BioCryst Pharmaceuticals, Inc. (BCRX) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the BioCryst conference call. [Operator Instructions] Please be advised that today's conference may be recorded. I'd now like to hand the conference over to your speaker today, John Bluth at BioCryst. Please go ahead.

Thanks very much, Liz. Good morning, and welcome to BioCryst conference call to provide a data update from our ongoing dose-ranging study in treatment-naïve PNH patients using monotherapy with our oral Factor D inhibitor, BCX9930. Today's press release and slides are available on our website. Participating with me today are CEO, Jon Stonehouse; Chief Medical Officer, Dr. Bill Sheridan; and Dr. Andrew McDonald, the leading clinical hematologist from Victoria South Africa who has enrolled several PNH patients in the trial. Before we begin, please note that today's conference call will contain forward-looking statements, including those statements regarding future results, unaudited and forward-looking financial information as well as the company's future performance and/or achievements. These statements are subject to known and unknown risks and uncertainties, which may cause our actual results, performance or achievements to be materially different from any future results or performance expressed or implied in this presentation. You should not place undue reliance on these forward-looking statements. For additional information, including a detailed discussion of our risk factors, please refer to the company's documents filed with the Securities and Exchange Commission, which can be accessed on our website. I'd now like to turn the call over to Jon Stonehouse.

Thanks, John, and thanks to everyone for joining us this morning. Our company is transforming. You need look no further than the next 90 days to see the evidence of this transformation. Multiple data readouts like the one we have today, a major market approvals, transforming BioCryst into a company with a meaningful commercial product and a robust pipeline. Today, we're very excited to be sharing new data for oral BCX99 therapy -- BCX9930 as monotherapy at doses through 400 milligrams BID in treatment-naïve patients. With 9930, we have an oral Factor D inhibitor that we believe is a pipeline in a molecule. You'll hear today from Bill and Dr. McDonald about the outstanding results we're seeing with this monotherapy in PNH patients. PNH is just one of many potential disease targets for this molecule, and we expect to move 9930 into multiple advanced development clinical trials in hematology and nephritis indications next year. The FDA has granted us both fast track status and orphan drug designation, and we have confirmed meetings with regulators in the fourth quarter to discuss next steps for our advanced development program. Now I'd like to turn the call over to Bill to walk you through the data. Bill?

