enGene Therapeutics Inc. (ENGN) Earnings Call Transcript

Greetings, and welcome to enGene conference call to discuss the company's preliminary LEGEND data. [Operator Instructions] As a reminder, this conference call is being recorded. It is now my pleasure to introduce Lauren Hopfer of Kendall Investor Relations. Thank you, Lauren. You may begin.

Thank you. Good morning, everyone, and thank you for joining our conference call to discuss enGene's preliminary data from the LEGEND study's pivotal cohort of patients with high-risk BCG-unresponsive nonmuscle invasive bladder cancer with carcinoma in situ or Cis. The company recently posted a slide deck on its website to which we will refer during this call. The slides are available on the Investors section of our website. Before we begin, I would like to remind you that in our remarks this morning and in the Q&A session that follows may include forward-looking statements for purposes of the U.S. and Canadian securities laws. These statements include, but are not limited to, our current expectations regarding the potential benefits of detalimogene, planned modification to the LEGEND study, timing of enrollment in the study, timing of regulatory submission and prospects for regulatory approval of detalimogene. They involve risks, uncertainties and assumptions that are difficult to predict and may not prove to be accurate. Actual results may vary. These statements should be considered only in conjunction with the information in our filings with Canadian Securities Regulators and the U.S. SEC, including in our Risk Factors section of our annual report on Form 10-K and most recent quarterly report on Form 10-Q. At this time, I'll turn the call over to Ron Cooper, enGene's CEO. Ron?

Thank you, Lauren, and thank you, everyone, for joining our call today to discuss the preliminary data from the pivotal arm of enGene's LEGEND study of detalimogene voraplasmid, formerly known as EG-70 in high-risk ECG unresponsive nonmuscle invasive bladder cancer with Cis. With me today are Ryan Daws, our Chief Financial Officer; and Dr. Raj Pruthi, our recently appointed Chief Medical Officer. I'm also pleased to welcome Dr. Suzanne Merrill. Dr. Merrill works at Colorado Urology, a large community urology practice serving patients in the greater Denver and Boulder areas. We will make a few prepared remarks and then we'll open up for Q&A. As this is my first corporate webcast since becoming the enGene CEO, I wanted to begin with a few observations. Since joining enGene, I've come to appreciate that there is a knowledge gap regarding enGene, detalimogene and some of the factors that drive NMIBC management decision in stage urology clinics. I'd like to make these 3 points. First, unlike most cancers, NMIBC is predominantly managed by urologists who have different product needs compared to medical oncologists. Second, we believe that more than 70% of NMIBC patients are managed in community practices, which often lack the specialized equipment and infrastructure found in [ teaching hospitals ]. Third, while any cancer is serious, NMIBC progresses slowly, with only about 20% of the patients advancing the muscle invasive bladder cancer over 10 years. This creates a treatment window in which a urologist could sequence the patients through multiple therapies to chronically manage their tumor over a multiyear time horizon. These 3 points indicate that a product design for the specific needs of urologists will be useful as they will have the opportunity for sequential therapies. Raj will review our initial data set momentarily, but I am delighted with the preliminary efficacy and tolerability data. Even in this early look data imaging has demonstrated clinical activity that when studied in similar patients in using similar protocols has the potential to match or exceed those of other agents in late-stage development. Why do I believe this? First, the Phase I data and preliminary pivotal trial data demonstrates that detalimogene is an active drug and with past regulatory precedent give us confidence on the prospect for potential regulatory approval. Second, detalimogene overall profile, which we believe will provide a unique combination of tolerability, efficacy and ease of use makes it the most practical therapy to use with the potential of becoming a foundational therapy for NMIBC. And third, detalimogene is showing -- has shown promising activity in our studies to date, we plan to implement protocol changes that we believe will be more consistent with those of other late-stage agents. This should illustrate detalimogene activity and durability in a manner more representative of a modern guidance-based practice. More on this later. Given the increasing number of treatments approved and in development, we believe that the NMIBC patients will be sequenced with multiple therapies to avoid radical cystectomy, growing the total market opportunity from approximately $2 billion to over $20 billion. I find this analogous to the multiple myeloma market, which had a value around $1 billion as Revlimid was being launched to greater than $20 billion with the advent of multiple new therapies. We believe that all new ranges for NMIBC will be used to some degree, but the question is, which product will become the foundational therapy. We expect that most patients will be treated first with practical therapies in the community setting. And upon exhaustion of these options, they will likely move to academic medical centers to undergo more complex treatment. Dr. Merrill will share her on the ground insights on the real-world management of patients. But let me first turn the call over to Dr. Pruthi. Raj?

