Rocket Pharmaceuticals, Inc. (RCKT) Earnings Call Transcript & Summary

Welcome to the company update on Danon trial conference call. My name is Vanessa, and I will be your operator for today. [Operator Instructions]. I will now turn the call over to your host, Claudine Prowse, Senior Vice President of Strategy and Corporate Development.

Thanks, Vanessa. Good afternoon, and thank you all for joining us. The purpose of this call is to share an important update on our Danon disease Phase I clinical trial as discussed this morning with the FDA and disclosed in today's first quarter 2021 financial results press release. Before we begin, I'd like to remind you that various remarks we will make today constitute forward-looking statements that are qualified by cautionary statements. Please refer to our SEC filings if you have any questions. Participating on today's call are Dr. Gaurav Shah, Chief Executive Officer; Kinnari Patel, President and Chief Operating Officer; Dr. Jonathan Schwartz, Chief Medical Officer and Senior Vice President of Clinical Development; and Dr. Jose Trevejo, Senior Vice President and Chief Development Officer of AAV. There will be a question-and-answer session at the end of this call, in which we will all participate. I'll now turn the call over to Gaurav.

Thank you, Claudine. Thank you, everyone, for joining us today. First, before addressing the Danon trial, overall on the earnings release, I wanted to mention that we are pleased with the momentum across clinical, regulatory and manufacturing activities that took place in the first quarter of 2021. We reported positive updated results from our LAD-I and PKD clinical trials and also announced RMAT designation from the FDA and prime designations from the EMA for our LAD-1 program, thus advancing our full pipeline forward toward regulatory submissions. Our clinical data and regulatory designations continue to validate the potential of our gene therapies for patients suffering from rare devastating diseases with no current treatment alternatives. In the first quarter, we also continued to strengthen our operations and general capabilities as we added to our leadership team and strengthened our balance sheet. Turning now to our Danon disease program. Last week, just as we were preparing to initiate the first patient in our low-dose pediatric cohort, we received notice from the FDA that dosing of our Phase I clinical trial in Danon disease was placed on pause. For background context, we have successfully dosed patients in our low- and high-dose young adult cohorts with preliminary low-dose data demonstrating early evidence of clinical benefit. Importantly, no new drug-related safety events have been observed in the trial since December. In addition, there are some updated new results from our low-dose cohort, which we will come back to later. We learned on a call today with the FDA that their inquiry relates to risk mitigation methods in the current protocol, specifically on refining the eligibility criteria for new patients and safety monitoring of all patients. This clinical hold, while it does qualify as a clinical hold, we have mutual commitment together with the FDA for a safe and expeditious path forward given the high unmet need in this patient population as we further risk -- as we further modified the risk management plan together with the FDA. Importantly, based on our discussions with the FDA this morning, this is not a CMC issue. It is also not a request for additional data that would otherwise result in a prolonged delay to the program. Now to shift focus to clinical benefit. In the last few weeks, new data in the low dose have emerged, which we also discussed with the FDA this morning that we would like to share with you. The data gave us increasing confidence in the low dose based on functional outcomes. And here is a brief summary. The full data package will be presented at a medical meeting in the fourth quarter. Patient 1002, who is the second patient treated in the low-dose cohort, has now been followed out to 18 months. And updated expression by immunohistochemistry is now 78%, the BNP continues to decline, now down to 200 from a baseline of 943. The 6-minute walk test has stabilized and actually improved slightly, and the New York Heart Association class has improved from Class II to Class I. So no functional limitations. Patient 1005, who is the third patient in the low-dose cohort, functional outcomes for this patient are mostly pending, but the 6-minute walk test is in a stable range. Patient 1001, the first patient treated and who has been followed the longest, has a 6-minute walk test that has improved from baseline in several recent visits. All 3 patients report feeling well on the quality of life measures. In fact, patient #1005, the third patient in the low-dose cohort has applied for college, which was never anticipated before. With this update and these outcomes, we have increasing confidence in the low dose as a potentially viable dose to move forward in development. With regard to the FDA request, we are optimistic that this matter can be resolved in a timely manner, and we look forward to resuming treatment in the low-dose pediatric cohort with an approximately 1 quarter anticipated delay. The next steps are to work with the agency and to ensure that risk management is accurately addressed and existing safety measures are further enhanced, and we expect to resume dosing now in the third quarter of 2021. While this is a delay, we have good reason to believe that our overall development time lines may not be effective. We have current inbound interest from approximately 20 patients for participation in the trial. As planned, we will present longer-term data on the high-dose patients and any new information from low-dose patients in the fourth quarter of this year. This concludes our prepared remarks. The Rocket executive team and I are now happy to address any questions on the update. And I'll turn the call back over to the operator for Q&A. Thank you.

