Syndax(SNDX) - 2018 Q4 - Annual Report

SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS The report contains forward-looking statements subject to risks and uncertainties that should not be considered predictions of future events - Forward-looking statements are identified by terms such as "anticipate," "believe," "could," "estimate," "expects," "intend," "may," "plan," "potential," "predict," "project," "should," "will," "would" or similar expressions[11] - Factors that may cause actual results to differ materially from current expectations are detailed in the "Risk Factors" section[12] - Key forward-looking statements include estimates regarding expenses, future revenues, capital requirements, financing needs, timing of clinical trial data (entinostat, SNDX-6352, SNDX-5613), regulatory approvals, license agreements, strategic plans, intellectual property, market adoption, and competitive developments[13] PART I Item 1. Business Syndax Pharmaceuticals is a clinical-stage biopharmaceutical company developing a pipeline of innovative cancer therapies Our Company - Syndax Pharmaceuticals is a clinical-stage biopharmaceutical company developing an innovative pipeline of cancer therapies[17] - The lead product candidate, entinostat, is a once-weekly, oral, small molecule, Class I HDAC inhibitor, currently in Phase 3 for HR+, HER2- breast cancer (with FDA Breakthrough Therapy Designation) and in Phase 1b/2 clinical trials in combination with PD-1/PD-L1 antagonists for non-small cell lung cancer and melanoma[17] - SNDX-6352, a monoclonal antibody targeting CSF-1R, is in Phase 1/1b trials for solid tumors (topline results expected Q2 2019) and Phase 1 for chronic graft versus host disease (cGVHD) (topline results expected Q4 2019)[18] - SNDX-5613, a lead compound from the preclinical Menin-MLL inhibitor portfolio, is being developed for MLLr and NPM1c acute leukemias, with an IND filing expected in Q2 2019[19] Our Strategy - Develop and obtain regulatory approval for entinostat in combination with hormone therapy in advanced HR+, HER2- breast cancer, with successful Phase 3 overall survival (OS) results potentially sufficient for regulatory approval[21] - Develop SNDX-5613 as a targeted therapy for MLL-r driven malignancies, including MLLr and NPM1c AML, with an IND filing planned for Q2 2019[21] - Establish entinostat as a combination therapy with immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) in patients where the response to these inhibitors can be improved[26] - Develop SNDX-6352 as monotherapy and in combination for one or more tumor types, and in chronic Graft Versus Host Disease (cGVHD), aiming to establish a recommended Phase 2 dose[26] - Leverage technical and business expertise to opportunistically license, acquire, and develop additional cancer therapies to expand the pipeline[26] Our Pipeline The company's clinical-stage pipeline includes entinostat, SNDX-6352, and SNDX-5613 for various cancer indications Product Pipeline Overview | Product Candidate | Stage | Indication(s) | Sponsor | | :---------------- | :---- | :------------ | :------ | | Entinostat (E2112) | Phase III | HR+, HER2- mBC | NCI/Syndax | | Entinostat (ENCORE 601) | Phase Ib/II | NSCLC / Melanoma | Syndax | | Entinostat (ENCORE 607) | Phase Ib/II | NSCLC | Syndax | | Entinostat (MORPHEUS) | Phase Ib/II | HR+, HER2- mBC | Roche | | SNDX-6352 (0502) | Phase I/Ib | Solid Tumors | Syndax | | SNDX-6352 (0503) | Phase I | Chronic GVHD | Syndax | | SNDX-5613 | Preclin./IND-enabling | MLLr leukemias, NPM1c AML | Syndax | Entinostat - Entinostat is an oral, small molecule, Class I HDAC inhibitor with a favorable safety profile demonstrated in over 1,200 cancer patients, and its long half-life allows for continuous therapeutic exposure[24] - Entinostat enhances the immune system's ability to target tumor cells by decreasing immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), potentially synergizing with immune checkpoint inhibitors[27] - The Phase 3 clinical trial (E2112) for advanced HR+, HER2- breast cancer in combination with exemestane did not meet its primary endpoint of improving progression-free survival (PFS) in October 2018 but is continuing for the overall survival (OS) endpoint, with the next interim analysis scheduled for Q2 2019[31] - In the ENCORE 601 trial (entinostat + Keytruda), the PD-L1 pretreated melanoma cohort showed six confirmed partial responses and three unconfirmed partial responses in 34 evaluable patients, while the PD-L1 pretreated NSCLC cohort showed seven confirmed partial responses among 72 efficacy-evaluable patients (10% objective response rate, median duration of response of 5.3 months, median PFS of 2.8 months)[37][38] - The ENCORE 602 trial (entinostat + Tecentriq for triple-negative breast cancer) and ENCORE 603 trial (entinostat + Bavencio for ovarian cancer) did not meet their primary endpoints of statistically significant improvement in PFS[40][43] - Clinical data from immuno-oncology trials suggest entinostat's beneficial effect