Chief Medical Officer, Biohaven
When Xenon files for FDA approval of azetukalner, expected this quarter, as the likely first Kv7 potassium channel activator approved for epilepsy since ezogabine was withdrawn from the market, it will enter a market already shaped by ezogabine’s cautionary arc: approved in 2011, pulled in 2017 over blue-gray skin and retinal pigmentation. Biohaven’s Kv7 activator, opakalim, arrives as a deliberate next-mover, posting a responder rate (54%) essentially level with azetukalner (56%), and staking its commercial case compared to azetukalner on a cleaner tolerability profile. That is either a disciplined read of what neurologists and patients actually need, or a very expensive way to find out that being second with comparable efficacy is a losing position. Irfan Qureshi, Biohaven’s Chief Medical Officer, has been thinking hard about that question. His answers, drawn from clinical practice and the company’s own development history with Nurtec ODT, sketch a case that is more grounded in patient behavior than in trial statistics.
Moe: Why do you believe a cleaner side-effect profile alone is enough to move entrenched prescribing behavior?
Irfan Qureshi: I’ll zoom out a bit. The first Kv7 potassium channel activator, ezogabine (known as retigabine in Europe), was an effective drug, but as you went up in dose it wasn’t well tolerated. The name itself explains why: ezo-GABA-ine. It had off-target activity on GABA receptors, and we know what GABAergic side effects look like. Think of a benzodiazepine. As you go up in dose, you get somnolence, dizziness, all of those things. On top of that, there were structural issues with the chemistry of the drug that caused instability, and that instability led to precipitates that would turn your skin blue and deposit in your retina. So ezogabine was taken off the market.
Azetukalner is a structural analog of ezogabine. What Chris Crean, who developed that molecule, did was take ezogabine and make it chemically stable. It no longer precipitates; it no longer turns you blue. But it still has GABA activity. And so, with azetukalner, it’s an effective drug, but as you get to higher doses, you still see high rates of CNS side effects. In the recent Phase 3 study, Xenon reported a 31.5% rate of dizziness. That is very high. And the discontinuation rate at that dose over 12 weeks, in a clinical trial population where you do everything you can to keep patients on drug, was 14.5%. What will happen in the real world? What will happen at 24 weeks, a year? Drugs do not work if you do not take them.
CNS tolerability is the biggest unmet need for patients. I can stop anybody’s seizures. I can give them pentobarbital, put them in a coma, and they won’t have seizures. But people can’t live their life in a coma. The question is whether you can get an effective drug that does not carry the tolerability burden of other anti-seizure medicines (ASMs). That is what we have tried to do with opakalim.
When I prescribe a drug, the first thing a patient asks me is not what the placebo-adjusted efficacy is. I don’t think I’ve ever had a patient ask me that. They say: Doc, what are the side effects? What is it going to do to me? Because they know they have to live with those side effects every day. CNS side effects like dizziness, somnolence, and cognitive impairment aren’t just a nuisance. They lead patients to stop taking their medications. It affects their ability to go to work, to go to school. And if you talk to patients with epilepsy, many will tell you they would rather risk having seizures once in a while than have these side effects every single day, guaranteed. To you and me that may seem like it doesn’t make sense, but these patients are voting with their feet.
When I get called to the emergency room to see a patient with epilepsy who had a seizure, their ASM blood levels are almost always low. When I ask them why they are not taking their prescribed medicine, they almost always say the same thing: “Doc, I don’t like how it makes me feel.” Or they tell me they had an important meeting, or a test at school, and they didn’t want to feel like they were cognitively dulled and couldn’t think. That’s the real-life issue these patients face, and it’s why we developed opakalim.
“A third of patients who have epilepsy remain refractory to any treatment we have available. And 100% of patients are refractory to treatments they don’t take.”
Moe: How do you separate “the mechanism failed” from “that molecule failed” when you sit across from a neurologist who lived through the ezogabine (retigabine) era?
Irfan Qureshi: People believe in Kv7 potassium channel activation. There’s no question about the mechanism, because it’s a genetically and clinically validated target. When you have a Kv7 potassium channel mutation that leads to loss of function, it causes seizures. And ezogabine worked; it was FDA approved for the treatment of seizures. It wasn’t the Kv7 mechanism that burned people. Ezogabine was a bad drug, with compound-specific issues. And because of that, people have been waiting, and they are very excited about having a Kv7 potassium channel activator available to treat patients.
When you think about the action potential and neuronal excitability, it’s really driven by two things: sodium channels, which lead to depolarization when they open, and potassium channels, which bring you back to resting membrane potential, when they open. So, when you think about rational combinations of treatments for patients with epilepsy, the most rational combination you can think of is a potassium channel activator and a sodium channel blocker. We have a large number of sodium channel blockers available, and people are still developing new ones. Today, there are no potassium channel activators that are available. That’s why people are excited about this class coming back.
Our profile adds to that excitement. Opakalim is once daily and does not require titration, unlike many of the older ASMs. So, you’re therapeutic effectively immediately. It doesn’t have a negative impact on comorbid conditions like neuropsychiatric problems. Comorbid depression is very common in epilepsy, and some medicines make it significantly worse. We don’t do that. We don’t cause weight gain. Overall, the profile is easy to use, effective, and carries a low burden of CNS side effects. The epileptologists in our clinical trials can’t get enough. They want this drug available commercially so they can treat more patients.
