Webcast: Crinetics Pharmaceuticals' Founder and CEO, Scott Struthers provides 2020 review and 2021 Plans at 39th Annual JP Morgan Healthcare Conference - January 13, 2021
Jess Fye:
Hey, good afternoon, everyone. My name’s Jess Fye, I’m one of the senior biotech analysts at JP Morgan, and we’re continuing the 2021 healthcare conference today with Crinetics. Things are a little different this year, so instead of going across the hall to the breakout room after the presentation, you can ask questions by using that blue ask a question button on your screen. That will submit them to me on the portal, and I can ask management during the Q and A session. So without any further delay, let me turn it over to Crinetics CEO, Scott Struthers.
Scott Struthers:
Thanks Jess. Thanks for the invite and thanks to everybody listening. I’m here with Alan Krasner, our chief medical officer, Gina Ford, our VP of commercial planning and Marc Wilson, our CFO who can help answer questions at the end of the talk portion. I’ll refer you to our forward-looking statements.
Scott Struthers:
Crinetics, as a reminder is in some ways a traditional drug discovery development company, with the goal of commercializing these drugs, ourselves. All our drugs are built from scratch in our own laboratories and built and engineered as best we can to make them high quality drug candidates for the target indication.
Scott Struthers:
Our whole strategy revolves around this set of criteria for the pipeline candidates. Obviously we’re working in areas of high unmet medical need as are most companies, but endocrinology is a little different in some ways. We have well-established biology in the most part, biomarkers, I think endocrinology invented biomarkers and in many cases there are registrational end points. Because of this, we can have clinical proof of concept early in development, including in healthy volunteer phase one studies. And because we’re working in a rare disease space, we generally have small registrational studies.
Scott Struthers:
This year is a really important one for us because it marks the culmination of our strategy to become a late stage company with multiple clinical assets. And you’ll hear about some of those in today’s talks. This is an overview of our pipeline. As I mentioned, everything has been discovered in house, we have no licenses to or from anybody, and you can see the depth of our patent estate and some of the backup materials on our website. But the IP for these goes out into the 2040s, so we’re planning for the longterm.
Scott Struthers:
Now it’s often a misconception that because we’re talking about rare diseases and endocrinology that we’re talking about small markets, and that’s simply not true. In our pipeline, we’re addressing number of rare diseases, but it adds up to a significant number of patients, over 200,000 in the U.S. and we list that for each of the indications in this slide. That’s a substantial market opportunity, as you can imagine. The lead program is Paltusotine, which is a somatostatin type two receptor agonist for the treatment of acromegaly and neuroendocrine tumors. I’ll spend some time on that in a minute. We’re introducing today, CRN4894, which is an ACTH antagonist for the treatment of Cushing’s disease and congenital adrenal hyperplasia and CRN4777, or 777 as I like to call it, which is a very lucky number for congenital hyperinsulinism. And both 4894 and 777 are getting ready to start phase one studies any day, and I’ll spend some time on those as well.
Scott Struthers:
Now, when I mentioned early proof of concept, I use this slide to illustrate it for the Paltusotine program. Now it’s a little bit old, because we’ve now moved on to show that this phase one data accurately predicted responses in an extensive phase two program, but it’s a fairly straightforward proposition from an endocrine maneuver point of view, and I’m on slide five at this point. At the upper part of this shows the cohort in the single ascending dose arm, where we’re looking at the mechanism of action of somatostatin, which is to inhibit growth hormone secretion. Now, to get a good amount of growth hormone to inhibit in this phase one healthy volunteer study, we give subjects a stimulus of growth hormone releasing hormone, and you can see that that’s rapidly followed by a rise in growth hormone that lasts about two hours, or temporary acromegaly. The next morning, the same patients get Paltusotine in this case, I’m showing you data from the 10 milligram cohort, the challenge with GHRH is repeated, and you can see that we blocked more than 90% of the GHRH stimulated growth hormone.
