What is BHV-4157?

2017, April (or so): Biohaven removed the sparse and cryptic one-sentence description of their BHV-4157 product from their website, and renamed BHV-4157 to trig·riluzole. There’s now a lot more information on their website. Below is what I wrote about it four months ago or so.

2017, October: After SCA trials failed, Biohaven was very quick to remove SCA-related information from their website (hence, broken URLs). See here.


It’s a riluzole prodrug. More detail:

It’s time to try to decipher a few layers of terminology, this time taken from the one-sentence description from the lion’s mouth, which is amazingly sparse:

http://biohavenpharma.com/pipeline/

BHV-4157 is a new chemical entity (NCE) that modulates glutamate, the most abundant excitatory neurotransmitter in the human body.

  • BHV presumably stands for BioHaVen.
  • The NCE term means this is something new, of which no part is FDA-approved. This means it’s (1) not a derivative of an FDA-approved substance, (2) not a combination of FDA-approved substances, and (3) not a repurposed substance. However, if the body metabolizes the new drug into an existing drug, it will be treated as an NCE. This is a big part of how pharmaceutical companies make money.
  • Glutamate vs. glutamine: this is dangerously confusing. In fact, there are so many facts mixed with nonsense out there, it’s not even possible for someone like me to make clear sense of it.
  • Glutamate is the conjugate base of the amino acid called glutamic acid, meaning it’s the amino acid with a proton donated in a chemical reaction: https://en.wikipedia.org/wiki/Glutamic_acid
  • Glutamine is an amino acid: https://en.wikipedia.org/wiki/Glutamine

Glutamate and glutamine, continued

SCA3 is a polyglutamine disease, but I think that is almost completely unrelated—or more coincidentally related—to glutamine’s presence and function in the body, and then to glutamate as well. Having the code for an amino acid in a gene area (that causes cerebellar degeneration) might have little to do with the same amino acid floating around in one’s bloodstream.

It’s not that glutamine causes ataxia. After all, it’s the most abundant amino acid in the body, it’s available as a supplement used in bodybuilding, and it’s easily bought in bulk.

Glutamic acid is also available as a supplement, touted as boosting brain function.

There is a cyclical relationship: https://en.wikipedia.org/wiki/Glutamate-glutamine_cycle. How does ataxia (the disease) fit in here, if at all? I don’t know.

Yikes! Even official-looking research can simply not care whether they refer to glutamate or glutamine. This is scary, bizarre, and an egregious misuse of information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788268/.

This is interesting, for details about glutamate: http://neurotransporter.org/glutamate.html.

And standard Wikipedia fare: https://en.wikipedia.org/wiki/Glutamate_(neurotransmitter).

It revolves around riluzole

Assuming a reliable Internet, BHV-4157 is a prodrug formulation of riluzole. Prodrugs are chemically-modifying wrappers around existing drugs that still allows them to be treated as NCEs and be FDA approved again, thereby gaining exclusivity rights.

Think prodrug is a word you’ve never heard before? Maybe, but here’s a prodrug relationship involving easily recognized drugs: heroin is a morphine prodrug—different chemicals, but the body ends up treating them the same after metabolization.

From this article, here are some possible benefits to prodrugs:

  • Achieve optimal solubility (absorption by the body).
  • Improve targeting to specific organ sites, tissues, and enzymes.
  • Protect against rapid metabolism and elimination.
  • Reduce toxic effects on other parts of the body.
  • Enhance patient compliance (e.g., improve taste, odor, reduce gastric irritation).

In other words, BHV-4157 is a chemical that metabolizes into riluzole. (Riluzole was FDA-approved in 1995.) It doesn’t modulate as much as it reduces glutamate; glutamate can damage nerve cells (so says the Internet).

Wikipedia focuses on riluzole being primarily a sodium channel blocker.

2017-09-25: More on glutamate

Perhaps there is more to having antiglutamatergic qualities than is apparent from much of the information about riluzole out there, even from just a general healthiness perspective:

Excitotoxicity is the process by which nerve cells are damaged or killed by excessive stimulation by neurotransmitters such as glutamate and similar substances.

In this context, here is some interesting information, from 2016, on reducing glutamate naturally. Some supplements to look into (I have not tried them):

Here is another article, from 2006, that reads a little speciously (the site was set up to criticize MSG) but again seems to contain some good information.

Bottom line (updated 2017)

My nonauthoritative conclusion is that reducing glutamate might be beneficial to those with high enough levels in the brain to cause problems to begin with. It won’t prevent an asymptomatic person with SCA from becoming symptomatic, and it won’t stop cerebellar degeneration due to a root polyQ problem. The inevitable march towards dysfunction will continue, possibly with a period of improvement when glutamate is initially reduced.

Update, 2016-12-22

http://www.prnewswire.com/news-releases/biohaven-enrolls-first-patient-in-pivotal-trial-of-bhv-4157-in-patients-with-hereditary-spinocerebellar-ataxia-300382831.html

The addition of the word brain shows up:

…a new chemical entity (NCE) that modulates brain glutamate…

The following is a bit disappointing to me, because I have never heard of SCA being classified as a disease that causes glutamate dysfunction:

Agents that modulate glutamate neurotransmission may have therapeutic potential in multiple disease states involving glutamate dysfunction, including SCA…

Another source: http://www.raredr.com/news/first-patient-enrolled-in-hereditary-spinocerebellar-ataxia-pivotal-trial

the body’s glutamate … is the major mediator of excitatory signals in the [central nervous system]

More updates

Latest articles reveal that BHV-4157 is a tripeptide, meaning simply that it consists of three amino acids bonded together, which as far as I can tell affects the delivery / solubility / metabolization of the substance. Since this bonding occurs at the molecular level, perhaps this helps garner the NCE classification.

Clinical trial links (2016/2017)

https://clinicaltrials.ucsf.edu/trial/NCT02960893
https://clinicaltrials.gov/ct2/show/NCT02960893

Note: QD means every day (literally quaque die in Latin).

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