Good morning, ladies and gentlemen, and welcome to the Crinetics PATHFNDR-2 conference call. At this time, all lines are in a listen-only mode. Following the presentation, we will conduct a question-and-answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. This call is being recorded on Tuesday, March nineteenth, two thousand and twenty-four. I would now like to turn the conference over to Corey Davis. Please go ahead.
Thanks, Ludy. Good morning, everyone, for some, an earlier morning than others, and thanks for joining us to discuss the paltusotine PATHFNDR-2 phase III results. Joining me today are Dr. Scott Struthers, founder and CEO, and Dr. Alan Krasner, Chief Endocrinologist. And also joining for the Q&A section of the call will be Dr. Dana Pizzuti, Chief Medical and Development Officer, Marc Wilson, Chief Financial Officer, and Jim Hassard, Chief Commercial Officer. Before we begin, I'll point out there is a slide deck for today's presentation, which is in the Events and Presentation section of the Investors page on the Crinetics website. In addition, a news release was issued this morning and is also available on the corporate website.
As the usual reminder, we will be making forward-looking statements, and I'd encourage you to learn more about the risks and uncertainties associated with these statements as disclosed in our SEC filings. Such forward-looking statements are not a guarantee of 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. 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 Crinetics SEC filings, including its annual report on Form 10-K. I'd 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, March 19, 2024.
Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. I will now hand the call over to Scott. Go ahead, Scott.
Thank you, Corey. Thank you all for joining us today as we discuss yet another positive phase III study for paltusotine. We're pleased to report paltusotine met the primary and all four predefined secondary endpoints in our second phase III study in people living with acromegaly, PATHFNDR-2 . In the primary endpoint, 56% of the participants receiving paltusotine achieved IGF levels at or below 1.0 times the upper limit of normal, compared to just 5% on placebo. This was highly statistically significant. It also demonstrated clear superiority to placebo on the secondary endpoints of decreasing IGF levels, achieving IGF levels below 1.3 times the upper limit of normal, decreasing total acromegaly symptom diary scores, and achieving growth hormone levels less than 1 nanogram per mL. In addition, paltusotine continued to be generally well-tolerated.
No serious drug-related adverse events or new safety signals were observed, and no pituitary tumor in patients treated with paltusotine showed evidence of growth on imaging. We hope the success of the PATHFNDR-1 last fall, and now Pathfinder Two today, clearly demonstrates the level of scientific rigor and patient focus that we put into all of our studies. Our core value of rigor is central to our long-term vision of Crinetics becoming the premier, fully integrated endocrine company that can sustainably innovate pioneering therapies across many different endocrine diseases. With today's results, the phase III program for acromegaly is complete. Highly experienced Crinetics teams are working hard on all aspects of the NDA preparation. We plan to submit this as soon as possible in the second half of this year. From the very beginning, paltusotine was designed with the needs of the patient in mind.
The current standard of care for people living with either acromegaly or carcinoid syndrome are painful injections given intramuscularly or deep subcutaneously. Most often, these require administration by a healthcare professional. For many, the injections wear off too soon, and then the patients experience breakthrough symptoms. Instead of one monthly injection, many patients have to take more frequent injections, sometimes every two or three weeks. Imagine managing all this in addition to dealing with your disease and the rest of everyday life. Imagine what consistent symptom control with a daily oral tablet could mean to someone living with acromegaly. Our vision for paltusotine is to help people focus on living their life, not managing their treatment. I believe we're a major step closer to that vision today. With that, I'll hand it over to Dr. Alan Krasner, our Chief Endocrinologist.
He'll talk about the results from today's study in more detail and how they support this vision for paltusotine. Al?
Thank you, Scott. Acromegaly is caused by benign pituitary tumors that secrete excessive growth hormones. That growth hormone acts at the liver to stimulate excessive secretion of excessive insulin-like growth factor one or IGF-1. Excessive exposure to these hormones, particularly IGF-1, results in a wide range of complications, beginning with progressive physical changes, including changed facial features, enlarged hands, and soft tissue swelling. These patients also report significant and recurring symptoms of headache, joint pain, sweating, fatigue, weakness in the legs, and numbness or tingling. A major unsolved problem to this day is the frequent, frequent recurrence of these symptoms, even when receiving modern first-line therapies. Acromegaly is also associated with some important comorbidities, including hyperglycemia, hypertension, sleep apnea, lung function abnormalities, and cardiovascular disease, which can lead to heart failure.
Increased mortality, largely from cardiovascular complications, is seen in patients with acromegaly who are not adequately controlled on treatment. Even mildly elevated IGF-1 levels can be associated with excess symptom burden in this disease. The treatment of acromegaly usually begins with surgery to remove as much of the pituitary tumor causing the disease as possible. Approximately half of these surgeries result in cure. Cure is generally defined as IGF-1 normalization three months or longer after the surgery. Those patients who are not cured have residual tumor tissue left after surgery, and as a result, have elevated IGF-1 postoperatively. Those who are not surgically cured, together with those who are not able to have surgery, are candidates for long-term medical therapy. Currently, first-line medical therapy is one of the injected SRLs, which suppress growth hormone secretion from the residual tumor tissue and thereby lower IGF-1.
