Crinetics Pharmaceuticals, Inc. (CRNX) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Crinetics Pharmaceuticals KOL Event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Crinetics website following the conclusion of the event. I'd now like to turn the call over to Scott Struthers, Founder and Chief Executive Officer of Crinetics Pharmaceuticals. Please go ahead, Scott.

Thank you, and welcome, everybody. Thank you for joining us today for our webinar on acromegaly. I'd like, as a reminder, we will be making forward-looking statements. I invite you to learn more about the risks and uncertainties associated with these as disclosed in our SEC filings. So for today's agenda, I'm very pleased to welcome Beverly Biller and Karen Liebert from Mass General Hospital to today's call. As many of you know, Mass General is one of the premier pituitary centers of excellence in the world. Beverly and Karen are key leaders there and their site has participated in the paltusotine clinical development program, and we hope in many of our future pituitary directed studies. Dr. Biller is a Professor of Medicine at Harvard Medical School and a Faculty Member in the Neuroendocrine Unit at Mass General. She directs the clinical fellowship in adult -- program in Adult Endocrinology and Metabolism at Mass General and research related to the pathogenesis, diagnosis and treatment of pituitary disorders. She has co-authored clinical practice guidelines on pituitary topics for the Endocrine Society, the American Association of Clinical Endocrinologists and the European Society of Endocrinology. Dr. Biller is a key leader in the global pituitary community and passionate about her patients with acromegaly, nonfunctioning pituitary adenomas and especially Cushing's disease. So we'll talk to her more about Cushing's in a future call. And I think we should all remember that endocrine nurses are on the front lines of patient care and payer interactions. They're the study coordinators, the people who actually make things happen at pituitary centers. And we're pleased to have Karen Liebert here, who is a research nurse and study coordinator of the Neuroendocrine Unit at Mass General. So she has extensive experience in caring for patients and medical issues related to the pituitary gland as well as recruiting and coordinating clinical trial participants, trial procedures and monitoring the overall health of study participants. She is a member of the Endocrine Nursing Society and has co-authored numerous peer-reviewed publications. And I think nurses from all around call Karen for advice and guidance. So after that brief introduction, I'll hand it over to them for an overview of acromegaly and potential limitations of current treatments. And then Alan Krasner, our Chief Medical Officer, will provide an overview of our PATHFNDR program, and then we'll close with Q&A. You can submit questions any time during the presentation, and we'll follow up with them in the back end. So just briefly from an introduction, if we look at Crinetics today, our goal is to build the world's leading fully integrated endocrine franchise that drives product development from discovery to commercialization around the world. I think we're unique in our commitment to the field of endocrinology. Our drug discovery platform targeting GPCRs is complemented by a global clinical development capability that is advanced paltusotine in a comprehensive Phase III program in more than 18 countries and 100 sites around the world. We expect data readout from the first of our Phase III PATHFNDR trials in September. And these same sites and investigators around the world will help us in the development of the rest of our endocrine pipeline. Looking beyond paltusotine, our pipeline includes product candidates with well-established POC. And in addition, over the next few years, we plan to move candidates for more higher prevalence indications from our research engine into clinical development. Our long-term goal is to have global approvals for multiple products and indications, commercial capabilities, multiple programs in mid- to late-stage development and continuing our work in discovery and advancing the field of endocrinology. Ultimately, this work creates foundation for a sustainable company that we hope will innovate again and again for the benefit of the endocrine community. And I often get asked why endocrinology? But I think it's important to remember that it's unique in the hormone systems touch every cell in the body. I challenge anybody to think of a cell that is not influenced by an endocrine factor. And peptide of hormones are the most extensive and diverse class of endocrine factors and have historically been very difficult to target, in many ways, leaving plenty of room for innovation in the field of endocrinology. Since peptide hormones are well understood from a biology point of view and well conserved across species, we're able to design early experiments that lead to a higher probability of success in the clinic. And just a small sampling of some of the indications we're interested in and addressing are shown on the right as well as some of the future opportunities that we hope to get to soon. There's lots of room to grow in endocrinology. And I think that's illustrated by our pipeline. And as you can see, we've got programs deep in Phase III, starting Phase II as well as multiple programs in discovery. We're going to focus today on paltusotine. It's deep in Phase III. We announced that we've completed and that we'll be announcing data for that PATHFNDR-1 in September. And then PATHFNDR-2 has completed enrollment, and we should be announcing data for that in the first quarter of next year. We also anticipate readouts for paltusotine in carcinoid syndrome later this year. So with that, let me hand it over to Beverly and Karen. Beverly first. As I mentioned, they work together at the Neuroendocrine Unit at Mass General, attract numerous patient referrals from around the world and not only have unique extensive clinical experience but there are great educators, and we, like many others, have learned much from them. So they've also participated in the paltusotine clinical trials and investigators since the beginning of the program. So I hope today, they'll teach us not only about acromegaly but also what challenges these patients face in the real world, getting treatment and living with today's treatment. And with that, I'd like to welcome Beverly and Karen. And Beverly, would you like to kick off the discussion.