Good morning, and thanks, Jon. It is exciting for me to be presenting an update on our Factor D program. The strong benefit in PNH patients and safety profile, at the higher doses, builds on our previously disclosed data and continue the path forward to advance clinical development studies with BCX9930. Before walking through the new data, it is important to frame why Factor D represents such an attractive target for complement-mediated diseases. As you can see on Slide 4, Factor D, the first enzyme in the complement alternative pathway. No active Factor B can be made without Factor D. Locking Factor D locks both alternative pathway amplification and downstream complement activity, and can allow for treatment of a wide variety of diseases, including a growing list of kidney and systemic illnesses as well as PNH. All of these are serious and potentially life-threatening diseases and have either no approved treatments or only lifelong intravenous infusions available. For our dose-ranging study of 9930, we chose PNH because it's a well-understood and reliable biomarker profile related to hemolysis and anemia. As you can see on Slide 5, the opportunities for treatment with the complement Factor D inhibitor are to control intravascular hemolysis in all PNH patients and control the extravascular hemolysis in PNH patients treated with C5 inhibitors. The most informative hemolysis biomarkers are lactate dehydrogenase or LDH for short, for interventional hemolysis and optimized PNH red blood cells for extravascular hemolysis. In both intravascular and extravascular hemolysis are controlled, the PNH red blood cells survived normally and the size of the PNH red cell climb relative to PNH granulocytes goes up. The measurable clinical outcome goals of controlling hemolysis in PNH are reduction or elimination of red blood cell transfusions, improvement in hemoglobin levels and reduction or elimination of PNH symptoms. Experts recommend that clinical responses in PNH are assessed over a month, and also take into account the underlying degree of impairment of the patient's bone marrow. Patients with impaired narrow function can show slower hemoglobin responses and more limited hemoglobin improvements after control of the molecules. With that background, now let's look at the data we've accumulated to date in PNH patients naïve-to-C5 inhibitor therapy and dosed with BCX9930 as monotherapy at 200 and 400 milligrams BID. The design of the trial and key eligibility criteria are summarized on Slide 6. As you can see on Slide 7, the PNH patients in our trial all had severe disease. 5 of 7 required transfusions, 4 had impaired bone marrow function and all had markedly elevated LDH levels, indicating active intravascular hemolysis. Duration and dosing for each patient is shown on Slide 8. 6 patients have been dosed with BCX9930 at 200 milligrams or higher. 3 of these patients had the dose titrated to 200 milligrams and then 400 milligrams after receiving lower doses in cohort 1. 3 treatment-naïve patients enrolled so far in cohort 2 of the trial began dosing twice daily at 200 milligrams for 14 days, and then the dose escalated to the 400-milligram dose level. At the time of the data cut, one of these patients had completed more than 28 days of therapy, and the other 2 are still dosing in the initial 28-day study window. You'll recall that even at our lower doses of 50 and 100 milligrams, which we reported in May, we are seeing rapid declines in LDH, increases in hemoglobin and significantly improved clinical outcomes for PNH patients. At these higher doses, we are seeing an even stronger response on these key metrics. As shown on Slides 9 and 10, even though the 4 patients who have progressed to 400 milligrams have only received that dose for an average of 53 days, all 4 are transfusion-free, with a mean change from baseline in hemoglobin of 3.8 grams per deciliter. 3 of 4 had average LDH less than 1.5x upper limit of normal, with a mean reduction in LDH from baseline of 70%, and mean red cell -- PNH red blood cell clone size relative to PNH granulocytes clone cells has approximately doubled from 48% pretreatment to 94%. This means that BCX9930 monotherapy is, on average, almost completely blocking hemolysis and preventing optimization. If we take a look at the individual patient plots on Slide 10, we can see clear evidence that the 400-milligram dose performed better than the 200-milligram dose. This is perhaps 15 patient B whose data is in the left-most panel. Although there was an excellent hemoglobin response at 100 milligrams and 200 milligrams, hemolysis persisted as indicated by the instability of LDH and hemoglobin. But with the 400-milligram dose, the hemoglobin is rising and LDH is at a too low. When interpreting LDH, we also need to remember that a higher hemoglobin from more PNH red blood cells will result in higher LDH, even with the same proportional rate of hemolysis. The right-most panel is also instructed. This is patient E, the first patient in cohort 2, where we started 200 milligrams and then increased to 400 milligrams on day 15. The response is immediate but again, the 400-milligram BID dose level is superior. When we look at the hemoglobin and LDH responses for all 4 patients together, we can see just how strong the data looks. The safety profile BCX9930 continues to be excellent. BCX9930 has been safe and well tolerated in the trial with no discontinuation due to related AEs, no related serious adverse events and no safety signals. The most common treatment immersion adverse event is mild-to-moderate headache, soon after starting dosing and lasting at most a few days. The fourth patient in cohort 1 had a mild rash during dosing of 50 milligrams that resolved during uninterrupted dosing through dose escalation to 100 milligram. This patient continues on therapy at 500 milligrams twice a day. One patient in cohort 2 had a mild rash at 200 milligrams that is resolving during uninterrupted dosing through dose escalation to 400 milligrams twice a day. Perhaps most importantly, PNH patients in the trial are reporting dramatic improvements in how they feel and their quality of life. To provide a further perspective on this, it is my pleasure to introduce Dr. Andrew McDonald, who has enrolled and treated several patients in our trial. Dr. McDonald is a leading clinical hematologist and private practices in Pretoria, South Africa. Dr. McDonald's research interest have included stem cell transplantation and novel treatments for leukemia, aplastic anemia, multiple myelomea -- myeloma and PNH, and he serves as principal investigator for drug trial such as institution. He is currently the Director of the Stem Cell Transplant program at Alberts Cellular Therapy in Pretoria. Andrew, many thanks for taking time out of your hectic schedule to join our call.

So thank you, Bill, and I would like to echo what you said in terms of the data and what we're seeing in our patients. So, so far, we've enrolled 3 patients, and we are about to enter the fourth active study drug tomorrow on 1st of October. And our experience with the drug has been excellent. We've had one patient who had a transient rush, who was patient 4. I just noted that the rash was very transient and not significant. All of our patients have had very mild headache, the first few days of administration of drug, which is rapidly settled with very minimal intervention. And all of our patients are actually doing excellently, and there's no other word for it. We -- the quality of life has improved. What they're telling us. They have much less fatigue, much more functional and as noted in the study, we haven't had any transfusion needs since starting drug. So from my experience so far on the study, we have had very good, if not excellent, responses to the drug. And as I said -- as noted, we are continuing to enroll patients on study and we are very happy with the performance of both the study drug and the trial at present. So I'm going to hand you -- just in terms -- say -- so I think this is a very bright future in terms of therapy in terms of PNH. And then obviously, we will need to see where it applies to any other complement opportunities. So I think back to you, Bill.

