Pharmacy under the brand
name Ketas®. Ketas® is the same Kyorin Pharmaceutical
product used in the USA Ibudilast trials.
Trial sponsor MediciNova is a Kyorin licensee,
approved to explore Ibudilast applications in Western nations.
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Dosage
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In the completed Phase 2 trial,
the dosage was 60mg per day. However, in new Phase 2b/3 trial NCT04057898 the
dosage has been raised to 100mg per
day.
Ibudilast (in the Ketas® formulation) is still an
Intermediate Release product, not the Extended Release innovation now under
development. So, extended release
must be approximated.
The Ketas®
literature (graph below) indicates that peak blood concentration is
reached at about 3 hours. So, to
maintain a non-stop peak of neural protection, the daily 100mg must be
distributed equally throughout the day, so that a continuous round-the-clock
peak is achieved.
Dose
Schedule. Thus, the patient would be wise to take a
10mg dose every two waking hours: (8a, 10a, Noon, 2p, 4p, 6p, 8p,
10p), plus two overnight.
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FDA Prohibition
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The
importation of Ibudilast (Ketas®) from Japan (or any drug from
overseas) is not strictly legal.
However, FDA allows it under certain circumstances which are outlined
in this
FDA document.
The following are the major points of the document. This is not
law or rule, but POLICY, and policy can be changed in an
instant. Here is what FDA says:
●
“In most circumstances, it is illegal
for individuals to import drugs into the United States for personal
use.” However, you can do so provided that:
●
The drug will
be used for a “a serious condition
for which effective treatment is not
available in the United
State;”
●
The treating
“doctor” must be identified;
●
No more than
a “3-month
supply” can be imported.
The above language and links to
source FDA websites are found within this
document. Further, FDA has a pdf
document with makes the same statements.
This 115-page FDA 2017 Regulatory
Procedures Manual is the main source of the summary above, and this
excerpt from the 115-page manual covers
most of the key “personal
importation” issues.
Of utmost importance: FDA is breaking the law by allowing such “personal importation.” It is using DISCRETION in order to help
sick people.
In addition, FDA’s current behavior is even more
lax. It is currently violating its own discretionary policies
(above), by allowing importation to exceed a “3-months supply” and by waiving the naming of the treating
physician.
So, the discretion could
change overnight and could change due to over-zealous interpretation
of the new, enormous
2018 drug control act – an excerpt on importation is here.
Heed
the following well:
●
Ibudilast
MUST be taken without any interruption. An interruption means neuro cell loss that
can never be recovered. Here are
some rules to follow.
●
Always keep a
3-month supply on hand – a never-touch hoard. That means an UNTOUCHED 3-month
cache. Whenever you are a few weeks
away from breaking the cache, order another 3-month supply.
●
To assure
safety, regular Liver Function tests should be undertaken. Engage a struggling physician, and tell
him your plan to take Ibudilast (do not say you are currently taking
it). That way you will learn whether
he can be relied upon, or whether you need someone else.
If you tell your
physician that you are taking Ibudilast, you risk being fired – by keeping
you he defacto endorses an illegal drug, creating a legal burden which neither
he, his company nor his insurer wants.
●
Contact FDA (contact info at
the bottom of this
linked document) to find out how the new drug law will affect personal
importation. Merely say you are you
represent a friend who has a deadly disease, and that he wants to import
one drug that has done well in human trials. Don’t name the client or the drug.
This is how one prevents misfortune
using contingency planning.
If you experience a
positive Ibudilast outcome, it is vital not to interrupt its action, otherwise
you will lose millions of unrecoverable
neuro cells each day.
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Immunotherapy (this section is incomplete)
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Introduction
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This excellent
2017 US report on immunotherapy describes the therapy mechanism and
summarizes the research to date.
Some therapies are shown
to be effective at slowing decline, some not effective. Masitinib, an immunotherapy described above, is cited in the report.
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T-lymphocyte (Tregs) immunotherapy
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A “first in human” trial
of regulatory T-lymphocyte (Tregs)
immunotherapy has just concluded.
Three patients participated, whose ALSFRS-R’s were approximately 40,
and whose symptoms began 14 to 38 months prior to Tregs infusion.
The Tregs were autologous, isolated from patient
blood and expanded ex vivo (in an artificial environment outside the living
organism).
Tregs were then administered IV in an early phase
(4 doses over 2 months) and a later phase (4 doses over 4 months) of the
disease.
The research findings:
●
“The infusions slowed [disease] progression rates during
early and later stages of disease . . . Measures of maximal inspiratory
pressure also stabilized . . . ”
●
It was found
that “the
beneficial effects on disease progression could be extended by increasing
the dosing interval” [by increasing the time between Tregs
infusions].
The shortcomings of the study:
●
“Increased
clinical [disease] progression rates were observed between each
round of infusions [between the two main infusion phases], but it was not
clear whether the progression was related to the cessation of Treg
infusions or would have occurred spontaneously.”
●
“Common to all patients was the occurrence of infections during the study.”
●
All patients
perceived an increase in fasciculations (muscular twitching of contiguous
groups of muscle fibers).
●
The trial
lacked blinding and placebo controls, which will be present during the next
phase, a Phase-2 clinical trial.
The Phase 1 trial report, dated July 2018, is available
here, and news account is available
here.
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More to follow
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Masitinib Trial
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Masitinib plus Riluzole may offer similar outcomes to
Ibudilast plus Riluzole. Masitinib
is an oral tyrosine kinase inhibitor which hinders nervous system
proliferation of microglia, macrophages and the mast cells CSFR1 and c-Kit. It is helpful in the control
of neuroinflammation, which is a hallmark of ALS.
A Phase 3 trial,
reported in 2017, evaluated 394 patients with disease duration less
than 36 months. They were randomized
to receive either Masitinib (4.5 mg/kg/day) or placebo, plus Riluzole
(100mg/kg).
The trial
results after 48 weeks were the following, as indicated in these
reports:
●
The rate of
decline of ALSFRS-R was –0.77 points per month with Masitinib compared to
–1.05 points with placebo — a 27% slowing
of ALSFRS-R over 48 weeks. This was
the case for "normal progressors," those with a progression rate
of less than 1.1 points per month.
●
Median
Survival was 20 months for Mastinib, compared to 16 months for placebo. As with other experimental drugs, there
were a large percentage of non-responders.
●
Better results were obtained
by those with milder symptoms and
for those who initiated Masitinib earlier. For disease duration less than 18 months,
there was a 32% slowing in ALSFRS-R
deterioration. For disease duration less than 24 months, there was a 25%
slowing of ALSFRS-R decline.
A new Phase 3,
trial is in the offing, but its recruitment date and “multicenter”
locations have not been announced.
It will have some helpful features:
●
The eligible
ages will be 18 to 81 years.
●
The trial
will be randomized and will enroll 406 patients.
●
This
multicenter trial MIGHT be based in the USA,
whereas the prior trial was based in Europe.
Problems. In 2016
French regulators temporarily
halted the Masitinib trial “to make sure the [study
conformed to] rules on trial conduct.” In 2017 French regulators again suspended
Masitinib trials temporarily citing “deviations.” But, press
reports do not specify the defects.
In 2018 European regulators
reprimanded the Masitinib-ALS effort, citing “a perceived lack of reliability of data
used to support a registration” for the drug.
Availability. Masitinib
has received FDA Orphan Drug
status. In 2016 its manufacture, AB Science of Paris, began
approving Compassionate Use
applications. AB Science will
continue to do so “until a clinical study can be initiated with Masitinib
in the USA,”
according
to an AB Science press release.
Masitinib, under trade
names Masivet and Kinavet, is also used to treat cancers in dogs.
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Memantine (TAME) Trial
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A new Phase 2 trial NCT02118727 combines Riluzole
with the Alzheimer’s drug Memantine
at 20mg BID (two times per day for a daily total of 40mg). Trial details can be found here.
Memantine is a NMDA receptor antagonist. Its neuroprotective effect is probably
due to the inhibition of spinal cord NMDA receptors. A Memantine overview is given here and the
product label and prescribing information is downloadable
here.
Trial leaders speculate that past Memantine trials did not do well
because, at 10mg BID (20mg per day), they “miss(ed) the potential efficacy of [higher]
non FDA approved doses” – thus a boost to 40mg daily for the new
trial.