As a class, literature shows that SRLs lower elevated IGF-1 values approximately 90% of the time. The very high rate of disease improvement and the established long-term safety record with SRLs account for these agents being used as first-line medical therapy. It is important to note, however, that because these patients can start with very elevated values, only the minority get to the normal range for IGF-1 with SRL therapy, especially using modern assays and reference ranges defining normal. As Scott discussed, these first-line injected treatments have room for improvement. The injections are painful and burdensome, and their ability to achieve stable control of breakthrough acromegaly symptoms has not been established. Many patients report these breakthrough symptoms in the third or fourth week after the last monthly injection.
Recent published research has also documented variations in IGF-1 control that can occur as the effects of the previous injection wears off. We are now over 30 years since the advent of SRL therapy for acromegaly, and achieving consistent disease control without undue patient discomfort and hassle is still not a solved problem. Our goal for paltusotine is to provide a simple, once-daily oral treatment for patients with acromegaly, which could someday help the patient not only with the burdens of their disease, but also with the burdens of their treatment. Slide six shows the design of the PATHFNDR-2 Phase III study. Last September, we reported the top-line results of PATHFNDR-1 . PATHFNDR-1 demonstrated the ability of oral paltusotine to maintain control after patients with normal IGF-1 levels on injections switched to once-daily paltusotine.
PATHFNDR-2 was designed to evaluate the ability of paltusotine to lower elevated IGF-1 levels in uncontrolled patients who are not currently on medication. In the real world, there can be a variety of settings in which patients who need medication are not on therapy, and the enrolled patient population in this study was designed to reflect that. Based on the results of previous studies that have evaluated such patients, PATHFNDR-2 includes two pre-specified strata of participants. Stratum 1 comprises participants who are naive to medical treatment or who have had no medical therapy within four months of screening. Stratum 2 includes participants who were controlled on prior injected SRLs but agreed to wash out during a three- to four-month screening period prior to enrolling. The study enrolled 111 total participants with acromegaly, 82 in Stratum 1 and 29 in Stratum 2.
Participants were randomized 1:1 to receive either a placebo or an initial dose of 20 mg of paltusotine. Dose titration to 40 mg occurred for all subjects at week 2. If IGF-1 was greater than 0.9 times the upper limit of normal on 40 mg, participants were titrated to 60 mg. Down titration to as low as 20 mg per day was also allowed based on study drug toleration. From week 12 through the end of the randomized controlled phase of this study at week 24, participants remained on a fixed dose. 54 participants were randomized to the paltusotine arm and 57 to the placebo arm. Consistent with FDA guidance, the primary endpoint was the proportion of participants who achieved IGF-1 levels of less than or equal to 1 times the upper limit of normal on paltusotine compared to placebo.
Endpoint IGF-1 levels were based on the mean of IGF-1 measurements from weeks 22 and 24. During the course of the study, IGF-1 levels were measured at least monthly, and if two consecutive measurements were greater than or equal to 1.5 times the upper limit of normal, and there was worsening of symptoms, as determined by the investigator, participants received rescue injections of either octreotide or lanreotide and were considered non-responders. We pre-specified additional metrics that are clinically relevant as secondary endpoints. The change from baseline in IGF-1, achieving IGF-1 levels of less than 1.3 times the upper limit of normal.... The change in acromegaly symptom score, scores using a fit-for-purpose acromegaly symptoms diary, and achieving growth hormone levels of less than 1 ng/mL. Slide seven shows participant disposition.
The distribution of patients in each stratum in the paltusotine and placebo groups was balanced. We were pleased that 95% of enrolled participants completed the randomized controlled portion of the study. Out of the enrolled population, a total of 5 discontinued the study, 2 from the paltusotine group and 3 from placebo. 97% of those who completed the study chose to enroll in the open-label extension. This is very similar to our previous high rate of enrollment in the PATHFNDR-1 OLE. Throughout our acromegaly clinical trials, we have had extremely low study discontinuation rates and high open-label extension rollover rates, and I think that says a lot of good things even before we get to the data. Participant characteristics for the two treatment arms are summarized in slide eight. Overall, age, geographic distribution, and BMI were well-balanced between the two treatment arms.
Slide nine shows the disease characteristics of the population studied. As you can see, mean baseline IGF-1 was roughly two times the upper limit of normal and similar between groups. The difference in baseline mean growth hormone in the placebo group was driven by one outlier. As you can see, the median growth hormone was balanced between groups. The bottom part of the slide shows the pre-trial medications used for the Stratum 2 patients who were treated at screening but washed out prior to enrollment. As Scott noted at the top of the call, PATHFNDR-2 met the primary and all secondary endpoints. The primary endpoint is shown on Slide 10. 56%, or 30 out of 54 participants receiving paltusotine, achieved IGF-1 levels of less than or equal to one times the upper limit of normal at the end of the randomized controlled phase.
