Q3 2024 Crinetics Pharmaceuticals Inc Earnings Call
Speaker Change: To all sites on hold, we appreciate your patience and ask that you please continue to stand by. Your program will begin in approximately one minute.
Speaker Change: Please stand by, your program is about to begin. If you need audio assistance during today's program, please press star zero.
Speaker Change: Welcome to the Chronetics Pharmaceuticals third quarter 2024 financial results conference call. At this time all participants are in a listen-only mode. Following management's prepared remarks we will hold a question-and-answer session. I would now like to turn the call over to Gaia Three Diwakar of Chronetics. Please go ahead.
Thank you all very much.
Speaker Change: Hello everyone and welcome to Kronetics Earnings Call. Joining me today are Dr. Scott Southers, Founder and Chief Executive Officer, and Marc Wilson, Chief Financial Officer. Also joining us for the Q&A portion of the call are Dr. Dana Pizzuti, Chief Medical and Development Officer, and Dr. Alan Krasner, Chief Endocrinologist.
Speaker Change: A press release announcing the third quarter 2024 financial results was issued today and is also available on our corporate website.
Speaker Change: As a reminder, we'll be making forward-looking statements, and I invite you to learn more about the risks and uncertainties associated with these statements as disclosed in our SEC filings.
Speaker Change: Such forward-looking statements are not a guaranteed performance and the company's actual results could differ materially from those stated or implied in such statements due to risks and uncertainties associated with the company's business.
Speaker Change: These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release, the company's other news releases, and Kronite's SEC filings, including its annual report on Form 10-K and quarterly reports on 10-Q.
Speaker Change: I would also like to specify that the content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, November 12, 2024.
Speaker Change: Chronetics take no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. With that, I'll turn the call over to Scott.
Scott Southers: Thank you, Gayathri. Good afternoon, everyone, and thank you for joining us on our third quarter 2024 results call. We've had yet another incredibly productive quarter with advancements up and down the pipeline, and we continue to strengthen our financial position.
Scott Southers: For today's call, I will summarize our recent accomplishments shown on slide 3, preview some of our upcoming events, and then hand the call over to Marc, Marc Wilson, for a review of our financials.
Lend as always by taking your questions.
Scott Southers: As some of you may know, November 1st was Acromegaly Awareness Day. We commemorated this day by hosting acromegaly patients at our headquarters to bring life to the impact of our mission of improving patients' lives.
Scott Southers: That was the picture you saw on the first slide of our presentation today.
Scott Southers: It was especially timely for Chronetics as we recently submitted our first NDA for our investigational drug, Paltucetine, for the treatment and long-term maintenance.
of Acromegaly.
Scott Southers: We very much look forward to Acromegaly Awareness Day next November. We believe palitucetine will represent a next-generation therapy for people living with acromegaly.
Scott Southers: In the meantime, we continue to focus on building our commercial capabilities and preparing for the anticipated launch of our first drug next fall.
Scott Southers: As part of these preparations, our National Accounts team is meeting with payers to discuss formulary placement and product coverage.
Scott Southers: We believe that having these conversations early and often allows us to positively influence formulary placement and coverage decisions with the goal of broad access for patients living with acromegaly.
Scott Southers: In addition, our medical science liaisons are in the field speaking with academic KOLs and community endocrinologists to get their feedback from these clinicians on how treatment protocols are established within their practices and to better understand the patient experience.
and Dana Pizzuti. Thank you. Thank you.
Speaker Change: In addition to preparing for the U.S. paltucetine launch, we're also in the early stages of building capabilities for commercialization of paltucetine and to support global clinical development of our other potential future drugs in the pipeline.
Speaker Change: As you are aware, we partnered Peltucetine in Japan with SKK and they are doing an excellent job of advancing a Japanese phase 3 trial in patients with acromegaly.
Speaker Change: Based on the strength of the clinical data for paltucetine and etumelanat.
Speaker Change: Towards this, we anticipate submitting the MAA in the first half of next year for the use of peltucetine in patients with acromegaly.
Speaker Change: We have also recently established operations in Switzerland, hired a general manager for Europe, and are recruiting supporting staff in the areas of regulatory, market access, medical affairs, and operations.
Speaker Change: We are committed to eventually bringing Peltucetine and our other future products to patients in Europe and the rest of the world.
Speaker Change: But as with all our investments, we will do so in a fiscally prudent way and consider the continuously evolving reimbursement landscape in making final decisions about where and when to launch.
Thank you. Bye.
Carcinoid syndrome is the second indication in development with paltucetine.
