Cullinan Therapeutics, Inc. (CGEM) Earnings Call Transcript & Summary

Good afternoon, ladies and gentlemen, and welcome to Cullinan Oncology's CLN-081, Clinical and Regulatory Update Conference Call. As a reminder, this call is being recorded. Earlier today, the company issued a press release providing a clinical and regulatory update on its CLN-081 program. This press release, along with a slide deck that you may find helpful while you listen to this call, are available on the Events section of Cullinan's Investor Relations website at investors.cullinanoncology.com. It is now my pleasure to turn the call over to Chad Messer, Vice President of Investor Relations at Cullinan Oncology.

Good morning, everyone, and thank you all for joining us for our update on the CLN-081 program. My name is Chad Messer, and I'm the Vice President of Investor Relations at Cullinan Oncology. Before we begin, I would like to remind you all of the safe harbor provisions outlined on Slide 2. During today's presentation, management will be making certain forward-looking statements, which are based on current information, assumptions and expectations that are subject to change and involve a number of risks and uncertainties which may cause actual results to differ materially from those contained in such forward-looking statements. These risks are described more fully in the company's filings made with the Securities and Exchange Commission, including our annual report on Form 10-K. You are cautioned not to place any undue reliance on these forward-looking statements, and we disclaim any obligation to update such statements. In addition, this call contains time-sensitive information accurate only as of the date of the live broadcast, March 28, 2022. Cullinan undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this call. As shown on Slide 3, joining me on the call today are Nadim Ahmed, Cullinan's Chief Executive Officer; Dr. Jeff Jones, Chief Medical Officer; Dr. Leigh Zawel, Chief Scientific Officer of small molecules; and Jeff Trigilio, Chief Financial Officer. It is my pleasure now to turn the call over to Cullinan CEO, Nadim Ahmed. Nadim?

Thank you, Chad. Good morning, everyone, and welcome to our update call on the CLN-081 program. Let me first start out by reviewing the significant recent progress across our portfolio on Slide 4. In December, we initiated dosing in the first-in-human clinical trials of both CLN-049 and CLN-619. As a reminder, CLN-049 is our bispecific antibody targeting FLT3 in relapsed/refractory AML patients. And CLN-619 is our novel antibody targeting the MICA, MICB pathway and has pan-cancer potential. So we now have 3 highly differentiated programs in the clinic. Earlier this month, we had a manuscript with the full preclinical characterization of CLN-049 published in the Journal for Immunotherapy of Cancer. We also recently announced 5 abstracts from our pipeline accepted as poster presentations at the upcoming AACR meeting, again, demonstrating the breadth and depth of our oncology pipeline. At the same time as our pipeline was advancing, we also added an eighth program to our portfolio. Through a new collaboration with Mount Sinai, where we're advancing a novel protein degrader program targeting HPK1, a key regulator of immune cell activation and a high-priority target in the immuno-oncology space. Let me now turn to our lead program, CLN-081, which is focus of today's call. As you remember, in December, we provided a clinical update from our ongoing Phase I/IIa trial, where CLN-081, showed a high response rate, impressive durability and favorable safety and tolerability, all supporting its differentiated clinical profile. In January, we were very pleased to announce that CLN-081 had received breakthrough therapy designation from the FDA. On today's call, our recently appointed Chief Medical Officer, Dr. Jeff Jones, will provide both a clinical and regulatory update on the program. We're excited Jeff joined Cullinan Oncology from Bristol Myers Squibb where he held a range of leadership roles in oncology clinical development. Jeff?