Hope for success is based on
two prior 20mg per day trials: (1) an American Phase 1 Pilot trial of 20
patients (no NCT registration) which showed positive performance and (2) a larger
Portuguese Phase 2/3 trial NCT00353665
of 63 patients whose researchers
concluded: “We
did not observe any evidence of efficacy.”
Unlike Ibudilast, no patient improved
and no patient was stabilized by Memantine.
Both trial were completed 10 years ago, and their reports
are dated 2010. One wonders why, if
this agent is presumed promising, researchers
waited 10 years to initiate a Phase 2 trial, especially since the
drug is readily available, costing nothing to develop.
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Phase 1 Pilot Trial. The 2010
report is downloadable
here.
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In
this 20-patient, 18-month trial 19 Memantine patients lost an average of 0.73
ALSFRS points per month. And a
subset of 12 patients lost 0.56 points per month on average. Historically, the ALSFRS loss is 0.9
points per month. It should be noted
that this research used the older 40-point ALSFRS rating system, not the
new 48-point ALSFRS-R system.
Small studies, such as this 20-patient effort, are
far less reliable than larger ones, like the 63-patient Portuguese trial
described next.
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Phase 2/3 Trial. The 2010
report is downloadable
here.
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Sixty-three
(63) patients participated in this well-designed, single-center,
randomized, double-blinded, parallel trial which lasted 12-months. It
was concluded in July 2008 and in 2010 reported the following findings (referenced
by page number and table number):
●
No therapeutic benefit in patients
with ALS was demonstrated (p4).
●
There was no significant difference
between Memantine and placebo groups in ALSFRS change from baseline to the
end of this trial (p3).
●
Secondary objective efficacy outcomes
(MRC score, FVC, MUNE, NI and SF-36 decline over 12 months) were also not different between treatment
groups (p3).
●
After
12 months ALSFRS declined 11.2 points
(32.0 to 20.6) in the Placebo group, but even a greater amount, 13.0 points (33.2 to 20.2), in the
Memantine group (Table 2).
●
ALSFRS decreased 3.27%/month and
2.97%/month in Memantine and placebo arms, respectively (p4).
●
Patient subjective
evaluation (for fasciculations, cramps, fatigue and stiffness) did not differ between groups (p3).
Of the Memantine group 25% (8 of 32)
were faster-declining bulbar-onset patients, compared to 16% (5 of 31) of
the Placebo group.
These findings may explain why
Memantine disappeared for 10 years as a therapy, and the Ethics Alert (next
section) might explain how it was revived.
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Ethics Alert
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To mislead recruits,
sponsors of the new NCT02118727 trial
deliberately misquote the Portuguese trial report.
The
Portuguese (Carvalho) report states, page 5: “The failure of this study to show a
change in the functional rate of decline does not preclude the possibility
that Memantine may have an effect on
survival, for which this study was underpowered.” The “underpowered”
refers to determining survival benefit, not to determining “rate of decline” or other research
outcome measures.
However,
the new NCT02118727 trial description, in the Detailed Description
section, seeks to disparage the Portuguese research by alleging that “the [Carvalho]
study was limited in terms of power” – a clear misrepresentation,
given that Portuguese researchers meant “power”
to refer ONLY to survival benefit determination – a “power” which the American Phase 1 Pilot study also lacked.
So
the Portuguese Phase
2/3 research is not in any respect inferior to the American Phase 1 research. The new trial’s false statement is an
unethical means to lure research recruits.
The ALS victim must heed the Portuguese research findings, keeping
in mind that the new
Phase 2 trial hopes to succeed using 40mg/day Memantine, where 20mg/day
failed.
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New Phase 2 Trial Features:
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●
Enrollment of
90 patients, aged 18 to 85, if they meet the ALS El Escorial criteria found
here
and here.
●
Randomized,
Double Blind, Placebo Controlled.
Some Patients may receive no treatment at all, based on this cryptic
note in the trial description: “This proposed study will test a , , , combination
with riluzole . . . compared to treatment with riluzole alone or no
treatment.” The “no treatment” raises alarms.
●
ALSFRS-R
>25, but onset of weakness must not be greater than 3 years.
Final
Notes. The two supporting studies conflict (the
smaller claims benefit; the larger dismisses benefit). However, the drug may do no harm. Consider:
This readily-available Alzheimer’s drug MIGHT be
prescribed outside a trial and thus avoid the placebo. And, Memantine MIGHT NOT conflict with
Ibudilast. Nevertheless, a
pharmacologist must be consulted in order to be certain.
The 40mg/day trial dose is
very large. The Maximum Recommended
Human Dose (MRHD) is 20mg/day (10mg BID).
However, animal studies have safely administered many times the MRHD
dosage. Refer to the Memantine prescribing
label, downloadable
here.
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Retigabine (Ezogabine)
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Retigabine (Ezogabine) was once a
readily-available anti-convulsant drug for epilepsy, brand name Potiga®. If a source can be found, it may be
something to try for a few months.
Retigabine works primarily as a potassium channel opener by activating
voltage-gated potassium channels
in the brain. This mechanism of action is unique among antiepileptic drugs.
According to this
2015 report, “Retigabine has been shown to reduce the
excitatory state and prolong neuron survival
in ALS cell models.”
[An ALS model is either in vitro (artificial
environment outside the living organism) or in vivo (within a living
organism, usually a mouse model, that is, ALS-inflicted mice). The research was probably in vitro.]
There have been only 2 human trials. The later, better trial has been
completed, and the results published in November 2020.
In the earlier trial (2018 report here),
which lasted only 1-2 days, 18 patients were given the drug and
excitability tested. The result: An “acute
reversal of previously abnormal variables [excitability].” But, the trial did not measure long-term ALS
symptom reduction, improved performance or life expectancy.
The latest human trial, a Phase 2 randomized
effort described
here, was completed in February 2018 and reported in November 2020. It involved 65 ALS patients.
Unfortunately, this trial also was not designed to
evaluate long-term ALS symptom reduction or improved life expectancy. It did, however, confirm that at the
proper dosage, “Ezogabine decreased cortical and spinal motor neuron
excitability” which (as the trial description asserts) “may
contribute to neurodegeneration in both sporadic and familial ALS.”
See the Phase 2 trial
report, available here. And, the
full report can be downloaded
here.
The report authors state: “Further evaluation is warranted to
determine whether longer treatment can sustain the [drug’s] effects on
excitability and slow disease progression.” But, they did not announce such a human
trial.
The trial drug, brand named Potiga®, may not be
available for non-research off-label use.
In October 2015 FDA
determined that retinal pigment
changes associated with the drug did not appear to affect vision,
and that the bluish skin discoloration appeared to be cosmetic, without
serious side effects. Nevertheless,
in June 2017 manufacturer Glaxosmithkline announced that it was withdrawing Retigabine from all
markets.
FDA’s Potiga® label
is downloadable here.
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Sleep Method:
How the stressed can fall asleep
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The following two methods avoid all
medications. The Bright
Light method was developed for cancer patients, who also have a lot on
their minds. Instead of the “light
box”, proposed in the article, an inexpensive clamp-on lamp could be
used. Such lamps sell for $5-10 at
Walmart or home centers.
The second method, developed
by PhilipJax, uses multiple distraction methods to end the racing
thoughts. If a tired person is
adequately distracted, he WILL fall asleep.
Try the method. You have
nothing to lose.
Also covered are means to
achieve Sleep Hygiene, a goal sought by all professional sleep specialists.
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Stem Cell Therapy
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Introduction – The Best Article on The Subject
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Specific Stem Cell trials will be detailed in the
section immediately below. Be sure
to review the section titled: Stem Cell Scams.
In the foreseeable future Stem Cell Therapy may
slow the disease, and in some case restore some functions, but no
researcher expects a cure.
This excellent
2017 UK article describes all variants
of Stem Cell Therapy, including the four types of Stem Cells (with emphasis
on Mesenchymal Stem Cells – MSCs) and the four means of delivery. In addition, the paper describes past
Stem Cell research from the earliest trials more than 10 years ago, right
up to the present, and the difficult in making the concept work.
To find definitions
install Wordweb.
For example, the term Differentiation
means the transformation of cultured cells into the desired body part.
