Why I’m Skeptical of Trigriluzole for SCA3

I’m skeptical of a 20-plus-year-old drug (riluzole)—mostly ineffective for SCA3—in a new prodrug package (trigriluzole) being then on-label repurposed for SCA/SCA3. This seems to me to be primarily a money-generating move, and yes, I do accept that, because I accept that pharmaceutical companies need to make money to thrive.

Riluzole has been FDA-approved on-label for ALS, patented and available for over 20 years, meaning it’s recently gone generic and revenues have plummeted. Techniques for stoking revenue include creating prodrugs and increasing the size of the customer base.

Riluzole has been tried by many with SCA (and SCA3 in particular), including many people in various ataxia Facebook groups, and no one there, yes no one, (publicly) perceived long-term benefits; short-term benefits, yes.

An irony is that even if riluzole were a slam dunk for SCA, and even if on-label ALS customers were clamoring for improvements, there is no financial incentive to roll the product in less than the full 20 years. The first change in over 20 years for ALS (BHV-0223) is early in the pipeline now.

For more mixed-bag results of riluzole testing with SCA, see NCT01104649 (results).

If trigriluzole is FDA-approved because of positive trial results, it will allow its maker to charge large amounts for it as they enter a period of exclusivity rights—for essentially a drug that has been around for 20+ years without gaining traction for treating SCA.

Trigriluzole used to be called BHV-4157. I wrote about it then, including the topic of prodrugs (i.e., how riluzole and trigriluzole relate).

Glutamate, shlutamate

Glutamate reduction posing as treatment for a polyglutamine genetic brain disease is what I’m the most skeptical about.

The claimed mechanism of action of riluzole (i.e., reducing glutamate, making it antiglutamatergic) gives me few positive expectations, even if the prodrug were somehow a perfect implementation of the desired result.

Talking about reducing glutamate makes as much sense to me as talking about how reducing free radicals and taking antioxidants (like trans-resveratrol) will improve everything from SCA to cancer. Reducing glutamate might be a positive thing for anybody, especially those with high levels, but as a genetic disease treatment? Seriously?

The last time people were talking about glutamate and SCA3 was with varenicline (which also reduces glutamate, because of its role in addiction). Some will remember the SCA3 repurposing trial results with varenicline a few years ago. And how many now take this FDA-approved drug, for SCA3? Very few. For most people (1) it doesn’t work, and (2) the side effects are unbearable.

2018-01-30: Some interesting information about glutamate.

Let’s see what happens

I’m not oblivious to there being some value to this whole song and dance. There are a few hit-or-miss substances being tested (trigriluzole, intravenous trehalose, trans-resveratrol, myricetin, celery oil), all of which are essentially in see-what-happens mode with SCA.

It’s fine to be in the mode of seeing what happens with SCA. If some degree of success is found along the way, more can perhaps (or perhaps not) be learned about human function, and the developer deserves some financial rewards. However, as someone with SCA3, I reserve the right to not get excited, especially when the substances being tested aim (somewhat wildly) for marginal disease amelioration at best.

Will I take it?

If trigriluzole trial results are positive, I will probably try it if it is available to me at a non-prohibitive cost (high cost example; more examples). I’ve tried a few FDA-approved neurological drugs for various reasons and durations, all of which provided a valuable learning experience despite them all having disturbing side effects. I am so skeptical of trigriluzole’s claimed mechanism of action that I would take it only if the side effects are truly minimal and the cost is non-prohibitive. In other words, I will not feel a loss if the side effects or cost were to outweigh my desire to try the drug.

Evaluating side effects can be tricky business. There are always trial participants who experience nausea; I tend to filter out that as noise. It’s like Yelp reviews for a popular restaurant: there are always a few people who say they got food poisoning. My only conclusion is that some people vomit whenever they ingest anything!

Side effects that especially concern me are hallucinations, nightmares, and REM sleep behavior disorder, which if developed are always longer-term, which might not be noticed or reported by trial participants, and which might not get flagged as side effects at all. They concern me because I have experienced them all as long-term side effects of neurological drugs.

Constipation sounds easy to deal with but if drug-related can be insurmountable. One of the most insidious side effects I’ve experienced is tooth sensitivity—completely insurmountable.

Phase 2 trial results of trigriluzole are expected in 2018. Phase 3 and later depend on what happens and cannot be scheduled ahead of time, but if successful, the drug is being fast tracked for FDA approval.


2017-10-02: Biohaven Reports Negative Topline Data from SCA Phase 2/3 Trial

For SCA, the placebo was more effective than the drug. Biohaven was very quick to remove SCA-related information from their website (hence, broken URLs) and refocus their repurposing efforts to Alzheimer’s disease and obsessive-compulsive disorder.

It’s worth noting that if trigriluzole gains FDA approval for a disease other than SCA, it can still be taken off-label for SCA. For that matter, BHV-0223—after assumed-to-be-approved for ALS—can be taken off-label for SCA.

4 Replies to “Why I’m Skeptical of Trigriluzole for SCA3”

  1. Hi. My daughter is in this trial study. I cannot only feel hopeful. She has SCA8. She seems better. Not as many tics. She has started College again. The true test is to see how much stress she can handle. Time will tell. Since hers is a slow progression maybe she will become progressively better slowly. We can only hope and pray.

  2. This is beautifully written, researched, citations credited, and rationally argued. I’m a general neurologist who treats a few people who have SCA, so of course I’m scrambling to have anything to offer them besides well wishes. Thank you for analyzing the latest great hope (hype?). +1 subscriber to your blog.

  3. My husband took Rilutek for four years. He did see a 20% improvement after eight weeks. (As per the ataxia tests administered by his physio ) I could see a big difference in his facial muscles after another three months: he could smile naturally again. He stopped taking it after four years. There had been no significant changes after the first year and the neurologist was not a fan of the drug. (We were the ones to tell him about the drug and his initial response was it couldn’t hurt to try.) It cost us $500/month. My husband has been off it for two years. He is still walking with a walker but he goes to a physical trainer twice a week and two different physios twice a week.
    He will try trigriluzole when it is approved. Because it might help.

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