Thanks very much, Andrew, for all the work you are doing on behalf of PNH patients in South Africa. Before year-end 2020, we expect to report data in PNH patients with an inadequate response to C5 therapy who will be dosed at the cohort 2 dose level of 200 and 400 milligrams BID. This data should provide our first look at the impact of BCX9930 in preventing extravascular hemolysis. We also plan to wrap up our dose explorations in PNH patients with 500 milligrams BID dosing. With every respect of additional experience we have achieved with BCX9930, we gained more confidence with this oral monotherapy will play a significant role in improving patient outcomes and quality of life for patients with PNH and other complement-mediated diseases.

Thanks, Bill, and thanks, Andrew. These data support our goal of bringing an oral monotherapy to patients with PNH. Bill laid out, we plan to complete this dose-ranging study, and we'll provide another update that includes data from patients who have an inadequate response to C5 inhibitors at year-end. Beyond that, we plan to progress into advanced development and clinical trials across multiple complement-mediated diseases next year. Bill and his team has spent a tremendous amount of time in advisory board meetings and other interactions with key opinion leaders in hematology and nephrology, and we have gained their insight into the best approaches to clinical trial design, and have clearly heard their enthusiasm for 9930. When you add it all together, 9930 moving into advanced development in multiple indications, revenues coming next year from the upcoming approvals of Orladeyo in the U.S., Japan and Europe, and the potential value to global public health as we report out data and advance our COVID-19 program with galidesivir, BioCryst is emerging into a commercial stage company with several outstanding assets that can deliver value to patients and shareholders. We look forward to updating you frequently over the remainder of the year and we -- as we continue to achieve our milestones. So that's it for the prepared remarks. Operator, we'll now open it up for questions.

[Operator Instructions] Our first question comes from Jessica Fye with JPMorgan.

Curious how reticular sites have trended over time, particularly on higher doses and in the context of this continued improvement in hemoglobin you're seeing?

Sure. I just -- let me refer you to the baseline characteristics of the subjects and the eligibility criteria. But the eligibility criteria included having a CSF count above 100,000. And so that was the case in all subjects. The 4 subjects at the higher doses we reported today, 2 had reticulocytes blood counts less than 150,000 at baseline and had stayed under that metric, which is in the expert guidelines about how to assess response, and the other 2 have fallen below 150,000. So all 4 are below 150,000.

Great. And then just a follow-up question on the -- you mentioned one of the patients continued on up to -- I think it was 500 milligrams BID. Can you just explain kind of what the possibilities are for continued up-dosing as patients stay on study?

Sure. So we're really happy with the results we're seeing at 400 milligrams twice a day, and it's certainly a potential dose to take forward. We want to round out, whether or not we can pick up the remaining 6% in terms of red cell to granulocytes clone size that I mentioned. And so we think it's worthwhile testing 500 milligrams twice a day to do that. So that will round out our dose explorations for twice-only dosing of the drug. And we'll be in good shape to move forward after that. So already, 3 subjects have escalated to that dose.

And is it the criteria for patients to do that based on the clone size to -- bring on that ratio? Or what is the criteria for doing that?

Not specifically. It's a clinical judgment for the site investigator to make as to whether it's reasonable to dose escalate with the combination of safety tolerability and hematological markers. And as I mentioned on the call, we haven't actually had any evidence at all of any dose-related safety, tolerability coming out of this. We can't distinguish the safety, tolerability, which is safe and well tolerated at 50 milligrams compared to 400 milligrams. That's a great result.

Our next question comes from Tyler Van Buren with Piper Sandler.

Great to see the results. I guess on the mean hemoglobin increase from baseline of 3.8 grams per deciliter. Can you just talk a little bit more about the time course to really achieve that magnitude? Clearly, some of the patients have a different follow-up times and from responded at different times. And then can you also just talk about how you expect that to change when you move from these naïve patients to patients who have inadequate response to C5 inhibitors as we look to compare it to, say, the PEGASUS datasets or comparative data?

Let me make a remark, and then I'll hand it to Dr. McDonald to put some color. As I mentioned, impaired bone marrow function is a feature of many patients with this disease. And depending on how well the bone marrow works and that commitment, the rate of hemoglobin increase. That being said, you can see from the data we presented today, for example, in the panel on Slide 9, that people who had pretty good bone marrow function can have pretty rapid increases in hemoglobin once Hemolysis is under control. So ultimately, the hemoglobin rest is going to really depend on the underlying marrow function. And it's pretty clear that we can get control of hemolysis of this drug. Andrew, I don't know, maybe, you want to add any color to that. But the lack of transfusions and the very substantial rise in hemoglobin is exactly what we wanted to see in that trial.

No. I mean I think from our side point of view, the -- within the first month, I think there were 1 or 2 patients who dropped the 2-week or the 1-week and 2-week mark. But by 28 days, all of them had increasing hemoglobins. But I think even more than the hemoglobin measurements, patients who are actually feeling significantly better, I mean, are reading significantly in a qualitative way, but they were feeling much better on drug, even in the first 1 to 2 weeks of therapy. So the hemoglobin lag by 28 days, they're much improved, and all of them are doing significantly better.