Yes. Thanks so much, Scott. I'm always delighted to talk about any kind of pituitary tumor, and I'm pleased today to talk about acromegaly, which represents a subtype of pituitary tumor in which cells are overproducing growth hormone. So all of the features are related to excess growth hormone and the subsequent downstream results. Before I start, I'm just going to say that I imagine that some of you are endocrinologists, like me or perhaps physicians in other specialties or PhD scientists. But I also recognize that some of you might be business experts without as much medical background. So I'm going to try to explain things in a way that everyone can understand. I'd like to start with this case. A 94 -- 45-year-old male was referred to us for diabetes that was found during admission for a bilateral carpal tunnel release. He was having preadmission testing and it turned out he has diabetes. He had a past medical history of high blood pressure for 5 years. And on review of systems, he had joint pains, fatigue, recent erectile dysfunction that he and his doctor ascribed to an increase in hypertension medicines and headaches, which the patient attributed to stress at work. His shoe size had increased from a size 10 to a size 12 EEE over 5 years. And when he came in for the carpal tunnel release, his wedding ring had to be cut off because its hands have gotten so much bigger. On exam, he had a deep gravely voice, a broad nose, prominent brow and jaw. He had spaces between his teeth. And he had a thick tongue, which you can actually see protruding a little bit. And he mentioned that people were starting to have trouble understanding what he was saying because his tongue was so large that he was kind of tripping over his words. He had large hands and feet, skin tags and enlarged thyroid gland. So this patient in his 40s is in the bell-shaped curve that you see here, showing all of the ages at which acromegaly can occur. And you can see that it really can occur at any age, although most commonly in the middle years. If acromegaly occurs in a child before their bone growth plates have finished growing or fused, we actually call it something else, we call it gigantism rather than acromegaly, but it's the same condition, growth hormone secreting pituitary tumor. In green and yellow, you can see that this is actually an equal opportunity disease with roughly equal proportions of men and women affected. It is a rare disease with only about 4 cases per million population, but it's important because it carries substantial morbidity and mortality. To me, one of the interesting things about this condition is how long it takes for the diagnosis to be made. It can take up to 15 years before the first symptom a patient has until they reach a diagnosis and move on to therapy. Why is that? Well, the first reason is what I just mentioned. It's a rare disease. And so busy health care providers with a room full of patients who have common diseases, often don't have time to think about the rarest possible conditions that could explain the troubles. And most of the symptoms are what we call nonspecific that is there could be many explanations for them. They're not pointing to just one potential illness. And so patients and their doctors suspect that they're due to more common causes just as you heard with this patient. And finally, there is also a very gradual progression of symptoms. It's kind of an insidious disease that comes on slowly. So day by day, patients or their families or their health care providers may not notice any difference. But over time, the changes accumulate. And I think you can see that very clearly here in the series of pictures in a chapter by my colleague, Mark Molitch from Northwestern. Look at the bottom right picture taken in 1988. This patient in this picture has a really classic features of acromegaly with coarsening of her facial appearance, a broad nose and full lips. But if you look back at the picture above that in 1981 and you compare it to the picture next to it from 1977, I think you can see that by 1981, she already had the beginning of acromegaly. Now if you're wondering how is it that Dr. Molitch had all of these pictures, which were unfortunately depicting the natural history of untreated acromegaly? The answer is that she was a high school teacher and the year book was showing the changes of acromegaly, but of course, they were not noticed until 1988. Many organ systems are affected with high levels of growth hormone and the downstream hormone, IGF-1, that we'll talk about in a moment. You can see on this diagram, all of the different body parts that are affected by excess of growth hormone and IGF-1. And the patient I told you about has many of them, the headache, the carpal tunnel syndrome and so on. Perhaps the most important comorbidities or associated problems that we see are depicted here. Hypertension, heart disease, cerebrovascular disease, including stroke and headache, fractures, arthritis, diabetes, and sleep apnea can all be potentially life threatening. Let's spend a minute talking about the normal production of growth hormone, so that we can understand how the diagnosis is made. This is a graph that shows growth hormone levels measured every 10 minutes in a healthy adult over 24 hours. So this is a graph depicting 145 tubes of blood collected over a 24-hour period. Focus first on the daytime, which is on the left side of the graph. And you see that during the day, most of the time growth hormone is undetectable or is the very bottom of the lower limit of normal with just 2 pulses kind of in the middle of the day there. Now look at the right side, where there's a box in yellow showing the time that this healthy person was asleep. In this case, you can see that there are 4 big pulses of growth hormone release. One of them as high as about 25 micrograms per liter. And so there's a big difference between the daytime and the nighttime production of growth hormone, which we term circadian variation. I've superimposed on that now the same protocol done in a patient who had confirmed acromegaly. And you can see that in his case, there are more pulses they continue throughout the day and night with no diurnal variation. And the nadirs never dropped down to an undetectable range during the day. So I think it's plain for you to see that the area under the orange curve would be much higher than the area under the black curve. But this is the important point. If we sent the healthy person and the patient with acromegaly to a laboratory at any of the times circled in green, their growth hormone levels are exactly the same. And I show you this so that you understand why in the diagnosis of acromegaly, measurements of a random growth hormone is not useful. It's too pulsatile. We don't know if it's the highest or the lowest level that person has had during that day. And so what do we do instead? We measure insulin-like growth factor 1, which used to be called somatomedin C. This is a hormone that's measured in the liver in response to all of the pulses of growth hormone that are flowing past the liver during the day. In a sense, it integrates the growth among pulses and provides us the area under that orange curve, and it's high in acromegaly and is considered the best screening test. Sometimes if the levels are borderline or we're not sure about the diagnosis, we also do an oral glucose suppression test, where we give a glucola drink, just as a woman would take for screening for diabetes during pregnancy, because we know that in healthy people, glucose suppresses the growth hormone to undetectable levels, whereas tumors are autonomous and continue making growth hormone regardless of whether glucola is given. If we do find that a patient has acromegaly based on these biochemical tests, we would move on to a head MRI scan. But before I talk more about that, I want to show you this slide from a paper by Martin Bidlingmaier in Munich, which depicts the reference range for IGF-1 values in a remarkable 15,000 healthy subjects with men on the left and women on the right across the life span. So you can see the ages across the bottom of the graph. I think you can also plainly see that IGF-1 is very age-dependent, which was the highest levels during the teenagers and then the IGF-1 levels gradually decline as we age. Now we often in sort of common conversation refer to this mistakenly as the normal range. But what this really represents is a depiction of the reference range showing lines between 2.5 and 97.5 percentiles around the range in a healthy population. The 2.5% and 97.5% were actually arbitrarily chosen because they represent 2 standard deviations from the mean, and that's commonly chosen for many different lab tests. In other words, this graph depicts the central 95% of these healthy people in terms of IGF-1. As with most biochemical tests, we're actually measuring a variable that's continuous, not binary, not absolutely normal or absolutely abnormal. And so the reference interval helps us interpret an individual patient's results, but it doesn't actually define normality. Notice that there are individual healthy people, both above the 97.5% line and below the 2.5% line, and that's part of what we would expect in a normal reference range like this. We also know that IGF-1 levels besides varying by age also vary by sex and between the lab or the method that's being used. And there have been studies done sending a single sample to several different labs with markedly different results. We also know that IGF-1 normal ranges have changed over time and are now lower than they were 20 or 30 years ago. On top of all that, there's individual variability. So if we take one person and measure their IGF-1 today and then again, in a couple of weeks, there could be anywhere between 10% and 30% variability. So what did my patient's IGF-1 turn out to be? Well, the answer is, as you can see, very high, over 1,000 and 4x the upper limit of normal. His growth hormone also did not suppress to below 1 with glucose. And in addition, he had a high prolactin and a low testosterone so that tells it was not his blood pressure medicines that we're causing his erectile dysfunction. So the first 2 tests makes the diagnosis of acromegaly, and the next step is to look at the pituitary region to see the size and location of the tumor. And I'm going to spend a minute just orienting those of you who don't think about the pituitary all the time to where the gland is located. The pituitary is situated in a little pocket of bone called the cell sella turcica. And it is about the size of a blueberry and hangs off a little stock, just like a blueberry would hang off a twig. Right in front of the pituitary, you see a pocket of air that little white kidney shaped item. And that is the what's called the sphenoid sinus and below that is the nasal cavity, and that's the route that a surgeon would take through the nose and through the sphenoid to reach the pituitary if they need to do an operation. This is an anatomic section showing you the same thing with the arrow pointing at the pituitary gland. And just below it, you can see that pocket of air, the sphenoid sinus and then the nasal cavity. We can also look at it as if this were a patient looking straight at us, and I've drawn a green box around the pituitary gland. Right above the pituitary gland is the optic chiasm. You can see a little bit of a wisp of tissue that's horizontal. That is the main nerve carrying vision from our eyes to the back of our brain. And there's very little distance between the top of the pituitary and the bottom of the optic chiasm, only a few millimeters. So if a tumor were to grow up and out of the pituitary area, it doesn't have far to go before it starts to compress the optic chiasm and can cause visual problems. So the size of the pituitary gland is an area called the cavernous sinus and the black circle that you see there is the main artery to the head called the carotid artery. There are also a number of nerves in that area that are very small, so hard to see here, that control the muscles of the eye and the face. So I want you to compare this anatomic section with a head MRI of the same area and this is showing the pituitary gland in the green box. And then you can see that little horizontal wisp of void, which is the optic chiasm. Again, you can see how very close they are to each other. And the cavernous sinus area on the right with that important blood vessel and some of the nerves are there as well. Let's zoom in on that area so that you can see the nerves better. In the center, that blueberry looking figure is the pituitary gland and right above it, the optic chiasm, the horizontal line. And then off to the sides are all of those nerves that control the muscles of the face and eyes. I've put on top of this diagram a pituitary tumor that we might see in a patient with acromegaly. And now I think you can see how easy it is for a tumor to lean on some of these important structures nearby. And doing so causes what we call mass effect symptoms. That is troubles that a patient develops because a mass is gradually growing and pushing on neurologic structures. Most commonly, patients develop visual field problems being unable to see, particularly in their peripheral vision if the optic chiasm is compressed from below. If the tumor grows out to the side and pushes on the cranial nerves, patients may have double vision or trouble opening their eye on that side and headaches as this patient had experienced. So I hope you can see that there are many important structures in a very small space. And this is relevant because the surgeon is going to try to take out the tumor, but leave the normal structures. And now I'll show you my patient's scan. I hope it's obvious to you at this point that he has a very large tumor, which I've circled in the teal oval there. It's extending up out of the pituitary area, which we call supraseller extension, and it's compressing the optic chiasm, which is actually difficult for us to see here. And that was borne out when he had vision testing and turned out to have subtle peripheral vision loss of which he was actually unaware. And so the next step for this patient is to undergo transsphenoidal surgery by an expert pituitary surgeon. That's recommended by all the guidelines, even when we are confident that the whole tumor can't be removed as in this case, in fact, because we know that all of the other treatment options work better, the smaller the amount of residual tumor. So there's almost always a role for debulking. So the surgeon goes through the nose, but not as easy a manner as shown here. In fact, we need an expert surgeon because the surgery is done through either an operative microscope or through an endoscope with a very small field of view. The surgeon isn't looking directly into the pituitary gland. They're looking into a microscope or an endoscope and manipulating the instruments while they are looking at what they're doing through the scope. Our patients postoperative head MRI is shown here, and this would be considered an excellent debulking because you can see that the optic chiasm has now been completely decompressed, we can see the horizontal line of optic chiasm. The rest of the sellar area, the pituitary area, is empty, that's the black appearance because all of the tumor has been removed from that area. But there is still residual tumor on the right side in the right cavernous sinus surrounding the carotid artery that round black circle. And it is not safe to operate in that area because we can't cut into the main artery to the head or the nerves that run adjacent to it. So after surgery, this patient was shown to have a growth hormone-staining pituitary adenoma as expected. And then at his 6-week visit, which is about the right time to assess the response biochemically, his IGF-1 had markedly improved but is still over 2x the upper limit of normal. His glucose suppress growth hormone is better, but is not below 1. His vision, though, normalized, which is great news for him. His rings and his shoe are looser, his headache is almost essentially gone, and he's very happy and actually initially thought he might be done with us. But in fact, he still has acromegaly. If he walked into our office with these numbers, we would make the diagnosis of acromegaly and tell him treatment is needed. So he does need to be treated. And what are the options for that? Well, this is the list of all the options, but I've already told you that in his case, further surgery wasn't feasible, given the location of the residual tumor. And in some cases, we would consider radiation. But I want to focus on the fact that there are many medicines that we can now use for patients with residual acromegaly and spend time mentioning somatostatin analogs. So how does somatostatin analogs, sometimes calls somatostatin receptor ligands instead, those are synonymous terms, work to lower growth hormone? They bind to somatostatin receptors on the tumor. And when they do so, they inhibit growth hormone secretion. As growth hormone decreases, then the liver output of IGF-1 decreases. Now it is important for the tumor to have functional somatostatin receptors because if they are not present on the tumor, then obviously, the drug cannot attach there. If we look over many studies that have been done, looking at the success of somatostatin analogs in decreasing IGF-1, we see that this hormone is lowered in most patients and that it is normalized in somewhere between about 1/3 to 2/3 of patients who are selected for studies because they had previously responded to another somatostatin analog. If we look over all patients, including those who are naive, meaning they have never taken a somatostatin analog before, then the IGF-1 normalization rate is lower than that. This was from a review article by Anamaria Colao looking at Stage III results across many different studies in patients who had previously been treated with somatostatin analogs before, and this is depicting the response rate in terms of normal IGF-1. Look at the graph that have round dots below them. Those represent patients who were specifically selected because they had responded well to somatostatin analogs in the past, and you'll see that they have the highest response rates. So to summarize that somatostatin analogs, of which we now have 3, they have advantages of being monthly injections so the patient only needs a treatment once a month. They can be quite well tolerated except for some gastrointestinal side effects the first couple of weeks. And that because they are treating the tumor itself, they can produce shrinkage of the tumor in about 1/3 of naive patients and certainly help maintain tumor stability in nearly all patients. What about disadvantages? Well, as I already mentioned, if there are no somatostatin receptors on the tumor, this class of drug is not going to work. There are some side effects, the GI side effects generally resolve quickly, but some patients may develop gallstones and require surgery for that. And these drugs can affect glucose metabolism, especially pasireotide which can cause diabetes due to inhibition of incretin and insulin secretion. Most of these are given as injections, and Karen will tell you about the burden to patients of those injections. And she'll also talk about the cumbersome process sometimes of getting access to the injections. And of course, there is expense involved. We do have now an oral option of twice daily oral octreotide, which was recently FDA approved based on a small study of 56 patients who had been controlled on octreotide or lanreotide and then were randomized in a double-blinded manner to take the study drug or placebo. And what you see here is that, as you would expect, the patients who were randomized to switch to placebo lost control at a higher rate than the patients who started taking oral octreotide. And so this was considered a successful study with no surprises in terms of side effects. The main issue with this medication is that there are food restrictions around both of the doses that the patient has to take because it must be taken on an empty stomach and not all patients are willing to kind of plan their eating around 2 intervals of dosing during the day. So what happened with this patient? He was treated with once-monthly injectable first-generation somatostatin analog. Interestingly, his diabetes, hypertension, erectile dysfunction and headaches all completely resolved. So that tells us that those were all co-morbidities related directly to his excess growth hormone and IGF-1. He was offered the opportunity to switch to oral octreotide when it was approved, but he declined because he did not want to have twice daily food restrictions. So in conclusion, growth hormone excess is associated with significant morbidity and increased mortality. But if we can achieve biochemical control, we can restore mortality to normal and improve morbidity. And so we are fortunate that now many effective treatments are available, but none of them is perfect, and I think patients will benefit from new medications that have less impact on their daily lives. And my colleague, Karen will now tell you about the impact of having to take monthly injections on some of the patients that we see. Karen.