[Operator Instructions] Our first question is from Gil Blum with Needham & Company.

So maybe you could give some examples of the kind of risk-mitigating tests that are potentially required here as you may need to change your protocol. Is this something relating to -- in the logical or other metrics?

Yes. I think there's 2 key buckets here. One is eligibility. So making sure that we're not enrolling patients who are far advanced in disease as an example and possibly other demographic requirements for eligibility. And the second is ways to further refine and enhance the AAV-related safety that we have in the protocol. We already have instituted, for example, the addition of tacrolimus and other measures to improve safety. There may be other modalities that we may do as well, but no further information on that just yet.

[indiscernible] a little bit in context, the improvements that you're currently seeing with your low-dose patients, improvement in the status, the NIH data as well as a 6-minute walk test too.

Sorry, the specific question is, are we seeing improvements in 6-minute walk test or...

Just in context compared to, let's say, a natural progression.

Yes. The natural progression, the natural history of disease is relatively rapid decline once the patients have floored onset of cardiomyopathy and heart failure. And I think what is reassuring to us is that we're seeing stabilization, even some modest improvements in the low-dose cohort, and that would potentially be in contrast to a natural history decline. And I also think that similar to 6-minute walk test, the New York Heart Association class stabilization in 2 patients, but actual improvement from 2 to 1 in 1 patient is pretty reassuring. Jonathan, go ahead.

Jonathan Schwartz, Rocket CMO. Just to add, certainly, the improvement in cardiac parameters that we have presented in -- over the prior months in 2 of the patients on a low-dose adult cohort, that is absolutely something that is not seen in the natural history of Danon disease patients. The cardiac status is the most critical parameter, that's what the FDA has asked us to concentrate on. And that is what kills essentially every male patient with Danon disease. So the fact that we've seen an uptick in some cardiac parameters on patients suggest that we're definitely impacting the natural history of the disease for the positive.

Our next question is from Yaron Werber with Cowen and Company.

Great. Maybe I have a couple of questions. Number one, can you -- I don't know if you can comment at all about the 2 patients at the higher doses and maybe preliminary data as to what you're seeing from them. And then secondly, I mean, it sounds like you've not enrolled, maybe correct me if I'm wrong, the third patient in the high-dose cohort, is that correct? And is that pending the risk mitigation efforts?

Yes. The high-dose cohort is still early, and we don't have any more information on that. We'll update in the fourth quarter, Yaron.

And it sounds like you did not enroll per patient yet, right, in that cohort?

Yes. We've enrolled the 2 that we've discussed before. Correct, not the third.

Are you still planning on enrolling that third patient? Or are you, at this point, really focusing more on the lower dose?

Yes. No, good question. So in discussions with FDA, the path is open to both. And I think we're not making any final dose determination at the moment until we see more data. And I think the updated low-dose results just give us more confidence in that cohort as a potential path forward.

And maybe a final question for me. In terms of the risk mitigation and ensuring that you're not enrolling patients who are too severe or 2 events, I should say in that and -- is there a predefined sort of clear criteria as to what's the speed was -- the sweet spot of you in terms of enrollment? What constitutes to advance the patients?

