Tag Archives: Amylyx

The unfolding of the unfolded protein response

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A bit of encouraging news this week.

As explained in my post of March 10 (“No panacea”),  the trial drug Relyvrio was found not to help amyotrophic lateral sclerosis.  This despite positive results last year from a smaller trial that had prompted the FDA to provisionally approve the drug for ALS.  After this new result, the company, Amylyx, withdrew the drug from the market.  However, an ongoing trial of Relyvrio for PSP will continue.

Relyvrio is also being tested not only in PSP, but also in patients with Wolfram syndrome. In case you haven’t heard of this genetic condition that’s about 2% as common as PSP, it causes a combination of insulin-requiring diabetes, excessive urine production (“diabetes insipidus”), blindness from degeneration of the optic nerve, and deafness, along with neurological issues such as seizures, mild cognitive loss and loss of respiratory drive.  Wolfram syndrome starts at an average age of only six, with a range of six weeks to 19 years.  Sufferers die by age 40, usually from complications of diabetes or from respiratory failure.  A sad picture, indeed.

So what’s the encouraging news?  Amylyx issued a press release on April 10 (three days ago) reporting interim results halfway through their 48-week, 12-patient, unblinded trial of Relyvrio in adults with Wolfram syndrome. Eight of the 12 patients had completed the trial by that date.  The levels of a protein involved in the synthesis of insulin, called C-peptide increased and do so more promptly after a meal.  C-peptide is a standard test in medical practice to assess the severity of diabetes.  There was also a small improvement or lack of worsening in hemoglobin A1C; the fraction of the day in the normal blood glucose range; visual acuity as measured by a standard wall chart; and global impressions by the doctor and patient (separately) of how well things are going overall.  Over 24 weeks, these patients would have been expected to worsen, on average, not to improve or stabilize as these eight patients apparently did.

Keep in mind that the comparator wasn’t a placebo group, but “historical controls,” meaning patients from previous research or from the study doctors’ regular practice.  (Unfortunately, the company’s press release didn’t say just how much people with with Wolfram syndrome would be expected worsen in these measures over 24 weeks.) This opens the possibility that the patients in the study might simply have taken better care of themselves, knowing they were being tested in the trial.  Another possibility is that the doctors themselves fell victim to their hopes for the patients, providing more aggressive general management of their symptoms during the trial.  That’s why we do double-blind trials.  If the current trial gives favorable results after all 12 patients have completed the 48 weeks, then presumably Amylyx will move to a larger and double-blind trial.

This is, provisionally, slightly good news for people with Wolfram syndrome, but what about PSP?  Both diseases involve abnormalities in the “unfolded protein response” (UFR) in the brain cells’ endoplasmic reticulum (ER).  After amino acids are strung together in the cell’s nucleus to make proteins, they’re transported to the ER, where they’re folded into the patterns they need to do their jobs.  In both Wolfram syndrome and PSP, there’s an abnormal overactivity of the UFR, and Relyvrio inhibits it.

To date, we know of 11 genes that each confers a slightly increased risk of developing PSP.  The most important is the MAPT gene, which encodes the tau protein.  The next-most important is a gene called EIF2AK3, which encodes a protein called PERK, which is an important part of the unfolded protein response. 

So let’s await the final results in this early-phase trial of Relyvrio in Wolfram syndrome.  More to the point, let’s await results from the 600-participant, double-blind trial of Relyvrio in PSP, which has only just started recruiting and should end in mid-2027.

Disclosure:  I’m a paid consultant for Amylyx.  I assisted in the design of their PSP trial and in teaching the study doctors how to properly use the PSP Rating Scale.  I have no stock in the company or any other financial interest in their commercial success.

No panacea

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In case you missed the front-page story three days ago (3/8/24) in The New York Times, the drug Relyvrio has failed to show benefit in a large (664 participants), Phase 3 trial in amyotrophic lateral sclerosis.  The drug did appear to show benefit in a much smaller (137 participants) Phase 2 ALS trial in 2020 and was provisionally approved for sale by the FDA on the strength of that result.  Now, the drug company, Amylyx, may have to discontinue marketing the drug for ALS. 