This is compared to 5%, or 3 out of 57 participants on placebo. This difference is highly statistically significant, with a p-value of less than 0.0001. As I mentioned in my introduction, as a class, only the minority of patients on injected SRLs actually normalize IGF-1 from elevated baseline levels, and the rate seen in this study meets or exceeds what would be expected from standard injections in this population of patients. The study was powered only to detect a statistically significant difference in the overall blended population, including Stratum 1 and 2. However, if we look at IGF-1 levels by stratum on slide 11, you can see that each population also achieved highly statistically significant IGF-1 normalization rates compared to placebo.
In the untreated group on the left, 43% achieved IGF-1 levels less than or equal to 1 times the upper limit of normal, compared to 2%, which is only 1 participant in the placebo group. On the right, 93% of participants who washed out of prior SRL achieved this threshold of IGF-1, compared to only 13% in the placebo group. The rates of IGF-1 normalization are important, but do not give the full picture of benefit in this population. Slide 12 shows baseline and ending IGF-1 levels on an individual participant basis. As you see on the left, 93% of participants in the paltusotine group experienced a decrease in IGF-1 at the end of the study. In contrast, participants in the placebo group showed little to no change in IGF-1 levels at the end of the study, as shown on the graph on the right.
All IGF-1 reduction in acromegaly is important because it's associated with lower risk of mortality and comorbidities and with lowering symptom burden of the disease. Also note, there were 13 participants in the placebo group who needed rescue, as shown in red, compared to only two in the paltusotine group. Because the reduction in IGF-1 is an important complement to the interpretation of results of rates of IGF-1 normalization, change from baseline in IGF-1 was identified as a key secondary endpoint. In this analysis, seen on slide 13, the paltusotine group as a whole demonstrated a decrease in average IGF-1 levels, while those on placebo rose, with a p-value for the difference of less than 0.0001. The decrease in IGF-1 levels shown on the previous slide occurred quite rapidly and were sustained throughout the entirety of the 24-week period.
As you can see in slide 14, IGF-1 reductions from baseline are already observed by 2 weeks and reach full effect between 4-8 weeks. I think it is important to take a moment here to appreciate the potential clinical significance of the rate of onset of the paltusotine effect. As discussed, monthly injections of depot SRLs are now the first-line medical therapy in this disease, and because of their prolonged half-lives, labeling instructions for these products recommend waiting 3 months or after 3 injections before evaluating the response to a particular dose. Octreotide LAR can be used at 4 different dose strengths, and there are 3 for lanreotide depot. As you can imagine, it might, in some cases, take upwards of a year for the patient to be titrated to a stable dose with the available products...
Over that period of time, I worry that it takes too long for these patients to get to a state of consistent control of their disease, or that some patients might even get lost to follow-up. I would imagine a product which can get to a stable degree of control reliably and more rapidly would be a welcome addition to the endocrinologist's toolkit. Slide 15 shows our next pre-specified secondary endpoint, which is the proportion of participants who achieved IGF-1 levels of less than 1.3 times the upper limit of normal. Although many patients with acromegaly still experience symptoms with IGF-1 levels between 1 and 1.3 times the upper limit of normal, this endpoint can provide a means of historical comparison to previous trials in which this threshold was used to measure efficacy.
As you can see in our study, 67% of the overall paltusotine group achieved IGF-1 levels of less than 1.3 times the upper limit of normal, compared to 14% in the placebo group. This difference is highly statistically significant, with a p-value of less than 0.0001. Each stratum, shown on the right, also achieves statistical significance, with 55% of untreated and 100% of washout participants achieving IGF-1 levels less than 1.3 times the upper limit of normal. This is compared to 10% and 27% of the placebo group, respectively. Objective biomarker measurements are important in the assessment of efficacy, but to get the full picture of paltusotine's impact, one must also carefully and systematically measure symptom control. It is not a given that lowering biomarkers automatically corrects the control of symptoms of the disease.
In fact, when you talk to patients on the injections, many express disappointment in the consistency of control of their acromegaly symptoms, despite the fact that their IGF-1 may be normal or close to normal. This is another important unsolved problem in the field and an area of much-needed research, in part because there is not much information on the impact of injected SRLs on symptoms, as reported by the patients themselves. For these reasons, symptom control, measured using the Acromegaly Symptom Diary, or ASD score, was identified as a pre-specified secondary endpoint in PATHFNDR-2 , as it was in PATHFNDR-1 . The ASD was developed in accordance with regulatory patient-reported outcome guidance and evaluated symptoms of headache, joint pain, sweating, fatigue, leg weakness, swelling and numbness, or toe pain.
Participants assigned each symptom a score based on a 0 to 10-point scale, ranging from no symptoms to the worst symptom intensity, with a total maximum score of 70. Participants reported their symptom severity on an electronic device on a daily basis prior to and during study treatment. Remember, the treatment period in this study was six months, and it was nine months in PATHFNDR-1 . You may think that filling out a diary every day for six to nine months in a row is a lot to ask, but ASDs were completed by our clinical trial participants on 80% of the requested days in both studies. I think this tells you how important this topic is for the patients who have to live with acromegaly and its current treatment options. Now let's look at the top-line ASD data from PATHFNDR-2 .
