UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
CURRENT REPORT
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Item 7.01 Regulation FD Disclosure.
The slides attached as Exhibit 99.1 to this Current Report contain certain additional information related to the clinical data results discussed in Item 8.01 below. Crinetics Pharmaceuticals, Inc. (the “Company” or “Crinetics”) intends to present the slides during a conference call and live webcast with the investment community on October 26, 2020, at 8:00 a.m. EDT.
The information contained in this Item 7.01, including in Exhibit 99.1 hereto, is being “furnished” and shall not be deemed “filed” for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended, is not subject to the liabilities of that section and is not deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Securities Exchange Act of 1934, as amended, except as shall be expressly set forth by specific reference in such a filing.
Item 8.01 Other Events.
On October 26, 2020, the Company 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 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. The Company plans to meet with the U.S. Food and Drug Administration (“FDA”) to share these results and finalize the protocol for its 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.
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Group |
Pre-Trial Therapy |
Baseline IGF-1 (x ULN) |
Total Enrolled |
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1 |
SRL monotherapy (octreotide or lanreotide) |
> 1.0 ≤ 2.5 |
25 |
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2 |
SRL + cabergoline |
> 1.0 ≤ 2.5 |
10 |
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3 |
SRL + cabergoline |
≤ 1.0 |
5 |
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4 |
Pasireotide |
≤ 1.0 |
4 |
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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 > 0.9 x ULN at Weeks 2 and 5, and if IGF-1 levels were > 1.0 x 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
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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.
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Parameter (units) |
Baseline |
End of Treatment |
Withdrawal Period |
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2 Weeks |
4 Weeks |
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Number of patients |
n=25 |
n=25 |
n=23 |
n=22 |
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IGF-1 (xULN) |
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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) |
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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) |
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Change in IGF-1 (xULN) |
Change from Baseline |
Change from End of Treatment |
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Mean (95%CI) |
-0.010 (-0.093, 0.074) |
0.614 (0.394, 0.834) |
0.676 (0.469, 0.882) |
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Median (IQR) |
-0.034 (-0.107, 0.107) |
0.477 (0.181, 1.068) |
0.552 (0.408, 1.024) |
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p-value^ |
>0.6 |
<0.0001 |
<0.0001 |
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Switching patients in the exploratory Edge populations in Groups 2 and 3 (n=15), who were treated with a combination of cabergoline and an SRL at baseline, to paltusotine monotherapy showed that cabergoline contributed to IGF-1 lowering. However, after withdrawal of paltusotine therapy in the washout period, it appeared that the magnitude of therapeutic activity of paltusotine was greater than that of cabergoline.
Although the small sample sizes in Group 4 (n=4) and Group 5 (n=3) were too low to assess paltusotine’s activity in the smaller patient populations represented by these groups, these data will contribute to the broader paltusotine safety database. Patients represented by Groups 2-5 will not be included in the Phase 3 program but are included in the safety analysis.
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 and completed participation in the study, 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 plans to present these findings at an upcoming medical conference.