Speaker Change: We reported positive results from our Phase 2 study earlier this year, and we remain on track to start the Phase 3 trial on our anticipated timeline.
Speaker Change: We've had productive interactions with the FDA regarding the Phase 3 protocol and received feedback on details of endpoints, inclusion criteria, rescue criteria, etc. We are finalizing the protocol and expect to begin site activation activities shortly.
Speaker Change: L2-cetine is just the first of many therapeutic candidates that we have been purposely designed in-house to transform the treatment of endocrine conditions.
Speaker Change: Beyond paltucetine, our investigational drug atumelanate is in phase 2 development for both congenital adrenal hyperplasia, or CAH, and Cushing's disease.
Speaker Change: We previously shared exciting initial data from both of Attu-Malnats Phase II studies earlier this year at the Endocrine Society's annual meeting in June.
Speaker Change: As a reminder, we previously showed partial data from a small subset of patients at Endo.
Speaker Change: By early next year, we plan to share the complete 12 weeks of data from all the 28 patients recruited across three doses, 40, 80, and 120 milligrams.
Speaker Change: We expect to initiate a Phase III study in adults with CAH in the first half of 2025.
Speaker Change: There is also a very high level of unmet need in children with CAH due to the irreversible effects of early hyperandrogenism and the consequences of supraphysiologic glucocorticoid use.
Speaker Change: We plan to initiate a pediatric CAH program with Atamelnet in 2025.
Speaker Change: We also shared remarkable initial data at the endocrine meeting about the use of abtumelanat in patients with Cushing's disease.
Speaker Change: Encouraged by the positive emergent data, we are also planning to initiate a full development program in Cushing's in 2025 pending regulatory feedback on program design.
Speaker Change: We've also continued to make great progress on our early stage pipeline, as shown on slide 4, with four new candidates currently the subject of first-in-human enabling activities with INDs anticipated next year, if these studies are positive.
Speaker Change: As we mentioned previously, IND-enabling studies of our PTH receptor antagonist in development for hyperparathyroidism are ongoing. Assuming positive results, we expect to file an IND for this candidate in 2025.
Speaker Change: We've also initiated IND enabling studies of our SST3 agonist for autosomal dominant polycystic kidney disease. Assuming positive results, we expect to file an IND in 2025.
Speaker Change: Today we are excited to announce that we recently nominated a development candidate for our TSH antagonist program.
Speaker Change: As you may recall, a TSH antagonist could be developed for both Graves hyperthyroidism and Graves ophthalmopathy, often referred to as thyroid eye disease or TED.
Speaker Change: We are initiating IND-enabling studies for this compound. Assuming positive results, we expect to file an IND in 2025.
Speaker Change: As you can see from our progress in these programs, our commitment to GPCR drug discovery continues to unlock scientific and medical innovations that have the potential to bring transformative therapies to patients and significant value to our co-owners.
Speaker Change: We believe we have a unique, deep pipeline of drug candidates.
Speaker Change: Our goal is to relieve the burden of disease so that patients can focus on living their lives.
Speaker Change: To date, our drug discovery and development efforts have been focused on novel therapies to manage endocrine disorders, including those caused by the secretory activity of endocrine tumors.
Speaker Change: Today I'd like to introduce you to Non-Peptide Drug Conjugates or NDCs.
Speaker Change: NDCs are a new technology that we've developed in-house, enabled by our premier in-house drug discovery capabilities in the area of GPCRs.
Speaker Change: This novel platform leverages endocrine receptors for highly selective targeting of anti-tumor agents with the goal of treating the underlying tumors themselves.
Speaker Change: If successful, we anticipate our NDC platform may be applicable to a wide range of different cancers.
We're extremely excited about the long-term potential of this approach.
Speaker Change: By way of background, we've all heard a lot about the success of antibody drug conjugates or ADCs in cancers.
Speaker Change: These combine a targeting antibody that recognizes tumor cell surface markers and delivers a cytotoxic payload to the constituent tumor cells.
Speaker Change: ADCs are now a well-validated platform and contribute to the therapeutic armamentarium for a wide range of different cancers.
Speaker Change: NDCs leverage Kronetic's deep expertise in small molecule ligand design for GPCR targets to replace the antibody of ADCs with a fit-for-purpose, novel small molecule.
And this is a nonpeptide.
Speaker Change: Our first NDC candidate from this platform is CRN09682 and its overall design is shown on slide 5.
The NDC approach is intended to enhance tumor penetration.
Selectively target specific GPCR-expressing tumor cells.
Induce internalization.