Scott Struthers:
Here we had proof of concept in, I think this was a third cohort in our single ascending dose arm. And you’ll see this play out throughout the rest of the pipeline. This is the information we had when we did our series B round, and then the MAD study down below, looking at a little longer dosing than some of the other important biomarkers in acromegaly, was the data we had for our IPO a couple of years ago. So you’ll see now, as the pipeline matures, we’ll have the same type of data for the next two programs entering our clinical pipeline.
Scott Struthers:
Let me first spend a little time on Paltusotine, which is a first in class oral, non peptides, somatostatin receptor type two agonist. And somatostatin receptor two is expressed on the pituitary cells that secrete growth hormone, but it’s also expressed on the neuroendocrine cells in the gut that can become cancerous and are endocrine tumors. And it has then, actions in acromegaly where it can inhibit growth hormone, which is the main cause of the disease, but in acromegaly, growth hormone acts at the liver to secrete another hormone called IGF-1. And IGF-1 is actually the biomarker with which physicians manage the disease and regulators approve drugs, because it’s a little more stable of a reporter for the disease state than growth hormone is, which can go up and down fairly quickly as you saw.
Scott Struthers:
There’s about 26,000 patients in the U.S. with acromegaly. Neuroendocrine tumors is a bit more common, it’s actually the second most common GI malignancy after colon cancer. Some of the more famous people that have suffered from it were Steve Jobs who died of a pancreatic NET, or more recently Aretha Franklin. There’s about 170,000 patients in the U.S. with neuroendocrine tumors. And about 20% of those patients have tumors in cells that make excess serotonin, which results in what’s called carcinoid syndrome. Those high levels of serotonin cause severe diarrhea and flushing, which is very symptomatic. And it was actually the treatment of carcinoid syndrome that resulted in the first approval of somatostatin peptide drugs for the treatment of neuroendocrine tumors.
Scott Struthers:
The neuroendocrine tumor market is actually, the treatment paradigm is quite a bit more complex than say acromegaly, but these are typically diagnosed as late stage, slower growing tumors where it’s metastatic, inoperable disease. And while there’s a variety of different threads of treatment, the somatostatin analogs are the backbone of therapy for most of the patients or many of the patients who suffer from neuroendocrine tumors, and then various other things are added on top of it. And we’ll be spending more time talking about this indication and some of the nuances of it, as the year goes by. But together with acromegaly and neuroendocrine tumors, the leading drugs in the field sell about $3 billion a year at this point. Sandostatin, Novartis’s number six largest drug, is the market leader with Somatuline from Ipsen closing the gap as relatively rapidly in recent years.
Scott Struthers:
Sandostatin, as an example is a two bill intramuscular injection that must be given by a healthcare professional and given once a month. And that IM injection is not something that patients look forward to, nor do they look forward to taking the time off work to go visit their healthcare provider. And our goal here is to replace this with a once a day oral pill that can do the same thing as these injectable depots. And we’re designing our clinical programs for the Paltusotine to be frontline therapy in all the patients that are currently being treated by these injectables.
Scott Struthers:
If we go onto slide 10, we start to get into some of the details on Paltusotine. As I mentioned, it was designed from scratch by our chemists in discovery lab, and the structure is shown here in the middle of this slide. It’s not a peptide, it’s a heterocyclic small molecule, it can be made in just a few steps from regulatory starting materials. And more importantly, it’s a drug built from scratch to do what we wanted it to do, which is be given once a day orally. It has high oral bioavailability, which is shown here, 70% in solution as a reference point for us. And it also has a long half life of about two days, which makes it consistent with once a day dosing. And these characteristics you’ll see play out through the target product profile, as we’re beginning to elaborate it in the development program.
