Kura Oncology(KURA) - 2023 Q4 - Annual Report

FORM 10-K Filing Information Filing Details Provides basic filing information for Kura Oncology, Inc.'s Annual Report on Form 10-K for FY2023 - The filing is an Annual Report on Form 10-K for the fiscal year ended December 31, 2023, filed by KURA ONCOLOGY, INC[2] Registrant Information | Field | Value | | :--- | :--- | | Registrant Name | KURA ONCOLOGY, INC. | | State of Incorporation | Delaware | | IRS Employer ID No. | 61-1547851 | | Telephone Number | (858) 500-8800 | | Trading Symbol | KURA | | Exchange Registered | The Nasdaq Global Select Market | | Well-known seasoned issuer | Yes | | Large accelerated filer | Yes | | Market Value of Non-Affiliate Common Equity (as of June 30, 2023) | ~$776.5 million | | Outstanding Shares (as of Feb 20, 2024) | 76,136,963 shares | Forward-Looking Statements Nature of Forward-Looking Statements Cautions that the report contains forward-looking statements with inherent uncertainties and risks that may cause actual results to differ - The report includes forward-looking statements related to future events or financial performance, identified by words like 'believe,' 'expect,' 'anticipate,' 'estimate,' 'intend,' 'may,' 'plan,' 'potential,' 'predict,' 'project,' 'targets,' 'likely,' 'will,' 'would,' 'could,' 'should,' 'continue,' and similar expressions[13] - Readers are cautioned not to place undue reliance on these statements, as actual results or events could differ materially due to known and unknown risks and uncertainties, particularly those discussed in the 'Risk Factors' section[13][15] Key Areas of Forward-Looking Statements Forward-looking statements encompass R&D, regulatory approvals, commercialization, IP, financing, and personnel aspects of operations - Initiation, cost, timing, progress, and results of R&D activities, clinical trials, and preclinical studies - Ability to obtain and maintain regulatory approval for product candidates, including any clinical holds or restrictions - Plans to research, develop, and commercialize future product candidates - Ability to attract collaborators with development, regulatory, and commercialization expertise - Ability to obtain and maintain intellectual property protection for product candidates - Ability to successfully commercialize product candidates and the rate/degree of market acceptance - Size and growth of markets for product candidates and ability to serve them - Success of competing drugs, government regulation, and regulatory developments - Performance of third-party suppliers and manufacturers and ability to obtain alternative raw materials - Ability to obtain additional financing and use of cash, capital requirements, and need for additional financing - Ability to attract and retain key management, scientific, or clinical personnel - Impact of geopolitical events and public health epidemics/pandemics on business and operations[14] Risk Factor Summary Overview of Key Risks Summarizes significant risks including ziftomenib dependence, clinical development challenges, financial sustainability, third-party reliance, and market competition - High dependence on the success of ziftomenib, which is still in clinical development and may not receive regulatory approval - Focus on targeted therapeutics for genetically defined cancers is a rapidly evolving area with uncertain outcomes - Clinical drug development is lengthy, expensive, and uncertain; preclinical/early clinical results may not predict final outcomes, potentially leading to delays or additional costs - Product candidates may be used in combination with third-party drugs, over which the company has limited control regarding supply or regulatory status - Potential for serious adverse events or unacceptable side effects from product candidates could delay or prevent development - Failure to develop, validate, and obtain regulatory approval for diagnostic testing platforms could harm drug development strategy - Expectation to incur losses and may never achieve profitability, being a clinical-stage company with no approved products or historical product revenue - Need for substantial additional capital, which may cause stockholder dilution or restrict operations - Reliance on third-party contractors for clinical trials and material supply, with risks of unsatisfactory performance or missed deadlines - Inability or delays in obtaining required regulatory approvals could materially impair revenue generation - Extensive post-approval regulatory requirements and potential for product withdrawal or penalties for non-compliance - Inability to obtain/maintain intellectual property protection or insufficient scope could allow competitors to commercialize similar products - Dependence on licensors to prosecute and maintain material patents and patent applications - Inadequate patent terms to protect competitive position for a commercially meaningful time - Challenges in obtaining or maintaining necessary third-party intellectual property rights through acquisitions and in-licenses - Harm to business and competitive position if trade secrets or confidential information are not maintained - Even with marketing approval, product candidates may fail to achieve sufficient market acceptance - Lack of sales personnel and potential inability to establish effective sales capabilities or third-party agreements - Substantial competition from other companies developing or commercializing competing products - High dependence on the Chief Executive Officer and ability to attract/retain qualified personnel - Significant fluctuation and volatility in stock price, influenced by numerous factors beyond control[18][20] PART I Item 1. Business Kura Oncology is a clinical-stage biopharmaceutical company developing precision cancer medicines with a pipeline of three small molecule candidates - Kura Oncology is a clinical-stage biopharmaceutical company dedicated to precision cancer medicines, with a pipeline of small molecule product candidates (ziftomenib, tipifarnib, KO-2806) targeting cancer signaling pathways[19] - The company's strategy includes pairing product candidates with molecular or cellular diagnostics to identify responsive patients, advancing development through internal efforts and strategic partnerships, and retaining significant development and commercial rights globally[19][48] Overview Kura Oncology is a clinical-stage biopharmaceutical