Speaker Change: and selectively release a potent anti-tumor agent intracellularly, all while minimizing systemic exposure and toxicities.
Speaker Change: Additionally, NDCs are manufactured by traditional chemical synthesis methods, avoiding the limitations of complex and heterogeneous manufacturing methods required by most ADCs.
and Dana Pizzuti.
Speaker Change: 9682 is made up of small-molecule SST2 agonists optimized to selectively bind with high affinity and potently induce internalization, then trafficking to specific intracellular targets.
Speaker Change: This is in contrast to Peltucetine, which was designed to minimize internalization in order to maximize G-protein signaling at the plasma membrane to inhibit growth hormone and serotonin secretion.
Speaker Change: A small molecule agonist in 9682 is linked to a monomethyl or a statin E or MMAE, which is a well-established cytotoxic payload in approved ADCs.
Speaker Change: The linker was designed to be selectively cleaved by enzymes only present in specific intracellular compartments and not present in the general circulation.
When intact, 9682 has little cytotoxicity.
Speaker Change: But when the MME portion is released inside the cell, it causes cell cycle arrest and subsequent apoptosis or cell death.
Speaker Change: The net result of all this craftsmanship is a low molecular weight compound that readily penetrates solid tumors, and as shown on slide 6, selectively delivers its payload to the inside of tumor cells where it accumulates and kills these cells with little circulating free payload and associated toxicities.
Speaker Change: In preclinical in vivo tumor models, 9682 is very effective at shrinking and often eliminating well-established tumors in mice.
Speaker Change: The IND-enabling toxicology study so far suggests a more than adequate preclinical safety margin to begin clinical evaluation.
Speaker Change: The IND enabling studies are nearly complete and we anticipate filing an IND to support the clinical development of 9682 in early 2025.
Details of the design and preclinical results for 9682.
Speaker Change: Clinical Development, the 9682 Clinical Development Plan will begin with a dose range finding study in patients with SST2 expressing tumors, including NETs.
Speaker Change: This leverages the routine use of SST2-targeted PET imaging agents in patients to precisely identify patients whose tumors express SST2 and are therefore good candidates for 9682.
Speaker Change: Strategically, we believe the development of 9682 in patients with non-functional NETs is complementary to the use of paltucetine in patients with the functional NETs who develop carcinoid syndrome.
Speaker Change: We'll be working with many of the same centers and investigators for the development of both compounds.
Speaker Change: When metastatic, NETs are typically incurable with surgery or current therapies, regardless of tumor grade.
Speaker Change: We believe this is a large population with high unmet need and we are excited to be developing 9682 for these patients.
Speaker Change: As you can probably tell, we're very excited about the potential of this first-in-class NDC that may provide an important new treatment option for patients with NETs.
and potentially multiple other SST2-expressing tumor types.
Speaker Change: Beyond SST2, we'll use our experience with 9682 to learn how to best optimize and develop future NDCs for other GPCR targets and cancer types.
Speaker Change: As you can see from this update, we have a robust pipeline shown on slide 7, spanning registration, late-stage development, and discovery.
Speaker Change: Our recent $575 million equity offering positions us to continue delivering important, innovative medicines well beyond the Peltucetine launch in Acromegaly next year.
Anticipated L-215 launch.
Speaker Change: Our existing pipeline is filled with possibilities to bring new hope to patients struggling with many different endocrine conditions and endocrine related tumors.
Speaker Change: Those who have followed the history of Kronetics know that we have always been judicious with our spending and thoughtful about deploying capital in a way that creates both hope for our patients and value for our co-owners.
Speaker Change: We will continue to carefully steward the resources with which we have been entrusted as we continue the exciting trajectory of growth and transformation at Chronetics.
Speaker Change: With that, I'll now hand it over to Marc to review the financials.
Thank you.
Marc Wilson: Thank you, Scott. Turning to slide 8, Frenetics continues to be in a strong financial position, having ended the third quarter with approximately $863 million in cash and investments.
Marc Wilson: As Scott mentioned, we completed a $575 million public offering that closed after the end of the third quarter.
Marc Wilson: This further strengthened our financial position, and our cash, cash equivalents, and investment securities following the equity offering totaled approximately $1.4 billion on a pro forma basis.
Marc Wilson: We project that, with the proceeds from the recent offering, we will be able to fund our current operating plan into 2029.
Marc Wilson: That operating plan includes the commercialization of Peltucetine for Acromegaly if approved.
Marc Wilson: as well as the initiation of multiple later stage clinical trials in carcinoid syndrome, in CAH, and in Cushing's disease.
