NeuroVoices: Irfan Qureshi, MD, on the Therapeutic Potential of Antiseizure Agent BHV-7000

Irfan Qureshi, MD

Despite the availability of antiseizure medications (ASMs), surgery, and dietary therapy, approximately one-third of patients with epilepsy remain refractory to treatment. In recent years, industry leaders have tried to find new ways to suppress seizures while offering patients the most personalized treatment plan. Developed by Biohaven as a novel, small molecule, selective activator of Kv7.2/7.3 potassium channels, BHV-7000 represents a potentially promising therapy for the epilepsy community.

At the 2023 American Epilepsy Society (AES) Annual Meeting, held December 1-5, in Orlando, Florida, Biohaven presented several different analyses on BHV-7000, including first-in-human phase 1 safety and pharmacokinetic data. In the single-ascending dose (SAD) and multiple-ascending dose (MAD) cohorts, 61 healthy volunteers received BHV-7000 (n = 46) or placebo (n = 15). Across the dosing cohorts over a 15-day period, investigators observed low rates of nervous system treatment-emergent adverse events (TEAEs).

A subsequent spectral analysis using a subgroup of participants from the study showed that BHV-7000 had dose-dependent pharmacodynamic effects on EEG parameters of healthy adults. As increases in spectral power were observed in treated patients, the incidence of central nervous system (CNS) AEs remained low. As part of a new iteration of NeuroVoices, Irfan Qureshi, MD, chief medical officer of Biohaven, sat down with NeurologyLive® after the meeting to discuss BHV-7000 as a therapy for drug-resistant epilepsy. He spoke on the early phase 1 data, the most notable takeaways, and why BHV-7000’s mechanism of action lowers the risk for CNS-associated AEs.

NeurologyLive^®: Can you provide an overview of some of the data presented at AES 2023?

Irfan Qureshi, MD: Biohaven changed the treatment paradigm for people suffering from migraines, and we're hoping to do that again for patients with epilepsy. Our compound, BHV-7000, is believed to be a best-in-class treatment for focal and generalized forms of epilepsy by targeting the Kv7 potassium channel—a validated target for epilepsy. BHV-7000 possesses a best-in-class molecule with a really nice safety tolerability profile. One of the studies presented at AES this year focused on the safety and tolerability data associated with BHV-7000. In the multiple ascending dose data, where we treated healthy volunteers with 120 milligrams daily of BHV 7000, we saw a remarkable safety tolerability profile with a very low incidence of CNS adverse events. That is critical for patients with epilepsy. Most people with epilepsy are on medicines that cause burdensome CNS side effects, such as somnolence. Our phase 1 data on BHV-7000 at doses that are therapeutic and those that are far above being therapeutic showed no AEs of somnolence. That is a big deal for patients with epilepsy.

What about BHV-7000’s mechanism of action makes it an attractive potential therapy?

While we have many anti-seizure medicines available to treat patients, there are no potassium channel openers currently available. When you think about rational combinations of anti-seizure medicines, you might think of something like a sodium channel blocker and a potassium channel opener—those are the two parts of the action potential. While there are many approved anti-seizure medicines, they all suffer from causing burdensome CNS adverse effects, such as somnolence and cognitive impairment. Patients don't like having those side effects, as they prevent them from having a high quality of life and being able to do the things they want to do. There is a huge unmet need for patients for effective treatments that don't have those burdensome CNS side effects, which we’re hoping to fill with Kv7 activation and BHV-7000. Not only has this been validated previously, but there was a drug that was previously available with the same mechanism of action, which is now no longer on the market because it had other issues and liabilities. BHV-7000 does not have those liabilities, and that's why we are so excited about its potential.

Do you foresee any drug-to-drug complications with this therapy and other concomitant medications?

That's a great question. We know for patients, particularly those with difficult-to-treat or refractory epilepsy, they're on multiple medications—rational combinations of medicines with different mechanisms that are complementary to each other. With BHV-7000, the great safety and tolerability data that we showed in phase 1 will make it preferred as a combination with other medicines because most of those other medicines do have those burdensome CNS side effects. We think that this phase one safety tolerability profile will translate into a similar phase 2, 3 safety tolerability profile. And that will be in combination with other anti-seizure medicines. When we do our phase one studies, the CNS adverse events that we're talking about, things like somnolence, don't take weeks or months to show up; they show up once you take the medicine. So in a phase one study, you will see if it makes somebody sleepy or somnolent, and we did not see that. That's why we're so excited. We think that makes the opportunity for BHV-7000 to be best in class for patients with focal epilepsy.

What went into the decision to use spectral power as a way to measure the efficacy of BHV-7000?

We did a study where we put BHV-7000 into healthy volunteers at multiple doses; we measured their EEG, and we looked at the spectral power in each band. Those bands are slow waves, like delta, and faster waves in different frequency bands. And that's a way to evaluate EEG quantitatively. What we showed is when you give BHV-7000 to healthy volunteers, you impact the EEG. You can increase the spectral power, and that increase in spectral power was maximal in the Alpha range. The Alpha range is associated with wakefulness and rest. We did not have significant increases in slow waves. If you increase the spectral power in slow waves, like the Delta range very significantly, that is what drugs that cause somnolence do. When we look at the healthy volunteer phase 1 data for safety tolerability, we don't see somnolence. And then in the EEG data, we don't see somnolence and slow wave increases that are very significant on the EEG. We see target engagement; we see that the alpha waves and other waves are increased in spectral power, and that's associated with target engagement in the brain. The summary is BHV-7000 gets into the brain, it's active in the brain, and it doesn't cause somnolence. It doesn't cause significant increases in slow waves, which are associated with somnolence that other medicines do.

Are there any future plans for BHV-7000?

We're super excited to be launching global phase two, three clinical trials for focal epilepsy with BHV 7000, bringing this potential best-in-class new treatment to patients with epilepsy.

Click here for more coverage of AES 2023.