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Why Stem Cell Success is Difficult to Achieve
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The 2017
UK article explains the supreme
difficulty of this therapy: “The transplanted cells should engraft, migrate to
affected areas of degeneration, survive, mature and integrate into the
preexisting neuronal circuits forming synapses (The junction between a nerve fiber and the muscle it
supplies).
“All this must occur within a hostile microenvironment where
other motor neurons are dying, and activated microglia (cells that destroy invading
microorganisms) and astrocytes (larger cells) are sustaining an inflammatory milieu (environment).”
To find definitions of
technical terms install free Wordweb. For example, the term Differentiation means the
transformation of cultured cells into the desired body part.
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Stem Cell Trials
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Not
all Stem Cell Therapies are equal.
Depending upon the type of Stem Cell used and the method and
location of deliver, the outcomes differ.
To find definitions install free Wordweb.
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Brainstorm NurOwn®
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2021 Update. The
disappointing results of the NurOwn®
Phase 3 trial, released in November 2020, are summarized at the bottom of
this section.
One of the most watched research projects is the Brainstorm NurOwn® testing. The product consists of autologous
bone-marrow derived Mesenchymal Stem Cells (MSCs) which are transplanted
into the patient intrathecally by standard lumbar puncture.
This report is presented in 3 parts: (1) The Phase
2 USA
trial, (2) the Phase 1/2 Israeli trial and (3) the new Phase 3 USA trial.
1.
The Phase 2
USA trial is complete, and Phase 3 is recruiting. Details on Phase
2 USA are here. In addition,
there is a 2018
news story which (unfortunately) combines Phase 2 and 3 outcomes, so it
is somewhat confusing.
In the Phase 2 USA trial NurOwn® has thusfar produced the following results:
1.1.
Response to
the therapy has been approximately 40%.
Response is not a cure, but a slowing of decline or a slight
betterment for a period of time.
About 60% of patients did NOT respond. They received NO benefit.
1.2.
There is no
data on longevity yet.
1.3.
As with all
randomized trials there is only a 20%
chance a patient will get any benefit at all. And those who get a
benefit won’t detect it, since the benefit
is a slowing of the decline.
Below, The Math, explains.
The Math. Only half (50%) of trial participants get
the therapy, and less than half (40%) of Stem Cell recipients gain any
benefit. So the math is 0.5 x 0.4 =
0.20 or 20%.
Meanwhile the patient must abandon all other therapies (except impotent
Riluzole) for a year or more.
2.
The new Phase
3 trial is described down this page.
But first, some findings from the Phase 1/2 Israeli effort. This
2016 report from Israeli researchers details the earliest NurOwn® trial, which had two parts:
A Phase 1/2 effort and a Phase 2A effort.
This trial may have been the first
time that Stem Cells were induced under culture conditions to produce
Neurotrophic Growth Factors (NTFs).
The research had the following results:
2.1.
Approximately
80% of all patients were considered “responders.” However, a “response” was considered a 25% reduction in the rate of decline. Later in the Phase
2 USA trial a different, stricter
definition of “response” produced far fewer responders.
2.2.
Intramuscular
(IM) and Intrathecal (IT) injection
methods were used, as well as combined IM + IT. “Only IT-treated
patients from both studies appeared to experience SYSTEMIC benefit.” And “most of the IT- or IT+IM-transplanted
patients [about 88% under the old definition] were defined as responders –
having a slower progression rate after treatment . . . ”
2.3.
A reduction
in muscle decline was more pronounced in the injected arm of the
IM-injected patients. But, “IM
administration induced only a minor local effect.”
3.
The new Phase 3 trial is described here NCT03280056
and at the bottom of this
document. The trial is available
at 6 sites on the east and west coasts and Minnesota and will accept 200 patients.
The new trial’s shortcomings
are:
3.1.
Eligibility is limited to
patients with scores, ALSFRS-R ≥ 25.
Calculate your ALSFRS-R online here,
or use the downloadable
form.
3.2.
Patient must
be in the age range: 18 to 60.
3.3.
The trial is randomized, double-blind,
placebo-controlled, so half the patients do not receive the experimental
treatment.
3.4.
If the
patient participates in one Stem Cell trial, he probably will NOT be
welcomed into other future Stem Cell trials.
3.5.
As with all
randomized trials there is only a 20%
chance a patient will get any benefit at all. Below, The Math,
explains.
The Math. Only half (50%) of trial participants get
the therapy, and less than half (40%) of Stem Cell recipients gain any
benefit. So the math is 0.5 x 0.4 =
0.20 or 20%.
Meanwhile the patient must abandon all other therapies (except impotent Riluzole) for
a year or more.
2021 Update. The eagerly-awaited Phase 3 trial results
were disappointing. For all participants the average change in ALSFRS-R
total score from baseline to week 28, was
-5.52 with NurOwn® vs. -5.88 on
placebo, only a 0.36 point difference, far less significant than
hoped. But, that was all
participants.
The study recruited 189 patients, nearly all
suffering from rapidly progressing ALS, and gave them either a placebo or stem
cell therapy developed by Brainstorm Therapeutics.
Brainstorm reported that, while its therapy
appeared to have a positive effect, it didn't
significantly outperform the placebo because the placebo group performed
better-than-expected.
One possible reason for the trial's high placebo
response could be the number of
participants with ADVANCED ALS, who are often less responsive to
treatment and whose responses are harder to measure.
However, a subset of patients, those with EARLY STAGE disease, did much better. The mean change from baseline to week 28
in their ALSFRS-R scores was -1.77 with NurOwn® and -3.78 for placebo.
And, early-disease patients had a better Response Rate: 34.6% for NurOwn® versus 15.6% for placebo.
A Response Rate of 34.6% means that only about
one-third of NurOwn® recipients,
called “Responders,” achieved a 1.25 point per month reduction in their ALSFRS-R
score declines. Such modest Response
Rates are common for all disease therapies.
Even Responders would likely need repeated NurOwn® transplants, and of course
cure is not a prospect.
A summary of the reports
can be downloaded here.
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Cedars-Sinai in Los Angeles
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This “first in humans” trial NCT02943850,
available only at Cedars-Sinai in Los Angeles, uses a new
deliver mode to inject a combined Stem-Cell-Gene-Therapy called Neural Progenitor Cells Secreting Glial
Cell Line-Derived Neurotrophic Factor (NPC-GDNF).
The NPC-GDNF trial accepts patients “18 Years and
older,” and prior Stem Cell therapy is exclusionary. The good news is that everyone gets the therapy. The bad
news: “You
should not expect to benefit from
taking part in this research study,” according to Page 8 of the
29-page trial
Consent Form.
Trial features and shortcomings are summarized
further down this page.
First, the underpinnings of this trial.
Animal Studies. The only prior test of NPC-GDNF in
creatures took place around 2012 and was published in this
2014 report. NPC-GDNF was “transplanted directly into the spinal [tissue]
of immuno-compromised young-adult rats, specifically chosen to avoid the
rejection of human cell xenografts.”
Some things to consider:
●
Like the
study animals, trial patients will be immuno-suppressed
using the drug Basiliximab, which creates many risks beyond infection. See Appendix C, pages 19-29, of the Consent
Form.
●
After the
immuno-suppressant wears off, the body will reject the transplanted cells.
●
Researchers
report that NPC-GDNF cells “survive long-term
(7.5 months) following
transplantation into the spinal cord [whereupon] cell numbers decreased significantly.” “This lower cell density suggests decreased cell survival [and] cell
migration away from the transplant site.”
●
Researchers
cite “tumor formation” (cancer)
as an “obvious concern.” At 7.5 months there were “no overt signs of cell overgrowth.”
However, the short rat lifespan “does not allow for long-term graft
[monitoring],” and 30 weeks is not a long time.
●
Unlike other
animal studies, this one did not determine increased lifetime or reduced
functional decline among the test animals.
Researchers could have
added a cohort of ALS-model rodents to determine comparative lifespan and
functionality – vital information for decision-making. But, they chose not to do so –
regrettably, expendable human rodents will reveal the first clues to
efficacy.
The report does not
even reveal the number of rats used in the study.
The Phase 1 Human Trial. Here are
some features and shortcomings of ongoing trial NCT02943850:
●
Unlike the Phase
2 tested NurOwn® agent, which
has a track record, this is the first test
in humans. And, there has
been no animal efficacy testing. So,
there is a chance this process COULD make matters worse.
