AES 2022 | SUDEP rates in the cenobamate development program

Unfortunately, sudden death in epilepsy does occur in some patients with epilepsy, and the overall mortality rate is higher than the general population. We decided to look at our full program in terms of all the studies that were done in terms of cenobamate over the course of the clinical development programs. That went over approximately 10 years. There were two double-blind placebo-controlled trials. There were the open label extensions, there was the long-term safety and pharmacokinetic study, and they’re doing some other additional studies now, in terms of primary generalized tonic-clonic seizures.

All of this was done in adult patients, and what we decided to look at was… We first looked at what were the overall rates in the past with studies. There are many papers that have been written about SUDEP over the years. One that particularly showed a lot of the clinical development programs was one by Judith Racoosin. Dr. Racoosin in 2001 in Neurology talked about four of the larger studies that had occurred in the 1990s. In her study, they had adults and children, but we’ll just again stick to the adults. They had over 9,000 person-years in terms of people who were on the various studies. There were four in particular that they looked at and in their studies, the overall mortality rate was essentially 9.1, I believe, in terms of the per thousand patient-years. And they had a SUDEP rate, sudden unexpected death in epilepsy rate of approximately 3.8 over the course of the four.

If you take patients with epilepsy in general, the risk of sudden unexpected death in patients that we see in our clinics, in the epileptologist office, the more uncontrolled, more treatment resistant, the rates probably range from about 3.3 to 4 for that grouping.

If you take patients that are pre-surgical, have failed other drugs, they’re looking for surgery, they’re often about nine per a thousand person-years. And if you take the community-based population that’s anybody with epilepsy may have had only one seizure in their life, two seizures, et cetera, it’s patients in general, the rates over the years have been listed as anywhere from 0.35 to 2.3 depending on which study. There are many different studies that were done. So we decided, okay, let’s compare. We compared it to the Racoosin and we compared it to populations in the past.

So we looked at the people that had been in the various cenobamate studies, and we had a total of 2,131 patients, most of those were focal epilepsy, there’s a little over a hundred person-years of patients who are in the primary GTC segment, but mainly these were the patients with focal epilepsy. And so there were 2,131 people, adults 18 and above, and we had a total of 5,693 person-years. It turned out that the overall mortality rate was 4 and the SUDEP rate, the sudden unexpected death in epilepsy rate was 0.88, so the numbers were quite favorable to patients. This was a good thing that we found out from the study.

And there’s also what’s called the standardized mortality ratios. We did those and those have been done for many of the drugs over the years. Standardized mortality ratio came out to 1.32, which was basically not significantly elevated from the general population. You could say indistinguishable from it because the confidence intervals are from 0.8 to 2.0. And if you look over the years of studies that were done with people with sudden death, what you find is that you’ll see rates anywhere from 1.5 to 15 for the standardized mortality ratio.

In conclusion, I would say the rates of overall mortality, all-cause and SUDEP compared favorably with previously reported studies of other anti-seizure medications. The SUDEP rate was basically similar to the community-based population. The SMRs, the standardized mortality ratio was lower than expected for a drug resistant population and was similar to the general population. And I think this suggests that treatment with cenobamate may reduce the excess mortality associated with epilepsy.

Why is that? And again, we have to guess, we can’t give exact reasons, but the bottom line is, I think it’s that we have more seizure freedom that we’ve seen with this drug than many other drugs at times in the past. We’ve seen numbers anywhere in the various studies from 20% in some of the double-blind placebo trials, up to 20 to 35% in some of the post hoc analyses. So I think that getting more patients seizure free makes a big difference. And I think that also just reducing seizures, 75, 90%, 100% reduction. In the past we always looked at 50% reduction or medium percent seizure reduction, and I think that’s great for our patients to be 50%, but I think it’s even better when we get to 75, 90 and a 100%. And I think that may be the marker for why we’re seeing the improvement in SUDEP as well as in overall mortality.