Tag Archives: Relyvrio

Under the hood

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In response to a reader’s request, here’s a brief description of the mechanism of action of Relyvrio, which is a combination of two drugs, sodium phenylbutyrate and taurursodiol.  The text in bold italics below is copied verbatim from the supplementary material attached to the publication reporting the results of the first ALS trial.  The same explanation applies to PSP and other neurodegenerative diseases. You may feel that any treatment that claims to address all of those complex diseases is claiming too much, and you could be right. But stranger things have happened. If you want more scientific detail, see the five references below. Note that Reference 5 discusses release of cytochrome C from mitochondria. That’s a cell signalling compound that causes cells to start up their “suicide machine,” more formally called the apoptotic pathway. Cells undergo apoptosis when they’re not working well or as a normal “pruning” procedure during growth and development. Taurursodiol prevents that from happening as easily.

Endoplasmic reticulum stress or dysfunction associated with protein misfolding and aggregation has been implicated in the pathogenesis of ALS,[1] as has disruption of mitochondrial function and structure.[2] Sodium phenylbutyrate is a histone deacetylase inhibitor that has been shown to upregulate heat shock proteins and act as a small molecular chaperone, thereby ameliorating toxicity from endoplasmic reticulum stress.[3,4] Taurursodiol recovers mitochondrial bioenergetic deficits through several mechanisms, including by preventing translocation of the Bax protein into the mitochondrial membrane, thus reducing mitochondrial permeability and increasing the apoptotic threshold of the cell.[5]

1. Jaronen M, Goldsteins G, Koistinaho J. ER stress and unfolded protein response in amyotrophic lateral sclerosis—a controversial role of protein disulphide isomerase. Front Cell Neurosci 2014;8:402.

2. Mehta AR, Walters R, Waldron FM, et al. Targeting mitochondrial dysfunction in amyotrophic lateral sclerosis: A systematic review and meta-analysis. Brain Commun 2019;1:fcz009.

3. Kaur B, Bhat A, Chakraborty R, et al. Proteomic profile of 4-PBA treated human neuronal cells during ER stress. Mol Omics 2018;14:53-63.

4. Suaud L, Miller K, Panichelli AE, Randell RL, Marando CM, Rubenstein RC. 4-Phenylbutyrate stimulates Hsp70 expression through the Elp2 component of elongator and STAT-3 in cystic fibrosis epithelial cells. J Biol Chem 2011;286:45083-92.

5. Rodrigues CM, Solá S, Sharpe JC, Moura JJ, Steer CJ. Tauroursodeoxycholic acid prevents Bax- induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry 2003;42:3070-80.

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.

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.

It’s awards season

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A caregiver has asked me, as CurePSP’s Chief Clinical Officer, to list the most important clinical research advances in PSP of 2023. Happy to oblige. Here are my top five in no particular order. 

  • The FDA approved a combination of two drugs called taurursodiol and sodium phenylbutyrate with the brand name “Relyvrio” for use in amyotrophic lateral sclerosis (ALS; Lou Gehrig disease).  A trial in PSP has already started to recruit patients.  The drugs address an issue in the mitochondria shared by the two diseases in different sets of neurons.
  • Tau PET ligand APN-1607 received go-ahead from the FDA to proceed to a pivotal Phase 3 trial.  Such a trial began recruitment in December in the US and will involve multiple other countries as well.  The compound would allow a diagnosis of PSP in early or equivocal cases by being taken up by the abnormal tau protein in the brain and imaged.
  • A drug called TPN-101 was found to be safe and well-tolerated in a Phase 1 trial of 30 patients with PSP.  The drug counters inflammation in the brain by reducing the transcription of ancient viral DNA in our genome.  Next is a small trial for efficacy.
  • A simple, remote, gait-monitoring system with only three sensors proved able to distinguish the gaits of PSP and PD.  Further testing for its ability to document progression or improvement will follow.
  • PET imaging of frontal lobe synapses showed good correlation with the PSP Rating Scale and with the results of cognitive testing.  This is different from typical PET in neurodegenerative disease, which images glucose utilization or protein aggregates.  The work suggests that synaptic imaging could be a good diagnostic marker in the earliest, pre-symptomatic stages of PSP.

But the most important piece of news is that several drug companies are planning to start clinical treatment trials in the next year or two. I’ll report on all that as it happens.