Milestone Pharmaceuticals Inc. (MIST) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the Milestone Pharmaceuticals update call. [Operator Instructions] I would now like to hand the conference to your speaker today, [ Melissa Forst ]. Please go ahead, ma'am.

Thank you, operator. Good morning, and thank you for joining us today. Before we begin, I'd like to remind you that any statements made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors, including those discussed in the risk factors section in the company's most recent annual report on Form 10-K as well as other reports filed with the SEC. Any forward-looking statements represent Milestone's views as of today, July 23, 2020, only. Delivering prepared remarks on today's call will be Joe Oliveto, President and Chief Executive Officer. And joining us for the Q&A session will be Dr. Francis Plat, Chief Medical Officer; Amit Hasija, Chief Financial Officer; Lorenz Muller, Chief Commercial Officer; and Jeff Nelson, Chief Operating Officer. Now I'll turn the call over to Milestone's CEO, Joe Oliveto. Joe?

Thank you, [ Melissa ], and special thanks to everyone for joining us today to hear the Milestone update. We are very pleased to be able to share updates on 2 aspects of the business today: Firstly, the outcome of our recent interactions with the FDA, which we believe establish a clear and efficient path forward for our etripamil program in patients with paroxysmal supraventricular tachycardia, or PSVT. This path saves us the time and expense of starting a new Phase III study and incorporates some key learnings from our first-of-its-kind NODE-301 study, the top line results of which we announced in March. Additionally, we will share some details on a $25 million financing with RTW Investments that enables operating runway beyond the expected data readout of our next pivotal efficacy study. Before we review today's updates, let me remind everyone of the important unmet needs PSVT presents for the medical community and, most importantly, the burden it places on patients. PSVT is a condition that afflicts approximately 2 million people in the United States. Patients experiencing an SVT episode may feel palpitations, while heart rate increases dramatically, sometimes exceeding 200 beats per minute. The condition commonly causes substantial disruption and distress, and standards of care are restricted to the burdensome and costly acute care setting, which often results in delaying or forgoing care altogether. Emergency department visits and hospitalizations associated with PSVT add significant cost to our health care system with at least 600,000 health care claims every year and an estimated $3 billion spent annually in the U.S. on this condition. Etripamil is nasally delivered, short-acting calcium channel blocker designed specifically to be the first self-administered therapy for terminating SVT episodes when and where they occur. Supported by our extensive market research, we believe that the opportunity for patients to self-treat their episodes and potentially take control of their condition is very significant. In March, we reported top line results from our first Phase III study, NODE-301. The study analyzed a total of 156 confirmed SVT events and was the first-of-its-kind study as no treatment for PSVT had been studied in the at-home setting prior to that time. While the study missed its primary endpoint of showing superiority of etripamil on time to conversion over the 5-hour duration of the study, etripamil was significantly more efficacious than placebo in converting patients to sinus rhythm over earlier time points. Furthermore, the study's secondary endpoints showed significant improvements in patient-reported treatment satisfaction, a trend toward reduced emergency department visits, and very importantly, it demonstrated a positive safety profile showing etripamil was well tolerated in the at-home setting. With these data in hand, we approached the FDA to determine the best path forward, and we're pleased to report that they accepted the following proposed changes. The FDA agreed that the NODE-301B study could be amended and expanded to serve as a second pivotal efficacy and safety study, now referred to as the RAPID study, which I'll discuss in greater detail shortly. RAPID and NODE-301 will serve to fulfill the efficacy requirements for the new drug application for etripamil in PSVT. Importantly, both studies will be analyzed using an updated statistical analysis plan, which the FDA has agreed to, with a target p-value for the primary endpoint of p less than 0.05. The updated statistical analysis plan will have 3 primary components that have changed from the NODE-301 Kaplan-Meier primary endpoint analysis. First, the window for measuring time to conversion will be shortened from 5 hours to 30 minutes, which corresponds with the pharmacological activity of etripamil and has the potential to demonstrate the rapid relief of symptoms that patients desire. Second, the statistical method will use the Wilcoxon test, which adds weighting to earlier events and is, therefore, more appropriate to assess the utility of a therapy that has demonstrated a rapid onset of action. And third, patients who take rescue medication, such as those who visit the emergency department, will