●
Enrollment is
limited to 18, and, according to a Cedars-Sinai
press release: “Participants will
come from the ALS Clinic at Cedars-Sinai.” This apparent recruitment source raises
two questions:
●
In the year
since launch why has the ALS Clinic not
found 18 eager participants?
Perhaps clinic patrons have heard feedback from participants.
●
When the 4th
annual report refers to trial participants as “patients from the state of
California,”
is that a requirement omitted from the Trial Description? The trial’s multi-million dollar funding
comes from California
research agency CIRM. So,
participation MAY be limited to California
residents. The question can be
resolved by a phone call to the project at 310.423.1791.
●
The SIDE of
the body to receive the therapy is randomized and blinded, so that,
according to the annual
report, “The [disease] progression
in the treated leg vs. the non treated leg will be compared.”
●
Each
transplant session requires a “5-hour
surgical procedure” followed by a 5-day hospital stay including
intensive care. The “neurosurgeon will remove . . . bone in
the lumbar region [and] will inject the stem cells directly into the
patient's spinal cord in a section that governs movement on only one side
of the body.”
●
There will be
several surgeries, 3-weeks to
one-month apart with tests in-between.
This process of transplant and monitoring will last 15 months.
●
Participants
must be “geographically accessible,”
so must reside within driving distance.
However, free long distance air travel MIGHT be available from Angel Flight at [email protected] or
1.877.4AN.ANGEL.
●
The project
requires that the patient MUST have a
caretaker to provide transportation and help with recovery following
the surgeries.
●
Any atypical ALS “disease phenotype” could exclude you. Be sure to study the trial Eligibility
Criteria here: NCT02943850.
●
All other therapies, except Riluzole, must cease
during the 15 month period. And, as
usual, this trial will likely exclude you
from all future Stem Cell trials.
●
As with all
disease therapies there is a Response Rate,
which is usually less than 50%. So,
even after all the struggle and expense, more than half of patents will get
NO benefit whatsoever.
Perhaps much less than
50%, because the body side to receive the agent is randomized.
Further, those who get
a benefit may not detect it, since the
benefit is often just a slowing of functional decline.
Other considerations. There are
two other possibilities for people on the east coast:
●
Q Therapeutics (reviewed below) MAY begin
its NON-randomized trial NCT02478450 in 2019 with sites on the east coast –
although a 2019 start-date is not certain.
Patients with gait
problems may wish to target the first (lumbar) cohort, because the lumbar
cord affects the lower limbs (whereas the cervical cord affects breathing).
● For the rare familial (heredity) patient with the
genetic SOD1 mutation or the
“misfolded SOD1” defect (less than 10% of all ALS cases) the BIIB067 Trial may offer better long-term prospects than
Stem Cell transplantation.
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Q Therapeutics Trial
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The Q Therapeutics
Phase 1/2 trial NCT02478450
is not yet recruiting, and the location(s) are not known. It will accept 80 year olds, and is
limited to 30 patients who will be divided into 6 cohorts – perhaps 5
patients per cohort (5 x 6 = 30).
Although all participants will receive the
therapy, each cohort will be treated differently. The “initial
cohort” will undergo Q-Cells®
transplantation to the lumbar
spinal cord at dose Level 1.
The remaining 5 cohorts will undergo Q-Cells® transplantation to the cervical spinal cord at dose Levels 1
through 5.
Animal Studies. This section is incomplete until I
discover the underlying animal study.
The Phase 1/2 QThera Trial. Upcoming
human trial NCT02478450
has downsides:
●
The patient
must not have received prior Stem Cell
therapy.
●
The patient
must reside “within
reasonable driving distance” and must
have a caregiver to assure transportation and after-surgery care.
●
And,
historically, the Stem Cell Response Rate
has been less than 50%, meaning that more than 50% of participants receive
no benefit at all.
Non-responders may be far more numerous than 50%
in this Phase 1/2 trial, because some patients will receive a low dose of Q-Cells® and others a relatively high
dose.
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AstroRx® Astrocyte Cells
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AstroRx®
astrocyte cells are derived from human embryonic stem cells. The commercial product is intended as an
eventual “off the shelf” therapy which will not require an autologous process. An autologous process harvests the
patient’s own stem cells and propagates them in an artificial environment
outside the body.
In Clinical Trial NCT03482050,
held in Israel,
AstroRx® cells are being injected into the cerebrospinal cord fluid of 21
patients using standard lumbar puncture procedure. Each of four 5-member cohorts receives a
different dose of AstroRx®.
The transplanted AstroRx® astrocyte cells are
intended to compensate for the patient’s malfunctioning astrocytes cells in
the brain and spinal cord, in an effort to slow disease progression and to improve
quality of life and life expectancy.
In late 2019 manufacturer Kadimastem Ltd of Israel, first
reported some results from Cohort A of its Phase 1/2a clinical trial. The four cohorts are being treated in
sequence, and all enrolled patients suffer from early-stage disease:
●
Cohort A is
finished; 5 patients received 100million cells; data is presented below.
●
Cohort B is
finished; 5 patients received 250million cells; Results are expected in
August 2020.
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Cohort C is
underway; 5 patients will receive two doses of 100million cells, separated
by an interval of 2-3 months. Results
are expected in the first half of 2021.
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Cohort D’s
patients will receive a repeat dose of 250million cells or a modified regimen
based on results of the previous cohorts.
Results for
Cohort A. Only data from Cohort A is
available. Some Cohort A data was released
in September 2019 with more data
in January 2020.
The following summarizes the January reports. Refer to the graph below which comes from
this
Kadimastem document.
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In the three
months before starting AstroRx® treatment,
patients’ ALS-FRS-R decreased at an average rate of 0.87 per month, a rate
of decline similar to that reported in the medical literature.
●
During the
3-month treatment period the average ALS-FRS-R change was +0.26 per month,
meaning that decline was halted, and patients
improved on average. See the
graph below.
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During the fourth month (treatment stopped at the
end of the third month), some benefit
continued, indicated by an average monthly decline of 0.32, rather than the
typical 0.87. See the graph below.
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Not shown on
the graph: All benefit ceased AFTER
the fourth month, and the patients’ decline returned to the same rate as they
experienced before this therapy. The
researchers
report: “In
the 5- and 6-months post-treatment periods, a statistically significant
difference was not observed between
the rate of disease deterioration during these periods and the rate during
the pre-treatment period.”
Cautions. The
results are based on the experiences of only
five experimental patients – an exceedingly small sample from which
to project future confidence. Thus, good
results from AstroRx®, at this stage, cannot
be assured to any extent – the apparently-good results could be mere
happenstance. On the other hand, the
very early results could signal the arrival of a useful therapy. Time and the other cohorts will resolve
the uncertainty.
There are at least two conditions which must be
overcome to assure a practical treatment:
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Currently,
benefit duration is fleeting, but might be extended. After AstroRx® injections stop, the
hostile environment eventually destroys the newly implanted cells. But, that problem could be overcome by repeated, sequential injections. The manufacturer intends AstroRx® to be a
readily-available “off the shelf” product, not requiring the costly autologous
propagation of the patient’s own cells.
So, ongoing injections are an economic possibility.
●
Life-long use
of anti-rejection drugs may be required. During the trial, rejection of the transplanted
alien allogenic stem cells was controlled using a “mild immunosuppression regimen for a
month during the treatment time (Mycophenolate
Mofetil 1gram twice daily).”
Although the anti-rejection drugs
could pose health risks, they are regularly used in other alien allogenic transplants.
Mycophenolate is an anti-rejection
drug often used in large
organ transplants.
An excellent 2017
UK article explains the supreme
difficulty facing stem cell therapy: “The transplanted cells [must] migrate
to affected areas of degeneration, survive, mature and integrate into the
preexisting neuronal circuits . . . All this must occur within a hostile
microenvironment where other motor neurons are dying . . . .”
Trial Acceptance. Although trial
NCT03482050’s
status is currently listed as “recruiting,” that condition will not last
long given the small enrollment total of 21.
Unfortunately, successful
completion of a future Phase 3 trial, one with a much larger enrollment,
will be needed before FDA approves AstroRx® for everyday clinical use. Phase 3
recruitment may not begin until late 2021 or 2022, and the FDA
ruling (if it occurs) may take place a year after the trial’s completion.
