UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
Emerging growth company
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Item 7.01 Regulation FD Disclosure.
During the week of January 9, 2023, Crinetics Pharmaceuticals, Inc. (the “Company” or “Crinetics”) will be attending meetings with investors, analysts and others at the 41st annual J.P. Morgan Healthcare Conference, which is taking place in San Francisco, CA from January 9-12, 2023. Scott Struthers, Ph.D., Founder & Chief Executive Officer of Crinetics, will present a company update on Wednesday, January 11th at 3:00 pm Pacific Time. A live audio webcast of Dr. Struthers’ presentation may be accessed on the Events section of the Company’s website or directly on the J.P. Morgan virtual meeting platform. During the presentation, the Company will reference the corporate slide presentation attached as Exhibit 99.1 to this Current Report on Form 8-K, which is incorporated herein by reference.
The presentation will feature an overview of Crinetics’ key priorities and anticipated milestones for 2023. These include:
Efforts to further increase commercial readiness so that the Company can rapidly provide patients with acromegaly with broad access to once-daily oral paltusotine, if approved.
The continued advancement of the Phase 2 trial of paltusotine in carcinoid syndrome, which remains on track for topline data in the second half of 2023.
Building off proof-of-concept Phase 1 results for CRN04894, an investigational adrenocorticotropic hormone (ACTH) antagonist, with the initiation of clinical trials in ACTH-dependent Cushing’s syndrome and congenital adrenal hyperplasia. Both studies are expected to begin in the first half of 2023.
The continued preclinical evaluation of investigational, oral small molecule parathyroid hormone receptor antagonists to identify a candidate for advancement into clinical trials. Initial target indications for this program may include primary hyperparathyroidism and hypercalcemia of malignancy, with potential opportunities in chronic kidney disease also being evaluated.
The Company’s updated corporate presentation has been posted to the Company’s website, www.crinetics.com . The Company plans to use its website to disseminate future updates to its corporate presentation and does not intend to file or furnish a Form 8-K alerting investors each time the presentation is updated.
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.
By filing this Current Report on Form 8-K and furnishing the information in this Item 7.01, the Company makes no admission as to the materiality of Item 7.01 in this report or the presentation available on the Company’s website. The information contained in the presentation is summary information that is intended to be considered in the context of the Company’s filings with the Securities and Exchange Commission (the “SEC”) and other public announcements that the Company makes, by press release or otherwise, from time to time. The Company undertakes no duty or obligation to publicly update or revise the information contained in this Current Report on Form 8-K, although it may do so from time to time as its management believes is appropriate or as required by applicable law. Any such updating may be made through the filing of other reports or documents with the SEC, through press releases, by updating the Company’s website or through other public disclosure.
Forward-Looking Statements
This report contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical facts contained in this report are forward-looking statements, including statements regarding the plans and timelines for the clinical development of paltusotine, CRN04777 and CRN04894, including the therapeutic potential and clinical benefits thereof; the expected timing of topline data from the ongoing Phase 3 clinical trials of paltusotine in acromegaly and Phase 2 trial of paltusotine in carcinoid syndrome; plans to submit data from the ongoing Phase 3 clinical trials of paltusotine in acromegaly to regulators in support of applications seeking approval for the use of paltusotine in acromegaly patients; the expected timing of the initiation of studies of CRN04894 in ACTH-dependent Cushing’s syndrome and congenital adrenal hyperplasia; plans to continue evaluation of investigational, oral small molecule parathyroid hormone receptor antagonists to identify a candidate for advancement into clinical trials; and plans to generate and develop additional small molecule new chemical entities with the potential to address nonfunctional pituitary adenomas, polycystic kidney disease, metabolic diseases and Graves’ Disease. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplates,” “believes,” “estimates,” “predicts,” “potential” or “continue” or the negative of these terms or other similar expressions. These forward-looking statements speak only as of the date of this report and are subject to a number of risks, uncertainties and assumptions, including, without limitation, topline data that we report may change following a more comprehensive review of the data related to the clinical trials and such 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; 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 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; unexpected adverse side effects or inadequate efficacy of the company’s product candidates that may limit their development, regulatory approval and/or commercialization; 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; regulatory developments in the United States and foreign countries; clinical trials and preclinical studies may not proceed at the time or in the manner expected, or at all; the timing and outcome of research, development and regulatory review is uncertain, and Crinetics’ drug candidates may not advance in development or be approved for marketing; Crinetics may use its capital resources sooner than expected; any future impacts to our business resulting from the conflict between Russia and Ukraine or other geopolitical developments outside our control; and the other risks and uncertainties described in the company’s periodic filings with the SEC. The events and circumstances reflected in the company’s forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Additional information on risks facing Crinetics can be found under the heading “Risk Factors” in Crinetics’ periodic reports, including its annual report on Form 10-K for the year ended December 31, 2021. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Except as required by applicable law, Crinetics does 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.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
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99.1 |
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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 thereunto duly authorized.