Why is this relevant to PSP?  Because four months ago Amylyx initiated a 600-participant Phase 3 trial of Relyvrio for PSP.  It’s called “ORION.” So far, recruitment has begun at only a handful of sites, all in the US, with plans to expand into Europe and Japan over the coming months.  The FDA’s permission to start ORION without a Phase 1 or 2 in PSP was based in part on the success of the drug in the Phase 2 ALS trial.  See my post of February 29 for details. 

Amylyx is also testing Relyvrio in people with Alzheimer’s disease, where a Phase 2 trial has demonstrated adequate safety and tolerability. I have no information on a Phase 3 in AD.

The question now is whether the ORION trial in PSP will continue.  So far, there’s been only one business day since the ALS news, and I’m not sure if the top brass at Amylyx — or the company’s sources of financing — have yet decided.  But the Times article reported that the FDA approved Relyvrio for ALS only after Amylyx agreed to withdraw the drug if the Phase 3 trial showed no benefit.  Furthermore, right after the ALS trial news hit, the stock price of Amylyx dropped from $19 to $3 and stayed about there.  Stock markets usually know how this sort of news is likely to play out.  Relyvrio is Amylyx’s only marketed product but they do have other drugs in the development pipeline.

The mechanism of action of Relyvrio addresses issues important to both disorders, which suggests that if it failed in one, it could well fail in the other.  But we don’t really understand the pathogenesis of either disease well enough to know if PSP might respond when ALS did not.

Meanwhile, if you were planning to try to enroll in the ORION trial, I’d advise you not to change your plans.  The ALS trial showed no important toxicity, at least in people with ALS, and you wouldn’t want to lose your potential spot at the study site because you delayed enrolling until definite information on the future of the ORION trial became available.  When other trials in PSP start enrolling, that advice could change, of course.

(I’ll repeat the disclosure I made in my 3/8/24 post: I’m a paid consultant for Amylyx, advising them on design of the ORION trial and training the participating neurologists on proper administration of the PSP Rating Scale.  But I have no stock in the company nor other financial interest in the drug’s success.)

A clinical trial out of the gates

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I hope you will forgive my 24-day posting hiatus.  To make it up to you, I bring good news: The trial of AMX-0035 in PSP is planning to expand its enrollment activities in the next few weeks, and this drug’s track record is unusually encouraging.

The trial, dubbed “ORION” for some reason, initiated enrollment over the past two months at eight sites in California, Florida, Massachusetts, Michigan, Tennessee and Texas.  32 other sites in the US and dozens in Europe and Japan will open in coming months, with a total enrollment target of 600 patients. Those interested can email clinicaltrials@amylyx.com, check clinicaltrials.gov or the company’s own site.   The trial will include a 12-month double-blind period with a 40% chance of assignment to the placebo group, followed by a 12-month open-label period. Trials like this usually take about a year or two to fully enroll, another year for the last enrolled participant to complete the double-blind and another few months to analyze the data.

The drug company is Amylyx Pharmaceuticals, based in Cambridge, Massachusetts.  They held a meeting a few days ago for their US sites’ neurologists and coordinators, where I gave a detailed lesson on proper administration of the PSP Rating Scale, which will be the study’s main outcome measure.  (Disclosure: Amylyx paid me for that presentation and for general advice on the trial’s design but I have no financial interest in the success of the company or the drug.)

The treatment in question is actually two drugs, taurursodiol and sodium phenylbutyrate, both administered orally as a powder stirred into water. The first addresses the dysfunction of the mitochondria in PSP.  The second reduces stress in the endoplasmic reticulum and enhances the unfolded protein response, both of which are also dysfunctional in PSP.  All of these cellular functions are related and lab experiments show that the two drugs combined work better than the sum of their individual effects.

Unlike any of the other new drugs currently or or soon to be tested for PSP, AMX-0035 has been found to help a related disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig disease), where it appears to slow the progression by about 25% and prolongs survival accordingly. The drug, branded “Relyvrio,” won approval from the FDA for ALS last year and is gaining widespread acceptance among neurologists in treating that condition.

The graph below (from Paganoni et al, New England Journal of Medicine, 2020) shows the worsening of the main ALS disability measure (vertical axis; note that the bottom is not zero) over the 24 weeks of the trial (horizontal axis). The orange line/shaded areas and the means/standard error bars represent the patients on AMX-0035 using two different statistical techniques. The patients on placebo are shown in green.