Thanks, Nadim. It's a great time to join Cullinan, and I'm excited to help the team advance the company's broad and deep pipeline of oncology programs. Today, however, I'll share clinical and regulatory updates from our lead program, CLN-081, an orally available irreversible epidermal growth factor receptor inhibitor that selectively target cells expressing EGFR exon 20 insertion mutations, while relatively sparing cells expressing wild-type EGFR. We are currently evaluating 081 in a Phase I/IIa trial in patients with non-small cell lung cancer harboring EGFR exon 20 insertion mutations whose disease has progressed on/or following prior therapy. On Slide 5, you can see that we have evaluated doses of 081 ranging from 30 to 150 milligrams BID and that we expanded enrollment at the 65, 100 and 150-milligram dose levels. We have now enrolled a total of 39 patients at the 100-milligram dose level, which includes the original protocol maximum of 36 patients, plus an additional 3 patients that were reassigned following our decision to discontinue enrollment at 150 milligrams based on an assessment of the overall clinical profile observed at that dose after 11 patients had been treated. Finally, at the bottom of this slide, you can see that the program has a broad geographic footprints, enrolling patients at U.S. and European sites as well as Asia Pacific. Slide 6 provides an efficacy update. When we last shared data in December 2021, we had observed 14 confirmed responses among 36 response evaluable patients treated at 100 mg, yielding a 39% confirmed response rate. Now including the 3 additional patients, 2 of whom achieved a confirmed response, the number of confirmed responses has increased to 16 of 39 patients and the confirmed overall response rate now stands at 41%. As shown here, almost every patient treated at 100 mg derives some degree of clinical benefit, 97% achieved a best response of partial response for stable disease. Equally important, the responses appear durable, we have observed an estimated median duration of response that was greater than 15 months among patients enrolled in the Phase I cohort of the 100-milligram dose level. In contrast, efficacy has appeared inferior at the 150-milligram dose. Patients treated at that dose achieved a lower 27% confirmed overall response rate and an estimated median duration of response of only 7 months. Slide 7 summarizes safety observations at the 100 and 150-milligram dose levels as well as the total for all patients. As we reported back in December, we have observed a favorable safety and tolerability profile at 100 milligrams. To date, no patients have experienced grade 3 or greater treatment-related diarrhea or rash at that dose. Events have been manageable with conventional supportive care, and we have not implemented systematic GI prophylaxis for diarrhea management. On the other hand, safety and tolerability appear inferior among patients treated at 150 milligrams. Adverse events at that dose level have included treatment-related grade 3 or higher diarrhea, rash and transaminitis. A notable increase in rates of dose reduction and dose discontinuation among patients treated at this dose likewise compares unfavorably to the experience at 100 mg, which could adversely impact therapeutic intensity and persistence. Coupled with inferior efficacy, these observations informed our decision to discontinue further enrollment at 150 milligrams. Overall, we're encouraged to see 081's clinical profile at 100 milligrams strengthen in a growing number of patients. This is a heavily pretreated patient population. 66% of the patients in our trial were progressing to their third or greater line of therapy, nearly 40% had received prior TKI and 50% prior immunotherapy. We are now observing a response rate of 41%, which is at the high end of other clinically or commercially available EGFR exon 20 agents. Just as important for patients, we are encouraged by a favorable toxicity profile and durability of response. We look forward to sharing additional insights into the data at upcoming medical conferences. Let's turn now to a regulatory update on Slide 8. Cullinan has been engaged in productive discussions with FDA. CLN-081's recent breakthrough therapy designation is facilitating these discussions and reflects the agency's interest in our program. We believe that we are well positioned to continue advancing 081 towards a pivotal second-line study in the second half of 2022. Thus far, 081 has only been administered under fasting conditions. In that setting, the data we reviewed earlier showed that 100 milligrams emerged as the dose level with the best efficacy and safety profile. Under the same fasted conditions, 150 milligrams was not well tolerated. 27% of patients experienced grade 3 EGFR associated toxicities such as rash and diarrhea, 27% of patients had dose reductions and 18% of patients had dose discontinuations. Under Project Optimus, an initiative undertaken by the FDA Oncology Center of Excellence, the agency aims to reform dose optimization and dose selection in the development of new oncology drugs such as CLN-081. Ultimately, Project Optimus is intended to enable drug developers to select doses that best balance the efficacy and safety of a therapeutic agent. Consistent with this initiative and after reviewing safety and efficacy data across the dose range, FDA has encouraged us to explore whether food intake can mitigate the toxicities observed at the 150-milligram dose level prior to the initiation of a pivotal study. Based on this feedback from FDA, we plan to conduct a small food effect study at the 150-milligram dose designed to evaluate the potential impact of food on exposure and other pharmacokinetic parameters of CLN-081. The study will enroll up to 20 cancer patients in a randomized single-dose, 2-way crossover design. The FDA has endorsed this plan, and we're committed to completing this food effect study as expeditiously as possible. The food effect study is designed to enable a seamless transition to a pivotal second-line study, which we expect to initiate in the second half of this year. And with that, I'll close and turn the call back over to Nadim.

Thanks, Jeff, and I'll now summarize our clinical and regulatory progress on Slide 9. As we reviewed today, CLN-081 continues to show a differentiated clinical profile relative to other EGFR exon 20 agents. The latest data at the 100 mg BID dose demonstrates a high response rate, above 40%, in a larger number of patients. In terms of quality of response, we saw promising response durability and a favorable safety and tolerability profile as we previously reported in December. On the regulatory front, we're very grateful for the productive engagement with the FDA, and we look forward to advancing expeditiously to a registrational study. The breakthrough therapy designation for CLN-081, underscores its differentiated clinical profile and the continued opportunity for accelerated approval. In terms of next steps, we plan to execute the agreed upon small 150 mg food effect study expeditiously with a seamless transition to a second-line pivotal study in the second half of 2022. At the same time, we also plan to expand CLN-081development into the frontline setting where even more patients can potentially benefit from this novel treatment. In closing, we're encouraged by our clinical and regulatory progress of CLN-081, and remain excited about the potential opportunity we have to improve the standard of care for non-small cell lung cancer patients, harboring EGFR exon 20 insertion mutations. With that, we'll open up the line for Q&A. Chad.

