IDEAYA Biosciences(IDYA) - 2019 Q4 - Annual Report

Product Development and Clinical Trials - The lead product candidate, IDE196, is a PKC inhibitor targeting genetically-defined cancers with GNAQ or GNA11 mutations, currently in a Phase 1/2 clinical trial[15]. - As of March 15, 2020, a total of 53 patients have been enrolled in the IDE196 monotherapy arm for metastatic uveal melanoma, with 49 patients specifically having GNAQ or GNA11 mutations[26]. - The Phase 2 monotherapy dose for IDE196 has been set at 400 mg BID, which has shown a 44% increase in average steady state exposure and a 40% increase in trough concentration compared to the 300 mg BID dose[26]. - The company plans to submit an IND for the MAT2A program targeting solid tumors with MTAP deletions in Q4 2020, representing a significant advancement in their synthetic lethality pipeline[16]. - The synthetic lethality program targeting Pol-theta for tumors with homologous recombination deficiency is expected to designate a development candidate in the second half of 2020[32]. - The company is collaborating with Pfizer to evaluate the safety and efficacy of IDE196 in combination with binimetinib in patients with tumors harboring GNAQ or GNA11 mutations, targeting to initiate this trial in mid-2020[15]. - The ongoing Phase 1/2 basket trial will continue to focus on patients with tumors having activating GNAQ or GNA11 hotspot mutations, while plans for other indications have been suspended due to lack of supporting data[50]. - A Phase 1 sub-study initiated in January 2020 is evaluating an immediate release tablet formulation of IDE196, with ongoing enrollment to assess pharmacokinetic properties[40]. - The FDA indicated that a proposed single-arm Phase 2 portion of the IDE196-001 trial may support a new drug application for accelerated approval in MUM, targeting enrollment of 60 evaluable patients[48]. - IDE196 was initially developed by Novartis, which completed enrollment of 68 patients in a Phase 1 clinical trial for metastatic uveal melanoma as of December 31, 2019[47]. Market and Competitive Landscape - Approximately 90% of uveal melanoma patients have activating mutations in GNAQ or GNA11, with an estimated annual incidence of about 3,500 cases of metastatic uveal melanoma in major market countries[34]. - The median overall survival for untreated patients with metastatic uveal melanoma is approximately 2 to 8 months, with historical response rates ranging from 0% to 10% across treatment types[35]. - The company faces potential competition from lower-priced products in foreign markets due to price controls on pharmaceuticals[183]. - Third-party payors are increasingly reducing reimbursements for medical products, which could adversely affect sales[182]. Intellectual Property and Collaborations - As of March 15, 2020, the company holds approximately 19 distinct patent families, including four issued U.S. patents and 47 pending foreign applications across 31 jurisdictions, with nominal expirations ranging from 2035 to 2040[87]. - The IDE196 portfolio includes three issued U.S. patents and approximately 31 pending applications, with a nominal expiration in 2035, and three pending U.S. applications solely owned by the company expiring in 2040[88]. - The company has entered into a clinical trial collaboration with Pfizer to evaluate IDE196 in combination with binimetinib, targeting a Phase 1/2 clinical trial initiation in mid-2020[93]. - The exclusive option and license agreement with Cancer Research UK allows the company to develop PARG inhibitors, with the option period extended for up to four additional years[111]. - The collaboration with Cancer Research UK includes a joint research committee to govern non-clinical research activities, with a focus on PARG inhibitors[110]. Financial Overview and Funding - As of December 31, 2019, the company had cash equivalents and marketable securities totaling $100.4 million[519]. - The license agreement with Novartis includes an upfront payment of $2.5 million and potential milestone payments totaling up to $29 million, along with tiered royalty payments based on annual worldwide net sales[103]. - The company plans to pay an upfront fee of £100,000 and, if the option is exercised, an additional one-time fee of £250,000, with potential milestone payments totaling up to £28.5 million per indication[117]. Regulatory Environment - The FDA review process for a new drug application (NDA) typically takes about 10 months from the date of filing, with a goal of 12 months for a complete review[140]. - The FDA may refer a novel drug application to an advisory committee for independent evaluation and recommendations[141]. - An approval letter from the FDA authorizes commercial marketing, while a Complete Response Letter indicates deficiencies that must be addressed before approval[142]. - Orphan drug designation can provide exclusivity for seven years if the product receives FDA approval for the designated rare disease[147]. - The FDA's fast track designation allows for rolling review of NDA sections, expediting the approval process for drugs addressing serious conditions[148]. - Priority review aims to expedite applications that offer significant improvements over existing therapies, with a target review time of six months[149]. - Accelerated approval may be granted based on surrogate endpoints that predict clinical benefit, with post-marketing trials required[150]. - Breakthrough therapy designation provides intensive FDA guidance and expedited development for drugs showing substantial improvement over existing therapies[151]. Research and Development - The company is leveraging technological innovations and regulatory developments to enhance patient selection for their precision medicine approach[17]. - The team comprises experienced professionals from leading oncology organizations, guided by a scientific advisory board of key thought leaders[18]. - The company aims to establish a leading franchise in synthetic lethality by broadening its pipeline of targeted therapies and collaborating with diagnostic leaders[20]. - The prevalence of MTAP deletions is approximately 15% of all human tumors, translating to an estimated addressable population of about 90,000 annually in major market countries (US, EU5, Japan) for patients with solid tumors with MTAP deletion[59]. - The company has observed significant reduction in tumor SAM levels in terminal samples from preclinical in vivo studies following treatment with the lead MAT2A inhibitor[60]. - The lead MAT2A inhibitor is reported to be over 20 times more potent than Agios compound AGI-25696 in an engineered HCT-116 MTAP -/- xenograft model[63]. - The company expects to designate a Pol-theta inhibitor development candidate in the second half of 2020[68]. - High microsatellite instability (MSI) is present in about 15% of gastrointestinal tumor cancers, including approximately 22% of stomach adenocarcinoma and 16% of colorectal cancer[70]. - The company has identified potent, selective PARG inhibitors exhibiting a dose-dependent cellular pharmacodynamic response in a HCC1806 XRCC1 -/- cell line[76]. - The company is collaborating with several academic and research institutions to evaluate in vivo efficacy of PARG inhibitors in relevant animal models[77]. - The company has solved the crystal structure of the Pol-theta ATPase domain, enabling ongoing structure-based drug design[66]. - The company has observed synergistic in vitro and in vivo combination activity with a PARPi, Olaparib, in the DLD1 BRCA2 -/- engineered xenograft model[67]. - The company is targeting to demonstrate in vivo proof of concept for small molecule inhibitors of the WRN helicase protein in relevant animal models in 2020[73]. Manufacturing and Commercialization - The company is responsible for the manufacturing and commercialization of licensed products under the Novartis agreement, with obligations to supply IDE196 for compassionate use programs[100]. - The company currently relies on third parties for the manufacture of product candidates and biomarker diagnostics, with no plans to establish its own manufacturing facilities[123]. - For the product candidate IDE196, the company has contractual rights to API supply from Novartis, which will support ongoing preclinical research and clinical development efforts[125]. - The company plans to establish agreements with contract manufacturing organizations (CMOs) for the synthesis and manufacturing of drug products[124]. - The company holds worldwide commercialization rights to its product candidates and aims to retain significant rights in key markets[120]. - The company intends to build its own sales force to commercialize approved products in the U.S. and potentially in Europe, with plans to initiate commercial readiness activities[121].