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Crinetics Pharmaceuticals, Inc. |
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Date: |
January 9, 2023 |
By: |
/s/ R. Scott Struthers, Ph.D. |
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R. Scott Struthers, Ph.D. |
Developing GPCR-targeted oral small molecules for endocrine disorders and endocrine-related tumors Corporate presentation January 2023 Exhibit 99.1
SAFE HARBOR STATEMENT This presentation contains forward-looking statements. Crinetics Pharmaceuticals, Inc. (“Crinetics”) cautions you that statements contained in this presentation 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 and patients with carcinoid syndrome; the potential for the PATHFNDR program to support registration of paltusotine for all acromegaly patients who require pharmacotherapy; the expected timing of topline data from the PATHFNDR-1 and PATHFNDR-2 trials and the Phase 2 trial in patients with carcinoid syndrome; the potential benefits of CRN04894 in patients across multiple indications and the expected plans and timing of the initiation of Phase 2 programs; the potential benefits of CRN04777 in patients with congenital or syndromic hyperinsulinism and the expected plans and timing of the initiation of a Phase 2 program; the potential benefits of PTH receptor antagonists for patients with hyperparathyroidism, the potential benefits of TSH antagonist for Graves’ Disease or Thyroid eye disease; the potential for any of our ongoing clinical trials to show safety or efficacy; the potential of our ongoing discovery efforts to target future indications for polycystic kidney disease, or diabetes/obesity; and our plans to identify and create new drug candidates for additional diseases. 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,” “laying the foundation,” “aspiring,” “target” 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: the risk that preliminary results of preclinical studies or clinical trials do not necessarily predict final results and that one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data, and as more patient data become available; potential delays in the commencement, enrollment and completion of clinical trials and the reporting of data therefrom; the FDA or other regulatory agencies may require additional clinical trials of paltusotine or suggest changes to our planned Phase 3 clinical trials prior to and in support of the approval of a New Drug Application or applicable foreign regulatory approval; 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, nonclinical studies and preclinical studies for paltusotine, CRN04894, CRN04777, our discovery efforts for hyperparathyroidism, polycystic kidney, Graves’ Disease & TED or diabetes/obesity product candidates; regulatory developments or price restrictions 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; our ability to obtain and maintain intellectual property protection for our product candidates; 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 (“SEC”). 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.