Scott Struthers:
Now, I’ll skip through quite a bit of additional data and just cut to the chase on our phase two study, which reported out here last fall. And we were super excited to see that we could essentially replace or switch patients from a once a month depot injection to a once a day oral and keep IGF-1 levels, the primary endpoint for registration later, at the same values they were when they were on the standard of care therapy. And this is illustrated on the graph on the left of slide 11. In gray is the patient’s baseline levels of IGF. After three months switching to Paltusotine and optimizing of the dose, you can see that these patients maintain the same IGF levels as they had on standard of care therapy at baseline. This is pretty exciting. Tells patients and their physicians that they should be comfortable switching from the painful depots, visits to their healthcare provider, to a once a day oral. And then as a formal proof of efficacy, we also had a withdrawal portion on this, and that’s the open circle, which shows the IGF levels four weeks after withdrawal of …
Scott Struthers:
… the open circle, which shows the IGF levels four weeks after withdrawal of paltusotine, when the drug is cleared from the system and you can see that the IGF levels are significantly higher. So the inverse of that is that if you had started them off washout and then given them the drug, you’d go back to the levels that you see in green, so very significant treatment effect. I’ll leave the safety and other information around that to another time, but I would encourage you to check our website, where we have fairly comprehensive KOL webinar discussing these data with our lead investigator, one of the experts in the field, also Peter Trainer, an expert in the field who has recently joined our clinical group. And they’ll talk about their experience with the drug, the background treatment of acromegaly, and kind of their thoughts.
Scott Struthers:
So I’d encourage you to look at that video on our website for more details. One of the most important things coming out of the phase two program was to really start to develop a better understanding of the dose response, and this integrates some data from across the program on slide 12. And we showed dose response here in a couple of ways. Behind this, there’s also some exposure response modeling, and some additional clinical trial simulation work, all of which points to what I think was illustrated well on the left-hand part of this slide. You can see that as you increase dose of paltusotine, the 40 milligram or the 30 milligram both have equivalent levels of control compared to baseline therapy on the injectable depots.
Scott Struthers:
And so this is expressed on the Y axis as a change in IGF from where they were on the baseline therapy. Now, the lower doses at 10 and 20 milligrams turned out to be somewhat less effective, and so we can consider taking them out of the phase three program. In fact, if you look at this, it would be a very reasonable dose selection to start all patients at 40 milligrams, and then I’ll show you some more data in a minute that seems to indicate we could go higher than that. We certainly seem to have the safety and tolerability profile to go higher than that. So a logical type of dosing for the upcoming phase three program would be to start everybody at 40 milligrams, if necessary for a few, bring them up to 60, and maybe provide a lower dose option in case there’s a tolerability issue for some.
Scott Struthers:
We’ll be able to provide more guidance to that later after we have our end of phase two meeting this quarter with the FDA, as well as more guidance around the final aspects of the phase three design. But one of the things that lets us consider those higher doses as well as some other aspects of phase three is we spent quite a bit of time improving the formulation of paltusotine. In phase two, we used a capsule formulation that we developed early in the program that had some limitations. It required a two-hour post-dose fast, which isn’t bad, but it could be better. More importantly though, after 40 milligrams, if we went up with that formulation, we didn’t see additional exposure with, say, 60 or 80 milligrams, and that was a significant limitation of the formulation.
Scott Struthers:
Also, we had interference with acid-lowering drugs like proton pump inhibitors, which reduced oral bioavailability of that formulation. And so when we’d seen that in phase one, we decided to move forward into phase two with these knowing the limitations, because we could address it in the phase two program, but at the same time started an extensive effort to improve the formulation, testing multiple ones in dogs and then later in healthy volunteers to come up with the tablet formulation, a picture of which is shown here on the right of slide 13. So there’s a number of improvements. Now, the post-dose fast has been reduced to half an hour to an hour. We see dose-proportional increases in exposure up to 80 milligrams, which is as high as we’ve gone at this point, and acid-lowering agents like proton pump inhibitors don’t reduce exposure significantly.