is evident in T-cell infiltrated (inflamed) tumors, overcoming resistance in PD-1 refractory NSCLC and melanoma, but not in microsatellite stable colorectal carcinoma (MSS-CRC), TNBC, and ovarian cancer[44] SNDX-6352 - SNDX-6352 is a humanized monoclonal antibody that binds to CSF-1R, aiming to disrupt the activity of immunosuppressive tumor-associated macrophages (TAMs) and enhance immune response, particularly in combination with checkpoint inhibitors[46] - The Phase 1 dose escalation trial (SNDX-6352-502) for solid tumors (alone or in combination with Imfinzi) is expected to provide topline results and a recommended Phase 2 dose (RP2D) and schedule in Q2 2019[48][50] - A Phase 1 dose escalation trial (SNDX-6352-503) for patients with chronic graft versus host disease (cGVHD) expects initial results and an RP2D and schedule in Q4 2019[51] SNDX-5613 - SNDX-5613 is a potent, orally active inhibitor of the Menin-MLL1 protein interaction, which is a key driver for two genetically defined acute leukemias: MLLr and NPM1c AML, both with poor prognoses[52] - Preclinical testing of SNDX-5613 has demonstrated complete tumor regression and profound, dose-dependent survival benefits in leukemic models[52] - An Investigational New Drug (IND) application is anticipated to be filed in Q2 2019, with a Phase 1 clinical trial in leukemia patients having relapsed or refractory MLLr or NPM1c AML expected to initiate shortly thereafter[52] Market and Competition - The market for advanced HR+ breast cancer is evolving with the introduction of CDK4/6 inhibitors (Ibrance, Kisqali, Verzenio) as standard of care, but these have not yet demonstrated a statistically significant improvement in overall survival (OS) in combination with hormone therapy[55][56] - Entinostat, if approved, could offer a favorable benefit-risk profile and OS improvement, potentially becoming a preferred treatment option for patients with advanced HR+ breast cancer who have stopped responding to first-line endocrine regimens[56] - Despite advances with immune checkpoint inhibitors in NSCLC and melanoma, most patients still experience disease progression, and response rates are low in patients with low PD-L1 expression, indicating a significant unmet need for combination therapies like entinostat[60][64] - The cGVHD market has limited approved therapies, with Imbruvica being the only FDA-approved option after one or more lines of therapy, showing a 68% overall response rate, but significant unmet need remains for long-term outcomes[67] - MLLr leukemias (approximately 4,000 cases/year worldwide) and NPM1c AML (approximately 20,000 cases/year) are genetically defined acute leukemias with poor prognoses, driven by the menin-MLL1 interaction, making them targets for novel inhibitors like SNDX-5613[68][69] Collaborations - Syndax has clinical collaborations with Merck (Keytruda for NSCLC/melanoma), Genentech (Tecentriq for TNBC and HR+, HER2- mBC), and Merck KGaA/Pfizer (Bavencio for ovarian cancer) to evaluate entinostat in combination with immune checkpoint inhibitors[71][72][73][74][75] - The ENCORE 602 (TNBC) and ENCORE 603 (ovarian cancer) trials did not meet their primary endpoints of statistically significant improvement in PFS for the combination regimens[73][75] - A clinical collaboration with Nektar Therapeutics to evaluate NKTR-214 in combination with entinostat for metastatic melanoma was terminated in January 2019[76] - Syndax collaborates with the National Cancer Institute (NCI) and ECOG-ACRIN for entinostat clinical studies, providing financial and operational support and drug supply, and gaining access to generated data[78][79][82] - Syndax has an exclusive license agreement with Kyowa Hakko Kirin (KHK) for the development and commercialization of entinostat in Japan and Korea, which included an upfront license fee of $17.5 million and potential milestone and royalty payments[88][89] Manufacturing - Syndax does not own or operate manufacturing facilities and relies entirely on third-party contract manufacturers for all raw materials, active pharmaceutical ingredients, and finished products for preclinical research and clinical trials[94] - There are no long-term agreements with current third-party manufacturers, nor any current contractual relationships for commercial supplies; future commercial production will require new agreements compliant with FDA and other regulatory cGMP requirements[94] Intellectual Property - Syndax protects its product candidates through a combination of owned and licensed patent protection in the United States and internationally, as well as trade secrets, know-how, and in-licensing opportunities[95] - The entinostat patent portfolio includes owned provisional/pending applications and granted patents (expiring between April 2029 and May 2039) covering methods of treating cancer patients with entinostat, including in combination with other agents[97][98] - Licensed entinostat patents from Bayer include a composition of matter patent (RE39,754) that expired in September 