Use of Zuranolone for Treatment of MDD

Andrew J. Cutler, MD: Well, Greg, you’ve alluded to zuranolone. You and I have been involved in the development program. Let me just ask you a little bit about your understanding of some of the data. There was a phase 2 study that was done with zuranolone. Can you tell me a little bit about that?

Gregory Mattingly, MD: Certainly. Zuranolone, once again is an oral derivative of this neurosteroid-allopregnanolone. Allopregnanolone begets brexanolone; the IV [intravenous] version and zuranolone is the oral version.

Andrew J. Cutler, MD: Right. And it’s a GABA-A-positive allosteric modulator. That’s a mouthful.

Gregory Mattingly, MD: It’s hitting that GABA-A receptor, and it’s modulating these receptors, both intrasynaptic and extrasynaptic. They said, “Can that medicine make a difference? Let’s go back to our original mechanism. Let’s look at postpartum depression.” Their first studies were done on postpartum depression. They’ve now replicated that data. We were in both of those postpartum studies, Andy, and it was fascinating. As Sagar said, if you’re a depressed mom, being depressed for months seems like a lifetime. So, could we get people better within days? Could we get people better within the2 weeks? In those studies, instead of taking a medicine for months on a chronic basis, we gave it to them daily for 2 weeks, and then we stopped the medicine. What we found is after 2 weeks, about 70% of women were in remission with their depression. For the majority of those women, the depression didn’t come back when we stopped the medicine. So, to have an oral version that you could give for 2 weeks for postpartum depression was something we hadn’t really thought about. It’s short-term and—I like Sagar’s analogy. It’s a steroid dose pack for inflammation when you talk about this receptor. That then has led to a series of studies asking how about people that just have recurrent depression. Not postpartum, not hormone-induced, but could that mechanism reset the thermostat for whatever’s going on in people that have recurrent depression? I’ve been a part of 3 of those studies, and Andy, I know you’ve been a part of a couple that went well and helped with the development. If we are going to have a medicine we take for 2 weeks, we want to know more about it. First of all, what’s the hit rate? Who does it work for? How quickly does it work? In those studies, Andy, we didn’t just look at efficacy after 2 weeks. We looked at efficacy after 2 days. Day 3 on the medicine. And to the best of my recollection, I think 6 out of 6 studies with that molecule have all separated from placebo at day 3. So, early onset, as Sagar said, has been 1 of our biggest unmet needs so let’s start to get you better and get you better pretty quickly. Now, did it work for everybody? Absolutely not. But, I think the hit rate, once again, was close to 70% of people. This mechanism seemed to give a very early onset of depression and seemed to have significant improvement by 2 weeks. We were then part of a long-term study where we said, “OK, forget placebo, clinicians don’t really care about placebo. I want to know if this mechanism works, how often will people have to take it over the course of a year?” In the study I was in, people took it for 2 weeks and everybody got the medicine. Once again, we saw within 2 days that the average person was starting to feel better. And then we said, “How many people need to come back in for treatment over the course of a year? “ We had 2 different doses, we had a 30-milligram [mg] and we had a 50-mg dose. In those studies, we found is it was something like 70% to 80% of people need the medicine once or twice over a year.

Andrew J. Cutler, MD: That’s exactly right, 1 or 2 courses of 2 weeks of treatment.

Gregory Mattingly, MD:Sagar, I’m curious what your thoughts are, but it changes even the way we think about treating depression. Instead of a chronic ongoing treatment model, it becomes an intermittent as-needed treatment model.

Andrew J. Cutler, MD: Yes, Sagar, what do you think about this new treatment design here; this new treatment modality?

Sagar V. Parikh, MD, FRCPC: Well, I think the first thing is we’re changing the paradigm in psychiatry. We’re not saying let’s wait 6 weeks. In those studies, I know there were multiple evaluation points like it, on day 3. And the primary endpoints could be a composite of multiple points across those 2 weeks. The bar has been set. Now, if you want to do a good job-fighting depression, do it soon. And here is a new way of measuring improvement. Not just at 4 weeks, 6 weeks, or 8 weeks, and maybe even not just at 2 weeks, but at multiple time points throughout those 2-weeks so you know that the person is starting to feel better soon and continues to stay well. That’s an important paradigm shift for psychiatry. We shouldn’t just accept that things take time. So, I think that was really important. The second thing is we’ve heard endlessly about problems with adherence. We all forget to take things after a certain time. So, if we could have a brief treatment, we’re going to sidestep a lot of the adherence things. We also talked about the willingness to put up with adverse effects if they feel the pain but once they’re feeling better; they don’t want to put up with adverse effects. If we have a medicine that is generally well tolerated and you only need to take it for 2 weeks, you’re not going to have side effects from it much later. Then again, you’re avoiding another thing that interferes with adherence and long-term compliance. It’s fast-acting, fewer adverse effects, and 1 and done, so to speak, patients get through it quickly. I think that’s a terrific boon. And what I also like is that that then sets you up for phase 2. And what I try to tell my patients is that psychotherapy is slower, but it’s the thing that’s going to keep you well and lead you more along a path of future wellness and reduce your risk factors for recurrence. So, one of the problems with psychotherapy, when you’re acutely depressed, is, of course, you don’t have motivation. Your cognition is a little bit off and it’s laborious to go to psychotherapy to some extent. Imagine if you could have a medication treatment that primed you, OK, you know you had a big serious illness, it was major depression. We’re going to jumpstart your improvement with this medication. Now that you’re feeling better, but you’re close enough to what happened that you don’t want to go there again, then those people are going to be primed to embrace psychotherapy, and they’re going to be cognitively able to participate in the psychotherapy better.

Andrew J. Cutler, MD: Well said. And of course, Greg mentioned earlier there are [in development] what we call PDTs, prescription digital therapies, that are essentially delivering CBT [cognitive behavior therapy] digitally to people. And of course, that really will be a boon spreading out the access to that.

Transcript edited for clarity