Building the World’s Premier Fully-Integrated Endocrine Company Leading GPCR drug discovery platform Global endocrinology clinical trial capabilities Two Phase 3 readouts expected in 2023 Pipeline: 3 product candidates with clinical POC Clinical POC in highly prevalent indications Global approvals for multiple products Fully integrated commercial capabilities Multiple programs in late clinical development Crinetics Today Crinetics Tomorrow Building a sustainable company to bring product after product to market by continuously innovating from discovery to commercialization GPCR: G protein-coupled receptor; POC: Proof-of-concept
Identify endocrine indications with unmet needs and well-understood targets Craft high quality, orally bioavailable, small molecule drug candidates Select best candidates with predictive endocrine biomarkers in preclinical models De-risk in healthy volunteers and then prove in patients with accepted hormone biomarker endpoints through registrational studies De-risk and Accelerate Time to POC with Crinetics’ Endocrine GPCR Discovery and Development Engine Well-Understood Targets Drug Discovery Expertise Highly Conserved Models Biomarker Development A fully integrated and reproducible strategy for crafting drug candidates and de-risking development programs against important, difficult and high value drug targets. POC: Proof-of-concept
Crinetics’ Discovery Laboratory Has Reproducibly Crafted Drug Candidates That Work Differentiation, speed and probability of success in drug discovery are determined by the teams operating these tools, the integrated strategies they employ, and the culture that drives them. Focused Team Med Chem In vivo biology Cellular biology DMPK Clinical input Discovery Guiding Principle: It’s the Team, not just the Tools Understanding the biology and medicine is key Every GPCR is different Every assay cascade is different No one technique will solve every challenge No checklist can capture what makes a compound into a drug Drug-hunter Culture
Approximately one-third of all approved drugs target GPCRs, but the majority of GPCR targets have been inaccessible.1 Many of these historically inaccessible endocrine GPCR targets possess: High-probability biology based on well characterized endocrine systems that are conserved across species, giving the ability to design early experiments that give highly translatable answers on both safety and efficacy (preclinical & clinical) High-value opportunities often addressing multiple highly prevalent indications Endocrine GPCRs: Wide Open Field with Many High Value Opportunities Acromegaly Neuroendocrine Tumors Hyperinsulinism Cushing’s Disease Congenital Adrenal Hyperplasia Hyperparathyroidism Polycystic Kidney Disease Graves’ Disease Thyroid Ophthalmopathy Diabetes Obesity Breast Cancer (RDNX) Other Endocrine Cancers (RDNX) Insulinoma Hypoglycemia Androgen Deficiency Infertility Thyroid Cancer Growth Hormone Deficiency Hypoparathyroidism NASH Nonfunctional Pituitary Adenomas … CRNX Targeting Today / Future Source: 1. Hauser AS, Chavali S, Masuho I, et al. 2018;172(1-2):41-54.e19. doi:10.1016/j.cell.2017.11.033 RDNX: Targeted by Radionetics Oncology
Building a Synergistic Commercial Product Portfolio With Growing Stream of Catalysts Program Discovery Preclin. Phase 1 Phase 2 Phase 3 Anticipated Milestones Paltusotine (SST2 agonist)* CRN04777 (SST5 agonist) CRN04894 (ACTH antagonist) PTH antagonist Undisclosed TSH antagonist Undisclosed (multiple) Crinetics is a known and trusted partner of the global endocrinology community who work with us on program after program Acromegaly (PATHFNDR-1) Carcinoid Syndrome Congenital Hyperinsulinism Hyperparathyroidism Polycystic Kidney Graves’ Disease & TED Diabetes/Obesity NEW high prevalence indications Acromegaly (PATHFNDR-2) Topline Results (3Q’23) Topline Results (4Q’23) Topline Results (2H’23) Cushing’s Disease Congenital Adrenal Hyperplasia Phase 2 Start (1Q’23) Phase 2 Start (1Q’23) Candidate Selection (2023) Candidate Selection (2023) *Partnered with Sanwa Kagaku Kenkyusho for development and commercialization in Japan; SST: Somatostatin receptor type; ACTH: Adrenocorticotropic hormone; PTH: Parathyroid hormone; TSH: Thyroid-stimulating hormone; TED: Thyroid eye disease