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Other Trials
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There are trials in Korea, Spain
and Poland
which MAY accept older early-stage patients. Each uses a different Stem Cell product
and delivery mode. Details can be
found at the Clinical
Trials website.
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How to Contact the
Trial Manager
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This section above tells you how to make contact.
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Virus, Retrovirus HERV-K As A Cause
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Newly opened clinical trial NCT02437110 will
test whether antiretroviral drugs can
benefit ALS victims, at least those pALS having a significant
presence of HIV-like viruses (HERV-K) in their spinal fluids.
Below, an outline of the research hypothesis
is given by a 2010
article by Amber Dance, titled: Does
an Ancient Retrovirus Come Out of Hiding in ALS?
Several abstracts accompany the Dance article. All are
downloadable here, the more recent on top.
Suspicions about HERV
involvement in ALS began in the 1990’s and continue to the present
time. NIH investigator Avindra Nath,
who leads the new trial, appears prominently in the decades-long research.
The good news is that many HIV victims, those experiencing
ALS-type symptoms, have experienced some relief from their ALS impairments. The bad news is that apparently there has
been no HERV-suppression research on “traditional” ALS patients.
Until now, no true ALS patient has been treated
with antiretroviral drugs, the object of Clinical Trial
NCT02437110. That Phase-1 trial,
which may still be open, will treat
20 ALS patients with a combination of four drugs over a 6-month period. There is no placebo control group, so all
20 receive the drugs. And,
transportation to and from NIH is paid by the research project.
At
this link there is a comprehensive 2018 journal article on the
potential roles of several viruses in ALS
development. Search for the
terms: HIV and separately HERV. You
will get about 22 hits for each.
Further, immediately
below the linked articles describe a relationship between HERV and ALS
symptoms. Researcher Avindra Nath is
a coauthor of most of the articles.
Each link title contains the publication date.
Finally, the related HERV-Suppression
trial description
is available here, and an MS Word version is downloadable
here.
Immediately following is the 2010
Amber Dance article. To help you
understand terminology of the article, install free Wordweb,
which is described here.
Does an Ancient Retrovirus
Come Out of Hiding in ALS?
Amber Dance | 27Dec2010 |
https://www.alzforum.org/news/research-news/does-ancient-retrovirus-come-out-hiding-als
The human genome is littered with scraps of
millennia-old retroviruses, which hopped in, never hopped back out, and now
pass from parents to children. Some
of those retroviruses may wake up
and contribute to amyotrophic lateral
sclerosis, according to researchers at Johns
Hopkins University
in Baltimore, Maryland. Their paper was accepted November 8 by
the Annals of Neurology and is
available online. If confirmed, the
results suggest that retroviral genes and proteins could be a useful
biomarker for ALS.
First author Renée Douville, who has since moved
to the Lady Davis Institute in Montréal,
Canada, led
the research in the Johns Hopkins laboratory of senior author Avindra Nath. She hunted down the retroviral gene pol,
which encodes reverse transcriptase, in a collection of frozen brain
samples: 28 cases of ALS (25 sporadic, three familial); 12 cases of chronic
systemic disease such as coronary artery disease or cancer; 10 control
cases of accidental death, mostly traffic accidents; and 12 cases of
Parkinson’s disease.
She found the retrovirus HERV-K was active, to varying levels, in nearly all people who had ALS, plus
the chronic disease cases. Viral
proteins could have been toxic to neurons or upset cellular metabolism, Nath
suggested. However, he noted that it
is too early to do much more than speculate about the results. “So far, all we have shown is association,”
Nath said. “The caveat of all this is it could be a
non-specific finding.”
The study is not the first to link ALS and
retroviruses. After all, TAR-DNA
binding protein 43, currently starring in many an ALS research program, was
first identified because it binds the HIV gene TAR (Ou
et al., 1995). Scientists have
found reverse transcriptase in serum from people with ALS before (MacGowan
et al., 2007; McCormick
et al., 2008), and hunted for evidence of infectious environmental
viruses such as HIV, which can cause ALS-like symptoms (see ARF
related news story on MacGowan
et al., 2001 and Moulignier
et al., 2001; also Verma
and Berger, 2006).
“They never found anything,” Nath said.
Instead, he and Douville sought evidence of endogenous retroviruses,
which jumped into human DNA and stayed put millions of years ago (reviewed
in Bannert
and Kurth, 2006). “Nine percent
of the human genome is retroviral sequences,” Nath said.
Nath studies neurological complications of
retroviruses such as HIV; he collaborated with Jeffrey Rothstein, an ALS
researcher in the laboratory next door, who provided the brain tissue. Douville screened mRNAs, via RT-PCR, with
a handful of primers for endogenous retroviral pol. She found that HERV-K pol was transcribed
in the ALS cases — sporadic and familial — as well as the systemic disease
samples. PD and accidental death
samples did not evince RT pol transcription. HERV-K has also been implicated in
multiple sclerosis (Dolei
et al., 2009; Perron
and Lang, 2010). Although HERV-K
was the strongest hit, the researchers note that their findings do not
eliminate the possibility that other retroviruses are active, too. HERV-K pol mRNA showed up strongly in the
prefrontal and sensory cortex, with less in the motor cortex. Nath suggested this is because so many
motor cortex cells have already died.
The researchers have not yet examined spinal cord tissue.
Is HERV-K expression a cause of neurodegeneration,
or merely the swan song of neurons dying for a different reason? The
researchers do not know, Nath said, although he pointed to the lack of
HERV-K pol transcription in Parkinson’s cases as evidence that it does not
show up in every neurodegenerative disease.
Douville further examined pol expression by
immunostaining. Ten of 13 ALS cases
were positive for RT, versus three of 10 systemic disease cases. Reverse transcriptase tended to show up
in clusters of neurons, in the kind of staining pattern one might expect if
the virus were made in one cell and released to attack neighboring neurons,
Nath noted. He added that the idea
was purely hypothetical.
Dozens of HERV-K sequences are sprinkled
throughout the human genome, so the researchers attempted to pinpoint the
ALS-related loci by sequencing DNA. They
used primers that started in the retroviral genes and followed the sequence
through into the native human DNA. They
found hits on the seventh chromosome, among others. ALS cases, in particular, expressed pol
genes at 7q34 and 7q36.1. Tantalizingly,
these loci sit within an unidentified motor neuron disease (MND) locus in
the 7q34-7q36 region (Gopinath
et al., 2007); Douville and Nath suggest the
unknown ALS gene could be a retroviral polymorphism.
Garth Nicholson of the University of Sydney,
Australia, authored the 2007 paper identifying the 7q34-36 MND locus, and
he was skeptical of the retroviral connection. “Our locus causes a non-lethal but disabling motor
neuron disease,” he wrote in an e-mail to ARF. “It would need to be a functional gene (rather than a
virus relic) and have a disease-specific mutation to be relevant to our
disorder.” Further, Nicholson cautioned, “Every now and again retroviruses have
been said to cause neurological disorders, but they have not stood the test
of time.” Most recently, researchers hypothesize a link between
Herpes viruses and Alzheimer’s disease (Porcellini
et al., 2010; for review, see also Itzhaki
and Wozniak, 2010).
Jeremy Garson of University College London, U.K.,
has studied RT expression in ALS serum (Andrews
et al., 2000; Steele
et al., 2005; McCormick
et al., 2008). He said this is
the first study to identify a specific retrovirus, but agreed the results
are very preliminary. “If the findings
are independently confirmed and extended by others, it is possible that
HERV-K expression might in future become a useful biomarker or
diagnostic/prognostic indicator (assuming, of course, that brain biopsy is
not required to measure it),” he mused in an e-mail to ARF. “Aberrant HERV-K expression might prove important in
understanding the pathogenesis of ALS,” he wrote.
Nath noted that drug
companies already possess libraries of retroviral drugs originally
developed for HIV. If, indeed,
HERV-K or another retrovirus proves important in ALS, it might be worth
testing [them] on endogenous [originating internally] retroviruses, he
suggested.
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Primary Lateral
Sclerosis
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Primary Lateral Sclerosis (PLS) is a rare motor neuron disease
characterized by progressive muscle weakness. There is no evidence of the degeneration
of spinal motor neurons or muscle wasting that occurs in ALS.