company focused on precision cancer medicines with a pipeline of small molecule candidates - Kura Oncology is a clinical-stage biopharmaceutical company focused on precision medicines for cancer, with a pipeline of small molecule product candidates (ziftomenib, tipifarnib, KO-2806) in clinical trials and additional discovery programs[19] - The company owns global commercial rights to all its programs and product candidates and plans to advance them through internal development and strategic partnerships[19] Ziftomenib Ziftomenib is an oral menin-KMT2A inhibitor, an orphan drug for AML, showing promising clinical trial results - Ziftomenib is an oral small molecule inhibitor blocking menin-KMT2A interaction, designated as an orphan drug for AML by the FDA in July 2019[21][22] - KOMET-001 (Phase 1/2 in relapsed/refractory AML): * Phase 1a showed wide therapeutic window and encouraging monotherapy activity in 30 patients * Phase 1b (53 patients) identified 600 mg as the recommended Phase 2 dose (RP2D) * Updated data (April 12, 2023 cutoff) showed 35% complete remission (CR) rate in NPM1-mutant AML patients (7/20) at 600 mg RP2D * Overall Response Rate (ORR) was 45% in NPM1-mutant AML patients at 600 mg dose * Median Duration of Response (DoR) for NPM1-mutant patients (200 mg or 600 mg) was 8.2 months (median follow-up 8.8 months) * Resistance mutation MEN1-M3271 detected in 3% (1/29) of patients post-treatment, suggesting low frequency of acquired resistance * Well-tolerated with manageable differentiation syndrome (DS) (15% Grade 1/2, 5% Grade 3)[22][23][24][25][26][27][28] - KOMET-007 (Combination Study): * Initiated in Q3 2023, evaluating ziftomenib with venetoclax/azacitidine (relapsed/refractory AML) and with 7+3 (newly diagnosed AML) * Preliminary data (Jan 11, 2024 cutoff) from first 20 patients: 100% CR rate (5/5) in newly diagnosed AML patients treated with ziftomenib and 7+3 * ORR of 53% (8/15) in relapsed/refractory patients treated with ziftomenib and venetoclax/azacitidine * Well-tolerated at 200 mg, no DS events, dose-limiting toxicities, QTc prolongation, drug-drug interactions, or additive myelosuppression reported[29][30][31][32] - KOMET-008 (Combination Study): * Initiated Feb 26, 2024, evaluating ziftomenib with gilteritinib or FLAG-IDA/LDAC in relapsed/refractory NPM1-mutant or KMT2A-rearranged AML[33][34] - Other Studies: * Phase 2 registration-directed portion of KOMET-001 for relapsed/refractory NPM1-mutant AML enrollment expected by mid-2024 * Sub-studies in ALL and non-NPM1-mutant/non-KMT2A-rearranged AML initiated in Q1 2024 and expected by mid-2024, respectively * Post-transplant maintenance program for NPM1-mutant or KMT2A-rearranged AML expected in Q1 2024 * Clinical collaboration with LLS for pediatric acute leukemia study announced Dec 8, 2023[35][36] Tipifarnib Tipifarnib, an oral farnesyl transferase inhibitor, received Breakthrough Therapy Designation for HRAS mutant HNSCC - Tipifarnib, an orally bioavailable farnesyl transferase inhibitor (FTI), received Breakthrough Therapy Designation from the FDA in February 2021 for recurrent or metastatic HRAS mutant HNSCC with high VAF[37][38] - A clinical collaboration with Novartis was announced in July 2021 to evaluate tipifarnib in combination with alpelisib (PI3 kinase alpha inhibitor) in HNSCC patients (KURRENT-HN trial), with dose escalation ongoing and optimal biologically active dose (OBAD) expected by end of 2024[39] KO-2806 KO-2806 is a next-generation FTI with improved properties, currently in Phase 1 trials for advanced solid tumors - KO-2806 is a next-generation FTI designed for improved potency and pharmacokinetic properties, with its IND application for advanced solid tumors cleared by the FDA in January 2023[40] - Preclinical data in 2023 supported KO-2806 development in combination with targeted therapies, including TKIs in ccRCC and KRAS G12C/G12D inhibitors in NSCLC[41][42] - Combination with adagrasib in KRAS G12C-mutant NSCLC models showed deepened signaling inhibition, tumor regressions, and enhanced duration/depth of antitumor response[43][44] - Phase 1 FIT-001 trial initiated in October 2023 for monotherapy, with combination cohorts (KO-2806 + cabozantinib in ccRCC, KO-2806 + adagrasib in KRAS G12C-mutant NSCLC) anticipated by mid-2024[45][46][47] Our Strategy The company's strategy focuses on developing novel small molecule cancer candidates, leveraging diagnostics, and pursuing rational combinations - Focus on developing novel, small molecule product candidates for cancer - Identify molecular, genetic, or tumor-related characteristics for patient selection - Leverage comprehensive tumor profiling and companion diagnostics - Pursue rational combinations to enhance clinical activity, minimize toxicity, and address resistance - Build a sustainable pipeline through internal discovery, development, and external partnerships - Maintain significant development and commercial rights - Invest in pre-commercial activities to maximize pipeline value[48] Precision Medicines in Cancer Treatment Precision medicine in cancer aims to improve patient outcomes and reduce costs by matching targeted therapeutics to specific cancer genetics - Precision medicine in cancer aims to improve patient outcomes and reduce healthcare costs by matching targeted therapeutics to patients most likely to benefit based on cancer genetics and molecular diagnostics[49] - This approach offers potential advantages such as higher translatability from preclinical to clinical studies, increased overall response rates, expedited clinical development, and improved safety compared to traditional chemotherapy[51] Our Approach to Development of Precision Medicines in Oncology The company uses translational research, existing diagnostics, and disciplined clinical development for precision oncology - The company employs translational research, synthesizing basic research, preclinical, and clinical data to guide its precision medicine approach, evaluating product candidates through in vitro and in vivo experiments, including patient-derived xenograft (PDX) models[52] - The strategy involves using existing diagnostic tools (NGS, PCR, IHC) to identify patient subsets and developing companion diagnostics with technology partners to support potential registration and marketing[53] - A disciplined clinical development approach focuses on well-defined patient populations to identify early response signals, potentially leading to rapid clinical development and expedited regulatory strategies[54][55] Clinical Programs and Pipeline This section details the company's clinical programs and pipeline, focusing on ziftomenib and farnesyl transferase inhibitors Ziftomenib – A Selective Inhibitor of the Menin-KMT2A Interaction Ziftomenib selectively inhibits the menin-KMT2A interaction, targeting acute leukemias with specific genetic alterations Acute Leukemias and Genetic Alterations Acute leukemias with KMT2A rearrangements or NPM1 mutations depend on menin-KMT2A interaction, a target for ziftomenib - Acute leukemias (AML, ALL) with KMT2A gene rearrangements or NPM1 mutations are characterized by oncogenic KMT2A fusion proteins, which depend on the menin-KMT2A interaction for function[57][58] - NPM1 mutations are common in AML (approx. 