2017, and a crystalline polymorph B patent (RE45,499) that expires in August 2029[99][100] - The SNDX-6352 patent portfolio, in-licensed from UCB, includes composition-of-matter and methods-of-use applications, with potential patent expiry in August 2034[103] - The Menin Asset patent portfolio, in-licensed from Vitae Pharmaceuticals (a subsidiary of Allergan), covers inhibitors of the Menin-MLL interaction, with potential patent expiry between December 2036 and September 2037[104] - Syndax holds a worldwide, exclusive license from Bayer for entinostat, involving an upfront fee of $2.0 million, potential development and marketing approval milestones up to $50.0 million, and tiered single-digit royalties on net sales[108][109] - Syndax holds a worldwide, exclusive license from UCB for SNDX-6352, involving a $5.0 million upfront payment, potential development and regulatory milestone payments up to $119.5 million, and low double-digit royalties on sales[112] - Syndax holds an exclusive, worldwide license from Vitae Pharmaceuticals (Allergan) for Menin Assets, involving a $5.0 million upfront payment, potential development and regulatory milestone payments up to $99 million, and low single to low double-digit royalties on sales[115] Government Regulation and Product Approval - Biopharmaceutical products in the United States are extensively regulated by the FDA under the FDCA and Public Health Service Act, covering all stages from testing and development to manufacturing, labeling, and post-market surveillance[119] - The product development process involves preclinical testing (GLP), submission of an Investigational New Drug (IND) application, and three sequential phases of human clinical trials (Phase 1 for safety/dosage, Phase 2 for preliminary efficacy/safety/optimal dosage, and Phase 3 for clinical efficacy/safety for approval)[120][121][123] - FDA approval requires submission of a New Drug Application (NDA) or Biologics License Application (BLA) demonstrating safety and effectiveness, satisfactory completion of cGMP inspections of manufacturing facilities, and potential review by an advisory committee[122][128][129] - Breakthrough Therapy Designation, granted to entinostat, can expedite development and review for drugs treating serious conditions with preliminary evidence of substantial improvement over existing therapies, but it does not guarantee faster approval or increase the likelihood of marketing approval[135][136] - Post-approval, products are subject to ongoing FDA regulation, including record-keeping, adverse experience reporting, cGMP compliance, and strict control over labeling, marketing, and promotion to prevent off-label uses[137][139][140] - Commercial sales depend on coverage and adequate reimbursement from third-party payors (government health programs, private insurers), which are increasingly attempting to limit prices and may disfavor new, innovative, or costly products[141][142] - The company is subject to federal and state anti-kickback, false claims, and data privacy/security laws (e.g., federal Anti-Kickback Statute, False Claims Act, HIPAA, Physician Payments Sunshine Act), with potential for significant civil, criminal, and administrative penalties for non-compliance[145][150] - Healthcare reform initiatives, including the Affordable Care Act and subsequent legislative changes, aim to contain healthcare costs and may impact drug pricing, reimbursement, and market access, potentially increasing commercialization difficulties[149][153][234][238] Employees - As of March 6, 2019, Syndax had 38 full-time employees, with 24 primarily engaged in research and development activities and 13 holding M.D. or Ph.D. degrees[158] - The company considers its relationship with employees to be good, and none are represented by labor unions or covered by collective bargaining agreements[158] Corporate and Other Information - Syndax Pharmaceuticals, Inc. was incorporated in Delaware in 2005 and operates in one segment[159] - The company's principal executive offices are located at 35 Gatehouse Drive, Building D, Floor 3, Waltham, Massachusetts 02451[160] - Annual reports on Form 10-K, quarterly reports on Form 10-Q, and current reports on Form 8-K are filed electronically with the SEC and made available free of charge on the company's website under "Investors"[161] Item 1A. Risk Factors The company faces significant risks in clinical trials, regulatory approval, third-party reliance, competition, and financing Risks Related to Our Business and Industry - The Phase 3 clinical trial (E2112) of entinostat in advanced HR+, HER2- breast cancer failed to meet its primary endpoint of improving PFS in October 2018, and failure to demonstrate OS efficacy could delay or prevent commercialization[165] - Reliance on ECOG-ACRIN and the NCI for the Phase 3 trial means limited control over their activities, which could lead to delays, termination, or unreliable data if they fail to adhere to GCPs or meet deadlines[169][170] - Delays in completing the Phase 3 clinical