Marc Wilson: In addition, we plan to continue investing in the product candidates that are emerging from our discovery pipeline, including the four development candidates that have been nominated this year.
Marc Wilson: With respect to the financial results, there were no revenues for the quarter end of September 30th, 2024, compared to 0.3 million for the same period in 2023.
Marc Wilson: The third quarter 2023 revenues were derived from the Paltuzatine Licensing Agreement with our Japanese partner, SKK.
Marc Wilson: Research and development expenses were $61.9 million for the quarter ended September 30, 2024, compared to $43.8 million for the same period in 2023.
Marc Wilson: The increase was primarily driven by higher personnel costs, outside services, and manufacturing activities.
Marc Wilson: The majority of which were attributable to the advancement of the Paltuzatine and Atumelnab development programs.
and the expansion of our preclinical portfolio.
Marc Wilson: For the quarter ended September 30th, 2024, general and administrative expenses were $25.9 million compared to $15.5 million for the same period in 2023.
Marc Wilson: These increases were primarily due to higher personnel costs and commercial plant activities.
Marc Wilson: Net loss for the quarter ended September 30, 2024 was $76.8 million compared to a net loss of $57.5 million for the same period in 2023.
Marc Wilson: Net cash used for operating activities for the quarter ended September 30th, 2024, $62.8 million.
Marc Wilson: We plan to provide updated financial guidance during our year-end earnings call in the first quarter of 2025.
Marc Wilson: It is worth highlighting that in the next year, we plan to initiate multiple phase 3 studies in carcinoid syndrome and in adults with CAH.
Marc Wilson: In addition, we are planning to initiate later stage development in pediatrics with CAH and in Cushing's disease.
Marc Wilson: As such, we expect our quarterly R&D spend will increase as we initiate and advance Pelticitin and Atumelanab into these clinical trials over the remainder of this year and throughout 2025.
Marc Wilson: We also anticipate increases in SG&A expenses as we prepare for the potential launch of altucitine for acromegaly.
Unknown Speaker
Speaker Change: Chronetics has practiced disciplined expense management and that continues to be our goal as we continue to grow the organization and invest in our deep pipeline.
and we are well financed to do so.
Scott Southers: I will now hand it back to Scott for closing remarks before we begin Q&A.
Thank you, Marc.
I'm incredibly excited about the future of kinetics.
Scott Southers: As we look to the end of 2024 and the start of 2025, we will continue to build on our strong progress.
Scott Southers: We've consistently delivered on our plans and we're committed to maintaining this level of execution.
Scott Southers: We look forward to sharing upcoming clinical and regulatory milestones from paltucetine and atumelanin and updates on the continued advancement of our deep pipeline of emerging candidates.
Scott Southers: Connecticut continues to be well-positioned to become the premier fully integrated endocrine focused global pharmaceutical company.
Scott Southers: Thank you all for your attention. Operator, we're ready to take your questions.
Speaker Change: Thank you sir. And at this time if you would like to ask a question, please press the star 1 on your telephone keypads.
Speaker Change: You may remove yourself from the queue at any time by pressing star 2.
Speaker Change: And once again, that is star one to ask a question. We'll take our first question from Corey Jubinville with Lifesci Capital. Please go ahead.
Corey Jubinville: Hey, congrats on the news and uh, thanks for taking our questions. The NDC is in CRN 09
Corey Jubinville: It's pretty exciting. Anything more you could tell us about this program?
Corey Jubinville: kind of where you see it best fitting within the existing paradigm. And, you know, I guess what else are some of the key challenges that needed to be overcome to develop an NDC? And what are some of the specific advantages you could point to of an NDC approach over say ADCs or radiotherapies?
Speaker Change: Thanks, Corey. So for more details, I'd encourage folks to come to Chicago for the NANETS meeting where we'll be presenting some of the preclinical data on 9682 and data on paltucetine and carcinoid syndrome and can talk at some more length with data in hand.
But broadly...
Speaker Change: The NDC platform is an extension of the types of ideas that led to the formation of Radionetics a few years ago.
Speaker Change: We believe that these non-peptides, small molecules, provide a variety of different advantages when targeting GPCRs over antibodies in the typical NDC formats.
Speaker Change: You know, for one thing, GPCRs are very difficult to make antibodies against, yet they're a whole class of selectively expressed cell surface targets.
Speaker Change: And unlike many of the targets of ADCs, binding of ligands to GPCRs can be tuned to selectively optimize internalization.
Speaker Change: of these conjugates into the inside of the cell, which is something you want to do for selective intracellular cleavage.