There are certainly some viable criteria that we can utilize. I'm not going to be able to get into specifics here. But I think we have a pretty clear picture from the Danon natural history with respect to what parameters decline relatively early, what parameters decline towards a more advanced end-stage heart failure and working together with the FDA and using the data that we have to date from our patients and from our natural history patients. I am highly confident that we'll be able to fashion a refined criteria that will exclude patients who are at higher risk of toxicity and lower risk of benefit while focusing the program on the great many patients who have relatively mild or modest progression of their cardiac disease and whom we can provide the greatest element of benefit with an acceptable safety.

We'll move on to our next question from Mani Foroohar with SVB Leerink.

So as I read it, and please correct me, we are still waiting further data from the 1.1e14 dose. We have an incremental update in hand from the patient at 6.7e13. My understanding that these patients, and correct me if I'm wrong, as we saw in December, tend to be on the older/heavier/more advanced side as there's some discussion on NYHA class in the PR. So wouldn't that suggest that if you're going to patients that are at lower risk, based on what we see in other gene therapy studies, you'd either be going to younger patients who are less advanced in disease or younger patients who are getting a lower absolute dose or a lower dose relative to [ kgs ], all of which should be addressed by the move to the pediatric study? Or are there other metrics that I'm missing around risk other than those 3?

Yes. Mani, these are good points, and we agree 100%. I think that moving into the pediatric cohort may be beneficial for numerous reasons. And I think we had a mandate to start the trial in older adolescent and adults because there do exist older adolescents and adults with Danon disease, but ultimately, the goal is to move into pediatrics as soon as possible. And I think with this discussion with the FDA, some clarifications are good, and we'll be able to do that really with a 1 quarter delay. I also want to add, you referenced the 1.1e14 dose. I want to make it clear that we do not anticipate going any higher than that 1.1e14 dose ever. So 1 of these 2 doses, we plan to move forward and it could even be the low dose.

So I'm going to follow up on that around the approximately 1 quarter delay as implied in the or [ stated applied ] in the press release. If you're not moving into higher doses, were there doses you expected to explore that you're taking out? Therefore, is there any opportunity to claw back some of that 1 quarter by just doing less dose escalation in the future? Might you, for example, only go -- only pursue 1 dose or the other in the pediatric study?

Yes, there is that possibility. I don't want to speculate on time lines. We have not given guidance on time lines, but certainly, if 1 of these 2 doses are moving forward, that's why we said also that the overall development time lines may not be affected with this FDA conversation. So great point.

Right. That's really helpful. And we should be expecting a fulsome update pretty much across both of those cohorts that you've discussed through so far in 4Q? Or is there an avenue to a potentially earlier regulatory update? Or is that still up in the air?

Our plan is 4Q. Were you asking if there's an update on like a regulatory update, if we would [indiscernible]...

Yes, yes.

We can't comment on that yet. It's a great question. We can't comment on that in a moment. But yes, certainly, by fourth quarter, we'll do the update.

Our next question is from Raju Prasad with William Blair.

Can you provide just maybe a little bit of context or color around the initiation of these discussions? Was this the FDA coming to you guys based on dosing in a higher dose cohort or dosing pediatric patients? Just trying to figure out exactly where the FDA is coming in here and from what position they're coming in. Is it to kind of refine the pediatric population? Or is it more to examine the data and discuss the potential their raw doses that are being given to these patients?

Yes. So we can't speculate on why now, except just to note that we haven't had any new drug-related SAEs since the last update. So yes, beyond that, it's tough to speculate.

Okay. And you mentioned that you shared this additional data on efficacy with the agency. Is there anything you can comment on how the agency views -- is viewing this 6-minute walk data? Is that seemed to be an endpoint that they view to be conferring of clinical benefit as well as BNP? It'd be interesting to kind of hear your thoughts on those endpoints moving forward.

Yes. So we've set up the Phase I pretty broadly to capture a variety of potential endpoints from biomarkers to functional endpoint, 6-minute walk test is one of them. It's an important one because it's been the -- an approvable endpoint in the past as has BNP and others that we're measuring. So I think FDA at the end of they will look at the totality of evidence to make that determination as to what a viable Phase II endpoint is. So it's too early to say, but it's reassuring that now the biomarkers and some of the functional endpoints are moving in the same direction.