be counted appropriately as study medication failures and censored at the end of the observation window to avoid the compounding effect seen in NODE-301. Under this updated analysis plan, ad hoc NODE-301 Kaplan-Meier results for the 156-patient efficacy data set show that 54% of etripamil patients versus 35% of placebo patients converted by 30 minutes, resulting in a hazard ratio of 1.87 and a p-value of 0.02 and thereby fulfilling 1 of the 2 efficacy study requirements. With -- while clinicians and cardiovascular thought leaders have consistently expressed that converting the majority or 50% of patients to sinus rhythm within 1 hour is clinically meaningful, we believe there is still room for improvement of the efficacy profile without compromising safety. To that end, an important program change that was achieved through the FDA interactions is the development of a new dose approach for the RAPID study. The favorable safety and tolerability profile seen in NODE-301 enables us to study a new treatment approach that will allow patients who do not experience a resolution of their symptoms after 10 minutes of taking their initial dose to administer a repeat dose of study drug. There are 3 factors that led us to the repeat administration of study drug to improve clinical benefit. One is pharmacokinetic studies and corresponding modeling, which indicated that the repeat dose delivers higher etripamil exposure and potential corresponding impact on the target of the drug, which is the AV node. Secondly, it provides another shot on goal. Specifically, the second dose provides a second opportunity to impact the AV node during the tachycardia and, hence, another chance to break the tachycardia. This is a similar approach to what is currently done with current standard of care drugs such as IV drugs in the emergency department. So practicing physicians are accustomed to thinking this way of having a second shot on goal to impact the tachycardia, and their counsel was instrumental to our decision to go with this dosing paradigm. And thirdly, we think it's smart to wait 10 minutes before giving the second dose because in NODE-301, approximately 1/3 of etripamil patients responded within 10 minutes. So while the drug was shown to be very well tolerated, we think it's a good practice to limit the use of the extra dose and extra exposure to only those patients and events that need it. I'd now like to provide some final details on the RAPID study. Under the amended plan, the RAPID study will enroll up to 500 patients, and this includes the 170 patients that have already enrolled as a result of being in the former NODE-301B study. The study will be completed when 180 adjudicated SVT events are treated, which makes it similar in size to the NODE-301 study. All patients, including those already enrolled who have yet to experience an event, will be randomized 1:1 to receive either etripamil or placebo with the repeat dose administration described above. We expect there to be approximately 30 events from the prior NODE-301B study that will have dosed with the original single dose administration for PSVT events, and those will contribute towards the 180 total events needed. Importantly, the repeat dose administration does not affect our sample size or powering requirements as the single and the repeat dose administrations will be pooled and compared to placebo for the primary analysis in accordance with the FDA's direction. The study will maintain other components of the original NODE-301 study that we believe were instrumental in the study's execution. These are components such as: maintaining the test dose for safety as well as for patient training; use of the same cardiac monitor that we used previously; patient support services in order for them to conduct procedures of the study appropriately; and lastly, access to open-label drug for subsequent PSVT episodes. The RAPID study will be conducted at many of the same high-performing clinical sites from NODE-301, but will also include additional clinical sites in North America and Europe. We're pleased with our new path forward for etripamil, and we have already begun executing against this plan. We expect to reopen enrollment in the RAPID study later this year and anticipate being able to share top line data from that study in late 2021 or early 2022. Moving to the other piece of business. We also announced today the closing of a $25 million financing with RTW Funds Investments, and this financing provides us critical added runway to reach the top line data readout of the RAPID study and advance the overall etripamil development program into Q2 2022. We're pleased to have the strong, continued support of our largest shareholder, RTW. In conclusion, we believe the agreed-upon changes to NODE-301 and the RAPID study solved for the challenges we encountered in the original NODE-301, and we look forward to understanding their full impact with the readout of the RAPID study. With the financing, we have the funds needed to fully execute on this plan, and most importantly, we believe these combined updates bring us one step closer to achieving our mission of bringing new treatments to those patients living with episodic cardiovascular conditions. And with that, let's open up the call for questions. Operator?