Thank you, Ron. It's a pleasure to be here today and to share the preliminary data from LEGEND pivotal cohort. We recently posted a slide deck on our website, which I refer to during this call. The slides are available on the Investors section of our website. As a brief introduction, I am a urologic oncologist by training and have sat across from bladder cancer patients for 25 years. I formally served as Professor and Chair of Urology at UCSF and at the University of North Carolina. After my academic career, I joined Johnson & Johnson, where I was involved in the development of their bladder cancer portfolio including the TAR program specifically, which, as many of you know, is a source of ongoing excitement, both within J&J and within the clinical trial community. I came to enGene because I see detalimogene as a product with similar exciting data as the TAR program and an incredible opportunity to transform the lives of patients with bladder cancer. There's an exciting world ahead for nonviral gene therapies in bladder cancer, and I'm thrilled to be part of it. Okay. Let's get started. I'd like to refer you to Slide 3 in the deck. As a reminder, the LEGEND study is evaluating the safety and efficacy of intravesicular administration of detalimogene to patients with high-risk non-muscle invasive bladder cancer. The study consists of 2 phases. First, a completed Phase I dose escalation to establish safety and select a go-forward dose. And second, a Phase II study with a single-arm open label pivotal cohort evaluating detalimogene in patients with high-risk BCG-unresponsive NMIBC with Cis. In this ongoing pivotal cohort, patients are treated for up to 4 12-week cycles with drug installation at weeks 1, 2, 5 and 6 in each cycle and with follow-up assessments conducted at the end of each 12-week cycle. The study's primary efficacy end point is the percentage of patients with complete response at 12 months based on cystoscopy, urine cytology and bladder biopsy. Importantly, when the LEGEND protocol was originally drafted, the protocol did not allow for a surgical resection or a therapeutic re-induction for recurrent Ta disease at 3 months. This means that so far in LEGEND, all patients with recurrent Ta tumors at 3 months have been classified as having progressive disease and correspondingly have been taken off study. We plan to amend our protocol going forward to allow for broader r-einduction at 3 months and specifically for resection and re-induction for recurrent Ta disease, which, in my view, is now common clinical practice. I'll talk about more about this shortly. I'd like to refer you to Slide 4. With that as a background, let's dig deeper into the preliminary data from the pivotal arm of the LEGEND study. Although our safety data phase includes all 42 patients dosed across the entire Phase II LEGEND study, our discussion of preliminary efficacy will focus exclusively on the 21 patients in the pivotal cohort for which we have a minimum of 3-month efficacy data. Please note that we will not be sharing further details on enrollment or efficacy for patients beyond the data shown here, and we will not be sharing any efficacy data beyond 6 months. Let's start with a review of the demographic data of these 21 patients from the pivotal cohort. These are typical NMIBC patients, predominantly male, generally older with a median age of 74 and having received a median of 11 prior BCG doses. All of these patients qualify as BCG unresponsive under the FDA's guidance. Note that 14% of the patients have [ concomitant ] Cis at stage T1 tumors, which is widely considered to be more difficult to treat. This is markedly higher than some recent late-stage studies, which have reported T1 percentages in the low single digits. I'd like to refer you now to Slide 5. We're particularly excited about the adverse event profile across all Phase II LEGEND cohorts. As you can see, detalimogene was generally well tolerated. Overall, 48% of patients experienced a treatment-related adverse events of any grade with patients experiencing mostly grade 1 or 2 AEs attributable to catheterization. There were no Grade 4 or 5 treatment-related adverse events, and all treatment-related AEs were reversible. There are 2 patients with Grade 3 AEs, both of whom had full resolution of symptoms and remained on the study. One patient experienced urosepsis that was felt by the investigator to be possibly related to the catheterization procedure. This patient had several risk factors for this infectious complication, including advantage and a myeloproliferative neoplasm. The other patient with peripheral edema had preexisting cardiovascular disease and developed mild bilateral lower extremity edema while on study that would help to be possibly treatment-related. Importantly, no patients have dropped out of the study due to treatment-related adverse events. I'd like to refer you now to Slide 6. Let's talk about the efficacy data. This slide shows a swimmers plot of 3-month and 6-month patient data from the pivotal cohort. Looking at the summary table, you'll see a complete response rate at any time of 71%, a 3-month CR of 67% and a 6-month CR of 47%. Some of you are more comfortable with Kaplan-Meier analysis and when calculated from this data set, we see an estimated 51% CR at 6 months. I'd like to also point out one patient, subject A, who converted from a nonresponse to a complete response at 6 months. While the 21 patients represent about 20% of our total target enrollment, I'm excited about the high levels of activity that detalimogene continues to show. I'd like to also take the opportunity to describe some of the important changes we plan to introduce in an upcoming protocol amendment, which I referred to earlier. Specifically in this amendment, we plan to modify our protocol to allow patients with high-grade Ta lesions after cycle 1 to remain on study and potentially benefit from continued treatment. Under this revised protocol, these patients would have any visible tumor removed and then receive a re-induction course of detalimogene. Prior to the planned amendment, many of these patients would have been ineligible to remain on study and no patients underwent additional restriction of tumors. Additionally, we plan to mandate that patients with T1 tumors undergo a re-resection procedure prior to enrollment. Re-resection of T1 tumors has been shown to decrease recurrence and progression and is now a guideline recommendation. This amendment is designed to align our protocol by what we, as a [ field ] are already doing with respect to T1 disease as well as re-induction, re-induction with BCG or with other FDA-approved agents in this space. With respect to Ta disease, it is well understood from other data sets and from current clinical practice that re-induction at 3 months using both resection as well as redosing of drug and lead to substantial increase in the response rate at subsequent time points, including 6 and 12 months. With this amendment in place, we expect our CR rates could increase as has been the case for other late-stage gene therapy studies adopting similar changes that move from Phase II to Phase III. By increasing eligibility for an additional course of detalimogene, we believe this will give patients a higher likelihood of benefiting from participating in LEGEND, which we also believe will improve enrollment. Last, while we're pleased with these preliminary response rates, especially given the protocol changes we are planning going forward. I think it's important to keep in mind that the numbers remain very small and correspondingly, even 1 to 2 patients can have an outsized impact on our nominal CR rate. For example, if 2 of our current patients for whom we have 3-month data achieved a CR at 6 months, our 6-month CR rate could shrink to 53%. I mentioned this to highlight the limitations of overinterpreting these CR rate at this point in the study. I'd like to refer you now to Slide 7. I want to summarize some key takeaways. First, we are very pleased with the efficacy detalimogene has demonstrated in this preliminary law and believe it represents only a snapshot of detalimogene larger potential. We are observing an exciting 71% complete response rate at any time and a group that contains a relatively large fraction of T1 tumors. I believe this speaks to the potency of our immunotherapy mechanism of action. Our planned protocol amendment should improve outcomes for T1 patients and will also allow patients who have evidence of recurrent Ta tumors to be treated with a repeat course of detalimogene, re-induction of therapy after surgical resection. We've already seen conversion of disease at 3 months to CR 6 months and the result of this protocol amendment, we expect to see a higher 6-month CR conversion rate in patients receiving re-induction after cycle 1. Second, detalimogene continues to be generally well tolerated. Most of the AEs are mild or catheterization-related with no treatment-related discontinuations. I've spoken with investigators who shared with me that giving detalimogene is similar to giving intravesical saline and that the patients experienced minimal discomfort. We have heard that even in the cases of patients who had prior difficulty tolerating intravesical agents such as gemcitabine or BCG. In contrast, these have led retreated patients in our study compared to tolerate detalimogene quite well. Third, this is a product candidate designed for use in high-volume community clinics, the setting with the majority of urologists practice. It is easy to use, easy to store and designed to be patient-friendly with minimal [ chair ] and clinic [ cost ]. Since assuming the CMO position, I have aggressively moved to increased sites, to refine our protocol and streamline our clinical operations and enrollment is improving. I am confident that we will deliver a positive result for LEGEND. Thank you for your attention. I'd like to now introduce you to Dr. Suzanne Merrill. Dr. Merrill graduate is honored from the University of Delaware and then attended the University of North Carolina School of Medicine. She completed her residency at Duke, followed by a Society of Urologic Oncology fellowship at the Mayo Clinic in Rochester, Minnesota. We're pleased to have here with us today. And with that, I'll turn it over to Dr. Merrill.