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Forward-Looking Statements
Crinetics cautions you that statements contained in this Current Report on Form 8-K 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; and Crinetics’ plans to meet with the FDA to finalize the protocol for a Phase 3 program for paltusotine. 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 Current Report on Form 8-K 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.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
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Exhibit No |
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Description |
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99.1 |
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Slide Presentation entitled “Topline Results from the ACROBAT Phase 2 Program in Acromegaly” |
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104 |
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Cover Page Interactive Data File (embedded within the Inline XBRL document) |
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SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
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Crinetics Pharmaceuticals, Inc. |
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Date: October 26, 2020 |
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/s/ R. Scott Struthers, Ph.D. |
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R. Scott Struthers, Ph.D. |
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President and Chief Executive Officer |
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Topline Results from the Acrobat Phase 2 program in Acromegaly October 26, 2020 Exhibit 99.1
This presentation contains forward-looking statements. All statements other than statements of historical facts contained in this presentation are forward-looking statements, including statements regarding: the potential benefits of paltusotine for acromegaly patients; the planned improvement of the paltusotine formulation and the timing thereof; the potential to initiate a Phase 3 program of paltusotine in acromegaly with our to-be-marketed formulation based on the Edge and Evolve results and the timing thereof; our plans to meet with the FDA and the timing of such meeting; 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 the initiation of a Phase 2 trial in these patients; the potential to initiate a Phase 1 trial of our lead ACTH antagonist and the timing thereof; and the potential to initiate a Phase 1 trial of CRN04777 and the timing thereof. In some cases, you can identify forward-looking statements by terms such as “may,” “believe,” “anticipate,” “could,” “should,” “estimate,” “expect,” “intend,” “plan,” “project,” “will,” “forecast” and similar terms. These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, without limitation: topline data that we report 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 our interpretation of such results; advancement of paltusotine into a Phase 3 program and our lead ACTH antagonist and CRN04777 into Phase 1 trials are dependent on and subject to the receipt of further feedback from the FDA; we may not be able to obtain, maintain and enforce our patents and other intellectual property rights, and it may be prohibitively difficult or costly to protect such rights; the COVID-19 pandemic may disrupt our business and that of the third parties on which we depend, including delaying or otherwise disrupting our clinical trials and preclinical studies, manufacturing and supply chain, or impairing employee productivity; our dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; the success of our clinical trials and nonclinical studies for paltusotine and our other product candidates; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval and/or commercialization; we may use our capital resources sooner than we expect; and other risks described under the heading “Risk Factors” in documents we file from time to time with the Securities and Exchange Commission. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond our control, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. 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 and, except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and growth and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions, and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. Safe Harbor Statement CRINETICS PHARMACEUTICALS |
