Press Release

ACROBAT Edge Results Showed Maintenance of IGF-1 Suppression with Paltusotine After Switching from Depot Somatostatin Receptor Ligand Monotherapy  

Paltusotine was observed to be well tolerated among the 60 participants in the ACROBAT Edge and Evolve Studies

On Track to Initiate Phase 3 Paltusotine Program in 1H 2021

SAN DIEGO, October 26, 2020 — Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), a clinical stage pharmaceutical company focused on the discovery, development and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors, today announced positive topline results from the company’s Phase 2 ACROBAT Edge and ACROBAT Evolve studies of paltusotine (formerly CRN00808), the company’s lead candidate for the treatment of acromegaly. The Company will hold a conference call at 8:00 a.m. Eastern Time today to discuss these results. In addition, a Key Opinion Leader (KOL) call will be held on November 20^th to discuss these results in the context of the current standard of care with clinical experts.

The prespecified primary endpoint in Edge was achieved, showing that once daily oral paltusotine maintained insulin-like growth factor-1 (IGF-1) levels at Week 13 in acromegaly patients who were switched from an injected somatostatin receptor ligand (SRL) depot of either octreotide or lanreotide monotherapy [change in IGF-1 = -0.034 (-0.107, 0.107), median (IQR)]. There were 25 patients enrolled in this prespecified primary analysis population (Group 1). During the four-week washout period after the 13-week treatment period, Group 1 patients showed a meaningful (>20%) and prompt (within two weeks) rise in IGF-1 levels from baseline, which characterized the magnitude of therapeutic activity of oral paltusotine in acromegaly patients. Edge also enrolled an additional 22 patients into four different exploratory populations (Groups 2-5).

Paltusotine was generally well tolerated among the 60 ACROBAT participants (including both Edge and Evolve), which is consistent with prior clinical findings in healthy volunteers. There were no discontinuations due to drug-related adverse events, no safety signals seen in clinical laboratory analyses, no treatment-related serious adverse events (SAEs), and no patients required rescue treatments with standard acromegaly medications during treatment. The most common treatment-emergent adverse events (>10%) included: headache, arthralgia, fatigue, peripheral swelling, paresthesia and hyperhidrosis.

“These results from Edge and Evolve support the potential to effectively switch acromegaly patients from their current depot injections to a once-daily oral treatment while maintaining hormonal control,” stated Alan Krasner M.D., Chief Medical Officer of Crinetics. “The heterogeneous nature of the ACROBAT patient population is representative of the real-world population, where acromegaly patients are prescribed a variety of treatments in an effort to control their IGF-1 levels, often unsuccessfully. The potential for once daily oral paltusotine to offer similar disease control provided by first-line injected depot SRLs gives us confidence to move into a Phase 3 program to further evaluate the efficacy and safety of paltusotine.”

Scott Struthers, Ph.D., founder and Chief Executive Officer of Crinetics, added, “Overall, we believe these findings support our thesis that once daily oral paltusotine has the potential to replace injected peptide depots for acromegaly therapy. We look forward to meeting with the FDA to share these results and finalize the protocol for our planned Phase 3 program, which remains on track to begin in the first half of 2021.”

 

Findings from ACROBAT Edge

Edge enrolled a total of 47 patients with confirmed diagnoses of acromegaly at 45 clinical sites in 13 countries. The prespecified primary analysis population (Group 1) included 25 patients who were previously treated with SRL monotherapy (octreotide or lanreotide) and had a baseline IGF-1 of >1.0x the upper limit of normal (ULN) and <2.5x ULN.  Groups 2-5 (n=22) were predefined as exploratory populations and are described in the table below.

 

Group	Pre-Trial Therapy	Baseline IGF-1 (x ULN)	Total Enrolled
1	SRL monotherapy (octreotide or lanreotide)	> 1.0 ≤ 2.5	25
2	SRL + cabergoline	> 1.0 ≤ 2.5	10
3	SRL + cabergoline	≤ 1.0	5
4	Pasireotide	≤ 1.0	4
5	SRL + Pegvisomant	≤ 1.0	3

 

Three IGF-1 measurements were taken during a four- to six-week screening period, the average of which was defined as the “baseline” value. Following screening and four weeks after the last depot injection, each patient was treated for 13 weeks with paltusotine. All patients were started on 10 mg of paltusotine and then titrated up to 20, 30 and 40 mg at Weeks 4, 7 and 10, respectively, if the study drug was well tolerated and if the previous IGF-1 levels were >0.9x ULN at Weeks 2 and 5, and if IGF-1 levels were >1.0x ULN at Week 8. At the end of 13 weeks, 18 of the Group 1 patients who completed the dosing period were on 40 mg, two were on 30 mg, two were on 20 mg, and one was on 10 mg.