Technology spun out of CRNX in 2021 $30 million funding from 5AM Ventures and Frazier CRNX retains significant ownership Milestones in excess of $1B and single-digit royalties on net sales from technology license Emerging broad clinical pipeline in oncology Target 1: IND filing in an endocrine cancer in 1Q’23 with imaging POC in ’23 Target 2: IND filing in relapsed/refractory breast cancer in 4Q’23/1Q’24 Potent leads against multiple additional targets for major cancers Extending and Externalizing the Impact of our Discovery Engine to Novel Precision Targeted Radiopharmaceuticals
Paltusotine: A First-in-Class, Oral Small Molecule Somatostatin Receptor Ligand for Acromegaly and Carcinoid syndrome Building Development and Commercial Capabilities
What is Acromegaly? Acromegaly is caused by a benign pituitary tumor secreting excess growth hormone (GH) IGF-I GH Liver Somatotroph Adenoma Excess GH secretion by the pituitary gland causes excess IGF-1 secretion by the liver Somatostatin Receptor Ligands (SRLs) inhibit GH secretion Sources: http://www.fipapatients.org; Bex M, Abs R, T’Sjoen G, et al. Eur J Endocrinol. 2007;157(4):399-409; http://acromegalycommunity.com Headache Hyperhidrosis/oily skin Bone and cartilage overgrowth Organ enlargement Cardiovascular disease/hypertension Changes in glucose and lipid metabolism Abnormal growth of hands and feet Alteration of facial features Acromegaly Symptoms/Complications Uncontrolled acromegaly is debilitating and increases risk of early death
What are Neuroendocrine Tumors (NETs) and Carcinoid Syndrome? Diarrhea Flushing Difficulty breathing Tachycardia Carcinoid heart disease (valvulopathy) Carcinoid crisis (life threatening) Stomach Liver Pancreas Intestine NETs arise from neuroendocrine cells in GI tract, pancreas or lungs serotonin + other factors Carcinoid syndrome is caused by excess secretion of serotonin and other humoral factors secreted by NETs, resulting in severe diarrhea, flushing, and heart disease SRLs inhibit tumor secretion Carcinoid Syndrome Symptoms/Complications Carcinoid Syndrome
Sandostatin (octreotide) Somatuline (lanreotide) Sponsor Administration Monthly intramuscular injections 5-mL vial; 1½” 19-gauge needle Monthly deep subcutaneous injections .2-.5ml; 18-gauge needle Global Net Sales (2021) $1,400M1 $1,300M1 U.S. Net Sales (2021) $843M1 $893M2 Approval date(s) 1988, 1998(LAR) 2007 Somatostatin Receptor Ligands (SRLs) for Acromegaly and NETs are a $2.7B Established Market Sources: 1. Net sales sourced from sponsor earnings reports; 2. IQVIA reported U.S. Net sales
19-30% of NETs patients have Carcinoid Syndrome Paltusotine: Initial Multi-Billion Dollar U.S. Market Opportunity in Acromegaly and Carcinoid Syndrome Current Patients (On Endocrine Therapy*) Diagnosed Prevalence Addressable Patients (Candidates for SRL) Acromegaly (U.S. Patients) 27,000 11,000 10,000 Neuroendocrine Tumor (U.S. Patients) 175,000 Carcinoid Syndrome 33,000 11,000 Not cured surgically $700M $800M $70K Current Market for Endocrine Therapy (U.S.) Total Addressable Market for Endocrine Therapy (U.S.) Average WAC for Monthly Injectables $1,100M $3,200M $100K *Endocrine therapy includes SRLs, dopamine agonists, and growth hormone antagonists WAC: Wholesale acquisition cost; Sources: Company data on file