Onset of PLS usually occurs spontaneously after
age 50 and progresses gradually over years. The disorder usually begins in
the legs, but it may start in the tongue or hands. Symptoms
may include balance difficulty, weakness and stiffness in the legs,
clumsiness, spasticity (involuntary muscle contraction), foot dragging, and
speech and swallowing problems.
Breathing may also become compromised in later
disease stages, requiring ventilatory support. More details in this informative
journal article.
PLS is not considered hereditary when onset occurs
in adulthood. Whether PLS exists as
a different entity from ALS is not clear, since some patients, initially
diagnosed as having PLS, ultimately develop lower motor neuron symptoms.
There are no specific diagnostic tests for
PLS. Diagnosis occurs by eliminating
other possible causes of symptoms.
That process, called Differential
Diagnosis, is detailed in this
outstanding paper and in this Medscape
report.
PLS is rare, occurring in 1 in 10 million
population, compared to ALS’s 2-3 per 100,000.
Currently, there is only one interventional trial for PLS, identified
as NCT02868567
in this
listing of past and present PLS clinical trials.
The Phase 1 trial tests Dalfampridine (Fampridine)
which improved
similar motor functions in Multiple Sclerosis patients, some
for long periods.
●
The trial
closes January 2019. Enrollment is
35.
●
Fampridine is
delivered in pill form.
●
Patients must
have taken NO therapeutic agents during the 30 days prior to enrolling.
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Multifocal Motor Neuropathy (MMN)
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Background
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MMN
and ALS tend to have similar symptoms, making MMN difficult to
diagnose. Both produce progressive
muscle weakness.
MMN, however, is not fatal, and the MMN victim can
expect to have normal life-expectancy if treated. MMN may be an autoimmune disease. More details in this fine 2017
journal article from Yale School of Medicine.
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Treatment
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Patients
respond well to Intravenous Immunoglobulin (IVIg). It is imperative that patients begin IVIg infusions immediately upon
diagnosis, since function loss often cannot be restored.
IVIg works well initially, increasing muscle strength
and restoring some function, but IVIg tends to lose effectiveness over the
years. Increased doses are helpful
but eventually decline in value. And,
the proper dose of IVIg Maintenance Therapy has not been established. See this 2018
journal article from Japanese researchers.
However, many immunotherapies are under
development for other diseases, and may be helpful in this one. They probably will not be needed for more
than a year.
An injected form of immunoglobulin
is available, called Subcutaneous Immunoglobulin (SIg). SIg may perform better than IVIg, since
its release into the body is time-extended.
See details in this 2017
journal article from Danish researchers.
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Daily Living Guide
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How
to manage daily ALS adversities. Diane
Huberty, a retired, certified neurology nurse and ALS patient, has
authored an extraordinarily helpful website, titled: ALS From Both Sides.
A gifted “teacher,” Ms Huberty has managed to
address nearly every issue that the ALS victim might encounter – in a
concise and thorough manner. A pdf version of her website, replicating its entire content, is
contained within this
downloadable, searchable guide.
The guide is monumental in scope, presenting
management plans for all of the following difficulties, and more – a splendid
resource:
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Cramping and
Spasticity
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Choking and
Swallowing
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Swollen Feet
and Blood Clots
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Osteoporosis
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Toilet
Troubles
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Feeding Tubes
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Respiratory
Options
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Remodel Home
or Move?
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Equipment
Needs
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Caregiver
Information
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An Uplifting
Message for the Disheartened
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Care Management
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Medical Terms,
Definitions
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To
learn the definitions of many medical (and other) terms install free Wordweb. Once installed, place the cursor over an
uncertain word, then Ctrl right-click to receive the definition. Wordweb
works in any medium: Webpage, html, pdf, doc and most vector graphics.
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Cancer Term Definitions
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Many cancer definitions
apply to ALS also, for example “Response Rate.” Such terms are defined here.
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Multi-Disciplinary ALS Centers
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Certified Multi-Disciplinary Centers (MDCs), of which there are 73 in the USA,
offer participants more health care services than typical facilities:
Specially-trained nurses, therapists, social workers, dieticians, and
in-home care providers.
The locations of all USA MDCs can be found at this website. George Washington
University is a
certified MDC. And its ALS Center staff is named in
this flyer.
Johns Hopkins is not a
certified MDC. In Maryland
the only certified MDC is the ALS Clinic at the University
of Maryland, Baltimore.
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The Correct Insurance
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Discard
Managed Health Plans. If the patient has a managed plan, be
certain that the 73 Multi-Disciplinary
ALS Centers and major academic centers are available under the plan (which
is unlikely under a managed plan).
If Medicare, make sure he has have ORIGINAL Medicare, plus a 100% Medigap plan. Medigap pays the 20% which Medicare does
not cover. Medigap Plans F & G
do that.
Plan G does not cover the $183 Part B deductable,
but its price savings nearly always exceeds the $183 deductible, so offers
a savings opportunity.
And, arrange Medigap
autopay with your bank – this avoids a late payment which could
cause a permanent Medigap cancellation.
If you have a Medicare Advantage plan, switch to
Original Medicare. Original Medicare plus Medigap will assure that
the patient is welcomed financially at the best
care facilities.
●
From Link-1
it appears that you can switch during the period January 01 through
February 14 each year and PERHAPS October 15 through December 07.
●
And,
according to Link-2,
you can be granted a Special Enrollment
Period (SEP), if you enrolled in the Medicare Advantage plan based
upon misleading or incorrect information provided by plan materials,
employees or insurance agents.
Link-2 covers Ohio,
but the conditions are the same in all 50 states.
● It is possible that you don’t actually have to PROVE
that you were misled. Your
reasonable, unwavering instance may be enough. Press hard; you have nothing to lose.
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Care Management
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Below are practices that should be adopted when
dealing with a life-taking disease.
1.
Family Researcher. The
family must identify at least one bright, skilled person, with excellent
computer savvy, to devote 100% of his time
to care management – and the family must support that person by taking over
the normal work and home responsibilities which he now must abandon. The lack of such good organization costs
lives.
2.
Care Manager. The family Care Manager
must maintain updates on all reports at
all times. And, be prepared
to convert them immediately into one clean, logically-sequenced pdf
file. Software can help the manager
– Fax, pdf and definition software.
Fax. For a
hospitalized patient, often the surest way to reach a physician is via
Fax. A physician will always read a
fax. All medical offices and nursing
stations are Fax-equipped. There are
online services, like eFax, and PC-based software like FaxTalk and (for
WinXP) WinFaxPro. Win8 and Win10
have built-in software, but you will need a $10 USB modem (buy on eBay) and
a landline.
PDF
conversion. PDFCreator will convert most documents
(graphic or text) to pdf, available free here.
Definitions. Many
medical (and other) terms are defined for you via free WordWeb, just Ctrl Right-Click over a difficult word and get
the definition. Free here.
3.
Planning Is Critical. The Care
Manager and patient must chart a COMPLETE course from the very beginning.
There must always be multiple irons
in the fire, so the patient can jump immediately to another best therapy
when one BEGINS to fail. Too often
managers make the fatal mistake of waiting
until one therapy fails before starting the search for another.
An “iron” is in the fire ONLY if the
therapy is suitable; the patient is eligible, and the related physician is
in agreement. “Thinking about it”
doesn’t count as an iron. See Item
7, below, for therapy sequencing.
4.
Financial Help. ALS victims MIGHT gain help
from the following Cancer organizations.
Perhaps they will assist ALS victims as well.
Travel and Financial Aid might be obtained
from Angel Flight and CancerNet. Charity grants can be found through CancerCare. And drug discounts and donations often
can be had by contacting the manufacturer’s customer assistance team.
More contact information for free Angel Flight is [email protected] and
1.877.4AN.ANGEL.
Certainly, travel is inconvenient,
but death is far more inconvenient.
We must seek help from those who
write the books, not from those who won’t find the time to read
them.
For example, only the most skilled
and experienced IRE practitioners should be used. IRE has a significant learning
curve. If the placement of
probe-pairs is incorrect or the pair spacing is 5mm outside specifications,
IRE ablation will be imperfect, as noted in this
report.
5.
Therapy Sequence. Sequence
and timing are critical. It is vital
that the patient or Care Manager (not the treating physician) selects the
best therapy path right from the beginning
(with adjustments along the journey).