With regard to the -- your question about cross-study comparison with different patient populations in different studies of different designs, that's always hard to do with that. And I think that data really stands on its own.

Yes. And just as a quick follow-up. There's 2 patients that had that initial hemoglobin drop. Is the magnitude of that drop concerning to you at all? And can you just explain why that's happening?

Dose was 50 milligrams twice a day, so the dose wasn't high enough basically. So we -- remember, this is our first exploration of different doses in this disease, that's really important to do. And so we set up the design because it's such a rare disease and the patient is so fragile that we don't want to be administering doses that are not high enough to many patients. And so we want to get through that very quickly. Fortunately, we've got the biomarkers to help guide us. So the LDH can tell us pretty quickly how well we're doing. And the hemoglobin, if it's falling, that tells you that the dose is not adequate. So as soon as the dose is increased to 100, that trajectory was reversed. And the 200 milligrams and 400 milligrams, clearly, the whole biomarker suite is telling us that the 400-milligram doses is superior.

Our next question comes from Brian Abrahams with RBC Capital Markets.

It looked like you saw potentially steeper biomarker improvements in patient E, that first patient who started at the 200 mg dose. I'm just wondering maybe even sort of qualitatively, if you're starting to see those same types of trends on hemoglobin and LDH for patients' F and G, realizing that the follow-up is much shorter there?

Thanks for the question, Brian. So at the time of the data cut, the follow-up is too short to comment. Patient E absolutely does look like a spectacular response because it is. And the clone size, as a proportion of the granulocytes clone size just in that short period, has gone up from 36% to 92%. So that's where we agree with you that that's a spectacular response. I think that each individual accounts and teaches us something. The other thing that we can see from the data is we can start the drug at high doses without a problem.

Got it. And then in the first few patients who had received dose 50 -- started the 50 mg dose and moved to 100 initially, it did look like you -- there was an LDH spike observed in those patients, which then resuppressed when the dose was further escalated. Just wondering if there was sort of anything associated with those LDH spikes, stress events, for instance? And your level of confidence that there's -- there won't be any sort of, I guess, tachyphylaxis type of events, even at the higher doses with longer dosing?

Very good question. So I think I'll take the tachyphylaxis question, first. It's a technical term for the development and tolerance to the actions of the drug and loss of efficacy. So if we look at the left-hand panel on Slide 9, the way those hemoglobins are staying up over now 6 months, teaches us that there's no tachyphylaxis with this drug. So I think we can rule that out. One wouldn't expect it from a biology because Factor D really is not regulated. There's no receptor involved, there's no potential for receptor down-regulation or other biological mechanisms that could go into the idea of the development of tolerance. With regard to the LDH spike, they tell a really interesting story. So if we look at patient D, the second panel from the right on Slide 10, the very brief spike at around about day 13 was associated with an [indiscernible] tract infection, and remember at day 13 in cohort 1, patients are taking an inadequate dose of 50 milligrams twice a day. So even though the LDH has started to fall with an infection, there was an episode of hemolysis in the [indiscernible] LDH rows that was quickly controlled with resolution of the infection, of course, but also with increase in the dose to 100 milligrams twice a day. And LDH, by the way, has a celcuity half-life of about 1.5 days. So 5 or 6.5 lives later, you had a new steady state in terms of interpreting hemolysis. And as we follow the LDH in that patient after that at the higher doses, it's been very well controlled. The other one that's -- there are another 2 panels actually that very helpful in dose response, looking at LDH. The patients see the second panel from the left, 100 milligrams is doing okay, but the LDH was rising a little bit. And similarly, at 100 milligrams in patient B, the LDH was rising despite the hemoglobin having responded. And what that's telling you is that there's still room for more hemolysis control despite the hemoglobin response. And in both subjects, when the dose was increased to 200 milligrams and then to 400 milligrams, we've got much better control. So the -- as I mentioned in my introductory remarks, one of the main reasons we chose PNH is because of the value of the biomarkers in teaching us what dose we need to use. So I think all of that hangs together. Finally, in terms of worry about breakthrough hemolysis, now that's a concern for all complement inhibitors, whether they're intravenous or oral. And the goal here is to get patients on a great dose and keep them on it, and keep them taking their therapies. And so we -- that's another reason we're exploring 500 milligrams twice a day because it might just give us a little bit more forgiveness from these doses.

That's really -- oh, go ahead, Brian. Go ahead.

No, I was just going to say that's really helpful color, Bill.

So Bill, I think Dr. McDonald has patients to see. So I just wanted to make sure -- he said he had stop at the top of the hour. So Andrew, again, thank you so much for both participating in the call today and participating in this study.