Thank you, Raj. It's a pleasure to be with you today. I'd like to take this opportunity to tell you a little bit about my practice setting, the current and real-world management of non-muscle invasive bladder cancer and then my perspective on the future of this disease state. As Ron indicated, I work in a large group practice in Denver. And broadly speaking, there are really 4 types of urology practices in the U.S. One is still a small independent practice, which contains only a handful of urologists. Another is a community hospital-based urology practice. Third, of course, are urologists practicing and academic medical centers. And fourth are the larger community-based practices. And this is the setting in which the majority of U.S. urologists practice today. It is the large urology community practice in which I work. My group has multiple practice sites across our nation and employees over 220 providers. In my region of Colorado, we have a total of 25 urologists, 13 advanced practice providers and over 11 offices. The goal of these large community practices is to provide comprehensive and specialized care in the community in the most efficient manner possible for both patient and practice. To this end, many such large practices have provider champions for specific urologic disease states, and I lead our Colorado bladder cancer program. High-risk, non-muscle invasive bladder cancer patients are usually diagnosed in their mid-70s. And at a time of diagnosis are usually treated with the standard of care, which is BCG. When these patients progress to BCG unresponsive disease, they fall into a category of disease for which there are currently few options and one of which is extreme which is the removal of their bladder, a procedure called radical cystectomy. While radical cystectomy has, of course, a 100% complete response rate for this stage of disease, there is significant mortality and morbidity associated with the procedure. For example, this surgery is associated with up to a 10% chance of death within the first 90 days. For the majority of cystectomy patients, quality of life is significantly altered. Patients are often left with a dissatisfying sense of body image on account of having a urostomy as a urinary diversion, and unfortunately, experienced sexual dysfunction due to these critical organs being negatively affected during surgical dissection. Thankfully, the future holds several exciting new potential therapies for BCG unresponsive disease. And I am optimistic that they will collectively offer patients more meaningful time before a radical cystectomy is required. As a result, a treatment paradigm shift appears on the horizon for non-muscle invasive bladder cancer patients, where such patients will not have to contemplate early on about losing their bladders. And instead, will have multiple nonsurgical intravesical therapies through which they can be sequenced. These therapies should make non-muscle invasive bladder cancer more like a chronic condition where patients will not have to succumb to their cancer but rather die of old age with intact bladders and a good urologic quality of life. In a world with multiple new promising bladder cancer therapies, drug selection will be individualized to the patient at hand. However, for large community urology practices like mine, we will prioritize use of an agent based on its efficacy, ease of administration, safety to patient and practice staff, drug availability and reimbursement factors. These are the factors that make the difference to our patients and to us. For example, even in a high-volume practice, such as mine, we do not have some of the specialized equipment, such as an ultra-low cold chain freezer or biosafety level 2 hoods, required to appropriately handle some of the upcoming viral-based therapies. Agents, which require us to make additional infrastructure investments have cumbersome reimbursement processes or that have challenges with product availability will likely be therapies reserved as last line or even reserve for use only at major academic medical centers. As a busy community practice, we try to maximize patient throughput and find it attractive that detalimogene has a favorable and familiar and easy administration. It does not require logistically time-consuming and potentially financially costly steps like drug [ sign ] ahead of patient visits, pre-installation bladder washes or post-procedural cleanup procedures. I'm very excited about detalimogene and assuming that it goes on to be approved, it has the potential to be one of the first, and if not, the first intravesical therapy used in our practice to treat BCG unresponsive nonmuscle invasive bladder cancer. Now let me turn the call back over to Ron.