Hi, everyone. My name is Karen Liebert. As Dr. Biller said, I'm a nurse at the Neuroendocrine Hospital -- Neuroendocrine Unit in the Massachusetts General Hospital. I've been with this group for about 25 years. So I've seen a lot of patients with acromegaly, and my task is to give you a little bit of a flavor for the types of issues that they encounter both with cost and insurance reimbursement as well as some of the injections. So from a patient perspective, patients just simply want treatments which control disease that are safe, that do not cause any significant side effects, they do not carry a financial burden and have very little impact on their personal and daily lives. Many patients tell me they just want to be a person rather than a patient. They don't want acromegaly to actually control their lives and be part of the main focus of their lives. For health care providers, when we think about medications, we want to maybe consider their current medical conditions, other medical conditions that are contraindicated for some of the therapies while a new therapy exacerbate current medical conditions, such as diabetes. Are there any drug-drug interactions we should consider when thinking about a medication. And physician preference is basically based on efficacy, on the side effect profile, the ease of monitoring and prescribing these medications and patient adherence. For patients, when we think about medications for patients, we do want to take in their personal preferences. So is an injection better than an oral medication for this particular patient, the frequency of administrations really matter to them? Or are they okay with daily administration. Are these medications administered at home or do they need to travel to a medical practice to receive them? And certainly, how these impact our personal schedule and lifestyle. Along with personal preference, definitely insurance coverage and cost becomes a major point that we need to consider. Does the patient have a plan that will actually cover the cost of these medications. What happens if the patient changes or loses insurance? And are they able to afford the co-pays? These medications are very expensive and co-pays can be very high. And this is a case just to highlight the insurance issues as well as traveling to a medical site for the interactions. This was one of our patients who was diagnosed with acromegaly, lives in Connecticut which is about 3.5 hour trip 1 way to that Mass General, had Medicare and an AARP supplemental insurance coverage. When we did the insurance verification, the medication was covered under a medical benefit, but the patient must receive the injections in the doctor's office. So she did travel for several months out to Mass General for the injections of LAR. But this got really burdensome. She was trying to find people that would help her, travel, she was unable to do it and the 6-hour round trip was very cumbersome to her. So she asked us to talk to some local physicians in Connecticut to see if we could find a provider that would like to do the injections locally. Under this, the prescription, the medication was covered 80% and then the supplemental insurance covered 20% of the remaining 20%. But after several calls to several physicians, the practices were unwilling to do this, they're unwilling to buy the drug upfront and then reimburse and they get reimbursement from the insurance companies for these costs. They were -- they claim that they were going to lose money on it and didn't want to risk the financial loss for this. So this is a good indication that we need to think about the patient's insurance, we need to think about the patient burden in terms of traveling to sites for injections. In terms of insurance verification, all of these medications require a prior authorization approval. This is a very time-consuming and burdensome process. It's usually done by either the nurse, a medical system or if you're lucky enough to have a prior authorization coordinator in your group and they will -- and may go to that person. But when a physician requests medication, this coordinator needs to initiate a new prior authorization request. This is paperwork that needs to be completed, includes patient information, includes possibly medical history, lab values, anything to support the diagnosis and the need for this medication. And then this form is then sent to the prior authorization group and insurance verification is then reviewed. The problem is that there's often issues with receipt of the information that requires multiple phone calls, e-mails and faxes that may request more IGF-1 levels and more information about the disease. And this creates the time-intensive burden for the office staff without any billable hours. So this is really an issue for many sites. These coordinators also manage expensive paperwork that's involved in this. Sometimes it's done on an annual basis. So you're one and done, but you're doing this continuously. And they may help coordinate shipments once the insurance is verified. And they continuously communicate with patients to make sure that they actually receive the drug, they're getting the drug, whether getting our time. So it's very time intensive and a lot of offices don't have the staff to be able to do these prior authorizations. The distribution process can also be very time consuming. So on the left-hand side, these are all the pieces that are involved in the cost of the drug. So we often get a question from the patients about what will this drug cost me? And it's a question that I can never answer. There's too many pieces in place that will dictate take what the cost to a patient would be. So it's a complicated system. There are many variables. It's often difficult to predict the cost and many decisions are not transparent to the patient or the physician. So in summary with just the cost challenges, prescribing an insurance process is often pretty cumbersome. It's challenging for doctors, it's confusing for patients. It's time intensive for practices without much compensation. Co-pays are often high and they may be prohibitive for many patients. And gaps in insurance coverage may lead to interruption to the therapy. So in terms of injection, the primary medical therapy we use are injections. So there's always issues with injections. And as I mentioned before, some require administration by a health care professional. So when you're picking a Medicaid, you need to consider the proximity from the patient to the medical facility. There are also may be scheduling challenges with the doctor's offices. The nurse giving the injection is only there 1 or 2 days a week, then that may impact when the patients can actually be seen for these injections. As mentioned before, there are work and family responsibilities that may interfere with business. And are there any services that can administer the medication outside the doctor's office. One of the companies had worked with a home nursing service that would do the injections. But fortunately, that's not available in all states. It wasn't available in Massachusetts so we couldn't take advantage of that. Despite all this, monthly -- once-monthly administration is appealing to some patients. They get an injection once a month and then they have to worry about it for the next month. So they're willing to think about the injections in order to just give 1 injection and forget about it until a month. And as I mentioned, IM injections, they're difficult. They're difficult injections. In the case of octreotide LAR, it's is a multistep reconstitution process. The needles are large. They tend to be either 19 or 18 gauge and can be anywhere between [ 3/4 of an inch ] or 1.5 inch long. The nurse giving these injections needs familiarity already with giving the IM injections. Basically, the area that we use primarily is the gluteal muscle, which is in the buttock and upper hip. And this area is very close to nerves and blood vessel, sciatica nerve and some of the major arteries run down the back of your buttock into the leg. So these are areas you want to stay away from. There can be pain and bruising at the injection site, and you can develop nodules where the medication is deposited. So these are actually pictures of the injection, the syringes used for the injections. On the top is Lanreotide Autogel. So this is a prefilled syringe. The medication comes in a gel formulation that's in the actual syringe. It delivers a 0.2 millimeter to 0.5 millimeter volume. And again, the needle size is an 18-gauge 20-millimeter or about 3/4-inch needle, and is considered a deep subcutaneous injection. On the bottom is octreotide LAR, and this is the medication that's a multistep process that I'll review on the next slide. But once in a syringe delivers a 2-millimeter volume, and it uses a 19-gauge needle with a 1.5-inch length. So this is supplied in the kit that the Sandostatin LAR is supplied. So thinking about octreotide LAR, this is the mixing and preparation steps that are involved in it. So on the upper left-hand corner is the kit that is supplied for the medication. So in the vial, it's a powder formulation. It comes with a prefilled syringe that has the diluent involved. It has a vial adapter and then it comes with that 1.5-inch needle. So when a patient arrives into the office for an injection -- this medication needs to be stored in the refrigerator. So when a patient arrives, we pull out the medication and allow for the vials to come up to room temperature, which is a minimum of 30 minutes. Once the 30 minutes is passed, then we'll use our vial adapter and place it on top of the vial of Sandostatin and then that allows for you to be able to screw the prefilled syringe to the top of the vial. And then you'll -- you push all of the liquid into the vial. And then you need to wait at least 5 minutes for that liquid to saturate the powder formulation that's in there. So that sits there for about 5 minutes. When it looks like it's all saturated, then you shake the vial because you want to gain sort of a milky consistency -- milky suspension. So once you have that milky suspension, then you withdraw that medication into the syringe and you want to make sure all the medication is withdrawn. This is a gritty mixture it tends to stick to the sides of the vials, you want to really make sure you go in and out and pull all the medication you can into the syringe. The mixture will remain okay. This is sort of a nuance to this particular drug as most nurses will think that the medication should be clear before it's given, but this will stay milky and almost has a gritty texture to it with the microspheres from the medication. So once the mixture is in the syringe, you attach the needle. And it's important to rock the injection -- the needle side to side to keep that mixture in suspension while you're positioning the patient for the interaction. You might remove the air from the syringe and then administer immediately. If you place the needle down to talk to the patient about anything, you need to make sure that you mix that syringe again because it will come out of solution and it may clump when you go to give the injection. So you got to make sure that it's in suspension before you actually give the injection. In terms of the administration, the actual injection administration, they can be tricky. So there was an injection study that was done by [indiscernible] in 2013 that observed nurses giving these IM injections specifically Sandostatin LAR and out of the 328 observed injections, 125 of them or almost 38% were given incorrectly. The author said that many of the injections were given outside of the dorsal gluteal area. And that's highlighted in the right -- on the right-hand side of the screen in the blue box is the area that you give these injections to. So it's the upper outer side of the buttock. And when injections were given outside of that area, as I mentioned before, there's potential damage to the nerves that run through that area. The other issue they saw was that some of the medication was actually given subcutaneously so not in the actual IM injection -- IM muscle. The subcutaneous tissue was either -- the width was greater than the needle, so the needle didn't reach the muscle, which is true for a lot of the acromegaly patients, they tend to have a higher BMI and bigger stature. So there is potential for delivering these medications into the subcutaneous area, or it just could be nurse, they were afraid to give this and only inserted it part of the way and therefore never really got the medication deposited into the muscle. In terms of the injection site reactions, we can see soreness and bruising at the site, some of the patients who have long-term therapy, you see skin and tissue scarring due to the repeated injections. We do rotate side left and right, but they're given in the same area. And if you have a patient who has been on this medication for 5, 10 years, then you can expect some scarring to happen. There has also been reports of nodules. So in this study by [ de Bono ] in 2008, the green arrows are pointing to areas where medication both Lanreotide and Sandostatin were given. So there's some inflammatory processes going on and even some granulomas that have formed in that area. So we are all very excited to see an oral formulation come to fruition and patients were very excited, we were very excited. So the oral formulations are appealing to patients because patients are very familiar with oral medications. There are less scary than an injection. Generally, they're easy to prescribe. The noninvasive route is appealing to patients and simple dosing may be motivated for some patients. It has minimal impact on daily life except with the timing of the food restrictions as Dr. Biller mentioned. And we have found since prescribing this, that the food restrictions have become an issue, especially with the evening dosing. I'll sort of end my slides on a case study of a patient of ours who wanted to -- was interested in switching to oral octreotide. He was on once-monthly octreotide LAR injections. But cited that the injections were painful, he had to take time out from work to go to the physician's to receive these and the oral formulation was really appealing to him. So the patient was started around oral octreotide, was well controlled on 40 milligrams BID without any side effects. And after a few months on treatment, the evening dose of oral octreotide, as I mentioned previously, was really challenging for him. He had difficult time predicting when he should stop eating prior to the dosing. His time for when he eat dinner was not the said time, he had dinner at various times during the day. So it was unsure when he would take the medication in terms of -- in relation to his dinner. And he also said that spontaneous invites out to dinner were problematic, like he had just taken his medication and then he was going to invite or meet somebody for dinner, and he couldn't do it because of the 2-hour wait after that point. So he was interested in participating in our paltusotine study for once daily oral administration because of the food restriction and the single dosing. So he's currently in the study and doing well. So in summary, as Dr. Biller mentioned, comorbidities and symptoms affect quality of life. So it's important to provide treatment for these patients. Effective medical therapies are available. Physicians can tailor the medical therapies to patients within limitations of insurance. And patients do have more options to accommodate their lifestyle of choice. Cost reimbursement process is cumbersome for both patients and medical practices and may delay or disrupt treatment. So it's important to consider that. IM injections are challenging and require the correct preparation to avoid injury, damage, discomfort and oral therapies allow for easy administration for patients. Once daily formulation will be more convenient than twice daily and minimal food restrictions are attractive to patients. So with that, I'm going to hand the mic over to Dr. Alan Krasner, who is the Chief Medical Officer at Crinetics.