See Many
Irons in the Fire, below.
This is a swiftly moving parade – one misstep and you cannot go back
and take a path previously forsaken.
For example:
Some clinical
trials require patients to be therapy naïve (that is, no prior
therapy). So, at the moment of
diagnosis, the Care Manager (skilled friend or relative) must begin an
intensive self-education and search effort.
That effort
requires a solid week of hard work.
But, that’s how this website helps.
See the section below on prudent
Clinical Trials. There is no
time for hand-ringing.
The physician will NOT do this work for you.
6.
Many Irons In The Fire. Most
families tend to seek care in SERIES, meaning that they seek treatment by
one therapy, and, when it fails, BEGIN the search for the next path – with
an enormous loss of life-taking time. In most cases the next step is a Clinical
Trial. How to search for them is detailed below.
This is a great mistake. One must have multiple irons in the fire (called “contingency planning”),
by which the family has identified MULTIPLE therapies and institutions to
undertake the next chapter of treatment.
●
Getting input from distant physicians, without traveling, is
possible, if you are organized and have computer skills (and have been wise
enough to collect the key diagnostic and treatment reports).
Gather the latest
key reports. Convert them into pdf format. Make them easy to read, large and
oriented properly – and remove all static and blemishes from the
pages. Send them by email in ONE
multi-page file, in logical order.
Use a cover letter which gets to the point in about 6 sentences and
avoids sentimentality. Don’t waste
the physician’s time. For example:
Dear
Dr X, Will you consider accepting X under your care? He suffers from X and has been treated
with X. He is physically strong and
well-insured. Attached are the
current reports. I am indebted to
you for your help.
●
When scanning
documents, set the TWAIN preferences to “line art” or “line drawing”, not
“color”, to produce a cleaner B/W product; then save it as .pdf, .png,
.bmp, .tif or .gif file, but not .jpg, since a .jpg will smear the pixels.
7.
Research. There are four principles to practice:
●
The patient
and family must be so well educated
about therapy that they know in advance
of the next physician meeting what the physician will recommend.
●
You must
fight hard to get any new therapy.
If you don’t seek it, you won’t get it.
●
Many family
“Care Managers” think that they will find a physician who will do all the
searching and future arrangements for them – those managers are often lazy
and looking for an excuse to avoid hard work. There is no such magic physician. And, if you find one, you wouldn’t know
whether he is correct unless you yourself do the research. A life is at stake; trust no one else.
●
If the physician disagrees with the medical literature, the physician is wrong. In medicine Truth and Falsity are
determined by carefully-designed clinical trials. No amount of physician anecdotal
experience can override the findings of clinical trials.
8.
Hospital Admission. Accept
financial responsibility for an incapacitated patient ONLY if he is a bona
fide legal dependant.
Never, under any
circumstances, sign for a non-dependent
(including parents) during hospital admission. This is how the facility hopes to bind
you to patient costs. If the patient
is incapable of signing, just write “Mr
XXX is unable to sign” in the signature space, and don’t draw attention to it. Every US hospital is obliged to treat
the patient without your legal commitment.
9.
Hospital-Acquired Infections. Infection
can cause life-taking delays in cancer therapy. Read about IV solutions, C. diff and
hospital acquired infections here.
The family must make sure that prevention measures are followed. And, if an infection occurs, the family
must understand the remedy thoroughly to assure that the treatment is
correct. Medical mistakes are too
common.
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How to Find the Best
Clinical Trials
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We are always urged to seek clinical trials. However, there must be great caution with
this particular disease. Over the
past 20 years clinical trials have led to FDA approval of only ONE new
agent: Edaravone.
During those 20 years all other agents failed, even though they were based on “successful” animal studies.
Summaries on all 34 current ALS trials (available
in the USA
as of August 2018) are contained in this
downloadable pdf file. Only
about half are worthy of consideration.
So, how should we evaluate clinical trials?
First, look for agents which ADD TO therapies
already known to be helpful. Then,
participate in the trail ONLY if the new agent has shown value in earlier HUMAN
trial phases. There are usually 3
trial phases. Dosage and efficacy
are usually determined in Phases 1 and 2.
So, at the end of Phase 1 or 2, some effectiveness will be known.
Thus, we want to find the agents and practices
which will LIKELY produce the greatest impact.
You will be offered Clinical Trials which you must
evaluate, and you should search for trials on your own. Here we will cover both approaches.
Trials Offered To You
Be wary.
Researchers have trials which they
must fill with human guinea pigs.
They hope to use your life for “the
benefit of mankind.” And they
know that you are desperate.
They know that, in your desperation, you will hear
ONLY the GOOD of the trial and NONE of the BAD. They know that you will hang on every
word of hope, like “we are hopeful about this new drug” and “we had good
results in preclinical trials” (preclinical is laboratory and
animal research). Such subjective
statements are interpreted differently by every listener.
They know that, in your fog of fear, you will
downplay their statements, like “The new drug slowed the disease for awhile”
and “there
is never any certainty in a disease like this.”
From the start trial researchers have you beaten
psychologically.
Meanwhile, the patient will tend to minimize or
overlook such clinical trial features as:
●
Randomization. Often half the patients
receive only a placebo drug or placebo surgery. And they will be expected to remain
within the trial until it ends, because drug efficacy can be determined
only by comparing the conditions of Experimental Subjects (the ones getting
the new agent) to Control Subjects (the non-recipients).
Of course, you can always depart at
any time, but your medical record will show future trial managers that you
are a quitter, meaning that you might quit their trials as well.
●
Other Therapies Delayed. During
the trial you will be expected to forsake other trials and most other
drugs. Researchers want to be sure
that THEIR trial drug is the only drug being tested.
●
Trial Banning. Some trials, like Stem
Cell trials, will preclude your participation in other Stem Cell trials in
the future. Future researchers want
subjects who are not tainted by prior failed trials.
So, early decisions must consider the ramifications all the way to the end. Thus, we must approach the trial decision
will cold calculation.
Consequently, if a trial is offered to you:
1.
Get the trial
number, which begins with NCT, and use it at the Clinical Trials
website to load the Trial Description which provides details like:
Experimental Agent, Trial Phase,
Treatment Arms, Randomized, How Administered, Eligibility Criteria,
Enrollment (number of participants), etc.
Sometimes (rarely) the Trial Description at the bottom lists
research reports relevant to the new trial.
Get those reports and study them.
2.
Use Google to
discover what is known about the experimental agent. Set Google response preferences to 100
replies. On the Google word line
enter the drug name plus “amyotrophic lateral sclerosis” in quotes. Press Search.
Then, in the column of search
results, if you see a response of interest, right-click
and open a new tab. That way you preserve the original search response page,
and you can open new tabs while the other tabs are loading. A scrolling mouse is essential for this
search. If you don’t have one, get
one.
3.
Our first priority is to find earlier trials
in which the drug was used.
Generally, new agents undergo human testing in three trial phases:
Phase 1 (dosage and some efficacy), Phase 2 (efficacy), Phase 3 (statistical
significance). So, if the offered
trial is Phase 2, there will be Phase 1 results available. You need to study those Phase 1 reports
carefully.
4.
In our Google
search we are looking for results from
human trials, and, if not available, from preclinical (animal)
research. There will be news reports
and research reports. We want to
study both for impact. What is
4.1.
The Response
Rate: The percentage of patients receiving benefit from the new drug –
usually this is less than 50% – so at least 50% receive no benefit at all.
4.2.
The nature of
the response: Was there a slowing of decline or an actual improvement?
4.3.
Durability of
Response: How long the response lasted.
5.
Repeat this process using PubMed. Just copy/paste the following text on the
search line, making sure to enter the drug name, spelled correctly:
DrugName[abstract] “amyotrophic lateral sclerosis”[abstract]
6.
If the new
agent was used previously only in animal
research, the results will be far
less reliable to humans. Only
one FDA drug has been approved in 20 years.
All other trials failed, and yet they all began as successful animal
research.
This search process should give you
hard performance evidence to be expected from the offered trial. Now you must compare that performance (a) to that of other trials AND
(b) to existing therapies, like Edaravone and
perhaps the not yet available Ibudilast + Riluzole
combination.