30%), leading to poor survival outcomes post-relapse. KMT2A-rearrangements (5-10% of AML, 70-80% of infant leukemias) also have poor prognoses[59][60] - Ziftomenib, by preventing the menin-KMT2A interaction, has the potential to address up to 50% of AML cases, including NPM1-mutant and KMT2A-rearranged AML, for which there are currently no approved therapies[60][61] Preclinical Data Supporting Ziftomenib as a Monotherapy and in Combination with Other Therapies Preclinical data supports ziftomenib's anti-tumor activity as monotherapy and in combination, targeting epigenetic dysregulation - Preclinical data supports ziftomenib's anti-tumor activity in genetically defined acute leukemia subsets (KMT2A-rearrangements, NPM1, DNMT3A, IDH1, IDH2 mutations), targeting epigenetic dysregulation and promoting cellular differentiation[62][63] - Co-treatment with ziftomenib and venetoclax demonstrated synergistic activity in patient-derived AML cells with KMT2A rearrangements or NPM1 mutations, prolonging survival in aggressive models[64] Clinical Development of Ziftomenib in AML Ziftomenib's clinical development in AML includes KOMET-001, KOMET-007, and KOMET-008 trials, showing promising results - KOMET-001 (Phase 1/2, relapsed/refractory AML): * Initiated September 2019 * Phase 1a showed encouraging monotherapy activity in 30 patients * Phase 1b (53 patients) identified 600 mg as the RP2D * Updated data (April 12, 2023 cutoff) showed 35% CR rate (7/20) in NPM1-mutant AML patients at 600 mg RP2D, with an ORR of 45% * Median DoR for NPM1-mutant patients was 8.2 months * Resistance mutation MEN1-M3271 developed in 3% (1/29) of patients post-treatment * Well-tolerated with manageable differentiation syndrome (DS) (15% Grade 1/2, 5% Grade 3) * Phase 2 registration-directed portion for relapsed/refractory NPM1-mutant AML initiated Feb 2023, with enrollment expected by mid-2024 * Sub-studies for ALL and non-NPM1-mutant/non-KMT2A-rearranged AML initiated in Q1 2024 and expected by mid-2024, respectively[22][23][24][25][26][27][28][65][66][67][68][69][70][71][72][73][74][75][76] - KOMET-007 (Combination Study): * Initiated Q3 2023, evaluating ziftomenib with venetoclax/azacitidine (relapsed/refractory AML) and with 7+3 (newly diagnosed AML) * Preliminary data (Jan 11, 2024 cutoff) from first 20 patients: 100% CR rate (5/5) in newly diagnosed AML patients treated with ziftomenib and 7+3 * ORR of 53% (8/15) in relapsed/refractory patients treated with ziftomenib and venetoclax/azacitidine * Well-tolerated at 200 mg, with no DS events, dose-limiting toxicities, QTc prolongation, drug-drug interactions, or additive myelosuppression * RP2D for combinations expected by mid-2024, followed by Phase 1b dose validation/expansion in newly diagnosed patients[29][30][31][32][77][78][79][80] - KOMET-008 (Combination Study): * First patient dosed Feb 26, 2024, evaluating ziftomenib with gilteritinib or FLAG-IDA/LDAC in relapsed/refractory NPM1-mutant or KMT2A-rearranged AML[33][34][81] Registration Strategy for Ziftomenib The registration strategy for ziftomenib in AML focuses on relapsed/refractory NPM1-mutant AML, with broader plans for combinations and pediatric leukemia - The immediate strategy for ziftomenib in AML is to generate data for marketing approval in relapsed or refractory NPM1-mutant AML, with broader plans to evaluate combinations, ALL, maintenance therapy, and pediatric acute leukemia[82] - The company is supporting an investigator-sponsored study and plans a company-sponsored study for ziftomenib as maintenance therapy post-HCT in NPM1-mutant or KMT2A-rearranged AML, expected to initiate in Q1 2024[35][83] - A clinical collaboration with The Leukemia & Lymphoma Society (LLS) was announced in December 2023 to evaluate ziftomenib in pediatric patients with relapsed or refractory KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant acute leukemia[36][84] Farnesyl Transferase Inhibitors Farnesyl transferase inhibitors block protein farnesylation, a mechanism crucial for cellular protein function in cancer Protein Farnesylation Protein farnesylation is a key mechanism for cellular protein function, targeted by FTIs to reverse cancer hallmarks - Protein farnesylation is a mechanism by which cellular proteins, including many involved in signaling, associate with the intracellular membrane to function. Farnesyl transferase inhibitors (FTIs) block this process, reversing several hallmarks of cancer[86][87] - HRAS is exclusively farnesylated, making FTIs a potential treatment for HRAS mutant solid tumors by inhibiting its membrane localization and switching it 'off'[88][90] Solid Tumors with HRAS Mutations HRAS mutations are prevalent in certain solid tumors, like HNSCC, which show sensitivity to tipifarnib - HRAS mutations, though less common than KRAS/NRAS, are prevalent in thyroid, urinary bladder, and head and neck squamous cell carcinomas (HNSCC), causing persistent activation of growth signals[89][90] - HNSCC is a disease with high unmet need, as current second-line agents show low response rates (13-16%). Preclinical and clinical data suggest HRAS mutant squamous cell tumors are sensitive to tipifarnib[91][92][93] Tipifarnib – An Oral Farnesyl Transferase Inhibitor Tipifarnib, an oral FTI, has been studied in many cancer patients, showing activity in selected populations Tipifarnib as a Monotherapy Tipifarnib monotherapy showed anti-cancer activity in selected patients, but its development has been discontinued - Tipifarnib, in-licensed from Janssen, has been studied in over 5,000 cancer