Scott Struthers:
We also expect this to be shipped at ambient temperatures. So if you put all this together from a patient perspective, think of their life now, which is a once-a-month healthcare visit on a painful intramuscular injection, trying to schedule your work, personal life, vacations around all that, versus a once-a-day tablet where presumably, you order your 90-day supply through a mail-order pharmacy, you take a bottle of capsules with you on your vacation. You get up in the morning, you take your tablet, get dressed, get ready, have breakfast half an hour, an hour later, and off about your day.
Scott Struthers:
I think that really has a potential to help normalize your life, and more data on this formulation will be presented at the Endocrine Society annual meeting in March. Actually, I don’t know all the abstracts which have been accepted yet, but I think there’ll be four or five presentations from our company at that meeting, so look forward to quite a bit of information there. So overall, a very exciting phase for this program. As I mentioned, all this data, the formulation, our trial designs are now in a summary document at the FDA. We have an end of phase two meeting on the books. We’ll complete that and be able to finalize our phase three plans by the end of the quarter, and I’ll communicate that out to the community. That’ll allow us to start the phase three and the second part of the first halves of the second quarter.
Scott Struthers:
And as soon as we get that off and running, we’ll begin the NETs trials in carcinoid syndrome, which is planned to start later half of this year. We feel quite good about the de-risking that the acromegaly side of the program provided, so it’s time to really get started on making sure this’ll help the NETs patients as well. So with that, let me just talk a little bit about the latest entrance on the pipeline, 4894, which is a first-in-class, non-peptide oral ACTH antagonist for congenital adrenal hyperplasia and Cushing’s disease. Now, as a reminder of the hypothalamic pituitary adrenal axis we illustrated here on slide 16, this is the center of mammals’ responses to the stress. When an animal is stressed or we’re stressed, maybe we have different things that stress us, but that stress results in the secretion from the pituitary of ACTH, or adrenocorticotropic hormone. That circulates through the blood, hits the adrenal gland where it activates a receptor called MC2.
Scott Struthers:
This receptor then activates a series of pathways in the adrenal cells that result in a synthesis of cortisol. Cortisol is the endogenous glucocorticoid in humans and most mammals. That cortisol then has a variety of actions at the peripheral tissues that help the body adapt to stress, so it’s really important for survival. And then as a part of its regulatory aspects, it comes back to the pituitary and hypothalamus, and it inhibits the production of ACTH so this is a classic endocrine negative feedback loop that’s tightly regulated and important for homeostasis. But it can go wrong in a couple of different ways, the first of which is illustrated on slide 17, which is Cushing’s disease. So very much like acromegaly, in Cushing’s disease, there’s a tumor of the pituitary gland. But in this case, the cells that gave rise to the tumor are those that specialize in making ACTH. You then end up with very high levels of ACTH, which in turn overstimulates the adrenal, which results in high levels of cortisol.
Scott Struthers:
And this can have a range of very profound, negative effects on patients, including some deposition of fat in odd places, such as a moon face, or many patients develop a fatty hump on their back. Malignant hypertension, bone loss, hyperglycemia, and it has a number of psychiatric issues as well. This is about 10,000 patients in the US, so it’s a little less prevalent than acromegaly, but it’s very severe. And if you ask a pituitary doc what they need most, they’ll say a new drug, a better drug for Cushing’s disease. The next thing they’ll say is a drug for non-functioning pituitary adenomas, which I’ll mention just briefly at the end of the talk. But again, a significant and high unmet medical need. But the other indication that is also a disease of ACTH excess is congenital adrenal hyperplasia, but this excess comes from a different mechanism. In this case, there’s a mutation in the enzymes that convert adrenal steroids into cortisol, so that last step of the synthesis is non-functional.