The graph below (also from Paganoni et al), called a Kaplan-Meier survival plot, shows the fraction of patients in the ALS trial remaining alive without tracheostomy or hospitalization (vertical axis) along the 24 weeks of the trial (horizontal axis).

This is great for people with ALS, but that’s not a tau-based disorder like PSP.  However, in a Phase 2 trial in Alzheimer’s disease, which is partly a tau disorder, AMX-0035 did reduce spinal fluid levels of both total tau and of a toxic form called p-tau 181.  That trial was too small and brief to reveal any efficacy of AMX-0035 to slow or halt AD progression but I assume a proper Phase 3 trial will follow. 

Side effects of AMX-0035 in the AD trial have not been published, but in the ALS trial, nausea, diarrhea, excess salivation, fatigue and dizziness occurred in 10% to 21% of patients on the drug and in slightly lesser percentages of those on placebo.

If AMX-0035 shows the same result in PSP as it did in ALS, that means about one additional year of survival for the average patient, and even more if the disease can be diagnosed earlier.  Potential game-changer.  I’ll keep you updated.

Another Fab Four from England

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Yet another, and not my last, installment of research reports from Neuro 2023, the PSP and CBD International Research Symposium held a month ago in London. Please note that many of these reports have not yet been peer-reviewed at a journal.

:: A review of speech therapy records compared various devices to improve communication in people with PSP with severe speech deficits.  In 37 patients, the most successful were large print for reading and a stylus or keyguard (photo) for typing.  As the combination of deficits in motor, cognitive and eye movement control progressed, even these methods lost most of their initial utility.  This study demonstrates the need for better devices to assist in communication by those with advanced PSP.  (CML Foy et al, Sussex Community NHS Foundation Trust, North Chailey, East Sussex, UK)

:: As you’re all aware, two similar anti-tau monoclonal antibodies tested a few years ago failed to slow PSP progression.  However, the trials provided valuable data on the course of the disease over a 12-month period for the middle-stage patients with PSP-Richardson’s syndrome whom the trials enrolled.  The most recent such analysis of the trial for AbbVie’s tilavonemab showed that the patients with greatest language deficits were the ones who progressed most quickly over the ensuing year.  The study measured language in a variety of ways, including naming pictures, following written instructions, writing a dictated sentence, and quickly generating words of a specified category. These results could be of use in understanding the mode of disease spread in PSP, in designing future disease-slowing trials and in counseling patients in routine care. (Indira García-Cordero, et al, University of Toronto, Canada)   

:: A study compared the ongoing production (technically called “expression”) of tau molecules in neurons and glial cells in autopsied PSP brain tissue, correlating the results with the presence of tau aggregates, the pathologic hallmark of PSP.  It found continued tau production in cells with existing tau aggregates.  In fact, in oligodendroglia, where the PSP process probably starts, production was greatest in those cells with the most aggregates.  These findings argue against the theory that existing tau aggregates exert their toxic effect by shutting down normal tau production.  Another conclusion is that the abnormal tau in oligodendroglia doesn’t just come from adjacent neurons, but also (or exclusively) from within the oligos themselves. The results have implications for design of new PSP-slowing drugs. (Shelley Forrest et al, Macquarie University, Sydney, Australia; and University of Toronto, Canada)

:: The Pharma company Amylyx has announced details of their upcoming trial of AMX0035, an orally administered combination of sodium phenylbutyrate and taurursodiol.  It has already shown modest success in ALS in slowing symptom progression and in Alzheimer’s disease at the level of spinal fluid chemistry.  The 600-patient trial in PSP is scheduled to start in December 2023 in 200 centers in Europe, Japan and North America.  The benefit will be measured by comparing the placebo and active-drug groups with regard to rate of progression in the PSP Rating Scale over a one-year period.  Amylyx has not yet posted contact information for prospective participants.   (Disclosure, I’m a consultant for Amylyx and one of the 16 authors of this presentation at Neuro 2023.  The lead author is Günter Höglinger, Ludwig Maximilian University, Munich, Germany.)