Primary endpoint achieved in Edge: Once daily oral paltusotine maintained insulin-like growth factor-1 (IGF-1) levels at week 13 after switching from injected somatostatin receptor ligand (SRL) depots of octreotide or lanreotide [DIGF-1 =-0.034 (-0.107, 0.107), median (IQR1)] Both IGF-1 and growth hormone (GH) levels promptly rose after withdrawing paltusotine which characterized the magnitude of therapeutic activity of oral paltusotine Paltusotine contributed to IGF-1 lowering in patients previously treated with injected SRLs + oral cabergoline combination therapy Post-hoc analysis of patients from both Edge (Group 1) and Evolve2 provided evidence of a dose response with higher doses being more effective Paltusotine was well tolerated Summary of ACROBAT Phase 2 Results 1Interquartile Range: 25th , 75th percentile 2Enrollment in ACROBAT Evolve was discontinued in April 2020. Previously enrolled patients continued in the study. Data from the Evolve patients (N=13) are included safety and dose-response analysis. CRINETICS PHARMACEUTICALS |
IGF-1 GH Pituitary Tumor 5HT SST2 agonist Carcinoid Syndrome Acromegaly Liver Neuroendocrine Tumors (NETs) Stomach Liver Pancreas Benign pituitary tumor Secretes excess growth hormone (GH) Excess GH causes excess secretion of insulin-like growth factor-1 (IGF-1) Results in: Bone and cartilage overgrowth Organ enlargement Changes in glucose and lipid metabolism Abnormal growth of hands and feet Alteration of facial features NETs arise from aberrant enteroendocrine cells In ~10% of cases, tumors are associated with excess secretion of serotonin and other hormones resulting in carcinoid syndrome Patients with grade 1 and 2 NETs and distant metastases have a 5-year survival ranging from 30-70% Prevalence: >25,000 in the U.S. Prevalence: ~171,000 in the U.S. Acromegaly and NETS are Currently Treated with Injected Somatostatin Receptor Ligand (SRL) Depots Intestine CRINETICS PHARMACEUTICALS |
Sandostatin (octreotide) Somatuline (lanreotide) Somavert (pegvisomant) Signifor (pasireotide) $1.6B $1.2B $264M $75M Monthly intramuscular 5-mL vial; 1½” 19-gauge needle Monthly deep subcutaneous .2-.5ml; 18-gauge needle Daily injections 1 ml; 28 – 31-gauge needle not supplied Monthly intramuscular 1 ml; 20-gauge needle Painful injections. Injection site reactions Inconvenient monthly visits to physician’s office interrupts normal life Limited Efficacy as many patients experience return of symptoms near end of month Painful injections. Injection site reactions Inconvenient monthly visits to physician’s office interrupts normal life Limited Efficacy as many patients experience return of symptoms near end of month Patients buy a second refrigerator for storage. Travel is difficult. Impaired glucose control and risk of diabetes. Approval date: 1988, 1998(LAR) Approval date: 2007 Approval date: 2003 Approval date: 2014 ~$3.1B (2019) Market, Despite Limitations of Injectables CRINETICS PHARMACEUTICALS |
WEEK -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Washout Paltusotine Treatment Screening Washout Last SRL Depot Dose Rec’d Last Dose of Adjunct Meds IGF IGF IGF * * * Baseline = average IGF-1 W13 W15 W17 10 Endpoint: ∆IGF-1 after switching from SRL peptide depot *Potential dose increases (20, 30, 40 mg) if study drug tolerated and previous IGF-1 > 0.9 x ULN at week 2 and 5 or > 1.0 x ULN at week 8 Dose Titration Period Magnitude of paltusotine effect: ∆IGF-1 after washout 10 mg Primary Endpoint: Change in IGF-1 at Week 13 vs. baseline (average of three IGF-1 screening values) Primary Hypothesis was: No change in the median IGF-1 at Week 13 versus baseline Primary Analysis Population: Group 1 patients (those previously on octreotide or lanreotide depot monotherapy) Key Eligibility Criteria: Patients not controlled (IGF-1 > 1.0, ≤ 2.5 x ULN) on octreotide or lanreotide depot monotherapy ACROBAT Edge Study Design CRINETICS PHARMACEUTICALS | A global clinical trial conducted at 45 clinical sites in 13 countries