Speaker Change: So I think it opens up new targets. It opens up simpler chemical synthesis. It opens up the ability to tune things in ways that you can't with antibodies. Something as simple as most antibodies will stick around for weeks, whereas we can clear small molecules in a day or two.
Speaker Change: So I think it offers a number of different potential advantages, but with 9682, we're going to go learn about what these are in a real-world setting and in the type of patients that we're already working with, with neuroendocrine tumors for those who have carcinoid syndrome.
Speaker Change: So it's highly synergistic with our ongoing efforts for paltucetine, the internal relationships we've developed with the investigators and the patient community, and it's pioneering this new idea about how we might branch out and use our core platform to expand into anti-tumor agents.
Speaker Change: Excellent. Thanks for taking our questions. I'll hop back in the queue.
Next we will go to Jessica Vai with J.P. Morgan.
Jessica Vai: My question, so with several products entering the clinic next year what's the soonest that we can expect phase one data from any of those and which will it be from? And then if I could sneak a couple in on 9682, can you talk about how you chose the MMAE toxin for that product and how different or similar the ligand is to Peltucetine?
Speaker Change: Okay there's a good batch. Thanks Jeff and look forward to seeing you later this week.
Speaker Change: I think we'll probably stick away from providing precise guidelines on each of those. Just have to stay tuned throughout the year and see how they come. In part, it's because you also don't know how far you need to go up in dose response curves.
Speaker Change: from those and some other compounds that are getting close, you know, over the next year and a little into 2026.
And then in terms of 9682,
Speaker Change: It's not Peltucetine, it's not a direct homologue of Peltucetine, it's another SST2 agonist.
Speaker Change: that was selectively optimized to be the best ligand we could get.
Speaker Change: for the purpose at hand, which is to bind selectively and internalize receptors and get the right bio distribution. So it spends very little time in the periphery.
Speaker Change: And all those various factors were considered as we built that conjugate, both the ligand and the linker group.
Speaker Change: and MMAE was chosen simply because it's a very well-established payload in the ADC world, but we have ongoing activities to explore alternative payloads as well, and that may be seen in some of our backup or follow-on compounds.
Thank you.
Speaker Change: Thank you. Next we're going to go to Jeff Hung with Morgan Stanley. Please go ahead.
Jeff Hung: Thanks for taking my question. From your early stage pipeline, how are you thinking about the obesity indications for candidate selection in 2025? What would you need to see with your GLP-1 or GIP programs in order to have confidence advancing those given the increasingly competitive landscape? Thanks.
Speaker Change: Thank you. And what I think we're seeing in the competitive landscape is some of the limitations that arise if you're not super careful about how you select candidates.
Speaker Change: These are things as simple as getting to easily manufactured dose levels.
Speaker Change: Clearly, there's questions around tolerability in some molecules and the doses needed for good weight loss versus good tolerability.
Speaker Change: And we have a variety of different hypotheses we're testing as we tune these molecules to be what we think can be the best-in-class profile for an easy-to-synthesize, small-molecule GLP-1 agonist.
Speaker Change: and basically the course limiting step is we want a really really good molecule and we're not going to settle for anything less than what we think is as close as reasonably expected to perfection.
Thank you.
Speaker Change: Thank you. Next we're going to go to Brian Skorney with Beard. Please go ahead.
Speaker Change: Hey guys, this is Charlie on for Brian. Just kind of piggybacking off the last question noting that your GLP-1 and NGIP assets are non-peptides. How are you guys thinking about the potential advantage of a non-peptide compound here relative to other assets in the space? Thanks.
Please see the complete disclaimer at https://sites.google.com or at https://sites.google.com
Speaker Change: Well, I think the whole field in the obesity space is moving towards
Speaker Change: alternative modes for delivery of the activity. And the main challenge
Speaker Change: on the peptides is two-fold. One is manufacturing that I think everybody and their brother has been hearing about. But also peptides just limit you in the physical chemical space that you can explore and the delivery methods that you can utilize.
Speaker Change: And with small molecules, you don't have those limitations. You can tune every dimension of chemical space to get the types of physiologic or pharmacologic activities, pharmacokinetic activities.
and test different types of hypotheses to get the right
Speaker Change: And so I think, you know, what this today's talk about 9-6-8-2 and peltucetine
Speaker Change: gives you a sense of some of the depth of types of things we try and optimize when we're making small molecule drugs. And you'll see us employ all these different type of techniques as we're applying it to the obesity space.
Speaker Change: and in molecules that can be made at scale because, you know, this is one of the biggest public health problems in the world, or at least in most Western societies.