patients, showing a manageable side effect profile and compelling anti-cancer activity in certain selected patient populations[94][95] - The AIM-HN Phase 2 study in R/M HRAS mutant HNSCC showed an objective response rate of 29% in second-line treatment, validating farnesyl transferase inhibition. However, monotherapy development for tipifarnib has been discontinued to prioritize other programs[96][97] Tipifarnib in Combinations Tipifarnib is being evaluated in combination with alpelisib in the KURRENT-HN trial for HNSCC - The KURRENT-HN trial, a Phase 1/2 collaboration with Novartis, is evaluating tipifarnib and alpelisib in HNSCC patients. It has demonstrated durable clinical responses in PIK3CA-dependent HNSCC, with dose escalation ongoing and optimal biologically active dose (OBAD) expected by end of 2024[98][99] - The KURRENT-LUNG trial, evaluating tipifarnib with osimertinib for EGFR mutated NSCLC, was closed in February 2023 to prioritize other programs, despite compelling preclinical data[100] KO-2806- Next-Generation Farnesyl Transferase Inhibitor KO-2806 is a next-generation FTI with improved properties, showing synergy in preclinical combinations - KO-2806 is a next-generation FTI developed to improve potency, pharmacokinetic, and physicochemical properties over earlier FTI candidates, with its IND application for advanced solid tumors cleared in January 2023[101][107] - Preclinical data in 2023 highlighted robust synergy between FTIs (tipifarnib and KO-2806) and targeted therapies, including antiangiogenic TKIs (axitinib, cabozantinib) in ccRCC and KRAS G12C/G12D inhibitors (adagrasib, sotorasib) in NSCLC[102][103] - Combination of KO-2806 with adagrasib in KRAS G12C-mutant NSCLC models induced tumor regressions and enhanced duration/depth of antitumor response by deepening signaling inhibition[104][105] - Phase 1 FIT-001 trial initiated in October 2023 for monotherapy, with combination cohorts (KO-2806 + cabozantinib in ccRCC, KO-2806 + adagrasib in KRAS G12C-mutant NSCLC via Mirati collaboration) anticipated by mid-2024[106][107] License Agreements The company holds exclusive licenses for its menin-KMT2A program (ziftomenib) and tipifarnib from third parties The University of Michigan Kura Oncology holds exclusive worldwide rights to its menin-KMT2A program, including ziftomenib, licensed from the University of Michigan - Kura Oncology holds exclusive worldwide rights to compounds in its menin-KMT2A program, including ziftomenib, licensed from the University of Michigan since December 2014[109] - Obligated to pay upfront, annual maintenance fees, and development/regulatory milestone payments up to $3.4 million for the first indication, with additional payments for subsequent indications - Tiered royalties of low single-digit percentages on net sales, with standard royalty offsets and sales-based milestones - University of Michigan retains rights for non-commercial research and can terminate the agreement for bankruptcy, payment failure, or material breach[109] Janssen Pharmaceutica NV Kura Oncology holds exclusive global rights to develop and commercialize tipifarnib from Janssen Pharmaceutica NV - Kura Oncology holds exclusive global rights to develop and commercialize tipifarnib in all indications other than virology, licensed from Janssen Pharmaceutica NV since December 2014[110] - Obligated to use commercially reasonable efforts for development and commercialization, bearing all future costs - Regulatory milestone payments up to $25.0 million for the first indication and additional payments for subsequent indications - Sales milestone payments up to $50.0 million if specified sales thresholds are surpassed - Tiered royalties of low teens percentages on net sales, with standard royalty offsets, until patent expiration, regulatory exclusivity expiration, or ten years from first commercial sale - Janssen can terminate for failure to meet diligence obligations or material breach[111][112] Competition The company faces intense competition in cancer product development from major pharmaceutical and biotechnology companies General Competition The cancer product market is intensely competitive, with Kura Oncology facing larger, better-resourced companies - The development and commercialization of new cancer products is intensely competitive and subject to rapid technological change, with Kura Oncology facing substantial competition from major pharmaceutical, specialty pharmaceutical, and biotechnology companies globally[113] - Competitors often possess significantly greater financial, technical, and human resources, potentially leading to earlier product discovery, development, or commercialization, or the acquisition of intellectual property rights that limit Kura's capabilities[113][114] - Competition also extends to recruiting personnel, establishing clinical trial sites, patient registration, and acquiring complementary technologies, as well as broader market competition from existing cost-effective and reimbursable cancer treatments (surgery, radiation, chemotherapy, hormone therapy, targeted therapy)[115][116] Menin Inhibitor Competition Several companies are developing menin-KMT2A inhibitors, and ziftomenib also competes with established AML therapies - Although no approved drugs specifically target the menin-KMT2A interaction, several companies (Syndax, Biomea Fusion, Janssen, Sumitomo Dainippon, Daiichi Sankyo) are engaged in discovery, preclinical, or clinical development of menin-KMT2A inhibitors[117] - Ziftomenib also competes with established AML therapies, including venetoclax (Abbvie/Genentech), midostaurin (Novartis), gilteritinib (Astellas), enasidenib (BMS), ivosidenib (Servier), olutasidenib (Rigel), and quizartinib (Daiichi-Sankyo)[118] FTI Competition No approved farnesyl transferase inhibitors exist, but several compounds are in development, and FTIs compete with existing therapies - Currently, there are no approved drugs targeting farnesyl transferase, but several compounds (Merck's lonafarnib, BMS's BMS-214662, Astellas Pharma's CP-609,754, AstraZeneca's AZD3409) have been in clinical development[119] - Tipifarnib and KO-2806 compete with various approved therapies for NSCLC (e.g., nivolumab, pembrolizumab, sotorasib, adagrasib), RCC (e.g., cabozantinib, axitinib), and HNSCC (e.g., cetuximab)[120] Commercialization Kura Oncology plans to build internal commercial capabilities for North America