trial for entinostat could increase development costs, shorten commercialization periods, and allow competitors to enter the market sooner[171] - A Special Protocol Assessment (SPA) agreement for the Phase 3 trial does not guarantee regulatory approval, as the FDA retains discretion to interpret data or require additional clinical trials[174] - Breakthrough Therapy Designation for entinostat does not assure a faster development or review process, nor does it increase the likelihood of marketing approval, and could be rescinded if Phase 3 OS results do not confirm earlier findings[175] - The company lacks internal sales, marketing, and distribution infrastructure, necessitating reliance on third parties, which entails risks of limited control, unsuccessful efforts, or non-compliance with regulatory requirements[176][177] - Failure to successfully complete clinical development, obtain regulatory approval, and commercialize entinostat, SNDX-6352, and SNDX-5613 would significantly harm the company's business prospects[178] - Strategies for developing combination therapies (entinostat with immune checkpoint inhibitors) and monotherapies (SNDX-6352, SNDX-5613) have undergone limited clinical testing and may fail to demonstrate sufficient safety, tolerability, or clinical benefit[182][183][185] - Inability to transfer, qualify, and validate an assay for determining peripheral monocyte levels for the forthcoming NSCLC registration trial could delay or prevent its initiation[186] - Difficulties in patient enrollment for clinical trials, influenced by factors such as perceived efficacy, competition, and eligibility criteria, could delay or prevent trial completion[187] - Dependence on collaborators (Merck, Genentech, Merck KGaA, Pfizer, AstraZeneca) for the performance of their responsibilities and cooperation carries risks of non-performance, disputes, or termination of agreements[189] - Actions of sublicensees (Kyowa Hakko Kirin, Eddingpharm) in foreign jurisdictions could have a material adverse effect on the global development and commercialization of entinostat[191] - Dependence on UCB to comply with the terms of the SNDX-6352 license agreement, including maintaining applicable third-party licenses, poses risks to the development and commercialization of SNDX-6352[192] - Collaborations, including future strategic collaborations, could require relinquishing important rights, assuming substantial liabilities, or may not materialize or succeed due to competition or unfavorable terms[194] - The regulatory approval processes of the FDA and foreign authorities are lengthy, time-consuming, and unpredictable, with no guarantee of approval or broad indications, potentially leading to delays or abandonment of development programs[196][197] - Shortages in the supply of combination drugs (exemestane, Keytruda, Tecentriq) or unexpected adverse events with these drugs could increase development costs and adversely affect the ability to commercialize entinostat[199][200] - Product candidates may not achieve adequate market acceptance among physicians, patients, and healthcare payors due to factors such as efficacy, safety, competition, cost, reimbursement, or unfavorable publicity[201] - Reliance on third-party suppliers for manufacturing clinical drug supplies and commercial production exposes the company to risks of non-compliance with cGMPs, facility approval issues, or supply disruptions[204] - Even if approved, product candidates are subject to ongoing regulatory requirements, potential labeling changes, risk evaluation and mitigation strategies (REMS), or withdrawal due to new safety information or manufacturing non-compliance[205][206] - Advertising and promotion are heavily scrutinized, with risks of enforcement actions, false claims litigation, and significant civil and criminal penalties for impermissible promotion, including off-label uses[209][210] - Undesirable side effects or other unexpected properties of product candidates could delay or prevent regulatory approval, limit commercial scope, or result in significant negative consequences such as recalls or product liability claims[211][212] - Failure to obtain regulatory approval in international jurisdictions would prevent marketing product candidates outside the United States, reducing target market and harming business prospects[215] - Significant competition from other biotechnology and pharmaceutical companies with greater financial, technical, and human resources could render Syndax's product candidates obsolete or non-competitive[219] - Adverse events in the field of immuno-oncology could damage public perception of the company's product candidates, leading to decreased demand, greater governmental regulation, or regulatory delays[221][222] - Risks of employee, consultant, and collaborator misconduct, including insider trading and non-compliance with regulatory standards and healthcare fraud and abuse laws, could lead to significant fines, sanctions, or reputational harm[224] - Difficulty in attracting