Scott Struthers:
That means there’s no cortisol to come back and complete the negative feedback loop to constrain the secretion of ACTH by the pituitary. That means you end up with very high levels of ACTH, which then act at the adrenal cause the adrenal to grow, hence the name hyperplasia. And then it overproduces all these precursors, which get stuck and can’t be converted into cortisol, and most of those precursors are androgens. So these patients then have a problem with… They don’t have enough cortisol, but they’ve got too much androgens, and there’s no approved therapies for these patients at this point. Now, this is a significantly larger population. It’s about 27,000 patients in the US, so not too far different from acromegaly, but in the case of acromegaly, surgery is successful maybe more than half the time, depending on the center. In CAH, there’s not a surgical cure for it, so all these patients need medical therapy.
Scott Struthers:
We’re pretty confident that we’ve identified the ideal pathway to inhibit by making an ACTH antagonist. Part is just because of all we know about the role of ACTH in human biology. This isn’t a new hormone. We discovered this hormone, not me, but in the 1930s, and Cushing’s disease was described by Harvey Cushing earlier than that back in 1910. So it’s a well-established biology with more than 60,000 papers in PubMed, but yet there’s no antagonists that have ever been in the clinic before, so this is a real milestone for endocrinology. But the other reason why we think we’ll be successful-
Scott Struthers:
For endocrinology. But the other reason why we think we’ll be successful is shown on slide 19, which is some proof of concept data we’ve generated in rats. And the endocrine systems are well conserved amongst all the mammals. So the proof of concept in rats has very high translatability and two proof of concept and healthy volunteers. And in this experiment shown on the left of slide 19 is a fairly standard endocrine type of study. The rats are given a bolus of ACTH at time zero, and then in the open circles, you measure corticosterone, which is the glucocorticoids made by rats. If you add then various doses of 4894, you can see we can dramatically blunt that response to ACTH or block that response to ACTH.
Scott Struthers:
This is very much the same paradigm that we’ll use in a healthy volunteer human phase one study. Moreover, if we look at the effects and the ability to block chronic ACTH stimulation such as happens in CHH is shown in rats on the right. Now in rats after seven days of chronic ACTH administration, their adrenal becomes hyperplasia. It could be very large, it’s inflamed and with once a day, oral 4894 you can see, we can keep those adrenals at a normal size despite this high levels of ACTH in their circulation.
Scott Struthers:
So both of these provided us a good deal of confidence in moving forward. More details on this will also be presented at an endo. And then of course we did all the normal pharmaceutical characterization, and safety toxicology studies to make sure we had what we believe to be a high quality drug candidate. And we don’t let anything go into the clinic unless we really believe in the molecule.
Scott Struthers:
So this now has an open USIND and a healthy volunteer study will be starting any day. The design is shown here on slide 20. It’s a combined single ascending dose, multiple ascending dose. The single ascending dose, though, very much analogous to the [Paltusa 00:24:14] team program will provide important proof of concept about whether this molecule is working, in addition to the normal PK safety tolerability type of aspects. And that’s illustrated on the right where we’re doing this ACTH challenge test.
Scott Struthers:
So very much like in the rats, the subjects will come into the clinic, in this case on day minus two, get settled. The morning of day minus one, they’ll receive the ACTH bolus. We’ll then draw blood at 30 and 60 minutes after that to measure the cortisol response, which should rise dramatically. And I should point out that this is a very common test endocrinologists perform to assess adrenal function. So we’re not inventing anything new here. We’re just using it in a new way. And the next day on day one, before the ACTH challenge, they’ll get 4894 at increasing doses orally. Two hours later, they get the ACTH stimulation and then we’ll measure blood cortisol levels.
Scott Struthers:
Comparing blood cortisol levels on day one versus on baseline will tell us about the efficacy of the molecule. And this should tell us whether or not it’s working at reasonable concentrations, but we’ll also get the normal how well has it been absorbed orally? What’s the half-life? What’s the safety tolerability profile look like? So super excited to see that data. Very important proof of concept for us. I hope that should be out before the end of the first half. That’s certainly our plan. With the multiple ascending dose arms reporting out in the second half of the year.