There are Treatment Challenges and a High Burden of Care with Currently Available SRLs Poor symptom control: 33 – 55% of acromegaly patients on injectable SRLs (octreotide/lanreotide) report worsening of symptoms at the end of each injection cycle1,2 Poor disease control: 42% of participants in a pivotal study of oral octreotide did not maintain IGF-1 biochemical response after switching from injectables3 The Crinetics Approach Efficacy Efficacy Crinetics Today Commercial Potential Tolerability Treatment-related injection site reactions reported by 77% of patients on monthly SRLs4 Gastrointestinal side effects reported by 74% of patients after SRL injections4 Why Endocrinology? Monthly SRL injections are painful and often are administered in a doctor’s office Oral octreotide requires two daily doses and fasting 1 hour before or 2 hours after administration Burden of Care SRL: Somatostatin receptor ligand; Sources: 1. Geer et al. BMC Endocrine Disorders, (2020) 20:117; 2. Strasburger et al. European Journal of Endocrinology, (2016) 174; MYCAPSSA label; 4. Fleseriu et al. Frontiers in Endocrinology; March 2021, Vol.12
Aspiring to bring the only once daily oral SRL to patients as a trusted member of the global endocrine community Properly Resourcing Commercial Functions Began building commercial team in Q1 2022 Making continued investments to inform a targeted and nimble market access plan Providing Value to Healthcare System Potential for reduced patient out of pocket costs At-home option reduces costs for payers compared to in-office administration At-home option saves resources for HCPs that would otherwise administer injections in-office Reducing the Burden on Patients* Once daily pill Consistent IGF-1 and symptom control Ship & store at room temperature Delivered to home Patient support services Ease of Adoption for Physicians* Confident IGF-1 control Simple dose selection: 40 mg or 60 mg (if needed) Low drug interaction risk Extensive data on switching from injectables HCP support services Laying the Foundation for a Successful Paltusotine Acromegaly Launch *Based on target product profile and company plans if paltusotine receives regulatory approval (clinical studies intended to demonstrate target product profile and support applications seeking regulatory approval are ongoing) HCP: Healthcare Provider
Diagnosis and Surgery Initiation of Pharmacotherapy Ongoing Assessment of Pharmacotherapy Concentrated Prescriber Bases at Key Stages of the Acromegaly Patient Journey in U.S. 200 endocrinologists in 40 pituitary centers write 80% of initial Rx’s 1,000 local endos write 80% of subsequent Rx’s for 10,000 patients 2,300 new patients/year 11,000 total addressable patients Dose Titration and Initial Management Payer Review and Authorization Source: Company data on file
SOC Injected SRL1 Untreated 2 Phase 2 Paltusotine Open Label Extension (OLE) Median IGF-1 ± IQR (x ULN) Acromegaly Patients on Paltusotine Maintained IGF-1 Levels for Up to Two Years in Open Label Study for Phase 2 Patients Eligible Phase 2 study participants opted to continue into the open label extension (OLE) 88% 89% OLE participants selected once-daily oral paltusotine as their preferred treatment option over injected standard-of-care(1) 43 43 43 0 42 0 39 2 37 3 37 3 10 6 27 6 31 5 21 6 38 3 # Patients Cumulative Discontinuations Week 3 15 31 39 51 103 77 64 90 47 1. SRL: Long-Acting Injected SRL baseline therapy during screening from Evolve/Edge Phase 2 studies before switching to paltusotine; 2.Untreated period following the Evolve/Edge Phase 2 studies when patients were washed out of paltusotine prior to starting the open label extension study; Source: Oral presentation, Gadelha, M. at the 35th Brazilian Congress of Endocrinology and Metabolism IGF-1 has been used as a registrational endpoint for acromegaly drugs
The Paltusotine Development Program Has Built a Global Development Capability for All Future Programs The Paltusotine Acromegaly Phase 3 Program is Designed to Support Potential, Broad First-Line Medical Therapy Label. Underway at ~100+ sites in Countries Around the World PATHFNDR-1: Switching from SOC Evaluate safety and efficacy of paltusotine in acromegaly patients switching from injectable octreotide or lanreotide depots, who are currently biochemically controlled (N=58, treatment duration 9 months, 1° endpoint: % responders vs placebo) PATHFNDR-2: Untreated Patients Evaluate safety and efficacy of paltusotine in untreated acromegaly patients who are biochemically uncontrolled (N=76, treatment duration 6 months, 1° endpoint: % responders vs placebo) PATHFNDR-1 enrollment was completed in October 2022 Topline data from both studies expected in 2H 2023 SOC: Standard of care