Thank you, Karen, and Beverly for those very helpful presentations. As Karen clearly outlined, current treatments for acromegaly are associated with a variety of challenges. Painful deep injections with large needles introduce significant additional burden into the lives of these patients. With injection therapy, there may be a return of acromegaly symptoms towards the end of the monthly injection cycle and even an exacerbation of drug-related side effects at the beginning of the cycle. Consistency of symptom control and IGF-1 control may be opportunities for improvement. Our goal is also to reduce the burden on patients and health care providers with a convenient once-daily oral treatment that has the potential to overcome many of the limitations we see with current standard of care. We are committed to offering patients convenient at-home delivery and white glove support services. And to assist the health care community, we plan to provide extensive physician support services. Finally, we intend to add real value to the health care system with the potential for reduced cost burden for patients, physicians and payers by reducing the number of in-office visits, by growing our commercial and medical affairs functions, we are actively preparing the company to be ready for anticipated approval and launch.

We've lost advancement of the slides. Someone in the back end could help them or hand control over to me, please?

Thanks, Scott.

I got it for you now, Alan.

Thank you. Next slide. Our Phase II parent and open-label extension study results seen on this slide allowed us to design our current Phase III PATHFNDR program. Results from our Phase II parent study called ACROBAT Edge are seen on the left. The study showed maintenance of IGF-1 suppression in patients who switched from injected standard of care to once-daily oral paltusotine. When paltusotine was withdrawn, there was a sharp increase in IGF-1 confirming a study drug effect. If you look at the graph on the right from our long-term extension study, ACROBAT Advance, you can see that suppression of IGF-1 is maintained for up to 2 years and counting on paltusotine. Importantly, 88% of eligible Phase II parent study participants opted to continue into the extension study. Of polled extension study participants, 89% selected once-daily oral paltusotine as their preference over the injected standard of care suggesting a positive patient experience. Our overarching goal of PATHFNDR-1 and 2 is to support a broad label for paltusotine comparable to those of the somatostatin injectables, which are current first-line standard of care treatments. Our broad label for both maintenance and treatment indications will optimize managed care coverage and allow us to best compete with injectables. Our PATHFNDR program was designed with this in mind. PATHFNDR-1 evaluating patients switched -- switching from standard of care and PATHFNDR-2 evaluating medically naive or untreated patients. Top line results from PATHFNDR-1, as we noted at the top of the call, are expected in September. I'm also pleased to report that enrollment was completed in PATHFNDR-2 and we anticipate top line data from this study in the first quarter of 2024. The FDA recently published draft guidance on developing treatments for acromegaly that I invite you to read. In the guidance, they've laid out the 2 distinct indicated patient populations just discussed, maintenance of treatment and treatment indications. For the maintenance indication, the FDA recommends sponsors evaluate currently treated patients who have controlled disease and switched to the investigational agent. This is the population under evaluation in PATHFNDR-1. For the treatment indication, the FDA recommends evaluating patients with uncontrolled disease. This is the group in PATHFNDR-2. As discussed, having success in both of these patient groups is important to achieve a broad label. The FDA guidance also provides clear direction on pivotal study design, the primary endpoint and other secondary measures. These areas nicely align with our PATHFNDR program design, providing us with confidence that we expect to have a strong package of data to be submitted and if approved, be competitive from a market and payer perspective. Let's briefly review the design of PATHFNDR-1 in more detail. In this study, acromegaly patients with IGF-1 less than or equal to the upper limit of normal or reference range, as Dr. Biller discussed earlier, are randomized to receive placebo or to switch therapy to paltusotine for a period of 9 months. The primary objective of the study is to demonstrate that the proportion of patients with IGF-1 less than or equal to the upper limit of normal at the end of the treatment period is statistically greater in the paltusotine arm compared to that in the placebo arm. We will also be exploring secondary endpoints compared to placebo, including change in IGF-1 from baseline, proportion of patients with mean growth hormone less than 1 nanogram per milliliter and acromegaly symptom scores using a symptom diary developed in-house following regulatory patient-reported outcome guidance. As mentioned, we anticipate disclosing the top line results from PATHFNDR-1 next month. In addition to our upcoming acromegaly PATHFNDR-1 top line results, paltusotine is also being studied in carcinoid syndrome. And preliminary data from an ongoing Phase II study in this patient population is expected in the fourth quarter of this year. Moving into 2024, we expect the release of PATHFNDR-2 top line data in the first quarter. If our PATHFNDR studies are successful, we plan to submit a new drug application to the FDA for the acromegaly indication next year. We have made remarkable progress on our pipeline over the years, including paltusotine, and we are approaching what could be a transformational time in the Crinetics' journey. We look forward to providing you with updates on these programs as data become available. Thank you all for joining us today. And I'd like to turn it now over to Tara to begin the Q&A portion of the event.