Scott Struthers:
So very important milestones for that program. With that phase one, sad and mad data we’ll know whether we have a drug or not, and then we’ll be gearing up for the late stage part of the program in 2022.
Scott Struthers:
Next molecule to enter the clinic is CRN 477 for the treatment of congenital hyperinsulinism. This is an SST5 non peptide oral agonist. And these kids with CHI or congenital hyperinsulinism have a pretty rough go of it. There’s about two to 4,000 of them in the U.S. making this a rare to ultra rare disease. We’re working to try and characterize that better, but there’s a fantastic patient group called congenital hyperinsulinism international. If you want to learn more about the disease and its impact on families, I’d encourage you to go to their website or follow their Twitter feed. And every day you’ll see some story about some young family or a kid or family, the challenges they’re facing, the successes they have and sometimes the tragedies they face.
Scott Struthers:
So it’s really compelling stuff. But what happens in these kids is normally when blood glucose goes down, say at night, and you haven’t eaten for a while, your insulin levels should stop secreting because insulin tells the peripheral tissues, muscle and outer post to take in blood glucose. And more insulin will continue to lower blood glucose. And the brain requires glucose as its only nutrient source. So the goal is to keep blood glucose in the normal range nor to keep the brain functioning healthily.
Scott Struthers:
Now, the problem is that in the regulation of insulin secretion is thrown off. And so at low blood glucose levels, these kids are still making insulin, which can cause profound hypoglycemia that must be managed 24/7. Now CRN 4777 is a potent inhibitor of insulin secretion and we think can make a real difference for these kids.
Scott Struthers:
Just to give you a sense of what they face. The unmedical mat need here is excruciating. There’s a couple of drugs that sometimes work for some of the patients. They have some issues associated with them, but overall you need very intensive 24 hour a day, seven day a week glucose management, including monitoring, feeding some of the kids like this little girl beside the pool, have G-tubes directly pumping glucose into their stomach to make sure that they have enough glucose on board.
Scott Struthers:
One of the things they’re trying to do is avoid a pancreatectomy, which is what some patients have had to resort to. And of course the pancreatectomy can cause long-term type one diabetes. But the goals for these patients and their parents are first and foremost, put your kid to bed at night and know they’re going to be safe because nighttime hypoglycemia can be lethal. But repeated episodes of hypoglycemia can cause neuro developmental disorders and preventing that is also super important.
Scott Struthers:
Clearly these G-tubes and the backpacks and all the injections and the glucose sticks are no fun for anybody. Pancreatectomy is a lifelong problem after that. Fortunately, we see that many of these kids resolve as they get into adolescence. And so if we can have a medical therapy that manages them to that point, that may be a real important breakthrough.
Scott Struthers:
If we go to slide 25, you can see some of the impact of these patients on the healthcare system and the impact of the healthcare system on the patients. On the left is a profile of utilization by a baby girl with CHI. This is part of claims database analysis that we’ve been working on in our commercial group. And each symbol on this plot shows an event that resulted in a healthcare claim. So this is a little girl diagnosed with CHI, she’s on Dias oxide. But despite that you can see all the seizures, the ER visits, the inpatient visits, outpatient visits, dextrose beatings. It’s a very intensive paradigm that they’re having to live with.
Scott Struthers:
On the right is an interesting study from the UK that looked at the pharmaco economic impact of a portion of these kids in the UK. In the first year of life, because of the severity of disease, they’re spending around 2 million pounds on care services, ICU time, sometimes the pancreatectomies, all this hard work being done to stabilize patients so that they can get home.
Scott Struthers:
So very, very high levels of unmet medical need. But now just like our previous examples I showed you on slide 26, we have some pretty good preclinical data to give us confidence that what we’re working on should translate to these patients. Again, insulin and pancreatic biology is conserved across species. On the left is an interesting rat study where we’re looking at the ability of sulfonylurea to induce hypoglycemia and the ability of 777 to reverse that.