and Europe, using third parties for other regions - Kura Oncology is in the planning stages of building commercial capabilities, intending to retain commercial rights in North America and potentially Europe for approved product candidates, utilizing a focused internal sales force[121][122] - For foreign jurisdictions outside its retained commercial rights, the company may enter into distribution and marketing arrangements with third parties. Commercial companion diagnostics are expected to be commercialized by third-party collaborators[122][124] Manufacturing The company relies on third parties for manufacturing its small molecule product candidates and companion diagnostics - Kura Oncology does not own or operate manufacturing facilities and relies on third parties for the manufacture of its small molecule product candidates for preclinical, clinical, and commercial testing[125] - The company aims to identify and qualify manufacturers for active pharmaceutical ingredients (API) and drug product services prior to NDA submission and relies on third parties for companion diagnostic manufacturing[126] Intellectual Property Commercial success depends on obtaining and maintaining IP protection for product candidates, biomarkers, and know-how Overview of IP Protection IP protection for product candidates, biomarkers, and know-how is crucial for commercial success and competitive advantage - Commercial success depends on obtaining and maintaining proprietary or intellectual property (IP) protection for product candidates, biomarkers, and know-how, and operating without infringing others' rights[128] - The company files or licenses U.S., international, and foreign patent applications for composition-of-matter, biomarkers, formulations, processes, and methods of use, and relies on trade secrets and confidentiality agreements[128][129][132] - Ziftomenib: Exclusively licensed from the University of Michigan, with issued U.S. and foreign patents covering composition of matter and methods of use. Additional patents are being pursued[130] - Tipifarnib: Exclusively licensed from Janssen, with composition-of-matter patents expired in 2016. Secured U.S. and foreign method of treatment patents for tipifarnib and FTIs more broadly, including a license from Memorial Sloan Kettering Cancer Center[131] Orange Book Listing Upon NDA approval, patents covering the product are listed in the FDA's Orange Book, impacting generic applications - Upon NDA approval, applicants must list patents covering their product with the FDA, which are then published in the Orange Book. Generic applicants (ANDA or 505(b)(2) NDA) must certify against these patents[133] - A Paragraph IV certification, if challenged by the NDA holder/patent owner within 45 days, can trigger a 30-month stay on FDA approval for the generic, or until patent expiration/settlement/favorable court decision[133][134] Non-Patent Exclusivity New chemical entities may receive five years of non-patent exclusivity, delaying certain generic applications - NDA holders for new chemical entities (NCEs) may receive five years of non-patent exclusivity, during which the FDA cannot accept for filing certain generic or 505(b)(2) applications for the same active moiety, with an exception after four years for Paragraph IV certifications[135] Patent Term Extension Relevant drug patents may be extended by up to five years post-NDA approval to compensate for regulatory review time - After NDA approval, relevant drug patents may be extended by up to five years to compensate for regulatory review time, with the total patent term not exceeding 14 years from NDA approval[136] - Interim patent extensions are available for patents expiring during the application phase, increasing the term by one year, renewable up to four times, and reducing the post-approval extension[137] Government Regulation Pharmaceutical products are subject to extensive government regulations covering development, approval, and post-market activities FDA Approval Process The FDA approval process involves extensive preclinical testing, IND submission, multi-phase clinical trials, and NDA review - Pharmaceutical products in the U.S. are subject to extensive FDA regulation governing research, development, testing, manufacturing, approval, labeling, promotion, distribution, and post-approval monitoring[138] - Preclinical Testing: Laboratory and animal tests to assess chemistry, formulation, toxicity, safety, and efficacy, complying with good laboratory practices (GLP). Results submitted in an IND[139][140] - IND Submission: Required before human clinical testing. A 30-day waiting period allows the FDA to place a hold[141][142] - Clinical Trials (Phase 1, 2, 3): Conducted under IND, complying with federal regulations and good clinical practice (GCP). Involve administration to healthy volunteers or patients to assess metabolism, pharmacokinetics, safety, and efficacy. Typically three phases, but may overlap[143][144][145] - NDA Submission: Prepared after required clinical testing, including preclinical, clinical, and manufacturing data. FDA reviews for safety and effectiveness[146][147] - FDA Review: 60-day filing acceptance, followed by in-depth review (12 months for standard, 8 months for priority). May involve advisory committees and facility inspections (cGMP)[148][149] - Approval/Complete Response Letter: FDA issues an approval letter or a complete response letter outlining deficiencies. Approval may include a Risk Evaluation and Mitigation Strategy (REMS) and post-approval testing[150][151] Project Optimus Project Optimus is an FDA initiative to reform dose optimization in oncology drug development, emphasizing efficacy and safety - Project Optimus, an FDA Oncology Center of Excellence initiative launched in 2021, aims to reform dose optimization and selection in oncology drug development, emphasizing the selection of an optimal dose that maximizes both efficacy and safety/tolerability[152] - This initiative requires early and efficient dose finding and optimization studies, leveraging nonclinical and clinical data, and may involve randomized evaluations of a range of doses in trials, potentially pre- or post-approval[152][153] Fast Track Designation and Accelerated Approval Fast Track expedites review for serious conditions, while Accelerated Approval uses surrogate endpoints for early market access - Fast Track Designation expedites development