Slide 17 shows a significant difference between treatment groups of 5.42 points favoring paltusotine in the total ASD score. The p-value for the difference was 0.004. It is instructive to look at these data by strata in this study. In the top right, Stratum 1 participants who were not on treatment prior to the trial showed a 4.19-point decrease in total symptoms, while the placebo group remained stable. This pattern is expected in a patient population who may most sense symptom relief on treatment in the paltusotine group. The placebo-treated patients are already symptomatic at baseline, and this does not change on placebo. In contrast, on the bottom right, participants in Stratum 2, who were treated and controlled then washed out for 3-4 months during the screening period, are shown on the right.
I should point out that this washout of pretrial long-acting injections was too short to be complete prior to randomization. The study was designed this way to prevent the participants from becoming too sick from their underlying acromegaly during the screening period prior to access to rescue. However, those randomized to placebo had their washout extended for the six-month treatment period of the study, during which time 13 subjects were rescued. As a result of the full washout in the placebo patient group, one can see the symptom scores continued to worsen from a relatively controlled baseline. This is evident in the 5.78-point increase in the ASD score in the placebo group. Those who were randomized to paltusotine showed stability of symptom control. Overall, Stratum 2 also showed a significant difference between the treatment groups.
These are the basic top-line ASD results from this study, but I am excited about the potential value of the unique and rich database from both PATHFNDR-1 and PATHFNDR-2 for future research. I hope it will enable better understanding of the links between mode of treatment, biochemical control, and symptom control. As discussed, more research has been needed for some time here, and we hope to contribute to this field with future useful scientific communications. The ultimate goal, of course, is to help patients living with acromegaly solve an unsolved problem, that is, achieving stable and consistent control of the symptoms that, with current therapies, can continue to linger on or flare between each monthly injection as frequent and unwelcome reminders of a suboptimally controlled disease. The study was not powered to show statistical significance of individual symptoms on the Acromegaly Symptom Diary.
However, if we look at individual components of the ASD on slide 18, paltusotine treatment resulted in improvements across all symptoms evaluated, and some of them even hit statistical significance. This was also seen in PATHFNDR-1 , and indicates that the total ASD score improvements on paltusotine are not driven by a single dominant symptom or two, but a totality of symptom burden in patients with acromegaly. Our fourth pre-specified secondary endpoint, shown on slide 19, was the proportion of participants achieving a growth hormone level of less than one nanogram per milliliter. Growth hormone levels are a supportive pharmacodynamic marker of biochemical control of the disease. In the paltusotine group, 57% achieved growth hormone less than one nanogram per milliliter, compared to 18% in the placebo group. This difference was highly statistically significant, with a P value of less than 0.0001.
In slide 20, we see a safety summary. Paltusotine was generally well tolerated, and most adverse events reported were mild or moderate. There were no serious adverse events on paltusotine, one on placebo. We discussed earlier the greater number of rescues on placebo compared to paltusotine. The most commonly observed treatment-emergent adverse events are shown on slide 21. These include symptoms commonly associated with acromegaly, such as headache, arthralgia, and paresthesia, most of which were verified by investigators on an individual basis to be related to the patient's underlying acromegaly. GI events such as diarrhea, abdominal pain, and nausea are known side effects of all SRLs, and as expected in this study, they tended to occur early in treatment, were transient in duration, and none resulted in study discontinuation.
Overall, taking into account the totality of safety labs as well as AE reports, there were no new safety signals observed in this study. Slide 22 shows a full summary of safety findings. Paltusotine was generally well tolerated, with no serious adverse events. The most frequently occurring adverse events are commonly associated with either acromegaly or SRL therapy. Pituitary tumor size was monitored by an MRI during this study, and paltusotine treatment was associated with stable or reduced tumor size. Overall, the safety profile observed in this study is comparable to the larger paltusotine clinical program safety database to date. Our open label extension studies of paltusotine remain ongoing. We currently have approximately 225 participants enrolled across both carcinoid syndrome and acromegaly programs. Some of these patients have now been treated with paltusotine for more than four years.
Before I hand the call back to Scott, I would like to express my personal, sincere gratitude to the many people who made it possible to report top-line results now from our second phase III trial. This would not have been possible were it not for the many dedicated investigative research personnel who actively conducted these studies at nearly 100 sites around the world. I'd also like to thank my many gifted colleagues at Crinetics and at partner organizations, whose commitment to excellence shows in the quality of the data we have seen. Most importantly, the people living with acromegaly around the world who volunteered for these clinical trials, many of whom continue to participate in extension studies, are incredibly inspiring.
These individuals probably could have found other things to do besides spend a good part of a year or more of their lives volunteering for all the work and time needed for clinical research. However, they chose to participate and did so with extraordinary follow-through and dedication. I can only conclude that they feel a deep desire to expand the body of knowledge needed in order to make progress with this difficult disease, and that they are willing to put themselves out there to make it happen. That is why they inspire me. I'll now hand it over to Scott to review the next steps for the paltusotine program.