Great. And maybe just one more question, a clarification question if I may. So if we're to kind of take a look at the potential changes that might come from the risk mitigation strategies, can you kind of put into context what type of, broadly even, what type of strategies are being put into place? Is this -- when to initiate a dose of [ sirolimus ]? Or is this like more of an enrollment criteria? That would be helpful.

Yes. So there's 2 buckets. One is eligibility, just making sure that with the devastating nature of this disease that we're not enrolling patients who are too far advanced and can't benefit from therapy without unreasonable safety risk. And the second is just refining or revising some of the safety measures around the toxicities that we've already discussed in the past that people are well aware of, such as the renal and thrombotic microangiopathy issues, so those are just some refinements around there as well as refinements to eligibility.

[Operator Instructions] Our next question comes from David Hoang with SMBC.

So I was just looking at the Clin trials entry for the Danon study, and there is some, I guess, updated info here that talks about, obviously, we know there's low and high doses in the study, but there's also some talk about an intermediate dose mentioned on the site. And then just some, I guess, closer age bands on the age ranges around the different cohorts in terms of the ages that would be enrolled. So I guess I just wanted to make sure how accurate is that? And is there -- are there considerations for multiple doses, maybe beyond what's been studied so far?

Yes. Great question and good time to clarify. So the original agreement with FDA was that we could go as high as 2e14. So the range would have been from 6.7e13 up to 2.0e14. And 1.1e14 was considered an intermediate dose, that's why we called it an intermediate dose. But now given what we're seeing in the low dose, we certainly don't anticipate going all the way up to 2.0e14 in this protocol ever. So what was the intermediate dose is now the high dose and the low dose remains a low dose. So there is no more intermediate dose. Oh, and sorry -- the age range, right? So the current low-dose patients that were treated, the first 3 were 15 years old or older. And same with the next pediatric low-dose cohort, it will be 8 to 14 years. And for the high dose, it's the same. We start in 15 or higher and then move to 8 to 14. So that has not changed, and it should be consistent with what you see on the ClinicalTrials.gov.

Okay. Currently, is there any upper ceiling to the age range? Or is that something that needs to be teased out with FDA?

Jonathan?

We don't have an upper ceiling per se. However, there are many other exclusion criteria and inclusion criteria regarding heart function and overall function that would preclude the overwhelming majority of older male Danon patients from participating. As we've emphasized, this is a disorder where a great many patients or male patients, unfortunately, pass away during their later teenage years and their early 20s. The oldest known male Danon patient, I think, was only somebody in their early 40s. So there's no upper age limit but many other factors that are likely to restrict participation of non-transplanted patients that are substantially above the age of 20.

[Operator Instructions] And we have our next question from Dae Gon Ha with Stifel.

Sorry, I missed sort of the earlier part of the call. So apologies if I ask something that's already been said. But Gaurav, can you remind us exactly what you're thinking in terms of anti-C5 used as a prophy given that we did see the complement activation? And I think you just mentioned the renal aspects on the AEs that we observed in the 1e14 dose. And in terms of the drug product, perhaps it's a little granular, but anything you can provide in terms of fill-to-empty capsid ratios I could perhaps speak to sort of the upper end of the dose triggering sort of that side effect that perhaps can be improved upon with the process?

Yes. These are good questions. Jonathan, you want to...

Certainly the protocol as it stands now, has already incorporated the potential for use of complement inhibitors. And it's certainly a possibility that going forward, a more rigorous or preemptive use of those agents maybe in the offing. Once we have specific guidance from the agency, we'll be able to speak more authoritatively on that. With respect to the full-empty question here comes...

Kinnari will jump in for this, please.

Based on the FDA discussion we had today, it's really focused on just risk mitigation and eligibility of the patient criteria. So at this point, the drug product or CMC aspects are not expected to change during this Phase I clinical study. Only anticipative we have, as we've announced in public, is eventually moving the in -- manufacturing in-house before starting the Phase II registrational-enabling study.