Got it. Thank you.
And Dennis, your line is open.
Speaker Change: Hi, thanks for taking our questions. I had one on the non-peptide drug conjugate. Can you remind us of the common toxicities associated with MMA, ADCs like Polivipat, Cev, and TivTac? And just curious around your confidence and your ability to thread the needle on efficacy and tolerability. Thank you.
Speaker Change: Thank you. It's a great question and certainly something we explored carefully in our preclinical program. Now we need to see it in a clinical setting. But we obviously were aware of the types of common toxicities for MMAE.
Speaker Change: and you know look carefully for that in the preclinical packages and we think we've got very very good margins and in part that's because we we tuned the molecule so there's very little circulating free MMAE
The conjugates are cleared rapidly from systemic accumulation.
Speaker Change: But cleaved MMAE is accumulated both rapidly and persistently in tumor cells. And we'll show this data at NANET.
Perfect. Thank you.
Speaker Change: And next we'll go to Joe Schwartz with Lerink Partners. Please go ahead.
Speaker Change: And how high is the hurdle here compared to what you needed to clear for other programs such as paltucetine and etumelanin? And then from a biological standpoint, how should we think about the relative degree of efficacy, which an IGF-1 or a TSH antagonist
Speaker Change: can inherently offer all of us equal based on crosstalk or any other factors. So just the chemistry and the biology, if you could address those, that would be great. Thank you.
Speaker Change: Yeah, great question, Joe. Philosophically, we try and make every molecule as high a quality of a drug candidate as we can.
Speaker Change: Frankly, I'll tell you that when we advanced peltucetine into the clinic, we took a couple risks.
Speaker Change: One is there was a slight risk of drug-drug interactions, which we disproved later in the clinic.
Speaker Change: And there is a slight risk of lower than hoped oral bioavailability, which we disproved later in the clinic.
So, um,
We did very well with Paltusatine, I think you'll agree.
Speaker Change: But as we get into some of these more prevalent indications like Graves disease or obesity
Speaker Change: We're adding extra layers of carefulness, including, you know, broad testing against any other potential liability, making sure the physical chemical properties are good, making sure it's scalable at high levels of
Speaker Change: you know, production, because you're going to have a lot more patients and Graves disease than you would in acromegaly, for example. So I don't think we've changed our goals that much, but we're just looking with a.
Speaker Change: And then I'm sorry I missed this. What was the second part about that?
Speaker Change: It just seems like your TSH antagonist has a different approach. Oh, yeah. Yeah, yeah. Yeah.
Speaker Change: Yes, so remember in Graves' disease, the root cause of the disease is auto antibodies which bind to the TSH receptor and activate cell signaling.
Speaker Change: and our candidates that are TSH receptor antagonists block the activity of those antibodies at the level of the receptor.
Speaker Change: Now in Graves eye disease what happens in the cells at the back of the eye is those antibodies bind to the TSH receptor that activates the TSH receptor which then signals down its main pathway of cyclic AMP.
But it also cross-activates the IGF-1 receptor.
Speaker Change: and that IGF receptor also starts signaling into the back of the eye.
Speaker Change: and Trapeza and the other drugs are aimed at IGF signaling or acting downstream of TSH.
Speaker Change: So if you block the activity of the TSH receptor, and we've shown this in preclinical studies that I believe we published at Endo last year, you also block the signaling of IGF and the cells from the back of the eye.
Speaker Change: So generally we expect this to be more efficacious, or at least as equally efficacious as the IGF approaches. And it can be used to treat the underlying graves at the level of the thyroid.
Speaker Change: And if we had the right drugs for the treatment of Graves' disease itself, we wouldn't be having thyroid eye disease.
Speaker Change: So one of the challenges for this program is to figure out the sequence of indications that we address in later stage trials.
Very helpful. Thank you.
Speaker Change: Thank you. Next we'll go to Douglas Sow with H.C. Wainwright. Please go ahead.
Speaker Change: Hi, good afternoon and thanks for taking the questions and congrats on the progress I guess, Scott, maybe as a follow up to that, I mean, historically, you as a company have been very innovative.
in terms of using sort of phase one studies.
Speaker Change: to provide very compelling proof-of-mechanism data that has really sort of given confidence in de-risked programs as they enter Phase II and ultimately Phase III. When you think about the TSH program and GRAVES as well as TED,
Speaker Change: You know, from your sort of initial sense, will you be able to accomplish that?
in sort of a Phase 1, Phase 1B study.
and will that necessarily inform...