ACROBAT Edge Patient Groups Prespecified Primary Analysis Population (Group 1)1 Patients treated with SRL (octreotide or lanreotide) with elevated IGF-1 at baseline—representing the majority of patients in clinical practice The primary hypothesis was that the group would show no change in the median IGF-1 at Week 13 versus baseline 1Prespecified in Edge Statistical Analysis Plan 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 Prespecified Primary Analysis Population Exploratory Populations CRINETICS PHARMACEUTICALS | Exploratory populations (Groups 2-5) The study also evaluated whether paltusotine can contribute to the care of patients treated with more intensive treatment regimens
ACROBAT Edge Patient Disposition CRINETICS PHARMACEUTICALS | 89% of patients completed the study Group 1 SRL Monotherapy n=25 (53.2%) Group 3 SRL + Cabergoline(IGF ≤1.0 ) n=5 Group 4 Pasireotide n=4 Group 5 SRL + Pegvisomant n=3 Completers n=22 (88% ) Discontinuations n=3 (12% ) Reasons: Withdrew consent n=1 Prohibited Med n=1 Unable to Travel n=1 Completers n=10 (100%) Completers n=4 (80%) Discontinuations n=1 (20%) Reason: COVID-19 n=1 Completers n=3 (75%) Discontinuations n=1 (25%) Reason: Prohibited Med n=1 Completers n=3 (100%) Total Enrolled n=47 Group 2 SRL + Cabergoline (IGF>1) n=10
Group 1 (N=25) Group 2 (N=10) Group 3 (N=5) Group 4 (N=4) Group 5 (N=3) Total (N=47) Demographics Median Age, years (Min, Max) 52 (31, 71) 53 (31, 70) 51 (43, 69) 56 (46, 67) 38 (35, 66) 51 (31, 71) Median Weight, kg (Min, Max) 91 (61, 155) 85 (56, 136) 87 (57, 91) 107 (73, 120) 78 (59, 82) 87 (56, 155) Sex Female 11 (44%) 7 (70%) 3 (60%) 3 (75%) 3 (100%) 27 (57%) Male 14 (56%) 3 (30%) 2 (40%) 1 (25%) 0 20 (43%) Prior Therapies Lanreotide depot Dose, mg/mo n=12 n=3 n=2 NA n=2 n=19 # patients on 60/90/120 mg/mo 1 / 4 / 7 0 / 0 / 3 0 / 0 / 2 -- 1 / 1 / 0 2 / 5 / 12 Octreotide LAR Dose, mg/mo n=13 n=7 n=3 NA n=1 n=24 # patients on 10/20/30/40 mg/mo 1 / 0 / 9 / 3 0 / 0 / 7 / 0 0 / 1 / 1 / 1 -- 0 / 0 / 0 / 1 1 / 1 / 17 / 5 Pasireotide dose, mg/mo NA NA NA n=4 NA n=4 # patients on 40/60 mg/mo -- -- -- 2 / 2 -- 2 / 2 Cabergoline dose, mg/week NA n=10 n=5 NA NA n=15 Median (Min, Max) -- 2.3 (0.5, 3.5) 1.5 (0.5, 2.0) -- -- 2 (0.5, 3.5) Pegvisomant dose, mg/week NA NA NA NA n=3 n=3 Median (Min, Max) -- -- -- -- 60 (20, 70) 60 (20, 70) ACROBAT Edge Patient Characteristics CRINETICS PHARMACEUTICALS |
Paltusotine Maintained IGF-1 and GH Levels After Switching From Injected SRL Peptide Depots CRINETICS PHARMACEUTICALS | Hormone levels observed in primary analysis population (Group 1) IGF-1 GH Data presented are median (Interquartile Range [IQR]: 25th percentile, 75th percentile) EoT = End of Treatment defined as Week 13 (Visit 14) or last on treatment value carried forward (LOCF). Wks after WD is defined as Week 17 or result at least 22 days after last dose. Note: p-values are based on non-parametric Wilcoxon Sign Rank test of whether the median change is different from zero. p>0.6 p>0.6
Paltusotine Maintained IGF-1 Levels After Switching From Injected SRL Peptide Depots CRINETICS PHARMACEUTICALS | 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 ^ p-values based on non-parametric Wilcoxon Signed Rank test of whether the median change is different from zero. *Calculated as mean and median of individual changes in IGF-1 IQR: Interquartile Range: 25th , 75th percentile Conclusions IGF-1 levels after 13 weeks of paltusotine treatment did not significantly change from baseline in patients previously treated with injected SRL depots (Group 1) Rise in IGF-1 after withdrawal (within 2 weeks) which characterized the magnitude of therapeutic activity for oral paltusotine