After all, if the new drug is no better than old
drugs, why risk the uncertain trial.
Finally, do not choose a trial just because it is
offered or is local. Find the BEST one available, and travel to it, if
necessary. Far more inconvenient
than travel is death.
If you seek a trial recommendation from your ALS
specialist, ask him to identify the BEST
one available regardless of geographic location.
If he names a trial that he himself administers,
consider: What a monumental coincidence that the BEST of all clinical
trials on earth is being conducted by your neurologist (one among the
multitude of neurologists), who is also being paid to find trial
subjects. That physician may not be
your friend, no matter what he pretends to be.
Often, neurologists
make a “God’s judgment”: Shall I make every effort to treat this
patient responsible and cleverly, which might help her somewhat but
postpone the inevitable, or should I use her life in an uncertain trial
which may help all mankind?
Frequently, they push the patient into the trial
without telling her the grave uncertainties. And, sometimes these oncologists prod
patients into trials which they administer (trials which are not the BEST
available) – that conflict-of-interest is unethical and frequent.
Search For Trials On Your
Own (to be provided later)
Before meeting with the physician, the patient or
family care manager must be so acquainted with ALS and its therapies that
he knows the specific options which the physician will recommend.
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Current ALS Trials. Not all
trials seek direct patient improvement.
Some just gather data.
Consequently, only about one-third of trials are worth
considering – they will have a therapy named in the Interventions column and a Phase named in the Characteristics column.
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Trials by Location
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Trials by Therapy
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How to Contact
the Trial Manager
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To make initial contact with the Trial Manager use
this
sample letter. It has the proper format and
content. It gets to the point
concisely and without sympathy.
If you omit the ALSFRS-R score
or your age, you run the risk of wasting travel time. Eventually, the trial staff will learn
them. Trial Inclusion and Exclusion
criteria are usually very strict, and the trial personnel are unlikely to
change them. But, there is no harm
in asking.
The trial leader’s email address is often
near the bottom of the Trial Description.
If missing, there is a reliable way to find it. Identify the leader’s mail domain; it is
part of the email addresses of other staffmembers, for example
“@ALSfacility.edu”. Then enter the
leader’s name and the mail domain on Google’s word line, and press
search. The full email address is
likely to be returned within the first several pages of search results.
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Stem Cell & Exosomes
Scams
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Seemingly “professional” clinics are offering fake
Stem Cell and Exosomes “cures” that FDA and insurance companies won’t
approve.
Here is how the Exosomes scam works. It’s very much like the sale of other
counterfeit merchandise.
1.
The Stem
con-man uses the name of a FUTURE therapy, Exosomes, to make it all sound
legitimate. But, the REAL medical
literature says that this technology is not ready yet and must await the
FUTURE:
1.1.
This October 2017 Harvard paper calls
Exosomes: “a
promising [future] next generation approach for treating diverse . . .
diseases,” but that there are “challenges in bringing exosome-based
therapies to clinic.” Clinic
means: “to use Exosomes on patients immediately.”
No one told these
Harvard researchers that the Stem Cell swindler has solved those problems.
1.2.
In this February
2018 news report, University of Georgia researchers, after studying
Exosomes in animal stroke victims (rats and pigs), reveal their “plans to
begin human studies in 2019.”
No one told them that
our local Stem fraudster has beat them to it.
1.3.
This 2017
report from multi-national researchers cautions: “With all of the apparent advantages that Exosome therapy might
offer, there remain barriers to be solved before these therapeutic
strategies can be widely implemented.”
Why don’t the Stem
crooks know this?
2.
For 20 years
in the Western world vastly-intelligent scientists at scores of research
centers have been trying to cure ALS using Stem Cells.
Over 17 years ago the first human
Stem Cell experiments took place; many more human experiments
followed. Read this brilliant
document, page 7, which describes the research struggle from yesteryear
to present.
Even now leading Stem Cell
researchers have slowed the disease only
temporarily in less than 40% of ALS victims (no cures) – but in a
randomized clinical trial the 40% likelihood of benefit is cut in half, to
20%, because only half get the drug.
Compare that to Ibudilast
which slows the disease in 32% of “Early ALS” patients – some of whom actually
see improvements.
How is it that the back-alley outfits
have solved the problem when no one in the
West has – and at the same time (mind you) they cure baldness with
the same mysterious brew?
3.
The Stem
charlatans plan intravenous deliver
(into the blood stream), which will NOT work. This fine
2017 article, page 6, states “The
engraftment efficiency of intravenous delivered cells within the CNS was
very low, with . . . cells almost
completely absent twenty days post-injection. [Stem cells] delivered by the intravenous
route . . . do not correlate with the efficiency of long-term engraftment
in the host.” In other words: IV-delivered Stem Cells do NOT make it to the target.
In contrast, Intrathecal Delivery (into the spinal canal) “allows the obstacle of
the brain blood barrier to be bypassed; moreover, the injected cells may
migrate along the spinal cord” (page 6). So, the scammer’s procedure will NOT
deliver the Stem Cells to where they MUST go – to the brain and to the
spinal cord.
4.
This
so-called umbilical cord blood might be prepared in some unsanitary Chinese, Vietnamese or
Indonesian sweatshop, and it could come from people (or animals) plagued by HIV AIDS, hepatitis,
cancer or other diseases or parasites.
IV-injection is not like a pill that gets cleansed by stomach
acid. It is a direct bloodstream
injection, which could traumatize the immune system.
5.
Legitimate
researchers around the world warn of Stem Cell frauds. Read this 2015
journal article from a university ethics and law center, entitled: Untested, Unproven and Unethical. And, read this 2018
journal article from 8 US and Japanese medical schools, entitled: Can Civil Lawsuits Stem The Tide Of . . . Unproven
Stem Cell Interventions?
6.
Before you
allow these swindlers to put that crap in your body, first insist on talking to a “cured” Exosomes ALS user. They won’t be able to find a single one. Which is interesting, because, if this
snake-oil worked, it would make banner headlines around the world.
7.
Your snake-oil
folks have no scholarly papers, no clinical trials, no peer-review to demonstrate
whether their “treatment” works.
8.
If this
process (perhaps costing many thousands of
dollars) is so great, why won’t insurance and FDA approve it?
9.
And, for a
$3,000 surcharge the frauds will let you return for more “therapy”
indefinitely. Why don’t the scammers
know on the front-end how much “therapy” will achieve success?
10. Read about Stem Cell scams here?
11. In this
fine article on Stem Cell scams, medical professionals point out
several critical fraud issues.
11.1.
“The FDA has made it clear that two
characteristics of a stem cell treatment make it subject to FDA regulations.
“First, any manipulation
of a harvested tissue (separation of cells from fat or culturing or
concentrating bone marrow cells) gives the treatment status as a drug.
“Second, taking cells from
one location (such as fat) and putting them into another location, such as the bloodstream, also means
that the cells must be regulated as a drug.”
So, these scammers violate two FDA mandates. Thus, they run a criminal enterprise.
11.2.
“Clinics often make patients sign agreements not to disparage them as
a condition of providing the treatment.
This makes it difficult for individuals
to sue the clinics for failing to provide a therapy that has the
positive effects advertised.”
That means you cannot get your money back
from these thieves.
The understandable desperation of ALS victims will
blind them. It is a double tragedy,
because scam victims will need their squandered money for care and comfort
in the future.
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Veterans’ (VA) Benefits
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Many benefits are available to veterans from the
Veterans Administration, including in-home
healthcare.
To learn whether you are eligible, use the online
VA Health Benefits Explorer to
answer about 15 questions.
Next, apply by telephone
at 1 877.222.VETS (8387). Or, fill
out the application online here, or
download the application
here.
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VA Foster Homes
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The VA’s Medical
Foster Home program has slightly more than 700 licensed caregivers who
live full time with no more than three veterans and provide round-the-clock care and supervision. It is not known whether ALS patients are
eligible.
Unlike typical community care facilities, foster
home caregivers are required to live on-site and tend to the needs of their
patients themselves 24/7 — or supply relief staff.
Because medical foster homes are not considered
institutional care, VA is not allowed to pay for it directly. Veterans pay their caregivers $1,500 to $3,000 a month. The average monthly fee is $2,300, which
most veterans cover via their VA compensation, Social Security and savings.
More details are given by
this Florida
chapter of the program.
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