Speaker Change: the initial direction you take with that program in terms of the sort of time at which you
Speaker Change: sort of intervene with GRAVES and, you know, if patients are already starting to show manifestations of eye disease. Thank you.
Thanks, why don't I let Alan answer that question.
Alan Krasner: Thanks Doug. Yeah, you know, I think actually a TSH antagonist is very, very, it would be a nice model in phase one to evaluate in the sense that we do have biomarkers.
Alan Krasner: that we can evaluate in real time as we've done in our previous phase one studies before.
Alan Krasner: In particular, thyroid hormone levels, TSH and T4 responses to a TSH antagonist could tell us, I think, in theory at least, very quickly whether we're hitting the intended pharmacologic target as we've done in other studies before.
Alan Krasner: So, now it's a typical Phase I study. That time course is a little short to measure efficacy in thyroid eye disease, but certainly this is still, I think, a good candidate for pharmacologic proof of concept, even in Phase I.
Okay, great. Thank you.
Speaker Change: Perfect. And next we're going to go to John Wolben with Citizens JMP. Please go ahead.
Speaker Change: Hi this is Catherine on for John. I have a question about the carcinoid syndrome program and if you can give any additional color on kind of the feedback from the FDA and how
Yeah, why don't I let Dana answer that question.
Speaker Change: Yeah, well, thanks for the question Yeah, the interaction with with the FDA on Carcinoid went very well I think that there were there were you know many areas that we had agreement on and then needed their
Speaker Change: perspective on issues like the endpoints and duration of the trial.
and Dana Pizzuti.
Speaker Change: But we had anticipated a lot of those potential perspectives and
Those changes into our proposed plan. So we're just
Speaker Change: finalizing that right now and we are you know continuing to be on track to get that started in the same time frame that we've always been saying.
Thank you so much.
Speaker Change: And next we're going to go to Leland Gershel with Oppenheimer. Please go ahead.
Speaker Change: Thanks for taking my questions and for unveiling this new program in NDC. Scott, I just wanted to ask a forward-looking question with respect to the opportunities here with this new approach as we think about
Speaker Change: Are you able to identify others that you could approach following the first compound for perhaps other tumor types with GPCRs? Thanks.
Speaker Change: Yeah, thanks Leland. I think there's lots of other opportunities but you know at this point we really want to learn from 9682 about what it's really going to take to be successful in the clinic.
Speaker Change: and I think those lessons that we'll learn there, both in pharmacokinetics and tumor responses and
Speaker Change: lines of therapy and things like that will be very informative for us. So in the meantime, the Discovery Group is exploring new ideas, new payloads, new targets, things like that. But before we advance the next one, we really want to see how this does.
Speaker Change: Got it. And then just a question on the TSH antagonist, good to see that be nominated. So will you be planning to study that in Graves and Ted as separate?
Speaker Change: kind of campaigns, or will you be looking at kind of an overarching graves development program with TED as, you know, constituting a sort of a subset of those patients? Thanks.
Speaker Change: I think it's maybe a little early to discuss the overall strategy there. You might imagine there's both some
and Dana Pizzuti. Thank you. Thank you.
Speaker Change: Questions we need to ask ourselves around the economics of the two different indications and the feasibility of recruiting in the different indications and the competitive environments.
Speaker Change: But honestly I think this is the absolutely best approach for both Graves hyperthyroidism and Graves associated ophthalmopathy or TED. We just have to figure out how to stage those investments.
Great, thanks very much.
Speaker Change: Thank you. And we'll take our next question from Catherine Novak with Jones Trading. Please go ahead.
Speaker Change: Hi, afternoon guys. Thank you so much for taking my questions.
Speaker Change: Just one on CAH, given that this is an area that has not really seen any new approvals in recent years.
Speaker Change: Is what learnings were you able to take from Neurocrin's pivotal programs when you go to design your own? Maybe you can, you know, learn from anything or have better designs.
Speaker Change: And then, what do you anticipate the standard of care would be following potential connoisseur-front approval next year?
Speaker Change: Well, I think Cronusterfond, if it's approved, will be the first drug specifically for CAH ever. You know, we've used glucocorticoids to treat patients, but...
Speaker Change: awarded by the FDA, assuming all goes well. And I think it will be incorporated into the standard of care for some patients.
Speaker Change: What we've learned is about the role of different hormones in this pathway.
Speaker Change: and you know we've speculated for years about how much of the HPA axis is controlled by CRF or vasopressin or ACTH.
Speaker Change: And I think it's pretty clear now with our early data and Neurocrine's phase 3 data that CRF contributes to the activation of the adrenal, but it's not...