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

Can you talk a little bit more about the 3 patients who previously received 150 milligrams. You mentioned 2 had a confirmed response. Was there a washout period before they went on to 100 milligrams? And what gives you confidence that it's not confounded by the 150-milligram dose?

Jeff, thanks for your question. I want to turn that question over to Jeff Jones.

Sure. Thanks, Nadim. Let me clarify. So those 3 patients were in screening at the time the 150-milligram dose was discontinued, so they never received treatment at 150 milligrams. The only dose at which they were ever treated was 100 milligrams. So again, they were in screening when we took the decision to discontinue the 150-milligram dose, so they began and continue treatment at 100 milligrams.

Great. And if I can follow up, can you just talk a little bit more about your current thoughts on the pivotal study? And like how many patients would this be? And given that it will be for accelerated approval, do you need a comparator? And if so, like what might that compare to be?

Jeff, thanks for the follow-up. So maybe I'll make a couple of remarks around it. As we've said previously, we would expect the pivotal study to be similar in size and design as the previously approved agents. And what I mean by that is a single-arm study under selected Phase II dose, we're not anticipating a randomized study, hence the context of continuing to pursue accelerated approval. Because, again, going back to the breakthrough therapy designation that underscores both the clinical profile of CLN-081, as well as it clearly designates that the accelerated approval pathway is open for us. So it would be of the size and magnitude of what we've seen before us, roughly around 100 patient efficacy database at the selective Phase II dose in a single arm manner.

[Operator Instructions] Our next question comes from the line of Gil Blum of Needham & Company.

Maybe a general question. Do you guys have any hypothesis as to the lower efficacy, kind of a mode of action, could this be driven by? I mean I would understand if that was due to missed doses, but that doesn't seem to be the case.

Yes, let me just clarify. I think your question is referring to the lower efficacy we observed at the 150 mg dose under fasting conditions. Is that correct?

Yes, that's correct. Sorry.

Let me turn that over to Jeff.

Thanks for your question. And so I think the observation is really based on the fact that the 150-milligram dose had a significantly inferior safety and efficacy profile. TKIs require persistence with therapy. And in the case of the patients treated at the 150-milligram dose, there were 27% of patients who required a dose reduction and 18% who required dose discontinuations. And so for this particular mechanism of action and true for all kinase inhibitors, persistence and intensity of therapy is necessary for efficacy. And we think that that's what likely explains the observed inferior response rate.

Okay. So this is due to dose reduction basically. Maybe a separate topic. Is there a precedence for a request like the one the FDA had ahead of a pivotal study. I mean I'm sure there are examples of this, but if you could provide any?

Yes. Let me just provide some context here then. So -- and the context is really important. So in recent times, through Project Optimus FDA has provided many companies with feedback on dose. So we're not the first and we certainly won't be the last. But I will say we've had very productive discussions with the FDA as a result of the BTD designation, very collegial also. And so -- going back to your question, what's clear is when we selected the dose of 100 mg, and remember, with this study, all patients were treated under fasting conditions because that's what you typically do at this stage of development, so you can roll out food as a variable. Within that context, 100 mg was clearly the best dose. And in fact, and importantly, the FDA did not ask us to dose any more patients at the 150 mg dose under fasting conditions. What they did ask is -- or they asked us to study is whether co-administration with food at the 150 mg dose, could that ameliorate toxicity and change the clinical profile. And so that's why we're now doing this small food effect study to test that hypothesis, which we plan to expeditiously continue, complete and then transition seamlessly to a pivotal study in the second half of this year.

At this time, I'd like to turn the call back over to Nadim Ahmed for closing remarks. Sir?

Thanks very much. Look, we're very pleased to see the strengthening of efficacy profile of CLN-081, both in terms of quantity of response, quality of response as well as the favorable safety profile. And we're very pleased with the discussions we've had with the agency. I think breakthrough therapy designation has facilitated a good ongoing dialogue. And a clear example of that is that when we received the feedback to test the 150 mg dose, we were able to come to a study design very quickly and agree with the agency very quickly. So we have a clear path and plan moving forward. We're going to expeditiously complete the food effect study, again, with a seamless transition to the start of a pivotal study in the second half of this year, and we look forward to pursuing accelerated approval under those conditions. Thanks very much for your attention, everyone, and your questions.

This concludes today's conference call. Thank you for participating. You may now disconnect.