Great. Thank you, Alan. At this time, we'll be conducting a question-and-answer session with our speakers. [Operator Instructions] So our first question comes from Yasmeen Rahimi from Piper.

Thank you, Tara. And thank you so much for, Dr. Biller and Karen, for the really thoughtful comments and presentation that you provided with us. I have 2 questions, 1 directed to both of our speakers. Maybe the first one is for Dr. Biller. Could you maybe help us understand what type of efficacy, especially around the primary endpoint of PATHFNDR-1, you would consider a win? As you know, PATHFNDR-1 is set to be reported out here in September. And so a lot of investors are trying to figure out what is the number that one wants to see. I would love it if you could put it into a round context. On the treatment side, also maybe give some color around the placebo? And then my second question is for Karen. Karen, could you remind us how many total patients do you have under care? And on positive data and availability of paltusotine, how many would you switch or would -- how many of the patients would want to be on paltusotine versus the monthly injection versus the subcu at-home injection?

Thanks so much for your questions. I'm going to start with the last one that you directed to Karen and say we actually are never going to have numbers for you, but she can give you some general answers. We -- there are 14 of us who are endocrinologists specializing exclusively in pituitary disorders in The Neuroendocrine & Pituitary Tumor Clinical Center. That is all the patients we see and all of our clinical care research and teaching relates solely to the sort of pituitary and acromegaly represents a sizable portion of that pie. So we never have an exact number of how many patients. We have a lot, but I will let Karen give you a sense in terms of what she thinks patients will be interested in taking if this drug is approved. So let me address the questions that you asked. I'm going to start with your second question first, which is what would I expect, I think, from the placebo arm. Is that right? That's what you asked?

Yes. Placebo as well as treatment arm. Yes.

Yes. So I expect that some of the placebo-treated patients will appear to be controlled because we see that all the time in this kind of study when a subset of patients is randomized to a new medication and a subset of patients is randomized to take placebo that is in a trial where the design starts with all patients being controlled. It's something we see in acromegaly. It's something we've seen in Cushing's. We spend a lot of time amongst our pituitary cells kind of talking about why is this, and there are a lot of potential theories, but it's -- the short answer is we don't know for sure. The most common theory is that it has to do with a carryover effect from patients being controlled and maybe not washed out long enough, and there are some data supporting that, but that's probably not the whole explanation. So it doesn't bother me when I see that there's a subset of placebo-treated patients that remain controlled. I expect that the majority should become uncontrolled. And on the flip side, for the first part of your question, I would want to see that the majority of patients remain controlled on paltusotine because if this drug is effective, it should be possible to switch patients from another somatostatin receptor ligand to this drug and maintain control in most of the patients. We wouldn't expect to see it in all of the patients. Nothing is 100% or 0% in medicine. But we would want to see a majority of patients who remain controlled.

Maybe before we go to Karen, just a clarification. I think what the investors are struggling with is trying to understand -- as you know, PATHFNDR-1 is powered for 70% on the treatment arm and 20% on placebo. So is there a difference, in your view, let's say, the data comes out to be 65% on the treatment arm versus 70% or 75%? How is each incremental delta difference in the response meaningful to you or not? Like that's what I'm trying to get at [ and by way of ] clarification. Sorry.

Thanks for the clarification. Unfortunately, as physicians, we don't think about it that way. So we don't think about the means in a main clinical trial. We look at each individual patient and ask are they controlled or not? If they're not controlled, the first thing we do actually is repeat the IGF-1 because, as I explained to you, there's a lot of variability and for many reasons in IGF-1 assays. And so if a patient has a value that's above the upper limit of normal, or I should say, the reference range for normal, the first thing I do is repeat it because it could have been an outlier that it was abnormal. But if more than 1 sample is elevated, then we would say, okay, we need better treatment. And if the patient's not on the maximum dose, we would raise the dose. If the patient is consistently above the upper limit of normal, then we sometimes think about adding a drug like cabergoline and there are many studies that have shown that, that can be effective. But we don't think about it in terms of a drug being good if 70% of patients in a big trial were controlled and bad, if only 65% of patients in a study were controlled. We take the drugs that are available and try them in individual patients and see if they work for that specific person. So maybe that's not as helpful as you hoped. But I'm describing how we think about it.

No, that's very helpful.

Karen, do you want to talk about sort of big picture, do you think patients will be enthusiastic about this?

Sure, Yes, I do think. I think, I mean, with all new medications, I think we do offer those to all of the patients as a potential if they want to try something new. I do think that this would be accepted widely by our patients. We do see a lot of patients that are on injectables and do complain of the injection. So I do think that the oral, especially having it the once a day is going to be really, really appealing to a lot of patients. It's an easy thing to wake up in the morning, take the medication, maybe go back to bed for a bit, have shower, go do your daily morning routine and then have breakfast. So the morning doses for these oral medications are not the issue. It's usually the afternoon dose or the evening doses that are a problem. So -- and the patients that may not think about doing it are maybe patients that are -- may not be compliant or adherent with the medication. If you're tasking a patient to take a daily dose of medication and that patient's forgetful or just does better with a once-a-month injection and then moves on, that may be more -- maybe those patients should stay on the once-monthly injections. But I think most patients, they are on many medications and vitamins and things like that, and this is just one more medication they take. So I think this will be pretty well accepted for a lot of our patients.

Thanks for the questions, Yasmeen. So our next question comes from Charles Duncan from Cantor Fitzgerald.

We don't hear you, Charles. You need to unmute. There you go.

Yes. Is that working?

Got you.

Okay. So first of all, to the Crinetics folks, congrats on the completion of PATHFNDR-2 enrollment. And to Dr. Biller and Ms. Liebert, I really want to tell you this has been very, very helpful. So appreciate you sharing your perspectives today. I had a couple of questions on PATHFNDR-1, and then 1 maybe on PATHFNDR-2. This first question is kind of a twist on the last one. But I guess if you think about the patient sample enroll, including considering the age range, what would you anticipate to be the placebo response? Is that 20% a reasonable number? And what's more interesting to you? Is it a placebo-adjusted response? Or would it be maybe an absolute response? And then how important is durability of the response to an oral agent for potentially adopting the drug in the future?

Why don't we let Alan take the first shot at that and then, Beverly, could you weigh in on your perspective? Some of it's technical around the study.

So regarding the suitability of the assumed placebo response rate, again, the PATHFNDR-1 study was designed after the CHIASMA OPTIMAL trial including eligibility criteria such as age range and control disease at baseline criteria. So I expect a fairly similar patient population enrolled in this study compared to what they saw. And again, the treatment duration is also the same, that 9-month period where they're either on active drug or placebo. So they did see 20% of their patient population, which also was a similar size overall in the 50s. I expect a similar placebo response rate to be observed in our study. As you know, our assumed placebo response rate was 20%, which is what they saw. Does that help you -- do you want me to...

Yes. Well, I'd be curious, Karen's -- or sorry, Beverly's perspective, too, because you've been an investigator in many acromegaly studies.