Speaker Change: The stimulation of the adrenal is not completely dependent on CRF, whereas it does appear to be nearly completely dependent upon ACTH, as we expect.
Speaker Change: So I think we've chosen an ideal target in the pathway and be looking forward to talking more about the rest of the data we have in the not too very distant future.
Speaker Change: And at that time, we should be able to clarify more about our Phase 3 plans, too.
Speaker Change: Great. Well, looking forward to the rest of the data. Thanks very much for taking my questions.
Speaker Change: We'll take our next question from Yasmeen Rahimi from Piper Sandler. Please go ahead.
Speaker Change: Good afternoon, team. Thank you so much for that really nice surprise. I definitely caught many of us for this really wonderful update, and I'm sure a ton of work went into this. So I guess the question to ask is,
Speaker Change: In terms of development for NETS, what would a path look like?
Speaker Change: I think many of us may think of these tumors more slow-growing, takes a long time to show its separation. Could you maybe educate us?
Speaker Change: what a path would look like. And next, if you decided to pursue that, that would be really important and how big that market would be if you've done any work in that regard.
Yeah, thanks, yes.
Speaker Change: You know, I hope we're able to provide a few surprises every now and then and You know, we've got a very active discovery group that is working really hard We just want to make sure we got things ready for prime time before we start talking about them
Speaker Change: But Alan, maybe you want to comment on some of our ideas on development for this?
Yeah, yeah, so, um, uh, we would, uh, we're.
Alan Krasner: planning on starting with an oncology style phase one study, which is a little bit different than our phase one endocrine trials.
Alan Krasner: The kinds of tumors we're talking about that would be included in such a trial would be patients who have SST2 receptor expressing tumors.
Alan Krasner: Those are largely patients with neuroendocrine tumors, although I will point out.
Alan Krasner: that there are variants of neuroendocrine tumors and even tumors which are not technically neuroendocrine tumors which can express these receptors. And we're
Alan Krasner: We're going to be pretty agnostic as to which patients we study because these are patients often who have a great deal of medical need.
Alan Krasner: These are patients who would have progressing disease, and we'll first define the right dose.
Alan Krasner: and then proceed to dose expansion cohorts where once we have sort of a dose which we expect to be well-tolerated and potentially therapeutic, we would explore a variety of different kinds of tumor types.
based on the origin of the neuroendocrine tumor.
Alan Krasner: Assuming that's all successful then we would look at this kind of novel potentially therapeutic compound in patients who have progressive disease and need adjunctive therapy to improve outcomes.
in phase two and potentially phase three as well.
Alan Krasner: So this is a very novel approach. It's a very exciting approach, and this is a, I would say, a fairly underserved patient population. There's a lot of research going on in the neuroendocrine tumor and related tumors now.
Alan Krasner: And then Youll see if you look in the radio pharmaceutical space, where there's a lot of entrants in the U S. T. Two targeted radiopharmaceuticals that theyre starting to expand out into some of the other tumor types in particular theres certain types of breast cancer that express SST too many head and neck cancers.
Alan Krasner: Express house seats, SST, two and some of the pheochromocytoma or other types of more rare cancers.
Alan Krasner: So that's something we're working on making sure we understand the full potential.
Alan Krasner: But it's it's not small.
Speaker Change: Thank you so much congrats again great great.
Alan Krasner: Great.
Alan Krasner: Yeah.
Speaker Change: Thank you I would now like to turn the call back over to Scott Struthers for any closing or additional remarks.
Scott Struthers: No. Thank you everybody. Thank you for your attention to our story and your support in our financing and participating with the success and growth of the company. We appreciate it and look forward to talking to many of you in the coming days and weeks.
Scott Struthers: Thank you and this does conclude today's program. Thank you for your participation you may disconnect at any time.
Scott Struthers: Okay.
Scott Struthers: Uh-huh.
Scott Struthers: Hum.
Scott Struthers: [music].
Scott Struthers: Uh-huh.
Scott Struthers: Uh-huh.
Scott Struthers: Okay.
Scott Struthers: Yes.
Scott Struthers: Sure.
Scott Struthers: Okay.
Scott Struthers: [music].
Scott Struthers: Okay.
Scott Struthers: Okay.
Scott Struthers: Okay.
Scott Struthers: Uh-huh.
Scott Struthers: [music].
Scott Struthers: Yes.
Scott Struthers: Hum.
Scott Struthers: Okay.
Uh-huh.
Scott Struthers: Uh-huh.
[music].
Scott Struthers: Hello, Matt.
Scott Struthers: Okay.
Scott Struthers: [music].