and review for drugs treating serious or life-threatening conditions with unmet medical needs, allowing more frequent FDA interactions and rolling NDA review[154][155] - Accelerated Approval allows drugs for serious illnesses to be approved based on surrogate endpoints that are reasonably likely to predict clinical benefit, but requires rigorous post-approval (Phase 4) studies to confirm clinical benefit[156][157] Breakthrough Therapy Designation Breakthrough Therapy Designation expedites development for serious conditions with substantial clinical improvement over existing therapies - Breakthrough Therapy Designation expedites development and review for drugs treating serious conditions where preliminary clinical evidence indicates substantial improvement over available therapies on clinically significant endpoints[158] - This designation includes all Fast Track features, offers intensive guidance on efficient development, and ensures senior FDA management commitment, though it does not guarantee faster approval or ultimate marketing approval[158][282][283] Orphan Drug Designation and Exclusivity Orphan Drug Designation provides incentives and market exclusivity for drugs treating rare diseases, like ziftomenib for AML - Orphan Drug Designation is granted for drugs treating rare diseases (fewer than 200,000 individuals in the U.S.) and provides incentives like research grants, tax credits, fee waivers, and market exclusivity[159][160] - If a product with orphan designation receives the first FDA approval for that indication, it gains seven years of market exclusivity in the U.S. (ten years in Europe), prohibiting approval of another product with the same active ingredient for the same indication, with limited exceptions[160][161] - Ziftomenib received orphan drug designation for AML in July 2019. However, this designation does not guarantee faster review or approval, nor does it prevent competition from different drugs for the same condition or off-label prescribing of generic versions[22][162][280][281] Post-Approval Requirements Approved products are subject to extensive post-approval regulations, including marketing standards, adverse event reporting, and cGMP compliance - Approved products are subject to extensive post-approval regulations, including marketing and promotion standards, adverse event reporting, periodic reports, cGMP compliance, and potential post-approval studies (Phase 4) or REMS[163][164] - Non-compliance or discovery of new problems can lead to severe sanctions, including product restrictions, withdrawal from the market, fines, and criminal penalties[164][287] Pediatric Information PREA requires pediatric data for NDA submissions, while BPCA offers exclusivity extensions for pediatric studies - The Pediatric Research Equity Act (PREA) requires NDA submissions to include data on safety and effectiveness in relevant pediatric subpopulations, with possible waivers or deferrals[165] - The Best Pharmaceuticals for Children Act (BPCA) offers a six-month extension of exclusivity for drugs if pediatric studies are requested by the FDA and performed by the applicant[166] FDA Regulation of Companion Diagnostics Companion diagnostics are regulated as medical devices by the FDA, requiring rigorous Premarket Approval (PMA) and post-market compliance - Companion diagnostics, crucial for selecting patients for cancer therapeutics, are regulated as medical devices by the FDA and typically require separate Premarket Approval (PMA) simultaneously with drug approval[167][168] - The PMA process is rigorous, lengthy, and expensive, requiring extensive preclinical and clinical data to establish safety and effectiveness, including reproducible results across multiple users and laboratories[169] - Post-market, devices remain subject to significant regulatory requirements, including marketing restrictions, registration, quality system regulation (QSR) compliance, and inspections. Non-compliance can lead to severe enforcement actions[171][172] Clinical Trials and IDEs Clinical trials are required for medical device PMA applications, often preceded by IDE studies for significant risk devices - Clinical trials are almost always required for PMA applications for medical devices. Investigational Device Exemption (IDE) studies may precede pivotal trials, especially if the investigational device poses a significant risk to patients[173][174] - IDE applications require data demonstrating safety for human testing and scientific soundness of the protocol. All clinical studies must comply with FDA's IDE requirements for investigator selection, monitoring, reporting, and record-keeping, as well as IRB approval[175][176] - Investigational devices must also conform to quality controls described in the IDE application, and the QSR design and development controls apply[177] Foreign Regulation The company is subject to diverse foreign regulations governing clinical trials, commercial sales, and data privacy - Beyond U.S. regulations, the company is subject to diverse foreign regulations governing clinical trials, commercial sales, distribution, product licensing, pricing, and reimbursement in regions like the European Union and Japan[178][179] - Foreign regulations also include data privacy and security laws, such as GDPR in the EU, which impose strict obligations and significant penalties for non-compliance[180] Additional Healthcare Regulations and Environmental Matters The company is subject to federal and state healthcare regulations, including anti-kickback and false claims laws, and environmental laws - The company is subject to various federal and state healthcare regulations, including anti-kickback statutes, false claims laws, HIPAA (privacy/security), and the Physician Payments Sunshine Act, which govern interactions with healthcare professionals and marketing practices[181][182][183][184][185][186][187] - Non-compliance with these laws can result in significant administrative, criminal, and civil penalties, fines, exclusion from government healthcare programs, and reputational harm[188] - The company is also subject to environmental, health, and safety laws governing hazardous materials, but does not expect them to materially impact current or planned activities[189] Coverage and Reimbursement Sales of approved products depend on third-party payor coverage and reimbursement, which may be limited, impacting profitability - Sales