Dan M

EndALS

Evidence N' Decisions:  ALS

 

 

 

And For Those Seeking

Assisted Living

For Less

Get More Space & Services

By

Sharing A Home &

8 Daily Caregiver Hours

Tell Your Older Friends

Meals Included

This is an opportunity for those wishing to live in Jacksonville, Florida, near St Johns Town Center.  Get all the information is this downloadable brochure.

 

How To Use This Site

Mission:

EndALS is devoted to Dan M and his welfare.  But the site is useable by everyone.

This website provides links to all the best and latest ALS therapy information.  This is the Evidence needed to make Decisions.

Time is an enemy; so patients need information they can use immediately.  Consequently, EndALS omits therapies that are years away from clinical use.

This site is managed by PhilipJax, who also authors the website EndPC, devoted to the management of Pancreatic Cancer, in honor of his brother Mark F.  A highly-detailed Decision Guide replicates the site’s content.

Have Questions?

Send emails to [email protected].  But, do not write until you have studied the related materials listed here.  Then, reference them in your question.

Another information source

 

Amyotrophic Lateral Sclerosis

 

 

 

Therapy & Research

 

 

 

 

Highlights

     2018 ALS Update, Mayo Clinic

     Promising Drug: Ibudilast

     Possible Therapy: Acthar® Gel

     BIIB067: Gene Therapy On The Cusp?

     Virus & Retrovirus As A Cause

     Primary Lateral Sclerosis (PLS)

     Care Management: How to Win

     Find the Best Clinical Trials

     Stem Cell Frauds

     How to Fall Asleep Without Drugs

 

 

 

 

 

 

 

 

Acthar® Gel Trial

 

 

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:

    The accepted age range is 18-75.

    The study is randomized on a 2:1 basis.  So, for every 2 patients receiving the experimental therapy, one will not (a placebo instead).

    Like most other agents, this one does NOT restore capabilities, but attempts to slow the physical decline.

    It requires daily visits to the treatment facility.

    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.

 

 

 

 

 

 

 

ALS History & Background

 

 

ALS Update 2018, Mayo Clinic

 

 

 

This excellent May 2018 article offers speculation on the causes of ALS, and outlines the prospects for current and some anticipated therapies.

 

 

Drugs in Development

 

 

 

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.

 

 

The Search For A Cause

 

 

 

This comprehensive 30-page article summarizes the findings of research on the possible causes of this disease.

 

 

20 Years of Disappointment

 

 

 

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.

 

 

ALSFRS-R, The ALS Functional Rating Scale

 

 

 

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.

 

 

 

 

 

 

 

 

 

AMX0035 Trial

 

 

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:

    TUDCA patients had “A lesser decline in lung function.”

    “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.

    “TUDCA treatment was also associated with a less pronounced deterioration in muscle strength and quality of life.

      “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.

 

 

AMX0035’s 2-Part Trial NCT03127514 & NCT03488524

 

 

 

The new AMX0035 trial, of which there are two parts, has the following features among others:

    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.

    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.

    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.

 

 

AMX0035’s 2-Part Trial Update

 

 

 

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.

 

 

AMX0035 Availability

 

 

 

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.

 

 

 

 

 

 

 

 

 

Arimoclomol

 

 

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.

 

 

Performance

 

 

 

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.”

 

 

Suitable for Sporadic ALS?

 

 

 

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.

 

 

Trial Features

 

 

 

The ongoing Phase 3 trial has the following features.  More information at NCT03491462.

      Patient enrollment is 231 at 23 study locations for a period of 19 months

      Patients 18 years and older are accepted

      Randomized double-blind design; so, only half get the experimental agent

      No more than 18 months since first symptoms, ALSFRS-R equal > 35 and SVC% > 80%.

 

 

 

 

 

 

 

 

 

BHV-0223 (Riluzole)

 

 

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).

 

 

 

 

 

 

 

 

 

BIIB067 (Tofersen) Trial

 

 

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:

    The trial did not show a reduction in SOD1 protein, a requirement for successful performance.  Further,

    “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:

    The BIIB067-treated mice maintained their weight 26 days longer and lived 37 days longer (22% longer) than the placebo mice.

    Treated SOD1 mice experienced improved muscle function over the weeks following treatment.

    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.

    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:

    Participants must have a diagnosis of SOD1-ALS.

    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.

    It enrolled 84 patients “18 years and older” and is operating at 17 locations, including Johns Hopkins and Massachusetts General Hospital.

    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.

    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.

 

 

Results, BIIB067 (Tofersen) Phase 1/2 Trial

 

 

 

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:

      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.