Carcinoid Syndrome: Label Expansion Opportunity for Paltusotine Key Eligibility Criteria Naïve or treated with octreotide or lanreotide Grade 1 or 2 NET Starting Dose: 40 mg Paltusotine (n=15) Starting Dose: 80 mg Paltusotine (n=15) Randomized Treatment Period: 8 weeks R 50 Week Extension Phase Dose range: 40 mg, 80 mg, or 120 mg Paltusotine dose adjusted as required Topline data expected in 2H 2023 Trial to be followed by a 50-week extension study for eligible patients Timelines Primary: Safety and Pharmacokinetics Assessments Secondary: Efficacy Assessments: Bowel movement frequency, flushing frequency, PRO measures, short-acting octreotide rescue use, 5-hydroxyindoleacetic acid (5-HIAA, serotonin metabolite) levels Objectives: Collect information needed for Phase 3 Design Ongoing Open-Label, Randomized, Phase 2 Trial in Patients with Carcinoid Syndrome NET: Neuroendocrine tumor; QD: Once daily; PRO: Patient reported outcome
Our Endocrine Franchise Is Expanding with Additional Product Candidates Entering Patient Trials CRN04894: A First-in-Class, Oral Small Molecule ACTH antagonist for Cushing’s Disease (CD) & Congenital Adrenal Hyperplasia (CAH) CRN04777: A First-in-Class, Oral Small Molecule SST5 Agonist for Hyperinsulinism
What is Cushing’s Disease? Cortisol ACTH Corticotroph Adenoma Excess ACTH secretion causes excess cortisol secretion by the adrenal Adrenal ACTH antagonist blocks the action of ACTH Cushing’s disease is caused by a benign pituitary tumor secreting excess ACTH Weight gain and fatty tissue deposits (midsection, face, shoulders) Stretch marks, thinning fragile skin, bruising, slow healing Reproductive dysfunction and hirsutism Fatigue, muscle weakness Emotional, cognitive or neuropsychiatric difficulties Hypertension Osteoporosis Cushing’s Symptoms/Complications Uncontrolled Cushing’s Disease is debilitating and increases risk of early death ACTH: Adrenocorticotropic hormone
What is Congenital Adrenal Hyperplasia (CAH)? CAH patients have too little cortisol resulting in excess ACTH and excess androgens Cortisol ACTH ACTH antagonist blocks the action of ACTH Adrenal X Androgens Low Cortisol: Low blood pressure, blood sugar, energy Adrenal crisis can be life threatening Androgen Excess Short stature, precocious puberty, acne Females: hirsutism, atypical genitalia, sex misassignment, menstrual dysfunction, infertility, acne, hair loss Males: adrenal rest tumors Over-treatment with Glucocorticoids can result in Cushing’s syndrome symptoms and signs Classic CAH Symptoms/Complications Uncontrolled CAH is debilitating and increases risk of early death ACTH: Adrenocorticotropic hormone
Requiring adjunct to GCs *No approved therapies to-date CRN04894: Initial Multi-Billion Dollar U.S. Market Opportunity in Cushing’s Disease and CAH $1,500M Current Patients (On Marketed Therapy) Diagnosed Prevalence Addressable Patients (Candidates for ‘4894) Cushing’s (U.S. Patients) 11,200 5,000 1,300 Total Addressable Market for Branded Therapy (U.S.) ~$2,500M CAH (U.S. Patients) 27,000 17,000 N/A* Surgery is non-curative Source: Company data on file.
Cortisol ACTH Pituitary Gland Pituitary Directed Agents to Suppress ACTH Secretion Available: glucocorticoids, pasireotide, cabergoline Limited efficacy Safety issues Target Cells Glucocorticoid Receptor Antagonist Available: mifepristone Efficacy difficult to assess Safety issues Adrenal Gland Adrenal Steroidogenesis Inhibitors Available: ketoconazole/ levoketoconazole metyrapone/osilodrostat, Limited Efficacy Safety Issues Low Adherence Current Therapeutics Have Limited Efficacy and/or Safety Issues, Leaving High Unmet Need Sources: Felders et al. Lancet Diab Endo 7:300-12, 2019. Castinetti JCEM 99: 1623-1639, 2014. Castinetti JCEM 106: 2114-2123, 2021. ACTH: Adrenocorticotropic hormone