Thank you for joining us, Dr. Merrill, and for sharing your insights. Before coming to enGene, I worked in big pharma for multiple decades where I successfully launched dozens of products. I move to startup biotech where we gained regulatory approval for our first-in-class product that was subsequently launched globally. I came to enGene because I believe detalimogene is a highly differentiated product candidate and that the NMIBC market is poised to expand rapidly. To close, this is how we see the future at enGene. We believe, one, we're at the forefront of a period of tremendous growth of the an NMIBC market with all newly approved agents having a role. Two, the efficacy and tolerability data are similar to what we observed in the Phase I trial. This more than doubles the amount of data at our recommended dose, demonstrating that we have an active drug. And this data set and the past regulatory precedents give us confidence in the prospects for potential regulatory approval of detalimogene. Three, with that global expansion underway and new clinical sites coming online, we believe we're on track to file our BLA by mid-2026. Four, with Dr. Pruthi informed oversight and our upcoming protocol revision, I feel confident we position the LEGEND study for success. The emerging profile of detalimogene underscores its potential to become the most practical NMIBC therapy for both physicians and patients. For physicians, we expect detalimogene will offer efficacy, tolerability and no change to the current practice. For patients, we expect detalimogene will offer a short treatment time of 1 hour with no pretreatment or post-treatment actions. It's an exciting time for enGene, and we look forward to providing additional updates as we make progress. I will now like to open the call up for Q&A.

[Operator Instructions] Your first question comes from the line of Jeff Hung with Morgan Stanley.

Congratulations on the progress. The first for Dr. Merrill, what types of patients do you think will be best treated with detalimogene versus [indiscernible] or TAR-200? And what proportion of your patients would fit that criteria? And then I have a follow-up for the company.