      By Day-85 the Tofersen 100mg cohort displayed a slowing of functional decline (ALSFRS-R): -1.1 vs -5.3.

      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.

      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.

      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.

 

 

Phase 3 Trial, Ongoing

 

 

 

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.

      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.

      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.

 

 

 

 

 

 

 

 

 

CK-2127107 (Reldesemtiv)Trial

 

 

 

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.

 

 

CK-2127107 Phase 2 Trial Update

 

 

 

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.

 

 

 

Some additional matters:

      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.

      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.

 

 

 

 

 

 

 

 

 

Diet and Exercise

 

 

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.

 

 

 

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.

 

 

Supplements

 

 

 

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.

 

 

Exercise

 

 

 

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.

 

 

 

 

 

 

 

 

 

Edaravone (Radicava)

 

 

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.”

 

 

Ethics Considerations, Research Reevaluation

 

 

 

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.”

 

 

Treatment Schedule

 

 

 

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.

 

 

 

 

 

 

 

GDC-0134 Trial

 

 

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.

 

 

 

 

 

 

 

 

 

Gene Therapy

 

 

Introduction

 

 

 

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.

 

 

BIIB067 (Tofersen) Trial

 

 

 

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

 

 

GDC-0134 Trial

 

 

 

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.

 

 

 

 

 

 

 

Ibudilast Trial

 

 

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.

 

 

Availability

 

 

 

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.

 

Dosage

 

 

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.

 

FDA Prohibition

 

 

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.

 

 

 

 

 

 

Immunotherapy (this section is incomplete)

 

 

Introduction

 

 

 

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.

 

 

T-lymphocyte (Tregs) immunotherapy

 

 

 

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.

 

 

More to follow

 

 

 

 

 

 

 

Masitinib Trial

 

 

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.

 

 

 

 

 

 

 

Memantine (TAME) Trial

 

 

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.

 

 

Phase 1 Pilot Trial.  The 2010 report is downloadable here.

 

 

 

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.

 

 

Phase 2/3 Trial.  The 2010 report is downloadable here.

 

 

 

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.

 

 

Ethics Alert

 

 

 

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.

 

 

New Phase 2 Trial Features:

 

 

    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.

 

 

 

 

 

 

 

Retigabine (Ezogabine)

 

 

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.

 

 

 

 

 

 

 

Sleep Method: How the stressed can fall asleep

 

 

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.

 

 

 

 

 

 

 

Stem Cell Therapy

 

 

Introduction – The Best Article on The Subject

 

 

 

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.

 

 

Why Stem Cell Success is Difficult to Achieve

 

 

 

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.

 

 

Stem Cell Trials

 

 

 

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.

 

 

 

Brainstorm NurOwn®

 

 

 

 

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.

 

 

 

Cedars-Sinai in Los Angeles

 

 

 

 

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.

 

 

 

Q Therapeutics Trial

 

 

 

 

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.

 

 

 

AstroRx® Astrocyte Cells

 

 

 

 

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.

      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.

      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.

      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.

      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.

      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:

      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.

 

 

 

Other Trials

 

 

 

 

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.

 

 

How to Contact the Trial Manager

 

 

 

This section above tells you how to make contact.

 

 

 

 

 

 

 

 

 

 

 

Virus, Retrovirus HERV-K As A Cause

 

 

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.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Primary Lateral Sclerosis

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.

 

 

 

 

Multifocal Motor Neuropathy (MMN)

 

 

Background

 

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.

Treatment

 

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.

 

 

 

 

Daily Living Guide

 

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:

 

      Cramping and Spasticity

      Choking and Swallowing

      Swollen Feet and Blood Clots

      Osteoporosis

      Toilet Troubles

      Feeding Tubes

      Respiratory Options

      Remodel Home or Move?

      Equipment Needs

      Caregiver Information

      An Uplifting Message for the Disheartened

 

 

 

 

Care Management

 

 

Medical Terms, Definitions

 

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.

 

 

 

 

Cancer Term Definitions

 

Many cancer definitions apply to ALS also, for example “Response Rate.”  Such terms are defined here.

 

 

 

 

Multi-Disciplinary ALS Centers

 

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.

 

 

 

 

The Correct Insurance

 

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.

 

 

 

 

Care Management

 

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.

 

 

 

 

How to Find the Best Clinical Trials

 

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.

 

 

 

 

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.

 

Trials by Location

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Trials by Therapy

 

 

 

 

 

 

 

 

 

How to Contact the Trial Manager

 

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.

 

 

 

 

 

 

Stem Cell & Exosomes Scams

 

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.

 

 

 

 

 

 

Veterans’ (VA) Benefits

 

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.

 

 

 

 

VA Foster Homes

 

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.