I'm going to start with the last part that you asked about, durability. Durability, I think, is essential because we always worry about potential tachyphylaxis with medications. So far it has not been seen commonly with the class of drugs of somatostatin analogs, but this is a new version. And so I think that is very important. And while some of the studies of other agents have produced data over the short term, I'm always going to want to see, does this drug keep on working and what happens to side effects in terms of long term, particularly if it's an injection. As Karen has shown you, there are long-term injection side effects like nodules and pain and so on. So I think durability in terms of effectiveness, but also long-term safety to me, are extremely important. And one of the things I'll mention about the data that you heard about so far is that it's really impressive to me that 88% of the patients wanted to stay in the extension study after the main Phase II study. When Karen and I have conducted studies of various medications, both for too much pituitary growth hormone or too little pituitary growth hormones, we are always impressed when people vote with their feet and say, I want to stay in the study as long as I possibly can. Because we have a lot of patients who are willing to participate in the study, sometimes because they see that as a way of giving back to our center that may have helped them and when the main study ends, if they say, I was glad I could contribute, now can I go back to my old drug? That tells us something about the new product as perhaps not being as appealing to patients. 88% of patients choosing to stay in a long-term extension is high. So I think that is impressive. And I think those long-term data will be very important in terms of telling us whether the response is as durable as we would hope. Now in terms of drug response versus placebo response and what are the numbers I want to see there, to be completely honest with you, what really matters to me is that whatever the numbers are, they're enough for the FDA to give an approval.

That's very helpful, Dr. Biller. And if I could ask you a question that would require you to speculate, and I apologize for this upfront. But just thinking about the mechanism on this drug versus -- of this drug versus a long-acting injectable, could you anticipate there to be any advantage over time in terms of outcomes with regard to efficacy, if we can assume good compliance with the oral? Is it possible that you may actually see improved efficacy and that this is not at all a convenience play or something else that patients actually perceive there to be some benefit of this drug?

I'm glad you asked about that and that you've acknowledged what I'm about to say is all speculation. But it's a really interesting question because it goes back to something Alan said. Remember that Alan mentioned that as the monthly injections wear off, some patients start to experience symptoms. And we definitely see this. Sometimes their headaches start to come back, sometimes they're sweating. Other things can appear. Each patient is different. And we definitely see that. In fact, we're looking, separate from any of this information we're talking about now, one of my colleagues, Lisa Nachtigall, is looking into more detail at that wear-off period in terms of what patients are experiencing. Some patients start to have those symptoms at 3 weeks after the injection, sometimes it's earlier, sometimes it's closer to the next injection. It's something that we, as endocrinologists, haven't paid much attention to because there's not been much we can do, until now, except to move the injections closer together. And there are definitely patients who take their monthly injections every 3 weeks because they can't wait until the next injection. And so it is interesting to speculate that a medication that continuously suppresses growth hormone and therefore, IGF-1, may offer better patient care than one that's resulting in peaks and values -- peaks and valleys in between the injections.

That's what I thought. Last quick question, Dr. Krasner and/or Dr. Biller. I guess I'm wondering, hopping over PATHFNDR-2, when you consider the 2 stratum, so 82 patients I guess, treatment naive or untreated for 4 months, versus 30 washed out, would you anticipate any difference in the responsiveness of those patients to paltusotine? And with that I'll stop and hop back in the queue.

Maybe I'll take the first crack at that. But, Beverly, maybe you can also comment. Chaz, what I would say is that in general, I would expect all the patients to have a reasonable response to paltusotine just like they would to another somatostatin receptor ligand. And when I say response, I'm referring to a decline from baseline in their IGF-1. Remember, in PATHFNDR-2, these patients often start out with quite high IGF-1s. And we are now showing that the drug can, in that situation, lower IGF-1. Now when you talk about the FDA definition of responder, that is not only lowering IGF-1, but bringing it down into the reference range, that, we know from published data, can range based on the stratum as we call it in this study. And that's based on the data from lanreotide's registrational trial, in which the responder rate in stratum 1 with the naive patients, is lower than you would expect in stratum 2, those patients who've already been responding to octreotide or lanreotide and now we're switching. So it makes sense that those patients have a good chance of being a responder when switched to paltusotine or started on -- or resuming on paltusotine after washing out. The stratum 1 patients who are -- have never seen medication or who have not been on medication for some time, now we're talking about unexpected higher IGF-1 range and a lower response rate. And that was all taken into account when sample size calculations were planned for this study.

Thanks for the questions, Charles. Our next question comes from Joseph Schwartz from Leerink.

Appreciate you taking my questions and hosting this very helpful event. I was wondering if Dr. Biller or perhaps Dr. Krasner have any thoughts on what factors determine whether a patient responds to SSRLs. And should we keep any of these factors in mind when we do see PATHFNDR-1 and PATHFNDR-2 data and who was enrolled in these trials in order to enhance our understanding of the profile? And then given that PATHFNDR-1 and PATHFNDR-2 trials are being performed at many sites outside the U.S., I was wondering if you could give us any insight into how these patients might present differently, if at all, and whether that could influence the results?

Beverly, that sounds like a good set of questions for you.

Sure. Well, I think the first part of your -- well, let me take the second part of your question first, and then we'll come back to your -- the first part of your question, which could occupy an hour itself actually and would be fun to talk about. But the second part of your question was about regional differences. That's a really interesting question. And it plays into many different variables related to patients with acromegaly. As a generalization, it's not clear that there are racial or ethnic differences in acromegaly. There are a few papers suggesting there might be and a few papers suggesting there aren't. So we kind of generally say there are not. In terms of regional differences in presentation, there's not been much data about that. But one big difference regionally potentially that could impact IGF-1 is diet and nutrition. And the person who I mentioned, Martin Bidlingmaier, who runs what I consider to be the best IGF-1 lab in Munich, published a more recent version of the reference range that I showed you just within the past year or so, and that included 1.4 million people from around the globe with results very similar as a generalization, but a few differences. And he found regional differences in the upper limit of the reference range. So that there -- it does matter, and he proposed actually that in the United States, we should have a slightly different reference range than they do in Europe. He spent a lot of time thinking about and writing about in this paper why that could be. And one of the potential explanations is nutritional differences. He looked carefully into whether it's BMI because, of course, in the United States, we have more patients with obesity than in many European countries, but it looks like that was not the whole answer. So it's kind of a long-winded answer, but just to say that we still are learning a lot more about potential regional differences. I'm not sure they'll be big enough to impact the results in these trials, but they've certainly piqued our interest and there's going to be more research related to them. Now the first part of your question was I think -- remind me if I don't have this right -- related to what we would expect might impact the response rate. Is that right?

Yes, sort of. I was wondering what factors determine whether a patient responds to SSRLs or is a known priority or...

No, it's a terrific question, as I say, could be a great hour lecture in fact, from Dr. Bidlingmaier. But the short -- I'll give you a short answer and then a medium answer, and I'll see if Alan wants to add anything. The short answer is whether the tumor has functional somatostatin receptors. That's the most important thing because if there aren't functional somatostatin receptors, it's unlikely that the patient is going to respond. And so that connects to the 2 different patient populations that Alan was just talking about, the previously treated patients and the naive patients. So if a patient has been previously treated with a somatostatin analog and has shown a decrease in their IGF-1, we know that they have receptors. And we know that the response rate, as I mentioned, in that previously successfully treated population is higher than it is in patients who never been treated, the naive patients. We think that part of the explanation for that is that the naive patients, having never been tried and succeeded on a somatostatin analog include a subpopulation without somatostatin receptors. And so I think that's the biggest predictor of response. But there's a host of other things: whether it's the study design; the inclusion/exclusion criteria of the statistical analysis that's planned; the time of measurement of the IGF-1; the definition of what a response will be; and so on. So there's many things. But I think the most important thing is what I've just mentioned. Alan, what would you like to add?

No, I think that's a great summary, Beverly. I mean baseline IGF-1 is a potential predictor of complete versus what I would call partial response. But of the patients who come down, but don't necessarily get to normal, that's more based on clinical experience and literature, but I would say that Beverly's summarized very nicely.

Thank you for the questions, Joseph. So our next question comes from Gavin Clark-Gartner from Evercore.

Can you hear me okay?

Yes.

Yes, we can.

Perfect. Two questions, and I'll do them separately. So the first question is when your acromegaly patients come in monthly today, is that only for the somatostatin analog injections? Or are there other reasons that patients need to be managed more frequently? I'm just trying to understand if there were an efficacious convenient oral available, how much do you think you could decrease the frequency that you see patients?

Karen, why don't you take that?

Yes. The patients come in monthly for the injection, specifically for the injections. They do maintain regular visits with the endocrinologists either [indiscernible] visit or every -- annually based where they are in their injection cycles and treatment plans. In terms of other things that they come in for, I mean, we draw their blood and will monitor IGF-1 levels while on injections. But one of the things that we've talked about as a nursing group with these oral octreotide and oral medications coming down the pike is will we lose contact with patients. We see them monthly. We look at their sort of symptoms and how they're doing on the drug, and we have a lot of contact with them when they do come in for the appointment. So having this oral, when we may not see them as frequently, sure, I think we'll lose a little bit of contact with them. As with any new drug, you sort of hold them closely and make sure that the drug is actually working and working for them and actually controlling symptoms as well as biochemical control. So other than coming in for their annual appointments or biannual appointments with their physicians, probably the most that we'll do is like monitor symptoms and maybe side effects and then draw their bloods to make sure that they're controlled on the medication.