Thank you, Alan. Today, as you've seen, paltusotine yet again continues to deliver. First, exceeding expectations last fall with the PATHFNDR-1 study results, then exceeding expectations in carcinoid syndrome just last week. Now exceeding expectations with today's PATHFNDR-2 results. As you can imagine, all of us at Crinetics are excited about the data presented today, with its rigorous measurement of biochemical and symptom control. We are eager to share these results with health authorities and our colleagues at upcoming scientific meetings. Together with the PATHFNDR-1 results we reported in September, we now have data from two phase III studies to support an NDA filing for the use of paltusotine for the treatment and maintenance of acromegaly. This includes both untreated patients from today's dataset and the maintenance of control when switching from injected SRL depots in the PATHFNDR-1 study results.
The team is working hard on the preparation and submission of the NDA, which will be submitted as soon as possible. Across the company, we are also working diligently on all aspects of launch preparation. This ranges from detailed scrutiny of the patient and prescriber experience, to best anticipate future needs, to conversations with payers and fortifying the company's infrastructure for a successful launch. Today, we are another step closer to delivering the first once daily oral treatment for people living with acromegaly. Our vision for paltusotine is to help people focus on living their life, not managing their treatment. I believe we're a major step closer to that vision today. Today also marks another important step in our long-range strategy for Crinetics, as we build the premier, fully integrated, endocrine-focused pharmaceutical company. In the coming years, this strategy should lead to tremendous growth and value creation.
In the second half of 2024, we will submit our first NDA and continue advancing additional indications and drug candidates. 2025 will be one of the most important inflection points in the company's history as we reach an anticipated acromegaly PDUFA date, leading to a potential FDA approval and launch of our first drug. Going into the second half of this decade, we intend to gain approval and launch of paltusotine for carcinoid syndrome. As sales of paltusotine grow, we plan to be self-sustaining. We'll continue to invest in our discovery and development efforts. We anticipate multiple launches and a continuous stream of clinical milestones throughout the rest of this decade and beyond. Endocrinology has the potential to impact almost all aspects of human health. There are a lot of patients who we can help. Crinetics is just getting started.
I'd like to close by once again thanking all of the patients who participated in this study and took time out of their lives to help all the other acromegaly patients. I'd also like to thank all the investigators, site staff, and Crinetics team around the globe who worked so hard to make this study a success. Thank you all for being here today. We'll now be happy to take your questions.
Thank you. And ladies and gentlemen, we will now begin the question-and-answer session. Should you have a question, please press the star followed by the one on your telephone keypad. Should you wish to decline from the polling process, please press the star followed by the two. And if you're using a speakerphone, please leave the handset before pressing any keys. And just a reminder, we ask everyone to please limit yourself from asking one question. One moment, please, for your first question. Your first question comes from the line of Gavin Clark-Gartner from Evercore ISI. Please, please go ahead.
Hey, good morning, and congrats on the very strong data. Just one question. What's your base case assumption for how much lower the U.S. net pricing for lanreotide may fall, given the price reductions we've seen over the last couple of years? And just wondering if that may impact paltusotine net pricing as you're thinking about launch in both of these indications. Thank you.
Hey, Gavin, I'm glad we left you speechless on questions about the data itself. And, you know, it's a little early to comment on pricing, but, I don't think that we should be comparing paltusotine to the injectable depots. If you look at today's data, it shows very clearly a consistent, fast, durable control of disease with measurement of symptoms and biochemical control, and there's nothing like that in any of the labels of any other products. Doesn't mean we'll get it in the label, but we certainly have the data to support it. So we'll see what happens with the depots as they, you know, mature throughout their lifecycle, but, that's not something I'm particularly worried about today.
Thank you. Your next question comes from the line of Yasmeen Rahimi from Piper Sandler. Your line is open.
Yeah. Congrats, team, on outstanding data release. I guess, team, when you step back, you articulated really thoughtfully all the various differentiations of paltusotine for the treatment of acromegaly, and you have spent a lot of time hearing patient voices and speaking with physicians. Could you maybe now put into perspective, like, what... Like, being oral matters, symptom quality improvement matters, rapid onset matters, but, like, which of these things are gonna, like, really be the driver of a strong uptake of paltusotine, and how will you ensure that those aspects are captured thoughtfully into the label?
Well, I guess, Yas, it's, you know, it's all of them, and I'm trying to think-
Yeah
of the best way to explain that. It's like-
Yeah.
What's the most important thing of your cell phone? It's not just voice quality, it's you've got GPS, you've got pictures of your kids, you've got texting to your grandkids, in my case. Look, I think all these things add up to taking away a very burdensome set of treatments, doing very well on controlling the disease itself and the symptoms of the disease, but taking the treatment out of your daily life, other than taking a tablet in the morning along with your vitamin or antacid or whatever else, you know, you need to take. So I think this simplicity matters more than you might, you know, any of us might guess.