Parameter (units) Baseline End of Treatment Withdrawal (4 Weeks) Number of patients n=25 n=25 n=22 GH (ng/mL) Mean (95% CI) 1.314 (0.813, 1.815) 1.213 (0.803, 1.624) 2.754 (1.646, 3.861) Median (IQR) 0.691 (0.491, 1.555) 0.717 (0.483, 1.753) 1.722 (1.283, 2.749) Change in GH (ng/mL)* Change from Baseline Change from End of Treatment Mean (95%CI) -0.100 (-0.486, 0.285) 1.511 (0.600, 2.422) Median (IQR) -0.049 (-0.289, 0.199) 0.721 (0.205, 1.915) p-value^ >0.6 <0.0001 Paltusotine Maintained GH Levels After Switching From Injected SRL Peptide Depots ^ p-values based on non-parametric Wilcoxon Signed Rank test of whether the median change is different from zero. *Calculated as mean and median of individual changes in integrated GH IQR: Interquartile Range: 25th , 75th percentile CRINETICS PHARMACEUTICALS | Conclusions GH levels after 13 weeks of paltusotine treatment did not significantly change from baseline levels when patients were previously treated with injected SRL depots (Group 1) Rise in GH after withdrawal characterized the magnitude of therapeutic activity of oral paltusotine
WEEK -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Paltusotine Treatment Screening Washout Washout Last SRL Depot Dose Rec’d Last Dose of Adjunct Meds Switch to paltusotine qd 10 mg 20 mg 30 mg 40 mg Number of patients at each dose level IGF at week 2 determines dose at week 4 IGF at week 5 determines dose at week 7 IGF at week 8 determines dose at week 10 10 mg n = 23 n = 20 n = 1 n = 2 n = 18 n = 1 n = 2 n = 2 n = 25 10 mg 20 mg 30 mg 40 mg 30 mg 20 mg 10 mg IGF>0.9 IGF>1.0 IGF>0.9 Dose escalation determined by central reader based on tolerability and IGF-1 (Site staff, patient, sponsor blinded to dose) ACROBAT Edge Dose Titration CRINETICS PHARMACEUTICALS | Most Group 1 patients up-titrated to the highest dose (40 mg) 20 mg
IGF-1 Levels Were Maintained After Switching to Paltusotine from Injected SRL Depots Potential dose increases (20, 30, 40 mg) if study drug tolerated and previous IGF-1 > 0.9 x ULN at week 2 and 5 or > 1.0 x ULN at week 8 Data presented are median (Interquartile Range [IQR]: 25th percentile, 75th percentile) from Group 1 patients in Acrobat Edge; Screening Period could range from 4-6 weeks. WD = Withdrawal, where 2 Wks after WD is defined as Week 15 or result within 7-21 days after last dose and 4 Wks after WD is defined as Week 17 or result at least 22 days after last dose. Paltusotine Treatment Screening Last Depot Dose Rec’d Washout Number of patients in Group 1 at each dose level n = 23 n = 20 n = 2 n = 18 n = 2 n = 2 n = 25 10 mg 20 mg 30 mg 40 mg 30 mg 20 mg CRINETICS PHARMACEUTICALS |
Switching to Once Daily Oral Paltusotine Maintained IGF-1 Levels in 87% of Group 1 Patients Individual patient percent change in IGF-1 at end of treatment vs. baseline and change at 4 weeks after withdrawal of paltusotine 20/231 patients (87%) who completed the dosing period achieved IGF-1 levels at EoT that were within 20% of baseline or lower 18/222 (82%) patients who completed the study showed a meaningful (>20%) rise from baseline in IGF-1 four weeks after withdrawal of paltusotine CRINETICS PHARMACEUTICALS | 1Two patients discontinued prior to the completion of the dosing period 2One patient discontinued during the washout period
Paltusotine Suppressed IGF-1 in Patients Previously Receiving Combination Therapy with Cabergoline Data presented are median (Interquartile Range [IQR]: 25th percentile, 75th percentile). EoT = End of Treatment defined as Week 13 (Visit 14) or last on treatment value carried forward (LOCF). WD = Withdrawal, where 2 Wks after WD is defined as Week 15 or result within 7-21 days after last dose and 4 Wks after WD is defined as Week 17 or result at least 22 days after last dose. Note: p-values are based on non-parametric Wilcoxon Signed Rank test of whether the median change is different from zero. Patients on SRL depots + oral cabergoline (Groups 2 and 3) Paltusotine contributed to IGF-1 lowering in patients previously treated with injected SRL peptide depots + oral cabergoline combination therapy Variable IGF-1 results were observed in Group 4 (n=4) and Group 5 (n=3) Patients represented by Groups 2-5 will not be included in Phase 3 program paltusotine contribution cabergoline contribution CRINETICS PHARMACEUTICALS |