And to follow up on that, I think -- I mean, it's a very good question because really what you're getting at is, could an oral agent that's well received actually decrease cost to the health care system because patients are not coming for doctors' visits so often and will it be beneficial to the patient's daily life because they're not coming to the office so often? And Karen is completely right. If we take care of patients with acromegaly, we see them only once or twice a year, and we would not be seeing them every month if they didn't need their monthly injections.

Yes. That's very helpful. And to get a better sense of patient preference, I'm going to ask a similar question in a different way. If you think back to the last 10 acromegaly patients that you saw, if you were to offer them an oral with paltusotine's profile or their current somatostatin injection, how many do you think would take the oral?

I think a majority. Yes, I don't know about the absolute numbers. I mean we have me with just a few patients that live within like 20 miles of the hospital, but everybody else is traveling. They're taking time off from work to come in. So I think the oral is really going to make a difference for that. And patients are always excited to think about oral medication over an injection. I think there's very few people, I guess, of the patients that may not be as adherent to the medication on a daily basis or do better with an injection in terms of like not having to worry about the medication for a month, that would remain on an injectable. But I think the majority. They take -- like I just said, they take medication on a daily basis, and this would just be one other medication that they would take.

I completely agree. In fact, when oral octreotide was approved, I expected most of our patients would switch over. But as Karen has described for you, some of those that did really had trouble with the evening dose. And so I think this is 1 step better because it doesn't interrupt the afternoon. So I think it will be a majority of patients that want to switch to this medication.

Thanks for the questions, Gavin. So our next question comes from Cory Jubinville from LifeSci Capital.

Thank you to Dr. Biller and Karen for the incredible insights. This one's for the KOLs. So we've seen quite poor uptake of MYCAPSSA throughout its launch. Would love to hear from your perspective, and we touched upon this in the last question with the fasting requirements, but more broadly, where and why has MYCAPSSA stumbled along the way? And how is or how can Crinetics and paltusotine be better suited to successfully disrupt the current injectables market?

Well, I think as you identified, we did just talk about one of the reasons, which is that we were surprised, I think, at how many patients are unwilling to alter their food intake, particularly in the second half of the day. As a generalization, I think Americans want to eat when we want to eat. And so having an afternoon that you have to think about, can I go out to dinner is restrictive. There is one other really important thing though that Alan touched on a bit in his presentation and that is that the way oral octreotide was approved was, of course, based on the study that was brought to the FDA, and that involved patients being switched from somatostatin analogs. And so the way the approval is written, some insurance companies are saying, you have to first treat the patient with injectable somatostatin analogs. And then if they work, because it's supposed to be given to patients who have been effectively controlled with injectable somatostatin analog, then this drug can be given to the patients. So this is a problem for 2 reasons. First of all, it's a huge hassle for the office, as you heard from Karen, unbelievable amounts of staff time with 0 reimbursement and we're doing this just for what, a few weeks, a few months to see if the drug works so that we can actually prescribe the drug that we want to give? That's not appealing. And then the second reason is the patients. We say to the patient, oh, there's this drug, you can take a pill, you don't have to have shots, except you have to have shots first. And if it's a de novo patient, a naive patient who's just finished having surgery and now they're not in remission and they need to take medicine, we talk about how there's an oral medicine, but by the way, you have to come in for shots for a while so that we can actually prescribe this other drug, that is not appealing to many patients. And so it's the combination of the insurance issue and the patient acceptability issue plus the burden to the practice that I think makes it problematic. And that is why the design of a broader label that includes both switch patients and new patients is so important for this product.

That's really helpful. And thinking about the concentration of care, what differences, if any, exist between subspecialist experts, like yourself and community endocrinologists that might be treating some of these patients on the fringe that might influence possible launch dynamics for paltusotine where MYCAPSSA kind of failed to attain broader uptake? And I guess, in your view, what would be the best way to reach both prescriber bases in a way that could achieve critical mass, if you will?

I think it's a great question to also talk about some of your education efforts because I think a lot of the world looks to you and Mass General as how to think about these things.

Yes. I like the question very much because I am very passionate about education. It's an astute question, and I think there are some differences, but I think most of them can be addressed with education. I think there's a lot that can be done about providing information at the time that the drug is launched so that people feel comfortable prescribing it. And the other thing that we've seen done with other sort of novel products that busy clinicians in general practice are not familiar with is that it makes sense at the very beginning when a product is first launched to offer the opportunity for patients to be started on the drug at the academic centers, but then handed back to the community physicians. And we've had a lot of success with that. We try very hard not to steal patients from the community, primarily because we want them to continue to refer patients to Mass General so their patients can have access to the best surgeons. That's actually more important. But we find that if we hand the patients back once they get controlled, and we explain how we sort of thought about titrating up to the right dose and now they're well controlled, many endocrinologists in the community are excited about trying new drugs. Other endocrinologists, which I guess you would call the early adopters, are eager to start from the very beginning, and that's where I think the educational programs going out into offices and offering some help in terms of how to start the drug will be valuable.

That's really helpful. And one last one from us and kind of adding to that point. Given the difficulties in accessing treatment with injectables, travel time, et cetera, how frequently are patients on injectables falling out of compliance or missing doses on an annual basis? And how do you feel compliance would differ on a once-daily oral? And to piggyback on that, what might be the impact of missing, say, one dose per week on an oral versus a once-monthly dose on an annual basis per year?

Those are all great questions, which would be very fun to study. But if we take -- let's take the analogy of pegvisomant, which we didn't talk about today, but that's the growth hormone receptor competitive -- competitor so that it blocks growth hormone at the liver. Doesn't treat the tumor, but it can lower IGF-1 very powerfully. The first clinical trials of pegvisomant, and which led to the FDA approval, were showing about 90% efficacy. The FDA mandated a Phase IV safety surveillance study because they were concerned about some liver test abnormalities and some question of tumor growth, neither of which really panned out very much in that safety surveillance study called ACROSTUDY. But what you do see, if you read the ACROSTUDY papers over the several decades since that was first initiated, is that the overall control rate in one of the main ACRO study papers was around 62%, 63%, not 90% because in real life, there are lots of things that actually happen when a patient is outside of study, and one of them is certainly a compliance or adherence. There are other potential explanations as well. But my hope is that the easier a drug is to take for acromegaly, the higher the compliance or adherence rate is likely to be. So I would be optimistic that we will do better because as your question implied, a lot of patients on somatostatin analogs miss doses and their care in terms of biochemical control is impacted.

Thanks for the questions, Cory. Our next question comes from Charlie Moore from Baird.

It's really great to hear your perspectives. I'd just kind of be curious kind of building off the last question on the heterogeneity of the disease. And do you see patients kind of abandoning treatment or missing doses, as you spoke about, what kind of proportion of the population of the patients you see is that happening in? And additionally, Ms. Liebert, you spoke to some of the insurance and logistical issues that come up with injectable treatments for acromegaly. I'm just curious what some of the greatest differences for patients would be if paltusotine were to be approved and successfully launched in terms of helping patients overcome these barriers to treatment?

Karen, do you want to start?

Sure. So I mean, I think cost is going to be an issue. We've had some medications that have been approved for other diseases and other things within the scope of the pituitary group here. And the cost that the pharmaceutical company put on them was cost prohibitive. And unfortunately, some of those medications we are not able to use because they're so much -- so expensive. So that's one. I'm hoping that this cost stays low so that patients are -- can afford it. Co-pays are usually a percentage of the cost, so if medication is high, usually, the co-pays are also high, and that may be prohibitive for a lot of patients. I think most of these medications now are going to require prior authorizations. I'm not sure you're going to get through with the prior authorization piece being any easier than with the current medications. I think it might be a little bit easier than the injectables because it's considered an oral medication. I think especially if it's not restrictive where patients needed to be on a somatostatin analog first in order to take it. So I think that might be a little bit helpful as well. So I'm hoping that insurance companies are a lot more eager to prescribe this and approve the medications than the current somatostatin analogs.

And it will certainly take away the problem that you described in that patient from Connecticut because they don't have to come to a doctor's office to get a pill. It's only the injection that was restricted that way. You asked about what proportion of our patients are uncontrolled. It's a tough question for me to answer because I mean, of course, I'd like to say none of them are uncontrolled, but that's not true. Nothing is 100% in medicine. But I think we have a bias sample. And I say that because patients seek out a major center of care, often because they're reading, they're very proactive about their disease, they want kind of the best that can be offered. And that includes taking some responsibility for their disease. If they've sought us out and come to visit us from another state, which many patients do, they're often very motivated to be controlled. So I would say certainly not 100%, but a large majority, the vast majority of our patients are controlled for whatever -- with whatever medical therapy they're taking because if they're not, we move on. We add something, we increase the dose and so on. But that's not the real world. And so what you really want to know is what is the lack of control rate in general across the U.S. or the world, for that matter. And that's substantially higher. Some of that has to do with what we've already talked about, adherence. But it also has to do, and Karen touched on this briefly, with the fact that the way our U.S. health care system currently works, if a patient loses their job, generally, they lose their insurance. And even if they get another job and insurance, there's going to be a gap in time where they're not able to take their medication. So I think there's a lot of work to be done about correcting things about our health care system, but there are plenty of uncontrolled patients. And if this drug is more easily accessible, more people will benefit from getting their acromegaly under biochemical control.