Yeah.
Maybe, Alan, you might wanna add in on that.
... No, you know, I, I agree. I also think of it not only from the patient's perspective, that's the most important, of course, but also, you know, from the physician's perspective, it has to be sort of, new products have to be easy to use, easy to prescribe, easy to access. People are not looking for, more clinic time to spend with patients where they have to get, just administrative kinds of things done. So I just, as Scott said, it's really that simplicity, that ease of use. I think that's what looks very elegant to me.
Just taking back from Alan's example of the physician trying to find the right dose of one of the monthly depots and four different dose levels, and you're supposed to wait three months to evaluate each dose level. Here, you know, we haven't figured out all the final dose response analysis, but it's either 40 or 60 milligrams, and you'll know in a few weeks.
Mm-hmm.
Seems pretty fundamentally different to me.
Yep. Thank you so much. Congrats again on the great data.
Thanks.
Thank you. And your next question comes from the line of Jessica Fye from JP Morgan. Your line is open.
Hey, guys. Good morning. Congrats on the results. Question on the tolerability side, specifically the GI tolerability, whether it's diarrhea, nausea, abdominal pain. Can you just talk about the degree to which those side effects wane over time, and if so, how long that usually takes?
Yeah, it does wane over time. These are typical side effects seen with any SRL. The timeframe we're talking about generally is, I would say, days to weeks, particularly in patients who are not currently on drug. These patients are more sensitive to these kinds of GI side effects. It usually occurs when the drugs are initiated, typically resolves without the need to discontinue the drug within a few weeks. That's pretty much what we saw in this trial.
Thank you.
Your next question comes from the line of Jeffrey Hung from Morgan Stanley. Your line is open.
Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our questions, and congratulations on the results. With 67% of patients achieving less than 1.3x and 56% achieving less than 1x ULN, how are you thinking about paltusotine and therapeutic potential for those patients who are benefiting, but not, like, adequately controlled at that threshold? And is there anything to suggest that they could benefit from, you know, going past 24 weeks and into the OLE? Thank you.
Yeah, I mean, it's a, it's a great thing to remember about SRLs in general. The reason they're the first-line medical therapy is because most patients benefit, as defined by a reduction in their IGF-1 value from a very high baseline. And that was also the case with paltusotine, as we saw. That benefit is translated into lower risk of mortality, lower comorbidities and improvement in their symptoms. I really think paltusotine, based on these data, are well positioned to compete as a first-line agent against the injections, with the obvious advantages over the injections.
Thank you. That's very helpful.
Thank you. And your next question comes from the line of Cory Jubinville from LifeSci Capital. Your line is open.
Thanks for taking our questions, and congrats again on these really exciting data. Quick one from us. If you look historically, in addition to IGF-1 normalization, a growth hormone threshold below 2.5 ng/mL was previously the standard. You've chosen to kind of set this bar higher, targeting a 1 ng/mL threshold. It's clearly worked out, but can you walk us through the rationale for choosing a more stringent endpoint? Especially in the context when a lot of these previous programs have struggled to hit that target. I believe injectables only achieve this threshold at a rate of in the 10%-20% range versus 57% of what we saw here with paltusotine.
And, as a quick related follow-up to that, I know there's high correlation between IGF-1 and growth hormone levels, but do you have data that show what percentage of patients achieve both IGF-1 normalization and growth hormone below 1 nanogram per ml? Thanks.
Thanks for that question. We chose, you're right, a more stringent target because it is what is clinically relevant in the modern age. So the Endocrine Society currently recommends that physicians target a random growth hormone level of less than 1 nanogram per ml in clinical practice. So that is important for physicians to understand that paltusotine is successful at achieving that target. You mentioned the old target that is in many of the older studies, and during my discussion, I mentioned sometimes it's helpful to have historical benchmarks. You're right, they used to use growth hormone less than 2.5 quite a bit, but the—as far as I can tell, that is a fairly arbitrary threshold.
There is no known clinical relevance to that number or no known, you know, that is not a known threshold for translating into clinical benefit versus any other growth hormone level. But we do know growth hormone less than one is an official, you know, clinical practice target. That's why we chose it. You know, you also asked about the combination of IGF-1 and growth hormone control. That is certainly something, the kind of thing we would potentially show at scientific congresses in the future. It's important to remember, though, that the registrational benchmark is simply IGF-1 control. And again, the FDA recommended primary endpoint is the percentage of patients who achieve a normal IGF-1, full stop, without growth hormone.
Cory , great, great job bringing up the nuances of assays. You know, you get a bunch of endocrinologists in a room, and they end up talking about assays. It's important to remember also that in our IGF-1 assay, we've used the top, gold standard assay that has the best, most extensive reference ranges, and frankly, is a bit of a higher bar than most of the previous assays you might look at historically. So another caution as you begin to interpret this versus prior results, but, you know, it's part of this rigor I talk about for the company.
Fantastic. Thanks for taking the questions, and congrats again.
Thanks, Cory .