and retaining highly skilled employees, particularly at the management level, due to intense competition in the pharmaceutical industry, could adversely affect business plan execution[225][226] - Unfavorable pricing regulations or third-party coverage and reimbursement practices could harm the commercialization and profitability of product candidates, potentially limiting demand or increasing costs[227][229][231][232] - Current and future healthcare reform legislation, such as the Affordable Care Act and drug price control measures, may increase the difficulty and cost of commercializing product candidates and affect pricing[234][238][240] - Product liability lawsuits related to clinical trials or commercial sales could result in substantial liabilities, limit commercialization, and potentially exceed insurance coverage[241][242] - Relationships with customers and third-party payors are subject to anti-kickback, fraud and abuse, transparency, and data privacy laws, with non-compliance potentially leading to criminal sanctions, civil penalties, and exclusion from government healthcare programs[243][244] Risks Related to Our Financial Position and Capital Needs - Syndax has incurred significant net losses since its inception ($74.0 million in 2018, $439.4 million accumulated deficit as of December 31, 2018) and anticipates continued losses, which will adversely affect stockholders' equity and working capital[247][248] - The company currently has no product revenue and its ability to achieve or maintain profitability depends on successful commercialization, which is uncertain and will incur significant launch and commercialization costs[249][250] - Additional capital will be required to finance planned operations, and if not available on acceptable terms, the company may need to delay, scale back, or discontinue development/commercialization efforts or relinquish rights to product candidates[253][254] - Future funding requirements are dependent on numerous factors, including the initiation, progress, timing, and costs of clinical trials, regulatory approvals, intellectual property maintenance, market acceptance, manufacturing capabilities, and reimbursement policies[255] - The ability to use net operating loss (NOL) carryforwards and certain other tax attributes may be limited by "ownership changes" under Sections 382 and 383 of the Internal Revenue Code, potentially resulting in increased future tax liability[257] - Comprehensive tax reform legislation, such as the Tax Cuts and Jobs Act of 2017, could adversely affect the company's business and financial condition through changes to corporate taxation, including tax rates and NOL deductions[258] Risks Related to Intellectual Property - Inability to obtain or protect intellectual property rights (patents, trade secrets) would impair the company's competitive position, as patent prosecution is expensive, time-consuming, and inherently uncertain[260][262] - The issuance, scope, validity, enforceability, and commercial value of the company's and its licensors' patent rights are highly uncertain, and pending applications may not result in patents that effectively protect technology or prevent competitors[263] - Patents protecting product candidates might expire before or shortly after commercialization; entinostat's composition of matter patent (RE39,754) expired in September 2017, while the crystalline polymorph B patent (RE45,499) expires in August 2029[264][266] - The company may not be successful in defending the validity of the RE45,499 reissue patent, which could allow generic versions of entinostat crystalline polymorph B to enter the market[267] - There is no guarantee that patents will be granted for SNDX-6352 (potential expiry 2034) or Menin Assets (potential expiry 2036-2037), or that granted claims will cover the desired compounds, compositions, and methods of use[268][269] - Protecting intellectual property rights globally is prohibitively expensive and challenging, as foreign laws may offer less protection, and enforcement can be difficult, potentially leading to competition from infringing products[271][272][273] - Breach or termination of license agreements (Bayer for entinostat, UCB for SNDX-6352, Allergan for SNDX-5613) would result in the loss of development, manufacturing, marketing, and sales rights, requiring new, potentially unfavorable, negotiations[274][278][279][282][284][287] - Changes in patent law (e.g., Supreme Court rulings, Leahy-Smith America Invents Act) could diminish the value of patents, increase prosecution costs, and weaken the ability to obtain or enforce existing and future patents[288][290] - Failure to comply with procedural, document submission, and fee payment requirements imposed by governmental patent agencies could lead to abandonment or lapse of patent or patent application rights[291] - Involvement in lawsuits to protect or enforce intellectual property, or defending against infringement claims, could be expensive, time-consuming, unsuccessful, and divert management