CRN04894 Target Product Profile: Normalize Adrenal Cortisol Levels and Symptoms The only once daily oral ACTH receptor antagonist to normalize adrenal cortisol levels and get patients back to normal without toxicity monitoring requirements Cushing’s Disease Normalize cortisol levels (UFC) & symptoms Body weight & central obesity Hypertension QoL and neuropsychiatric effects No increase in androgens, hirsutism, acne Low risk of hypoadrenalism A once-daily oral medication Favorable profile for patient compliance No toxicity monitoring requirements No expected QTc prolongation / monitoring No expected liver toxicity / monitoring Congenital Adrenal Hyperplasia Reduce GC dosage to physiological levels Avoid body weight gain, hypertension, and neuropsychiatric effects Normalize adrenal androgens (e.g. A4) & symptoms: Women: menstruation, infertility, hirsutism Men: Reduce testicular adrenal rest tumor size, secondary gonadal failure
PBO (n=9) 40 mg (n=6) 60 mg (n=6) 80 mg (n=6) CRN04894 Potently Suppressed Adrenal Activity as Measured by Urinary Free Cortisol* 24-Hour Urinary Free Cortisol (day 9) Normalization of 24-hour urinary free cortisol has been the registrational endpoint for Cushing’s disease drugs -31% -72% -75% 3% *Results from Phase 1 clinical trial in healthy volunteers. Data shown are median ± IQR. Includes data from subjects receiving glucocorticoid rescue. UFC: Urinary free cortisol; CFB: Change from baseline; PBO: Placebo Source: Oral presentation, Krasner et al. at ENDO 2022
Open-Label Trial of CRN04894 in Patients with ACTH-Dependent Cushing’s Syndrome (ADCS) Screening/Washout: 14 Days Key Eligibility Criteria N = 18 ADCS: Cushing’s disease Ectopic ACTH syndrome Failed surgery or are awaiting surgery Treatment Periods: 3 cohorts, each 10 days Company-sponsored trial is being conducted in collaboration with the NIH Clinical Center Data expected in 2024 Collaborator & Timeline Primary Assessments: Safety and Pharmacokinetics Assessments Secondary Efficacy Assessments 24-hour urinary free cortisol: Change from baseline to Day 11 Percentage of patients who normalize 24-hour urinary free cortisol on Day 11 Early morning and 24-hour serum cortisol: Change from baseline to Day 11 Objectives: Collect information needed for Phase 3 Design 80 mg QD (n=6) 120 mg QD (n=6) 160 mg QD (n=6) Sequential Multiple Ascending Dose Cohorts up to 160 mg QD QD: Once daily
Proposed Open-Label Trial of CRN04894 in Patients with Congenital Adrenal Hyperplasia (CAH) Screening: 4 weeks Key Eligibility Criteria N = 18-30 Participants with CAH and high A4 (≥1.5xULN) at screening Age: ≥16 years Treatment Periods: 3 cohorts (one optional), each 12 weeks SRC review of 3 patients at week 2 prior to dose escalation in next cohort Data expected in 2024 Timeline Primary Efficacy Assessment: Change from baseline in morning serum A4 at week 12 Secondary Efficacy Assessment: Change from baseline in morning serum 17 hydroxyprogesterone (17-OHP) at week 12 Primary Safety Assessment: Incidence of TEAEs Objectives: Collect information needed for Phase 3 Design 80 mg QD (n=6-12) 120 mg QD (n=6-12) Sequential Multiple Ascending Dose Cohorts up to 160 mg QD; GC therapy maintained through trial GC: Glucocorticoid; A4: Androstenedione; ULN: Upper limit of normal; QD: Once daily; SRC: Safety review committee; TEAE: Treatment emergent adverse event SRC review SRC review Optional cohort 160 mg QD (n=6)
What is Congenital Hyperinsulinism (CHI)? Excess insulin produces life-threatening hypoglycemia (low blood glucose) Pancreas Liver Tissues Insulin (b-cells) Glucose Release Glucose Uptake Glucagon (a-cells) X Pancreatic Beta-cell mutations cause inappropriate insulin secretion Inappropriate insulin causes hypoglycemia Recurrent hypoglycemia episodes lead to: Neurodevelopmental/behavior disorders (26-48% of patients) Epilepsy/seizures Severe hypoglycemia can lead to coma and death SST5 agonist blocks the secretion of insulin 1. Meissner T, et al..2003. Eur J Endocrinol. 149(1):43–51.; 2. Menni F, et al. 2001. Pediatrics, 107: 476-79 3. Lord K, et al. 2015. High Risk of Diabetes and Neurobehavioral Deficits in Individuals With Surgically Treated Hyperinsulinism J Clin Endocrinol Metab.100(11):4133– 4139. SST5: Somatostatin receptor type 5