Scott Struthers:
So the diabetes class, a sulfonylurea have a pharmacology that exactly mimics the mutation in about half the kids with CHI. And so we use this as an animal model. In gray and the dash line has shown a normal glucose level and a rat. In black is the plunging glucose towards hypoglycemia that you see given a sulfonylurea. And then at time zero, if we get back varying doses of 777, that hypoglycemia can be reversed.
Scott Struthers:
So this is we think pretty strong proof of concept. We’ll do a very similar type of a study in healthy volunteers in phase one. Of the data on the right may be even a little more relevant. As I mentioned, sometimes these kids need pancreatectomies and we were fortunate in this case where the parents have a little girl with an syndromic type of CHI called Beckwith Wiedemann syndrome. Had a pancreatectomy and we were able to get access to those eyelids. And it’s pretty compelling data. And the blue shows the response of insulin secretion to a glucose ramp. You can see the large spike in insulin as well as due to depolarization later in the study with potassium chloride. Now those same things in the presence of one of our model compounds. One of our model SST5 agonists are shown in purple with a dramatic reduction in insulin secretion. So this type of…
Scott Struthers:
The dramatic reduction in insulin secretion. So this type of thing gives us great confidence in moving forward. Very sadly, this little girl didn’t survive her CHI, but in the healthy volunteer study, this again, we’ve completed the whole pre-clinical package, in addition to these ethicacy experiments I showed. We’ve done all the preclinical safety and drug pharmaceutical characterization that we would normally do. We’re doing this study in Germany because they have a very specialized phase 1 unit for glucose studies. And so we have approval from the German regulatory authorities to start dosing, and this’ll start dosing in the coming weeks.
Scott Struthers:
Again, it’s a combined sad, bad study. And in the sad study, just like in the rat experiment that we showed a minute ago, we’ll be using sulfonylureas to stimulate insulin secretion, and then look at the ability of 477 to block that sulfonylureas stimulated insulin secretion. Now it’s not safe to give hypoglycemia to a healthy, healthy volunteer. So this is done in what’s called a glucose clamp setting where they’re hooked up to an IV glucose drip, their glucose levels are carefully monitored, and glucose is infused at a rate to keep their blood glucose at normal levels. We can then see how much glucose is required to do that. So that’s one measure of the insulin activity, but then we’ll also measure insulin directly, as well as the peptide, and a variety of other metabolic markers.
Scott Struthers:
So this type of glucose clamp study is a very powerful way of looking at the function of the pancreas. And again, as a type of study that’s been optimized in the treatment of diabetes that we’re now repurposing for essentially what is an anti diabetes indication. In addition, we can use a IB glucose tolerance test, which stimulates insulin secretion, and look again at the ability to block that. So some of the outline of this study is shown on the left. Again, multiple ascending groups in the sad portion, transitioning into a multiple ascending dose portion.
Scott Struthers:
This study is just a little bit behind the 4894 program, just a matter of weeks, but we do expect to report out the phase one proof of concepts sad data towards the middle of the year. And again, complete the MAD arm in 2021. We’ve had remarkably encouraging interactions with the US and European regulators on this, who fully understand the severity of the disease, the high-end medical need. This resulted in a US rare disease designation and EU orphan drug designation that we’re very happy with, but perhaps more importantly, we’ve had very encouraging feedback from these agencies, and we think it would be quite reasonable to begin to consider going straight from this phase one study into our registrational program in 2022. Depending of course on the results from the phase one.
Scott Struthers:
So while this is a little bit behind 477 to start, this very much could be then the second molecule after Paltusotine to submit an NDA. So I would encourage you not to forget about 777. So overall as I started to talk with, this is a very important year for us, as we transition into a multi clinical compound company with its most advanced program in registrational studies. The milestones for 2021, I’ve talked about, and are shown in the middle. We’re also very excited to get started on the next part of the Paltusotine development program. But in 2023, it starts to get even more exciting as we transition the two new programs, assuming that phase one is successful, into late stage studies, and we’re beginning to now, all our molecules, we try and have backups for, so that if something goes wrong, we can not kill the program. We just go to the next molecule in line, but those are done by our discovery group already.