[Operator Instructions] Our first question will come from the line of Chris Howerton from Jefferies.

Great. Congratulations, Joe and the rest of the team. Really glad to see the nice update here. So I guess I just had a couple of questions with respect to the RAPID trial and maybe one on AFib. So I guess with respect to the RAPID trial, one is that my perception would be that the patients that have already been enrolled in this study may have a bias to a lower event rate. And if you agree with that perspective, how might that change our interpretation of the final results? And then a second one on the RAPID study would be, if repeat dosing does matter, why not just exclude those events that have already occurred where they wouldn't have had that opportunity to get that repeat dosing? And then I'll have a follow-up on AFib.

Right. Thanks a lot, Chris. I'll handle the questions in the order that you asked them. And you're exactly right. So patients that remain in -- or that are already enrolled in the RAPID study and, if you will, are left over from -- or a part of 301B are expected to have a lower event rate. They've been in the study longer and are still waiting for their first event, if you will. The good news is that when we evaluated the NODE-301 trial, and we evaluated across the continuum of patients, those that had fast events quickly after entering the trial and those that had events after a prolonged period of entering this trial, we did -- entering the trial, we saw no difference in efficacy amongst those patients. So as a result of that, we have confidence that even patients that have just taken a little longer to have their first episode would still respond in the same manner or with the same level of efficacy as those that had their episode only after being in the trial for a very short period of time. That's our view on that. With regard to your second question, which is another excellent question, we debated this. We do believe that the repeat dose administration will provide increased exposure and increased efficacy. However, we don't rely on this. We believe that even if we match the results of 301, we know that from a physician's belief in what we've done recently, that, that's still a valuable profile and, if you will, model the study to at least achieve that. And if you will, any additional efficacy that comes from the second dose administration is additional. And as we thought about that, we thought, why not take advantage of the -- all the data and, if you will, the 30 or 40 events that we would expect to see from the single-dose administration in there. And lastly, to that point of keeping them in there. Remember that in NODE-301, approximately 1/3 of the patients responded with one administration. So at the end of the study, we will have a fair number of patients with only one administration and not needing to take the second dose. If it matches NODE-301, it would be about 1/3. So this group of about 30 events or so would add to that group and allow for a more balanced assessment of single versus double administration.

Sure. Okay. I mean that makes sense to me. Okay. And then I guess with respect to kind of thinking about other indications and potentially, I guess, just spending more broadly, what is the plans to kind of continue forward with a "proof-of-concept" study within atrial fibrillation? And as a corollary to that, is there any modifications in terms of OpEx that you're expecting over the intervening 18 months?

Right. So let me hand -- I'll maybe reference -- ask Amit Hasija to talk about our OpEx expenses in more detail. But with regard to the AFib study, we learned from 401 the end corresponding PK studies that, if anything, etripamil is a little longer acting than we originally thought. And that gave us even more confidence to go into the AFib study. That study is teed up to start. We are holding off a little bit primarily due to COVID, and starting -- that's an inpatient study, and starting a study that's inpatient we thought not appropriate until COVID comes down. But we have that study teed up and ready to go. And our expectation for that study is always to have it read out after our pivotal studies and PSVT anyway. So we don't see it as a problem strategically, and what we're raring to go as soon as COVID allows us to start the study, yes. And with regard to OpEx, I'll just maybe say and then, again, ask Amit, we did reduce OpEx with the idea that we wanted to focus on getting on the right path with this new study. And now that we have that, we'll continue to focus, obviously, on PSVT and getting to the goal line here. But we'll start to look at getting ready for things like NDA filing and commercial preparations as we get the RAPID study started. And I'll ask Amit if he has any other expansion on that.

The only thing I would add, Chris, Joe is exactly right. We did cut some of our OpEx, and we announced that recently. With the additional investment from RTW, we have a runway now until -- into Q2 '22, which would include getting the data point on PSVT as well as the POC study that you mentioned earlier with AFib.

And our next question will come from the line of Ted Tenthoff from Piper Sandler.