Thanks, Charlie. Our next question comes from Jon Wolleben from JMP Securities.

Can you guys hear me?

Yes.

Perfect. A couple for Dr. Biller, but all in the same vein. You touched on this a little bit earlier, but I'm wondering how well does IGF correlate to symptoms? How should we think about symptom control in PATHFNDR-1? And then how do you actually manage patients today? Is it the upper limit of normal being the end all be all to make these adjustments you discussed? Or is it a combination of symptoms? Is it 1.3x upper limit normal? Can you walk us through kind of your practice management and what's guiding those decisions?

Yes. So the first part of your question was about patients' well-being and symptoms. Is that right?

Correct. IGF and symptoms.

IGF and symptoms, yes. You asked how well they were correlated. Actually, not as well as you might think. There's not a nice perfect linear correlation. And we think that it's more that each patient kind of has their own set point where if their IGF-1 is above that, they're going to start to develop symptoms. We see this in the setting of doing clinical trials where patients are randomized to enter a study and then they're withdrawn from their current treatment. And some patients develop symptoms right away, often headaches may start developing. Other patients, they can go for several months. And we keep saying, are you having sweating, are you having joint pains? Are you having headaches? No, no, I feel fine. And those 2 people might have the same IGF-1. So there's a lot of individual variability in terms of how an elevated IGF-1 affects an individual patient. There's not enough research done about why that is. We could speculate about a lot of potential explanations. But I don't think it's well understood. So there's not a tight correlation, but there is some relationship. And we certainly know from some recent studies and also the one I mentioned that my colleague, Dr. Nachtigall, is doing that -- or has hypothesized will be the case, is that as IGF-1 rises, in general, symptoms do develop. Not every single patient, and there's variability from patient to patient, as I mentioned, but in general, we want to keep the IGF-1 in the normal range. We don't actually want to drive it below the lower limit of normal because that's another disease that Karen and I treat, growth hormone deficiency. And that was one of the problems with pegvisomant is that some patients were being driven way too low. But you asked what are we looking for. I'd like to see the IGF-1 in the normal range. Although if we look back at some of the old studies, some of the early studies actually targeted an IGF-1 at 1.2x the upper limit of normal is what they were -- or 1.2x the reference range is what they were looking for. And so we generally are aiming for in the normal range, but we don't get concerned about an occasional elevated IGF-1. As I mentioned, I would just repeat that, see if it's consistently high. And if an IGF-1 is consistently high, I am going to do something else, whether it's raising the dose or add another medication. So we're seeking the normal range, but we're not obsessed with being just under that 97.5 percentile that I showed you on the graph.

Thanks for the questions, Jon. Our next question comes from Douglas Tsao from H.C. Wainwright.

Maybe, Dr. Biller, as a start, and you touched on this a little bit in the last question, but I'm just curious because obviously with PATHFNDR-1, the primary endpoint is just sort of maintaining control below the upper limit of normal for IGF-1 level, I'm just curious how much do you focus on just the absolute levels when you look at patients? Are you going to be focused on seeing patients have their absolute IGF-1 levels basically stay the same as what they were at baseline or even go lower? Or from your perspective, is it just a matter of making sure that they stay below the upper limit of normal?

I think that's the general goal is to keep the levels in general within that reference range, although allowing that occasional elevated value is okay as long as there's not an upward trend. But this prompts me to say something that I didn't get a chance to say with the prior questioner, which is that we actually know that from some recent studies, mainly done in Europe, that we are bad at understanding what -- how the patients feel. And we do have some patient surveys that are used, which is interesting and useful. But there's been a publication or 2 saying that patients and doctors don't always see eye to eye on how the patients are doing. And we are perhaps a little too focused on the IGF-1s and not as focused on how the patient is feeling. I don't know if Karen wants to comment any further on that because she has sometimes worked with patients who represent patient support groups.

Yes, that's true. I mean there's -- we see that in a lot of the studies as well, that patients will often complain that they still are symptomatic or they still have joint pain or they still have swelling, even when their IGF-1 is in the normal range. And we've done a lot of patient support group education pieces and with patients involved and that is one of the number ones. They're like there's got to be more that can be done, even when the IGF-1 is normal because I am still feeling symptomatic and not feeling like my acromegaly is under control. So there are definitely symptoms despite having normalized IGF-1.

And that comes back to the question really is what is the right IGF-1 level? Because we are focused in a patient with acromegaly on bringing it down just inside the upper end of the reference range and in patients with growth hormone deficiency and bringing it up just inside to the lower end of the reference range. But what we really need to know for each individual patient is before they got this pituitary tumor, what was their IGF-1 as normal and could we put them back where they were supposed to be? And that's something that we haven't done yet, but that may be part of the explanation because as I just said, each patient has a different response to what their IGF-1 is. And some people are symptomatic as soon as it creeps up a slight bit above normal and other patients can be 2x the upper limit of normal as they're withdrawing from somatostatin analogs and tell us they're feeling fine. So I think there's a lot of interindividual variability in how an IGF-1 impacts an individual patient. And I am curious to see whether a drug that can push an IGF-1 further down into the normal range, might help some of those patients who are telling us, I'm still not okay.

And as a follow-up question, Dr. Biller, I'm just curious when you think about the data from PATHFNDR-2 or, I guess, just if we look ahead, what do you need to see from the PATHFNDR-2 or even PATHFNDR-1 to just make paltusotine in theory your sort of first-line treatment, right? Because if they are successful, they'll have a broad label, unlike MYCAPSSA. And so would that automatically just make it sort of your go-to option? Or is there something that you're going to need to see to sort of move it up that hierarchy?

Yes, that would be terrific. As I mentioned earlier, what I'm eager to see is that the drug meets its primary endpoint, has no surprising side effects and gets FDA approved because I would be eager to try it.

And would that apply both equally to treatment naive as well as patients who have been on injectables?

Absolutely. It would be delightful to take a patient who's just gone through pituitary surgery. They're 6 weeks later, we're telling them, as I had to tell the patient I had presented, that they're better, but they still have acromegaly, we can start you on a once-a-day pill. That would be wonderful.

Thanks for the questions, Doug. Due to the interest of time, we'll take one more question before we close out the meeting. So with that, our final question comes from Catherine Novack from Jones Research.

I guess for my question, I'd like to talk about the cost of paltusotine and MYCAPSSA versus injectable somatostatin analogs. Can you discuss how much uptake you've seen for the generic form of these injectables in recent years? And how much would cost factor into the prescribing condition decision when considering a branded oral medication?

Yes. I'm going to start by asking Karen if she knows because I haven't seen many patients, if any, in fact, prescribed the generic. Karen, have you?

No. I have not seen the generic.

Yes, the uptake has been almost nonexistent, at least in our center, but I don't keep track of marketing data, so I don't know. In terms of cost, what we are most focused on as providers is the cost to the patient, that is, can they actually pay the out-of-pocket cost to be able to get the drug. That's the #1 concern because if they can't afford it, they can't get the drug. Let's take a step back, though, and it is important to say that I think health care providers now in 2023 are much more cost conscious than even 10 years ago in 2013, where the only thing providers focused on was cost to patient. I think now there's a much greater understanding among providers and even the patients of the expense of our health care system. And so some providers are reluctant to prescribe drugs that are extremely expensive. And thinking of other drugs in the category of pituitary disorders besides acromegaly, I have seen providers say that drug is too expensive. I'm going to use an older drug. So just to mention that there's more awareness about the importance of keeping costs down as much as possible. Having said all that, of course, I know it's expensive to develop a drug. We've been involved in trials. We know that there's a lot of time and resources that go into it. But there must be a sweet spot where it can be enough to recoup some of the development costs, but also doesn't break the bank.

Thanks for the questions, Catherine. So this concludes our question-and-answer session for today's event. As a reminder, this event has been recorded and a replay will be made available on the Crinetics website. I'll now turn it back over to Scott for closing remarks.

Well, thank you, and thank you, Karen and Beverly very much. I think it was super helpful for people to hear about what's going on in the front lines. And I know we closed a bit on costs and prior auths. And I can just say from a company point of view, one of the things we're doing is trying to lay the foundation so that we can help make sure the burden of this actual prescribing is reduced as much as we're allowed and also try and keep the out-of-pocket costs for patients down as much as we can because as you say, a drug's no good if you can't get it out there to people. But thank you, everybody, for your questions and involvement, and I look forward to talking to many of you again soon in September when we can stop speculating about what this drug might look like and actually look at some data. So with that, thank you, everybody, and enjoy the rest of your day and week.