of approved product candidates depend on coverage and reimbursement by third-party payors, who may limit coverage or offer inadequate reimbursement rates, impacting profitability[190][191] - Companion diagnostics will also require separate coverage and reimbursement determinations. Government and state legislatures show increased interest in cost containment, including price controls and generic substitution, which could limit payments for pharmaceuticals[190][191] Health Reform Health reform initiatives, like the ACA and IRA, could significantly impact drug pricing, reimbursement, and market access - U.S. and foreign jurisdictions have enacted or are considering legislative and regulatory proposals to reform healthcare, such as the ACA and the Inflation Reduction Act (IRA), which could affect drug pricing, reimbursement, and market access[192][193] - The IRA, in particular, directs HHS to negotiate Medicare drug prices and imposes rebates for price increases exceeding inflation, with significant potential impact on the pharmaceutical industry[193] - Heightened governmental scrutiny over drug pricing, potential use of 'march-in rights' under the Bayh-Dole Act, and state-level initiatives (e.g., drug importation programs) could further reduce drug prices and impact revenues[193][194] Human Capital The company employs 142 full-time staff, investing in benefits, compensation, and training, guided by ethical conduct and DE&I Employee Distribution (as of December 31, 2023) | Department | Number of Employees | | :--- | :--- | | Research, Development and Supply Chain | 89 | | Commercial and General & Administrative | 53 | | Total Full-Time Employees | 142 | - The company invests in employees through high-quality benefits, competitive compensation, and training, guided by a Code of Business Conduct and Ethics emphasizing respect, integrity, collaboration, innovation, trust, and excellence[198][199] - A Diversity, Equity and Inclusion (DE&I) Committee, established in 2020, focuses on corporate culture, internal education, women's professional development, community outreach, external mentoring, and clinical trial equity[200] Corporate Information Kura Oncology's headquarters are in San Diego, California, with additional offices and lab space - Kura Oncology's corporate headquarters are in San Diego, California, with additional offices in Boston, Massachusetts, and lab space in San Diego[201] - The company's website (www.kuraoncology.com) provides access to SEC filings, but the website content itself is not incorporated by reference into the Annual Report[201] Item 1A. Risk Factors Details significant risks affecting Kura Oncology's business, including product development, financial needs, third-party reliance, regulatory, IP, commercialization, and stock ownership - The company's actual results may differ materially from forward-looking statements due to various factors, including those discussed in this section, which could adversely affect its business, operating results, financial condition, and stock value[205] - Readers are advised to carefully consider these risk factors, as each, alone or together, could significantly impair the business and financial position, and there may be additional unknown or currently immaterial risks[205] Risks Related to the Discovery and Development of Our Product Candidates Risks include high dependence on ziftomenib, challenges in clinical development, patient enrollment, and potential adverse events - High dependence on ziftomenib's success, which is still in clinical development and may not receive regulatory approval - The development of targeted therapeutics for genetically defined cancers is a new and rapidly evolving area with uncertain outcomes, and the approach may not lead to marketable products - Difficulty in enrolling patients for clinical trials due to small populations, strict eligibility criteria, and challenges in identifying specific genetic alterations - Clinical drug development is lengthy, expensive, and uncertain; preclinical/early clinical results may not predict final outcomes, leading to potential delays, increased costs, or inability to complete development - Reliance on third-party drugs for combination therapies, with limited control over their supply, regulatory status, or approval - Product candidates may cause serious adverse events or unacceptable side effects, potentially delaying or abandoning development - Failure to develop, validate, and obtain regulatory approval for diagnostic testing platforms could harm the drug development strategy and operational results[206][207][208][209][210][211][212][213][214][215][216][217][218][219][220][221][222][223][224][225][226][227][228][229][230][231][232][233][234][235][236][237][238][239][240][241][242][243][244] Risks Related to Our Financial Position and Need for Additional Capital Risks include expected losses, varying financial results, limited operating history, and the need for substantial additional capital - Expects to incur significant losses and may never achieve or maintain profitability, as the company is clinical-stage with no approved products or historical product revenue - Financial and operating results are expected to vary significantly due to factors like clinical trial success, regulatory approvals, competition, and intellectual property costs - Limited operating history makes it difficult to evaluate future viability and success - Requires substantial additional capital for ongoing operations, which may lead to stockholder dilution, restrictive debt covenants, or relinquishing rights to technologies/product candidates - Adverse developments in the financial services industry (e.g., bank failures) could impact liquidity and access to capital, potentially delaying or terminating development/commercialization efforts[245][246][247][248][249][250][251][252][253][254][255][256][257][258][259][260] Risks Related to Our Dependence on Third Parties Risks include reliance on third-party contractors for clinical trials and manufacturing, and potential supply chain disruptions - Reliance on third-party contractors (CROs, data management, clinical investigators) to conduct clinical trials increases risks of unsatisfactory performance, delays, or termination of engagements - Competition for third-party resources, especially with larger pharmaceutical companies, may lead to prioritization of other clients - Dependence on third parties for manufacturing product candidates for preclinical, clinical, and commercial testing increases risks of insufficient quantities, unacceptable cost/quality, and supply disruptions - Manufacturing is complex and subject to difficulties in production, quality control, and regulatory compliance (cGMP). Failure to comply could lead to sanctions or delays - Geopolitical events or public health epidemics could negatively impact third-party operations and supply chains, delaying clinical trials and business operations[261][262][263][264][265][266][267][268][269][270][271][272][273][274][275] Risks Related to Regulatory Approval of Our Product Candidates and Other Legal Compliance Matters Risks include delays in regulatory approvals, non-compliance with post-approval requirements, and exposure to fraud and abuse laws - Inability or delays in obtaining required regulatory approvals (FDA, EMA, etc.) would prevent or delay commercialization and materially impair revenue generation - May not benefit from available regulatory exclusivity periods (e.g., NCE, orphan drug) if competitors obtain approval first or if conditions for exclusivity are not met - Breakthrough Therapy Designation does not guarantee faster development, review, or approval - Failure to obtain marketing approval in international jurisdictions would prevent product candidates from being marketed abroad - Approved products are subject to extensive post-approval regulatory requirements, and non-compliance or unanticipated problems could lead to restrictions, withdrawal from the market, or penalties - Combination product candidates may require more extensive or expensive trials to demonstrate the contribution of each component - Relationships with healthcare professionals, customers, and third-party payors are subject to fraud and abuse laws (Anti-Kickback Statute, False Claims Act, HIPAA, Sunshine Act), privacy laws (GDPR, CCPA), and other healthcare regulations, exposing the company to significant penalties for non-compliance - Recently enacted and future legislation (e.g., ACA, IRA) may increase the difficulty and cost of obtaining marketing approval, restrict post-approval activities, and affect pricing and reimbursement[276][277][278][279][280][281][282][283][284][285][286][287][288][289][290][291][292][293][294][295][296][297][298][299][300][301][302][303][304][305][306][307][308][309][310][311][312][313] Risks Related to Our Intellectual Property Risks include challenges to IP protection, dependence on licensors, potential litigation, and global IP enforcement issues - Inability to obtain and maintain sufficiently broad intellectual property (IP) protection for product candidates could allow competitors to commercialize similar products, impairing commercialization efforts - Patent rights for ziftomenib and tipifarnib may be challenged, invalidated, or circumvented, and patent terms may be inadequate due to lengthy development times - Dependence on licensors (University of Michigan, Janssen) to prosecute and maintain material patents and patent applications, with limited control over these activities - Breach of license agreements could lead to loss of critical license rights for product candidates - The patent position of biotechnology companies is highly uncertain, involving complex legal and factual questions, and changes in patent laws (e.g., Unitary Patent Court in Europe) could diminish patent value - Risk of involvement in lawsuits to protect or enforce patents, or defending against third-party infringement claims, which can be expensive, time-consuming, and unsuccessful - Inability to obtain or maintain necessary third-party IP rights through acquisitions and in-licenses could hinder business growth - Failure to maintain confidentiality of trade secrets or other confidential information would harm competitive position - IP discovered through government-funded programs may be subject to 'march-in' rights, reporting requirements, and U.S.-based manufacturing preferences, limiting exclusive rights - Inability to protect IP rights globally, especially due to geopolitical actions (e.g., Russia's decree on inventions from certain countries), could impair competitive position[314][315][316][317][318][319][320][321][322][323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339][340][341][342][343][344] Risks Related to the Commercialization of Our Product Candidates Risks include insufficient market acceptance, lack of sales force, intense competition, and uncertain reimbursement - Even with marketing approval, product candidates may fail to achieve sufficient market acceptance by physicians, patients, and third-party payors, impacting revenue generation - Lack of an established sales force means the company must build or partner for sales, marketing, and distribution capabilities, which is expensive and time-consuming - Substantial competition from other companies developing or commercializing competing products, potentially leading to safer, more effective, or less expensive alternatives - Uncertainty regarding insurance coverage and adequate reimbursement for newly approved products, including companion diagnostics, could limit market access and profitability - Product liability lawsuits related to clinical trials or commercial sales could result in substantial liabilities, costly legal expenses, and damage to reputation, potentially exceeding insurance coverage[345][346][347][348][349][350][351][352][353][354][355][356][357][358][359][360] Risks Related to Employee Matters, Managing Growth and Macroeconomic Conditions Risks include dependence on key personnel, challenges in managing growth, ESG expectations, and macroeconomic impacts - High dependence on the Chief Executive Officer and ability to retain key executives and attract/motivate qualified scientific, clinical, manufacturing, sales, and market access personnel - Expected expansion in development, regulatory, operations, medical affairs, and marketing capabilities may lead to difficulties in managing growth, disrupting operations - Third-party expectations regarding environmental, social, and governance (ESG) factors may impose additional costs and risks, potentially impacting reputation and investment desirability - Unfavorable global economic conditions (e.g., pandemics, bank failures, inflation) could adversely affect business, financial condition, and ability to raise ca