Rain Oncology (RAIN) - 2022 Q4 - Annual Report

PART I Rain Oncology Inc. is a late-stage precision oncology company developing tumor-agnostic therapies for oncogenic drivers Item 1. Business Rain Oncology Inc. is a late-stage precision oncology company focused on developing therapies targeting oncogenic drivers, primarily through a tumor-agnostic strategy. Its lead product candidate, milademetan, an oral MDM2 inhibitor, is in pivotal Phase 3 trials for liposarcoma (LPS) and Phase 2 for MDM2-amplified solid tumors, with a Phase 1/2 combination trial planned. The company relies on in-licensed assets, third-party manufacturing, and aims for global regulatory approvals, while discontinuing other preclinical programs to focus resources Company Overview - Rain Oncology Inc. is a late-stage precision oncology company developing therapies that target oncogenic drivers, using a tumor-agnostic strategy[18] - Milademetan (RAIN-32), an oral MDM2 inhibitor, is the lead product candidate, in-licensed from Daiichi Sankyo in September 2020[19] - A pivotal Phase 3 trial in LPS (MANTRA) commenced in July 2021 with topline data expected in Q2 2023, and a Phase 2 tumor-agnostic basket trial (MANTRA-2) started in November 2021. A Phase 1/2 combination trial (MANTRA-4) is anticipated in mid-2023[19] Our Strategy - Rapidly advance milademetan through clinical development towards approval in LPS and expansion across MDM2-dependent tumors, engaging regulatory authorities for potential commercial launch[20] - Increase the probability of clinical benefit by utilizing biomarker-driven patient selection through comprehensive next-generation sequencing (NGS) diagnostic tests[20] - Maximize commercial success by focusing on tumor-agnostic clinical trials, leveraging existing NGS for rapid patient enrollment and data collection[20] - Expand the precision oncology pipeline by identifying novel oncogenic drivers, improving existing therapies with narrow therapeutic windows, and targeting emerging classes like synthetic lethality[24] Overview of Precision Oncology and Our Approach - Precision oncology harnesses tumor biology to design effective cancer treatments, with recent advancements in companion diagnostics and multi-gene NGS assays facilitating biomarker identification[22] - The company's approach prioritizes a tumor's biological driver over its type for treatment selection, focusing on therapeutics that target genetic alterations in cell-signaling pathways[23] - Key pillars for successful programs include targeting unambiguous oncogenic addiction, achieving sufficient therapeutic exposure, and strong target engagement during dosing[28] Our Development Pipeline - Rain Oncology retains global development and commercialization rights to all its product candidates, unified by a strategy to target oncogenic drivers[26] Milademetan (RAIN-32) Clinical Development Pipeline | INDICATION | MANTRA | PRECLINICAL | PHASE 1 | PHASE 2 | PHASE 3 | PARTNER | PLANNED DATA | | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | | DD Liposarcoma | - | Mila monotherapy | | Enrollment Completed | | | 2Q 2023 | | MDM2-amp Basket | 2 | Mila monotherapy | Enrolling | | | | | | CDKN2A loss, p53 WT Adv Solid Tumors | ব | Mila + atezolizumab | Planned: Mid 2023 | | | Roche | | Our Lead Product Candidate, Milademetan - Milademetan is an oral MDM2 inhibitor developed for MDM2-dependent cancers, utilizing a rationally designed dosing schedule to mitigate hematologic toxicities and widen the therapeutic window[29] - Milademetan reactivates p53 by inhibiting MDM2, targeting tumors with wild-type p53 that is functionally suppressed by MDM2 overexpression[30][31] - Phase 1 clinical data showed meaningful antitumor activity in MDM2-amplified liposarcoma (LPS) and other solid tumors, with a 58.5% disease control rate in LPS patients[32][35] - The pivotal Phase 3 MANTRA trial in DDLPS completed enrollment in August 2022, with topline data expected in Q2 2023. The Phase 2 MANTRA-2 trial for MDM2-amplified solid tumors showed preliminary unconfirmed partial responses in pancreatic and lung cancer[42][45] - A Phase 1/2 MANTRA-4 trial evaluating milademetan in combination with atezolizumab for CDKN2A loss and wildtype p53 advanced solid tumors is planned for mid-2023, based on nonclinical data[47][50] - The Phase 2 MANTRA-3 trial in Merkel cell carcinoma has been deprioritized to rationalize capital use[46] Preclinical RAD52 Program - The preclinical program targeting RAD52 in the DNA damage repair pathway was discontinued in February 2023 to focus financial and personnel resources on the milademetan clinical program[51][62] Collaboration and License Agreements - The company holds an exclusive worldwide license for milademetan from Daiichi Sankyo, involving an initial $5.0 million upfront payment and potential future milestone payments up to $223.5 million, plus high single-digit royalties on net sales[52][54][58] - A $5.5 million milestone fee was recorded in 2021 for the MANTRA Phase 3 trial initiation, later reduced by $1.0 million in 2022, with the remaining $2.0 million due by June 30, 2023[54][55] - A clinical supply agreement with Roche provides atezolizumab for combination trials (MANTRA-4), with Rain Oncology as the sponsor and no financial commitments to Roche[63] - The Drexel License Agreement for RAD52 inhibitors was terminated in February 2023 to reallocate resources to the milademetan program[61][62] Manufacturing and Supply - The company relies entirely on third-party contract manufacturing organizations (CMOs) for the manufacture of drug candidates for preclinical, clinical, and potential commercial supplies[64][65] - Manufacturing processes, including those transferred from Daiichi Sankyo, are subject to extensive regulations, including Current Good Manufacturing Practice (cGMP) requirements and periodic FDA inspections[67][68] Intellectual Property - The company protects its proprietary technologies through patents, trademarks, trade secrets, know-how, and in-licensing, focusing on composition of matter, methods of use, and related technologies for product candidates[69] - As of December 31, 2022, the milademetan patent portfolio, exclusively licensed from Daiichi Sankyo, includes 14 issued U.S. patents, over 100 issued foreign patents, and numerous pending applications, with expected expirations between 2032 and 2037[74][75] - Patent terms are generally 20 years from filing, with potential for extensions (e.g., Hatch-Waxman Act in the U.S.) to compensate for regulatory review periods, though such extensions are not guaranteed[77][78] - Trade secret protection and confidentiality agreements are also utilized for proprietary information not amenable to patent protection, though these can be challenging to enforce[80] Government Regulations - Drug development and commercialization are subject to extensive regulation by authorities like the FDA in the U.S. and EMA in Europe, covering research, testing, approval, manufacturing, and marketing[81][132] - The U.S. regulatory process involves preclinical studies (GLP), IND applications, multi-phase human clinical trials (cGCP), and New Drug Application (NDA) submission and review, with potential for expedited programs like Orphan Drug, Fast Track, Breakthrough Therapy, and Accelerated Approval[82][84][86][88][96][105][110][113][114] - In the EU, clinical trials are governed by the Clinical Trials Regulation (CTR), and marketing authorization requires compliance with EMA procedures, with provisions for data and market exclusivity (e.g., 8+2 years for New Chemical Entities) and Orphan