Your next question comes from the line of Brian Skorney from Baird. Your line is open.
Hey, good morning, everyone. Great data. Congrats on that. I guess looking forward, as we think about sort of the commercial launch here, you know, we hear Mycapssa gets a lot of payer pushback due to the switch dynamic on their label, among other product-specific issues. But I was hoping you could maybe provide some perspective on how you kind of see the commercial opportunity expand beyond that sort of switch label in the major markets, when, you know, you'll obviously look like you'll have included here the non-medically treated patients, but would be candidates for treatment, seeking treatment. And also, what sort of commercial opportunity that opens up relative to the potential SRL switches?
Well, maybe I'll start and then let Jim finish. But, remember, we designed this program to satisfy the recent guidance from the FDA about developing drugs for the treatment and the maintenance of treatment of acromegaly. And PATHFNDR-2 and PATHFNDR-1 , respectively, were designed to meet those guidelines so that we should be able to argue for a broad use in all acromegaly patients. And, you know, apart from that, I'll let Jim maybe comment further on how we anticipate this to be used in a commercial setting.
Yeah, thanks, Brian. You know, really, the switch opportunity from the numbers that we see from claims data and we've communicated to the marketplace, about 10,000 patients are prevalently treated with pharmacotherapy, so that's the switch opportunity. And every year, there are somewhere between 300 and 500 new incident patients. And as Scott mentioned, we expect to be able to access and make paltusotine available to all of all those patients, whether prevalent or incident.
Thank you. Your next question comes from the line of Douglas Tsao from H.C. Wainwright. Your line is open.
Hi, good morning, and congrats for a real landmark achievement with this data. Just looking at, you know, the dosing, obviously, most patients did incredibly well with the 40 and 60, but just given... Do you think there could be some incremental value for some patients to perhaps have access to the 80 milligram, and which you're obviously testing in carcinoid syndrome? Thank you very much.
Thanks, Doug. I think that, you know, we've designed this program to be with 40 and 60, to be high and higher. You know, we still have some work to do to understand whether dose increases to, from 40 to 60 made a difference. And perhaps there's the occasional patients, maybe especially larger with some other, unusual characteristic, that might benefit from a higher dose. But I think we've done such a good job of covering the vast majority of patients with this dose range, that as part of the development program, I think we've got it covered. Is there anything you wanted to add to that, Al?
No, I agree. We, of course, are underway with formal dose and exposure response modeling, and that modeling, of course, will be very important as we decide on, you know, doses to put in the NDA for approval. But I am quite confident, based on what we've seen with these data, that we're in the right range.
Okay, great. Thank you so much.
Your next question comes from the line of Catherine Novack from Jones Research. Your line is open.
Hi, morning, guys. Congrats on the fantastic data again. I wanted to ask about the compliance rate on this study, and any feedback from providers on, you know, the ease of use for paltusotine versus Mycapssa, which, you know, we have, has had, some current concerns about ease of dosing, which twice daily, requiring fasting due to food effect, et cetera. You know, if you could just discuss that.
Thanks, Catherine, and maybe comment on the participation rates.
Yeah. No, thank you for the question, Catherine. Because I mentioned during my discussion how engaged the patients were with filling out their symptom diaries. But another way to measure compliance in a clinical trial is the routine pill counts that all the sites perform, and the compliance rates we saw here and in PATHFNDR-1 were over 95%. These patients were very, very, as I said, dedicated and committed to this study, and I'm quite sure that, you know, the fact that paltusotine requires only once a day administration was very helpful as well.
I think also, Catherine, that, you know, the so few dropouts and such high participation in the open label extension also was a tribute to the dedication of these patients. And, you know, remember, these trials take a lot of work. You know, you need to go in and get various measurements and blood draws and visits, and it's an impressive group of patients that we've been privileged to have in these studies.
Great, that's very helpful. Thanks so much, and congrats again.
Thank you.
Your next question comes from the line of Jon Wolleben from JMP. Your line is open.
Hey, just wanna share my congrats. Question on the tumor data you mentioned towards the end. Can you talk about how that was monitored, and any details about, you know, the reduction you saw, any changes in the placebo arm, and, you know, how important that is from a product profile?
Right. Thanks for that question, too, Jon. So one of the reasons SRLs are our first-line treatment for this disease is because not only do they control the disease biochemically, but they're also known to be associated with stabilizing the residual pituitary tumor that's left behind in the uncured patients. And also, octreotide and lanreotide can also be associated with some shrinkages in residual pituitary tumor. That's exactly what we saw with paltusotine. And we look forward to presenting that data in more detail at scientific congresses. In the placebo arm, generally, in this kind of short timeframe of a six-month study, we also largely saw stability. There were some increases on placebo, whereas on paltusotine, we saw no significant increases in tumor size.
So basically, overall, my impression as of now is that we're seeing exactly what one would expect with an effective SRL with regard to tumor control.
Got it. Thanks, Alan. Congrats, congrats again.
Thank you. Your next question comes from the line of Joseph Schwartz from Leerink Partners. Your line is open.