The primary endpoint in the primary analysis population prespecified in the Statistical Analysis Plan (Group 1) showed that at the end of the 13-week treatment period, the median IGF-1 was 1.343, compared to the median IGF-1 of 1.335 at baseline (p>0.6 for change from baseline), indicating there was no statistically significant difference in IGF-1 control after patients had switched from pre-trial injected therapy to oral paltusotine monotherapy. Furthermore, the statistically significant rise in IGF-1 levels during the four-week washout period (p<0.0001) compared to the end of treatment time point at Week 13, shows the magnitude of the therapeutic activity of paltusotine in these patients and is shown in the table below. At every timepoint throughout the 13-week dose titration treatment period, median IGF-1 levels were maintained similar to baseline levels.

 

Parameter (units)	Baseline	End of Treatment	Withdrawal Period
			2 Weeks	4 Weeks
Number of patients	n=25	n=25	n=23	n=22
IGF-1 (xULN)
Mean (95% CI)	1.337 (1.217, 1.456)	1.327 (1.205, 1.449)	1.983 (1.729, 2.237)	2.031 (1.785, 2.277)
Median (IQR)	1.335 (1.078, 1.471)	1.343 (1.169, 1.448)	1.795 (1.512, 2.382)	2.053 (1.689, 2.511)
Change in IGF-1 (xULN)		Change from Baseline	Change from End of Treatment
Mean (95%CI)		-0.010 (-0.093, 0.074)	0.614 (0.394, 0.834)	0.676 (0.469, 0.882)
Median (IQR)		-0.034 (-0.107, 0.107)	0.477 (0.181, 1.068)	0.552 (0.408, 1.024)
p-value		>0.6	<0.0001	<0.0001

 

Findings from ACROBAT Evolve

Evolve was designed as a double-blind, placebo-controlled, randomized withdrawal study conducted at 44 clinical sites in 13 countries. As previously announced, the enrollment was terminated early, enabling data to be available for the end of Phase 2 regulatory interactions on the Edge study. The thirteen patients enrolled in the study with confirmed diagnoses of acromegaly whose levels of IGF-1 were biochemically controlled (<1.0x ULN) on standard-of-care SRL depot injections completed participation in the study. They were included in the safety analysis and provided additional response data at the low end of the dose range.

All patients were switched to 10 mg of paltusotine once daily, four weeks after receiving the last injection of depot SRL during the screening period. At predetermined timepoints, IGF levels and tolerability were assessed and doses were increased in 10 mg increments as dictated by the protocol up to a maximum of 30 mg. After this dose titration phase, participants were randomized to receive paltusotine or placebo for four additional weeks if their week eight IGF-1 was <1.0x ULN. Prior to randomization, only three patients advanced to the 30 mg dose, six were on 20 mg and three on 10 mg (one patient discontinued prior to randomization).  Seven patients met the criteria for randomization (n=3 paltusotine and n=4 placebo); the other five patients remained on paltusotine. As in Edge, paltusotine was withdrawn for four weeks following the conclusion of the 13-week treatment period.

The reduced sample size did not allow for meaningful statistical comparisons between groups in the randomized withdrawal period. Data from these patients on lower doses of paltusotine were included in the post-hoc dose response analyses in combination with data from patients in the Edge study, most of whom received the higher doses.

Dose Response Analyses

Post-hoc analyses of patients in Edge (Group 1; n=25) and Evolve (n=13) were conducted in order to explore the effect of paltusotine dose on IGF-1 suppression. These analyses provided evidence of a dose response across the dose range of 10 to 40 mg.  Dose-dependent results were observed when evaluating the effect on IGF-1 levels from: 1) switching from injectable SRL to paltusotine, and 2) withdrawing paltusotine during the washout phase. These data and ongoing exposure response analysis will inform the selection of doses to be included the Phase 3 program that will be finalized after consultation with the FDA.

Patient Reported Outcome Measures

Several different patient-reported outcome instruments were evaluated in the ACROBAT studies. Analyses of the performance of these tools are still being conducted, and Crinetics looks forward to presenting findings at an upcoming medical conference.

Conference Call Information:

Crinetics will hold a conference call and live audio webcast today, October 26, 2020 at 8:00 a.m. Eastern Time to discuss the topline results of the ACROBAT trials. To participate, please dial 877-407-0789 (domestic) or 201-689-8562 (international) and refer to conference ID 13712345. To access the webcast, please visit this link to the event. The archived webcast will be available for 90 days.

KOL Event:

Crinetics will hold a KOL event via webcast on Thursday, November 20, 2020. A live webcast of the presentation will be accessible under Events in the Investors section of the company website at crinetics.com and will be archived there following the presentation for 30 days.