CRN04777: Initial Meaningful Market Opportunity in Congenital and Syndromic Hyperinsulinism Source: Company data on file Diagnosed Prevalence Addressable Congenital HI (U.S. Patients) 2,200 1,500 ? Not cured surgically ? Syndromic HI (U.S. Patients) 1,700 1,700 Diagnosed Prevalence CHI Hypoglycemia Seizure ER Inpatient Outpatient Diazoxide Glucagon HGH Dextrose Genetic Testing PET/MRI Claims history from baby girl born in 2014. Original CHI diagnosis 12/2014, first Diazoxide Tx 3/161. Each shape and associated time stamp represents a medical claim over 5 years Total Addressable Market for Branded Therapy (U.S.) ~$960M High unmet medical need and high healthcare system burden remain with current standard of care
Treatment Challenges and High Burden of Care with Currently Available CHI Therapies Safety, efficacy, & route of administration all need better options Medical Diazoxide Ineffective in ~50% of patients; black box warning Injectable SST2 agonists Tachyphylaxis, no pediatric dosing guidelines, painful Glucose Support IV glucose Enteral dextrose Surgical Pancreatectomy (complete or partial) Type 1 diabetes likely if complete resection successful Rescue Injectable glucagon analogs SST2: Somatostatin receptor type 2
CRN04777 Target Product Profile Designed for Kids, Their Caregivers, and the Healthcare System Bringing the only kid friendly, once daily oral therapy to patients as a trusted member of the global CHI community Kid and Family Friendly Raspberry flavored sweetened syrup taken orally Take with breakfast once a day Minimize doctor visits Delivered to home Patient/caregiver support services Laying Foundations for Global Access Strong engagement with global patient groups Strong engagement with global centers of excellence Global clinical development plan Ease of Adoption for Physicians Effective for all patients with hyperinsulinism Confident hypoglycemia prevention Simple dose adjustment based on glucose Minimal drug-drug interactions HCP support services Providing Value to Healthcare System Potential for reduced patient out of pocket costs At-home option reduces costs for payers compared to in-office administration Prevent expensive hospitalizations Prevent life-long complications HCP: Healthcare provider
CRN04777 Reduced Insulin Secretion & IV Glucose Support in Healthy Volunteer Model of HI# -76% -83% -97% Change in Glucose Infusion Rate % Insulin Reduction Compared to Baseline Change in Insulin %Glucose Infusion Rate Reduction Compared to Baseline * * #Data on file from a Phase 1 trial in healthy volunteers; Data shown are mean ± SEM, reduction of each subject’s AUC on Day 10 vs. baseline (Day -2); HI: Hyperinsulinism; QD: once daily; * n=1 subject withdrew consent (not treatment related);
Our GPCR Discovery and Development Engine Is Continuing to Craft and advance new assets Targeting highly prevalent endocrine disorders with a favorable probability of success
* The portion of each market that could be addressable will depend on relevant indication subpopulations and clinical development plans pursued Sources: Company data on file Current Clinical Pipeline Future Opportunity Paltusotine ‘4777 ‘4894 $820Mn $3,200Mn $960Mn $1,500Mn $2,500Mn $23Bn $84Bn $16Bn $65Bn+ PTH Antagonist TSH Antagonist Undisclosed Target Undisclosed Targets Growing Franchise Addresses Multi-Billion Dollar Market Opportunity Across Endocrinology
Investment Highlights: Expected Milestones and Financial Position Strong Financial Position to Execute Through 2024 $368.4 million in cash & investments as of September 30, 2022 3Q23 PATHFNDR-1 Topline Data 4Q23 PATHFNDR-2 Topline Data 2H23 Carcinoid syndrome P2 data 2023 New drug candidates from discovery efforts Acromegaly NDA Submission Cushing’s Disease P2 data Congenital Adrenal Hyperplasia P2 data New drug candidates from discovery efforts 2023 2024 TED: Thyroid eye disease; NDA: New drug application