Scott Struthers:
And so we’ve been able to turn that effort onto the next programs. And so I look forward in the coming year more to start to tell you more about the things that are coming out of the discovery pipeline. A very interesting approach to hyperparathyroidism, both primary due to dysfunction of the hyperparathyroid gland due to MEN1 tumors, or secondary hyperparathyroidism due to kidney failure. As I mentioned, the pituitary docs have a real challenge with non-functioning pituitary adenomas. These are tumors in the pituitary that they don’t secrete a hormone like acromegaly or Cushing’s tumors, but they just keep growing and there’s no medical therapy. So these patients end up with just year, after year, after year of neurosurgery, which is not an ideal treatment paradigm.
Scott Struthers:
And maybe the last one, the polycystic kidney is a little bit of an outlier, because it’s not truly an indication that most endocrinologists would manage, but certainly impacted by endocrinology. And we got into it because we happen to have some very drug-like looking good lead molecules. There we recognized that the biology may, it seems to be pretty compelling theoretical argument for using it in polycystic kidney disease. So we’ve decided to invest in exploring that. We need to decide as we move forward with that, depending on the growth of the company, whether that’s something we develop fully and commercialize ourselves, or if that’s something that we work with some partner who has more expertise in kidney disease.
Scott Struthers:
Then again, maybe we just grow into that kidney disease expertise. And finally, the discovery group has not slowed down, there’s more and more going on, a lot of other things that we haven’t talked about, and I’m super excited to be able to talk to you about that in the coming years. So I hope you’ll see that we’re on the verge of this year of really seeing the fruition of some of our strategic planning, or the execution of our strategic planning, and looking forward to the next phase after this, which is getting ready for the market and completing our registrational work in acromegaly and maybe in 777, not too long for hyperinsulinemia. So with that, thank you very much. I’ll stop and let Jessica guide your questions.
Jess Fye:
Great. Thanks, Scott. We only have one minute to go here, so maybe I’ll just try and sneak in one quick question.
Scott Struthers:
Oh, I went a little over, there’s a lot to talk about. I’m sorry.
Jess Fye:
Just heading into your end of phase two meeting, what are you seeking to get clarity on from the FDA, and what are your latest thoughts about the design of a phase three trial for Paltusotine?
Scott Struthers:
Great. Well, why don’t I let Allen, our chief medical officer answer that for you?
Allen:
Thanks, Jess. We have our very recent regulatory precedent for approval of a new acromegaly drug. And I do believe it would be a fair assumption that we would have to hit many of the same kind of endpoints that has in previously used in the recent past for this. That was long-term placebo controlled trial, nine months placebo controlled trial, so I would envision that would be the core of our phase three program. Of course, this is all pending our regulatory interaction.
Scott Struthers:
But maybe just to elaborate a little bit more fully, Jessica, we want to converge on dose. So we think we can do 40 milligrams and go up to a higher dose as well, but we need to agree on that. We’re also curious about these patients who are the bulk of the market, which are patients with IGF levels above one times upper limit of normal, which are the ones where we showed we could keep IGF levels the same, and it’d be very nice to incorporate them into the program, in addition to those patients who are well controlled and are part of the placebo trial.
Scott Struthers:
But it doesn’t make sense to put those patients into a placebo arm because we know they’re above one times the upper limit of normal in the standard of care anyway. So maybe we should consider those patients in an active control arm. And these are all the conversations we’re having with the regulators, but like I’ve always said, our goal is to build a molecule, and a label, and a clinical program, which enables it to be used as frontline therapy for all patients with acromegaly who need medical therapy.
Jess Fye:
Okay, great. We’ll leave it there. Thanks, Scott. Thanks, Allen.
Scott Struthers:
Thank you.
Allen:
Thank you.