Okay. Thank you for your question. So in regards to the first part, what patients would fit more the criteria for detalimogene versus some other novel agents coming on board? So detalimogene overall, I think, will be attractive to patients in that, one, it's a familiar administration process, okay, in which all these patients have already had a routine administration with placement of the drug via catheter into their bladder. But detalimogene as compared to BCG has more of an infrequent administration. These patients have already had multiple TURBTs, the bladder installations. Their bladders have become more hostile and not friendly organs. And so they're looking for something that's going to be tolerable, minimal side effects and is not given very frequently. So that's going to be very attractive. Whereas some of these other novel agents are administered very similar like BCG or even along with BCG. And so that is something that is going to deter patients.

Okay. Great. And I guess for management, what gives you confidence that protocol amendments won't slow your time lines down and increase potential risk your program from either clinical or regulatory standpoint? And can you just clarify if you've discussed the protocol amendments with the FDA?

So yes, I'll take the first bit of that and Raj can talk about the protocol amendment. So I think we're really pleased where enrollment is going. Since Dr. Pruthi has become our CMO, sites have come up quickly. We're actually pretty excited that we're getting close to getting sites up and going in some of the other countries. So like a lot of these clinical trials, it starts a little bit bumpy, right? But once you get a group of sites up and going and get some momentum, I think you're in good shape. So I think we feel pretty good about that. And I think the protocol amendments, a relatively routine process, but Raj, maybe you can talk more about that.

Yes. Thanks, Ron. That's a great question, Jeff. I think it's -- we won't comment on our specific interactions with the FDA. But we think that these protocol revisions align us with the standard of care and what's being done for BCG and it's what being done in other protocols. I don't think there'll be controversial amendments such as this are not uncommon in the course of a clinical trial.

Your next question comes from the line of Yanan Zhu with Wells Fargo.

Congrats on the data. So firstly, I was wondering, could you give some detail about the -- about patient 17 through 21. Those are the patients who discontinued after month 3 assessment, do you think because they didn't respond, but you just highlighted if a patient had a Ta or T1 only and in those situations with the new protocol, they have -- they will have a second chance at re-induction. So could you give some clarity there? And could you confirm that patient 8 and patient 9 did not have Ta or T1 and that's why they continue to be treated on the trial.

Thanks for that question. I'll start with your comments on 8 9. And you are correct, they did not have Ta and T1. So they had Cis, which allowed them to continue. We believe that Cis Ta patients have not had the full opportunity to benefit from detalimogene. Thereby the resecting or recurrent Ta, 2 to 3 months and reinducing -- I think we're aligning with what our urologists are already doing in the context of BCG. We do think this will yield an increase in the CR as more patients will have the opportunity to benefit. Regarding those patients you mentioned at the bottom of the swimmers plot. I don't want to go patient by patient, but I think it's fair to say that with about 14% of our study enrolled as Ta stage disease, with what others have reported 20%. I think when you look at a 100-patient trial, this could have a very meaningful impact.

Got it. Could you talk about durability or perhaps a question on following up on the prior question about the amendment. I was just curious roughly at -- what patient number enrolled or treated? Will you have the amendment in place and therefore will have an impact potentially on the CR rate after that in number of patients relative to the 100-patient enrollment total enrollment size?

Yanan. Thanks for that question. Look, that's pretty difficult to answer, right, because the process for amendments, the standard process is, you submit it to the FDA. And then concurrently you go to the sites and you go through the local [ IRBs ] at the site. So we'll be working as quickly as possible but to project that into the 80-odd patients to come, that would be difficult to do. But rest assured, we're moving quickly.

Your next question comes from the line of Mani Foroohar with Leerink Partners.

A quick clarification in terms of number of patients with 6-month follow-up. Seeing a swimmer plot of 12 patients. I think the press release said, 17 patients, that time line of follow-up. When can we expect to see a little more data from the remaining patients that have hit that landmark time point?

Mani, thanks for the question. Look, we're very excited. We're absolutely delighted with the data that we've presented, right? Really promising data that actually shows that at this early [indiscernible] detalimogene demonstrated the clinical activity when studied in similar patients similar protocols, it has potential to match or exceed other agents. As you know, I've only recently stepped into this role. And we're right now in the planning process. And so as we go through the planning process and align with our Board, we'll then come back to you with some updates, but we'll plan to an update sometime next year.

Okay. That's helpful. And I think secondarily, as we sort of look at this data, how should we think about path and time line to a pivotal data set and more broadly and competitively in terms of ultimate approval and label negotiations. Are there specific things we should be looking for, your future data sets to allow you to have a label that is more suitable for use in a broader population?