Got it. And I guess we'll be expecting more data towards Q4 of this year. But anything you can speak to on the low dose 3 patients with regards to ex cardiovascular manifestations, how they might be improving on that 6.7e13 dose?

Yes. So I think from a quality of life viewpoint, all low-dose patients that we're talking about here and that we followed up for a year or longer, all 3 of them are feeling strong, healthy. Anecdotally, I can say that they all feel better than they did before the gene therapy treatment. And we'll also be following up with some more dedicated batteries of tests that we've been doing in various time points, and we'll disclose these at the end of the year.

Our next question is from Patrick Dolezal with LifeSci Capital.

Just one on time lines. Had FDA -- previously you had an opportunity to review the first line patients of data, meaning this would be a bit of a shift in their thoughts from prior interactions. Or was this kind of the first interaction with FDA since bringing together the data set from the initial 5 patients?

Patrick, it's a great question. So we've been in dialogue with the agency. Our initial data that was publicly made available in December before making it publicly available, we did share that with the agency. And we've been having an ongoing dialogue of just sharing information as further information is available on the efficacy and/or safety parameters.

Got it. That's helpful. And I guess, I know it's really early, but thinking about potentially moving forward with the lower dose. Does this lead you to any further thoughts as to what might be appropriate pivotal endpoints? Is there any shift in thinking?

At this point, we're just looking at the totality of all the data. I think the data we see seem very promising. But at this point, until the end of phase meeting -- end of Phase I meeting with the agency, we won't have the specificity of the primary endpoint.

Yes. I would say that there's really no shift in thinking. I think the news today do constitute a 1 quarter delay. So the next dosing would be third quarter. And if anything, it gives us increased confidence in the low dose. But other than that, there's no shift in our strategy or Danon at all.

[Operator Instructions] Our next question is from Eric Joseph with JPMorgan.

This is Hannah on for Eric. Just a few from us. You had mentioned that there were no new safety events that came about like in the FDA decision to -- and to [ cease ] the clinical hold. Just wondering if the FDA specifically has seen Phase II data. And on that, can you talk about the immune regimen that you have currently going on for not Phase II, I mean, the high-dose cohort, the immune management regimen you have for patients in the high-dose cohort and how that might inform any changes to the protocol. And I have a follow-up after that.

Yes. So yes, there were no new drug-related safety serious adverse events reported since the last update. So just to clarify, we have not sent in any new information that led to this discussion that people -- that folks publicly have not seen before. I also wanted to note that all of those SAEs are resolved for the low dose, the drug-related SAEs are resolved for the low-dose patients. And now you mentioned the regimen for -- that we modified for the higher dose and that includes pretreatment with rituximab. It includes initiation of treatment with tacrolimus at the same time as the gene therapy. And it also includes steroids, although with a much more rapid steroid taper than previously. And those are the 3 main changes. I think these are -- have already been publicly disclosed. So nothing new since we've last talked about it.

Okay. That's helpful. And with regards to the new exclusion-inclusion criteria that you're considering, do you have an idea of what effect that might have on the number of addressable patients?

Yes. I had mentioned earlier that we have approximately 20 patients identified for enrollment in the trial. And I would say we haven't finalized these eligibility criteria with the FDA yet. So it's hard for me to comment, but the patients that we've identified would -- they're not on the severe end of the spectrum of disease or on the very high weight end of disease. So it could be that none of them would be affected by eligibility criteria. But again, I don't want to -- that speculation, I don't want to specify further until we know what the eligibility is.

[Operator Instructions] I see no further questions at this time.

Okay. Thank you.

Speakers, do we have any closing remarks before we conclude?

I think all in all, this represents a beginning of a discussion with the FDA to clarify certain things. And development for Danon remains on track, and we'll have other updates this week at ASGCT for the rest of the pipeline, and manufacturing facility is also moving forward as planned. So no real changes to the overall plans for Rocket here. So thank you for your time today.

And thank you, presenters. And thank you, ladies and gentlemen. This concludes our conference. Thank you for participating. You may now disconnect.