And importantly, the majority of epilepsy is not treated by epileptologists. It’s treated in the general neurology community. A drug that is easy to use, effective, and without significant CNS side effects creates a low burden not only on the patient but on the prescribing physician or nurse practitioner as well. If a physician can prescribe a drug that works and doesn’t cause side effects, the patient is not going to call two days later saying they don’t feel good, or come in a week later asking for something different. That’s a profile that I think is a winner.
Moe: How do you keep your own team from over-reading an encouraging but underpowered tolerability signal?
Irfan Qureshi: When we think about the safety and tolerability of opakalim, it’s really across the totality of data we have. Preclinically, the hypothesis was that it would be effective with a high therapeutic index. We showed that, compared to other drugs in the class, we had a better therapeutic index. Then in the Phase 1 program, we saw the same thing: at projected therapeutic doses, much lower rates of CNS side effects. Other drugs had dose limits in their Phase 1 studies because of the CNS tolerability issues they saw. In Phase 2 and 3 studies, they continued to see the same CNS tolerability issues, and we’ve seen a better profile throughout.
So, the opakalim tolerability profile is not indexed to a single small study. Across the full clinical development program, we have treated more than 1,000 people across multiple indications, including hundreds of patients with epilepsy who are also on other ASMs. The data is consistent: preclinical, Phase 1, Phase 2 and 3.
On the efficacy side, in IGE, we used a time-to-event design because we thought it was more patient-centric than a fixed-dose, fixed-duration study where you measure reduction in baseline seizure frequency. The time-to-event approach looks at the time to the next milestone, in this case the second day with a generalized tonic-clonic seizure. That endpoint has been modeled and published and is an accepted time-to-event design for epilepsy. We prolonged that time in highly refractory IGE patients by 3X compared to placebo.
We can’t over-index on any single piece of data. We also saw, over 24 weeks, that 20% of opakalim-treated patients were seizure-free. You would not expect that based on their baseline seizure frequency. These are highly refractory patients who do not spontaneously become seizure-free. All the other measures we looked at, including patient-reported outcomes like the PGI-C, are consistently trending the same direction. When you have a spurious effect, you typically see noise, where one measure goes one way and another goes the other way. We’re not seeing that.
We also shared this data with the expert community and got their feedback. At our R&D Day in May, Dr. Matthias Koepp, a professor at University College London and Queen Square, said the IGE data was extremely compelling and that effects like these are not seen spontaneously in these patients.
That said, we don’t have the randomized, double-blind, placebo-controlled focal epilepsy data yet. Our first study reads out in the second half of this year. Until we have that data, all we can do is report the data we do have and interpret the totality of it.
All the data we have to date supports the belief that opakalim will be potentially safe and effective with the differentiated profile we projected. If that holds, we believe it will be a meaningful advance for people suffering from epilepsy.
Moe: Why does a tolerability-differentiated second mover keep earning capital inside Biohaven’s portfolio?
Irfan Qureshi: We have three priority areas at Biohaven: our degraders, our obesity program, and our epilepsy program with opakalim. Those are really where we spend our time, energy, and money, because we believe those are the places where we have the potential for the highest impact on patients’ lives.
On our epilepsy program with opakalim, specifically, a third of patients who have epilepsy remain refractory to any treatment we have available. And 100% of patients are refractory to treatments they don’t take. So, while we do have other ASMs available, there is a significant unmet need for new medicines with novel mechanisms of action that are easy to use, that can be combined with existing medications with different mechanisms, and that are safe, well-tolerated, and effective. There is no silver-bullet ASM out there.
We believe opakalim has the opportunity to differentiate across the entire class of ASMs, as well as against the direct Kv7 competitor. And the reason is that azetukalner’s rates of somnolence and dizziness look like those of all the other ASMs. They have not solved the tolerability problem for patients, and we believe we have.
We have seen examples across drug development where being the second entrant in a novel mechanism but having a more compelling profile leads to broad adoption. In migraine, Nurtec ODT came out second to Ubrelvy and did very well.
There is room for multiple Kv7 activators. The two things that most drive prescribing decisions are better safety and tolerability, and better efficacy. If we come out as a Kv7 activator with better tolerability, and the competition has a 14.5% discontinuation rate at 12 weeks due to adverse events in a clinical trial setting, there is no question that is clinically important.
We also believe our profile could potentially get us into earlier and earlier lines of treatment, because the ease of use, safety, tolerability, and efficacy profile is the combination that prescribers and patients are both looking for.
“In migraine, Nurtec ODT came out second to Ubrelvy and did very well. If you have a drug that is perhaps a second entrant in a mechanism but has a really compelling profile, there will be general adoption.”
Irfan Qureshi, M.D., is Chief Medical Officer at Biohaven.
Moe Alsumidaie is Chief Editor of The Clinical Trial Vanguard. Moe holds decades of experience in the clinical trials industry. Moe also serves as Head of Research at CliniBiz and Chief Data Scientist at Annex Clinical Corporation.
