I’m skeptical of a 20-plus-year-old drug (riluzole)—shown mostly ineffective for SCA3 (and SCA2)—in a new prodrug package (named BHV-4157 in 2016; also called trigriluzole in 2017; renamed to troriluzole in 2018) 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 in general 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. This is not surprising. The short-term benefits can be real or spurious, but the disease will continue to worsen no matter the person nor their attitude; maybe it will worsen at an otherwise slower rate, but there’s no way to know how the rate might have been affected.
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 in 2017; it failed FDA approval in 2019 and was removed from the Biohaven website in 2020.
In the most confusing and misleading move ever, the name given to BHV-0223 was then reused for their migraine medicine [rimegepant] that did get FDA approval in 2020—Nurtec.
For more mixed-bag results of riluzole testing with SCA, see NCT01104649 (results).
If troriluzole 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.
Troriluzole used to be called trigriluzole and before that, BHV-4157. I wrote about it then, including the topic of prodrugs (i.e., how riluzole and troriluzole relate). Also, see that link for the news of the 2018-08-14 rename to troriluzole from trigriluzole.
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? Few. For most people (1) it doesn’t work, and (2) the side effects are unbearable.
2018-01-30: Some interesting information about glutamate and Huntington’s disease.
2019-02-04. Some interesting information about glutamate and SCA.
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 (troriluzole, intravenous trehalose, trans-resveratrol, myricetin, celery oil [in case of link breakage, it’s DL-3-n-butylphthalide], Tanganil), 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?
[This section is obsolete as of 2017-10-02, when trial results were negative.]
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.
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.
Results
2017-10-02: Biohaven Reports Negative Topline Data from SCA Phase 2/3 Trial
For SCA, the placebo was more effective than the drug, meaning the efficacy was 0%. Biohaven was quick to remove SCA-related information from their website (hence, broken URLs) and refocus their repurposing efforts to Alzheimer’s disease [disappointing 2021-01-18 results], obsessive-compulsive disorder [disappointing 2020-06-24 results], and less visibly, generalized anxiety disorder [disappointing 2020-02-10 results]. Also, an ALS treatment [failure announced 2022-09-29] in a different drug called Verdiperstat or BHV-3241.
It’s worth noting that if troriluzole gains FDA approval for a disease other than SCA, it can still be taken off-label for SCA.
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