WEEK -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Washout Paltusotine Treatment Screening Washout 10 mg Last Depot Dose Rec’d IGF IGF IGF * * Baseline IGF-1 W13 W15 W17 *Potential dose increases (20, 30 mg) if study drug tolerated and previous IGF-1 > 0.9 x ULN at week 2 or > 1.0 x ULN at week 5 Dose Titration Period paltusotine placebo Evolve Enrollment discontinued April 2020 Edge enrollment was complete at the time and interim results were positive Discontinuing Evolve enabled data to be available for end of Phase 2 regulatory interactions on Edge timeline 13 previously enrolled patients were allowed to complete participation in the study Reduced sample size did not allow for meaningful statistical comparisons between groups in the randomized withdrawal period Exposure response data were analyzed in conjunction with Edge Group 1 patients Randomize if IGF ≤ 1.0 Randomized Withdrawal Key Eligibility Criteria: Patients controlled (IGF-1 ≤ 1.0 x ULN on octreotide or lanreotide depot monotherapy 10 Endpoint: Proportion of responders (IGF ≤ 1.0x ULN) vs placebo at week 13 ACROBAT Evolve Trial Design Randomized, double-blind global clinical trial conducted at 44 clinical sites in 13 countries CRINETICS PHARMACEUTICALS |
WEEK -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Paltusotine Treatment Screening Washout Randomized Withdrawal Washout Last SRL Depot Dose Rec’d Switch to paltusotine qd Randomize if IGF ≤ 1.0 at wk 8 paltusotine Do not randomize if IGF > 1.0 x ULN at wk 8; continue on paltusotine Number of patients at each dose level IGF at week 2 determines dose at week 4 IGF at week 5 determines dose at week 7 Dose escalation determined by central reader based on tolerability and IGF-1 (site staff, patient, and sponsor blinded to dose) 10 mg 20 mg 30 mg IGF>0.9 IGF>0.9 n= 13 n=9 n= 3 n= 6 n= 3 n= 3 20 mg 10 mg 10 mg paltusotine Placebo ACROBAT Evolve Dose Titration CRINETICS PHARMACEUTICALS | Most patients did not reach the highest dose (30 mg)
Evolve Results Provided Additional Response Data at the Low End of the Dose Range Data presented are median (Interquartile Range [IQR]: 25th percentile, 75th percentile). Screening Period could range from 4-6 weeks. EoT = End of Treatment defined as Week 13 (Visit 14) or last on treatment value carried forward (LOCF). WD = Withdrawal, where 2 Wks after WD is defined as Week 15 or result within 7-21 days after last dose and 4 Wks after WD is defined as Week 17 or result at least 22 days after last dose. Randomized Withdrawal Titration Period Screening Last Depot Dose Rec’d Washout 10 mg 20 mg 30 mg n= 13 n=9 n= 3 n= 6 n= 3 n= 3 20 mg 10 mg 10 mg Randomize if IGF ≤ 1.0 at wk 8 Number of patients at each dose level CRINETICS PHARMACEUTICALS |
Post-Hoc Analysis of Edge (Group 1) and Evolve Provide Evidence of a Dose Response Steady state IGF-1 at the indicated dose: Patients were on the indicated dose for at least 12 days. Data prior to Week 7 were excluded because of insufficient washout of depot injection during this window. Data are shown from Week 7, Week 10, and Week 13. Data presented are median +/- IQR. EoT = End of Treatment defined as Week 13 (Visit 14) or last on treatment value carried forward (LOCF). WD = Withdrawal, where 2 Wks after WD is defined as Week 15 or result within 7-21 days after last dose and 4 Wks after WD is defined as Week 17 or result at least 22 days after last dose. One subject is missing 4 Weeks after withdrawal observation. Octreotide and lanreotide concentrations were measured 17 weeks after depot dose (W13 of the treatment period). Octreotide was completely washed out. Lanreotide concentrations were >75% reduced from baseline. Magnitude of Paltusotine Activity: Change in IGF-1 from Steady State to 4 Weeks After Withdrawal Results from Switching to Paltusotine: Change in IGF-1 from Baseline to Steady State at Indicated Dose CRINETICS PHARMACEUTICALS |