About Paltusotine

Paltusotine (formerly CRN00808) is an orally available nonpeptide biased agonist that is designed to be highly selective for the somatostatin receptor subtype 2. It was designed by the Crinetics discovery team to provide a once daily option for patients with acromegaly and neuroendocrine tumors that are currently treated by injected therapies that sell approximately $3.1 billion annually. Non-clinical chronic toxicology studies are complete and no dose limiting toxicity was identified at the maximum feasible doses in rats and dogs. Crinetics previously completed a Phase 1 trial that showed potent suppression of the growth hormone (GH) axis in healthy volunteers, which provided clinical proof-of-concept. In addition, the molecule’s observed plasma half-life of ~2 days suggested the potential for paltusotine for once daily oral administration. A subsequent Phase 1 trial showed that paltusotine was 70% orally bioavailable.

About Acromegaly

Acromegaly is a serious disease generally caused by a benign growth hormone (GH) secreting tumor in the pituitary. Excess GH secretion causes excess secretion of IGF-1 from the liver, which causes bone and cartilage overgrowth, organ enlargement, and changes in glucose and lipid metabolism. The symptoms of acromegaly include abnormal growth of hands and feet and changes in shape of the bone and cartilage that result in alteration of facial features. Overgrowth of bone and cartilage and thickening of tissue leads to arthritis, carpal tunnel syndrome, joint aches, enlarged lips, nose and tongue, deepening of voice due to enlarged vocal cords, sleep apnea due to obstruction of airways and enlargement of heart, liver and other organs.

Surgical removal of pituitary adenomas, if possible, is the preferred initial treatment for most acromegaly patients. Pharmacological treatments are used for patients that are not candidates for surgery, or when surgery is unsuccessful in achieving treatment goals. Approximately 50% of patients with acromegaly prove to be candidates for pharmacological treatment. Long-acting SRLs are usually the initial pharmacologic treatment, however these drugs require monthly injections and are commonly associated with pain, injection site reactions, and increased burden in the lives of patients. Although over 90% of patients have demonstrable responses to SRLs (Annals of Internal Medicine. 1992; 117:711-718) only 20-40% of patients achieve normalization of IGF-1 (J Clin Endocrinol Metab 99: 791–799, 2014). Additional pharmacological treatment options include dopamine agonists or GH receptor antagonists which may be used in combination with SRLs.

About Crinetics Pharmaceuticals

Crinetics Pharmaceuticals is a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors. The company’s lead product candidate, paltusotine (formerly CRN00808), is an oral selective nonpeptide somatostatin receptor type 2 biased agonist for the treatment of acromegaly, an orphan disease affecting more than 25,000 people in the United States. Crinetics plans to advance paltusotine into a Phase 3 program in acromegaly and a Phase 2 trial for the treatment of carcinoid syndrome associated with NETs in 2021. The company is also developing CRN04777, an oral nonpeptide somatostatin receptor type 5 (SST5) agonist for hyperinsulinism, as well as an oral nonpeptide ACTH antagonist for the treatment of Cushing’s disease, congenital adrenal hyperplasia and other diseases of excess ACTH. All of the company’s drug candidates are new chemical entities resulting from in-house drug discovery efforts and are wholly owned by the company. For more information, please visit crinetics.com.

Forward-Looking Statements

Crinetics cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on the company’s current beliefs and expectations. Such forward-looking statements include, but are not limited to, statements regarding: the potential benefits of paltusotine for acromegaly patients; the potential to initiate a Phase 3 program of paltusotine in acromegaly based on the Edge and Evolve topline results and the timing thereof; Crinetics’ plans to meet with the FDA to finalize the protocol for a Phase 3 program for paltusotine; and the planned expansion of the paltusotine development program to include the treatment of carcinoid syndrome in patients with NETs and the expected timing thereof, including initiation of a Phase 2 trial in these patients. The inclusion of forward-looking statements should not be regarded as a representation by Crinetics that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in Crinetics’ business, including, without limitation: topline data that Crinetics reports is based on a preliminary analysis of key efficacy and safety data, and such data may change following a more comprehensive review of the data related to the clinical trials and such topline data may not accurately reflect the complete results of a clinical trial, and the FDA and other regulatory authorities may not agree with Crinetics’ interpretation of such results; advancement of paltusotine into a Phase 3 program is dependent on and subject to the receipt of further feedback from the FDA; the COVID-19 pandemic may disrupt Crinetics’ business and that of the third parties on which it depends, including delaying or otherwise disrupting its clinical trials and preclinical studies, manufacturing and supply chain, or impairing employee productivity; the company’s dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; the success of Crinetics’ clinical trials and nonclinical studies for paltusotine and its other product candidates; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of the company’s product candidates that may limit their development, regulatory approval and/or commercialization; Crinetics may use its capital resources sooner than it expects; and other risks described under the heading “Risk Factors” in documents the company files from time to time with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Crinetics undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.