Thank you, and congratulations on yet another successful study. It's impressive how you've been able to enroll patients in so many centers around the world. So I'm wondering if you can talk about what you've learned about patients' willingness to participate as you executed PATHFNDR-1 and 2 , that you can use as you go to market, or perhaps that we should keep in mind as we model the commercial launch.
Yeah, we have just had a very positive experience with our colleagues around the world who helped to recruit the patients and manage them during our clinical trials and monitor them carefully for safety during our trials. And we feel like we have a very established network now of neuroendocrinology colleagues in many countries around the world that we intend to maintain long-term relationships with as we proceed in our portfolio of drug development, not just for paltusotine. But as you can imagine, a lot of the doctors, for example, who treat acromegaly, also treat Cushing's disease and other endocrine diseases that we are interested in evaluating new therapeutic options for in the future.
So I think it's a matter of slowly over time since our phase II program, growing these relationships, establishing them, and solidifying those relationships with a very positive clinical trial experience.
I think, you know, that highlights also, Joe, that it's part of us being dedicated to the field of endocrinology, Alan and myself and many others, our whole careers. And so we work with these people, you know, as colleagues in the societies, as investigators in our trials, as colleagues at various scientific meetings. But even underneath that, there's also operational aspects, things as simple as making sure you streamline the contracting process with an institution. You get to know the study coordinators. You get to know the local logistics around operating in these different countries. And so we try and learn from each trial to the next about how to do a little better in each country, each site, and which sites are able to recruit, which might have some challenges.
So I think it's, it's been very helpful in allowing us to continue to grow, and frankly, can't barely talk to any of the acromegaly investigators without them wanting to know what's next in Cushing's or CAH. So very excited to talk about those data, but next quarter, I think we've had enough data releases for this quarter.
Two days, guys.
Thanks, Joe.
Your next question comes from the line of David Lebowitz from Citi. Your line is open.
Thank you very much for taking my questions. When you looked at the not medically treated data, how do we benchmark that versus the depots and what was achieved over there? Are the populations similar? And then on the washed out population, why would the results be so much better than the not medically treated population? Are they truly washed out, or is there something different about these patients at baseline?
Yeah. Thanks for the question. You know, this study was actually modeled after the lanreotide registrational trial, which enrolled a very similar group of not medically treated patients. And yes, it is expected and we expected based on the results of that study, that the, quote, "washed out patients" would have a higher IGF-I normalization rates, that is, the Stratum 2 would have a higher normalization rate than Stratum 1. But we have to recall a couple things. You know, I actually don't think the groups of patients are really that much different. They're really both off medication with high IGF-I at the beginning.
The real difference is that the washed out patients, first of all, as I mentioned during my discussion, they're not, we don't allow them to, quote, "fully wash out" because it wouldn't be safe or well-tolerated. They do, on placebo, sort of further wash out during the additional six months where they're not, in theory, getting treatment. However, even that, you know, it's not the same as somebody who's been off drug for years or has never been on a drug in their life. So I suspect, you and I think you, you mentioned this, that if we just wait long enough, eventually their IGF-I levels would climb, off treatment, you know, to the kinds of higher IGF-I levels you would see at baseline in stratum one.
And again, if I had to pick one thing that predicts response, it's how high their IGF-I is when they come in. So, yeah, this is, we powered this study according to a precedent that predictive. The predictive power or the precedent we used was very high and accurately predicted what we saw, and that was all taken into account in our statistical planning for the study.
Well, it predicted, you know, trends among different groups, but, in fact, this response rate was above our best-case scenario, so we're very pleased to see that.
Thank you for taking my question.
Your next question comes from the line of Rohan Mathur from Oppenheimer. Your line is open.
Hi, this is Rohan speaking on behalf of Venu Garikipati. Congratulations on another set of strong data. I just wanted to ask about the NDA submission. Do you expect to see or include any additional data and submission package from the open label or otherwise? Thank you.
Let me ask Dana, our Chief Medical and Development Officer, to answer that one.
Yeah, sure. Well, as you know, we have these two, you know, phase III trials that will be the real basis for the establishment of the sort of indication for acromegaly. In addition to that, we have a lot of supplementary data that we will submit from the phase II. We're still gonna be working on the sort of dose response analyses and putting the finishing touches on the the symptoms questionnaire. There's also a requirement to do a 120-day safety update, but that wouldn't necessarily add anything to the efficacy side of things.
I think that, as we continue to collect information in the open label extension, we can decide whether or not we wanna eventually supplement the, application and, try to, introduce some of those additional data into the label. But for the initial filing, it will be mainly the phase III trials and the, phase II trials that led up to that.
Thank you, and congrats again.
Thank you. Ladies and gentlemen, this concludes the Q&A portion of today's call. I will now turn the call back to Scott Struthers for closing comments.
Thank you, everybody, for all your support and good questions today. Look forward to talking to you in the not too distant future.
Thank you, presenters, and thank you everyone for joining. That concludes our conference call this morning. I hope all of you enjoy the rest of your day. You may now disconnect.