Paltusotine was Generally Well Tolerated Across Clinical Trials Treatment Emergent Adverse Events ≥ 5%* Edge/Evolve Patients (N=60) n (%) Healthy volunteers (N=128^) n (%) Common Acromegaly Symptoms Headache 19 (32%) 23 (18%) Arthralgia 15 (25%) 0 Fatigue 13 (22%) 6 (5%) Peripheral swelling 11 (18%) 0 Paraesthesia 10 (17%) 1 (1%) Hyperhidrosis 10 (17%) 0 Sleep apnoea syndrome 4 (7%) 0 Common SRL Side Effects Diarrhoea 5 (8%) 27 (21%) Abd pain/Abd pain upper 5 (8%)/2(3%) 25 (20%)/6(5%) Abdominal discomfort 4 (7%) 12 (9%) Abdominal distension 3 (5%) 7 (6%) Other Catheter site pain 0 9 (7%) Nausea 0 9 (7%) Back pain 5 (8%) 2 (2%) Dyspepsia 3 (5%) 0 Urinary tract infection 3 (5%) 0 *TEAEs include any AE that newly appears, increases in frequency, or worsens in severity following initiation of study drug through 28 days after last dose. ^ Treated with 1 or more doses of CRN00808.HCl as of 31 August 2020 Acrobat Edge and Evolve No study discontinuations due to adverse events No patients required rescue treatments with standard acromegaly medications during treatment No safety signals seen with vital signs No safety signals seen in clinical laboratories, including no amylase/lipase elevations > 3x ULN, HbA1c, LFTs, ECGs No treatment related SAEs; 2 non-treatment related SAEs: Nephrolithiasis: lithotripsy for pre-existing kidney stone Headache: admission for diagnostic evaluation CRINETICS PHARMACEUTICALS |
Primary endpoint achieved in Edge: Once daily oral paltusotine maintained IGF-1 levels at week 13 after switching from injected somatostatin receptor ligand (SRL) depots of octreotide or lanreotide [DIGF-1 =-0.034 (-0.107, 0.107), median (IQR1)] Both IGF-1 and GH levels promptly rose after withdrawing paltusotine which characterized the magnitude of therapeutic activity of oral paltusotine Paltusotine contributed to IGF-1 lowering in patients previously treated with injected SRLs + oral cabergoline combination therapy Post-hoc analysis of patients from both Edge (Group 1) and Evolve2 provided evidence of a dose response with higher doses being more effective Paltusotine was well tolerated Summary of ACROBAT Phase 2 Results 1Interquartile Range: 25th , 75th percentile 2Enrollment in ACROBAT Evolve was discontinued in April 2020. Previously enrolled patients continued in the study. Data from the Evolve patients (N=13) are included safety and dose-response analysis. CRINETICS PHARMACEUTICALS |
KOL webinar on November 20th to discuss acromegaly and ACROBAT results Update on improved formulation of paltusotine planned for use in Phase 3 Additional analysis of ACROBAT data including exposure/response and patient reported outcome (PRO) instruments to be presented at future medical meetings End-of-phase 2 meeting with FDA in 1Q 2021 Planned initiation of Phase 3 acromegaly program in 1H 2021 with to-be-marketed formulation Planned initiation of NETs trial in carcinoid syndrome in 2021 Paltusotine Development Program Plans CRINETICS PHARMACEUTICALS |
Paltusotine is Protected by a Strong IP Portfolio CRINETICS PHARMACEUTICALS | Multiple U.S. patents granted; national stage applications filed in 2017 Additional intellectual property protection Crinetics holds U.S. composition of matter patents for 3 additional classes of nonpeptide SST2 agonists Paltusotine is eligible for 7 years of market exclusivity upon approval (independent of patents) 2015 2020 2025 2030 2035 2040 2045 2050 2010 Pending Granted Composition of Matter U.S. 9,896,432; U.S. 10,351,547; U.S. 10,597,377 Expiration July 2037 New Formulation Provisional application pending Est. Expiration 2041 HCl Salt and its Polymorph Form U.S. 10,464,918 Expiration January 2039 Pending in foreign jurisdictions representing >96% of pharmaceutical markets Pending in foreign jurisdictions representing >96% of pharmaceutical markets Will be filed in foreign jurisdictions accordingly
Pipeline: Rare Disease Franchise in Endocrinology PROGRAM DISCOVERY PRECLIN PHASE 1 PHASE 2 PHASE 3 ANTICIPATED NEXT MILESTONE Paltusotine Acromegaly Neuroendocrine Tumors (NETs) End-of-Phase 2 meeting with FDA 1Q2021 Initiate Phase 3 acromegaly 1H 2021 Initiate Phase 2 in 2021 Oral ACTH Antagonist Cushing’s Disease, Congenital Adrenal Hyperplasia (CAH) Initiate Phase 1 late 2020/early 2021 CRN04777 Congenital Hyperinsulinism (CHI) Initiate Phase 1 early 2021 All product candidates discovered and developed internally. Global rights retained and no licensing obligations. CRINETICS PHARMACEUTICALS |
CRINETICS PHARMACEUTICALS |
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