resources, potentially leading to patent invalidation or monetary damages[292][294][296][297] - The company may be subject to claims by third parties, including former employers of its personnel, asserting misappropriation of intellectual property or claiming ownership of the company's IP, leading to costly litigation and potential loss of rights[298][300][301] - Inability to protect confidential information and trade secrets, despite non-disclosure agreements, would harm the business and competitive position if proprietary information is disclosed or independently developed by competitors[302] - Significant disruptions of information technology systems or data security incidents (e.g., attacks, breaches) could result in substantial financial, legal, regulatory, business, and reputational harm, including loss of sensitive information or clinical trial data[303][305][306] Risks Related to Ownership of Our Common Stock - The market price of Syndax's common stock is highly volatile and subject to wide fluctuations due to various factors, including competitive products, regulatory actions, financial results, financing efforts, and general market conditions, potentially leading to loss of investment[308][309] - Future sales of additional equity or debt securities to fund operations may result in dilution to existing stockholders and/or impose restrictions or limitations on the business[310] - If securities or industry analysts do not publish research or reports about the business, or if they issue an adverse or misleading opinion, the stock price and trading volume could decline[311] - Principal stockholders and management beneficially own approximately 60.8% of outstanding voting stock (as of December 31, 2018), enabling them to exert significant control over stockholder-approved matters, potentially conflicting with the interests of other stockholders[312] - As an "emerging growth company" under the JOBS Act, Syndax may avail itself of reduced disclosure requirements, which could make its common stock less attractive to investors and adversely affect its market price[313][315] - Operating as a public company incurs significant legal, accounting, and other expenses, and management must devote substantial time to compliance initiatives[316] - Sales of a substantial number of common stock shares in the public market, including by holders with registration rights, could cause the stock price to fall[317][318] - The company may be subject to securities litigation due to stock price volatility, which is expensive and could divert management attention, seriously harming the business[319] - Failure to maintain an effective system of internal control over financial reporting could adversely affect investor confidence and the value of common stock, potentially leading to sanctions or investigations[320][321] - Provisions in the company's charter documents and Delaware law (e.g., classified board, prohibition on written consent, ability to issue preferred stock) may have anti-takeover effects, discouraging acquisitions or preventing attempts to replace current management[322] Item 1B. Unresolved Staff Comments There are no unresolved staff comments - No unresolved staff comments[323] Item 2. Properties The company leases office space in Waltham, Massachusetts and New York, New York - Syndax's headquarters are located in Waltham, Massachusetts, consisting of 12,207 square feet of leased office space under a lease that expires on March 1, 2022[324] - The company also leases 4,039 square feet of office space in New York, New York, under a lease that expires on February 28, 2021[324] - Management believes that existing facilities are sufficient for foreseeable needs, and additional or new facilities would be available on commercially reasonable terms if required[324] Item 3. Legal Proceedings Syndax is not currently a party to any material legal proceedings - Syndax is not currently a party to any material legal proceedings[325] Item 4. Mine Safety Disclosures This item is not applicable to Syndax Pharmaceuticals - This item is not applicable[326] PART II Item 5. Market for Registrant's Common Equity, Related Stockholder Matters and Issuers Purchases of Equity Securities This section details the company's common stock market, dividend policy, and use of IPO proceeds Market Information - Syndax's common stock began trading on the Nasdaq Global Select Market under the symbol "SNDX" on March 2, 2016[329] Holders of Record - As of March 6, 2019, there were approximately 26 holders of record of the company's common stock[330] Dividend Policy - Syndax has never declared or paid any cash dividends on its common stock and currently intends to retain future earnings to fund business development and growth[331] Use of Proceeds - The initial public offering (IPO) in March 2016 generated aggregate net proceeds of $50.5 million from the sale of 4,809,475 shares of common stock at $12.00 per share[332] - As of December 31, 2018, all proceeds from the IPO have been utilized[333] Item 6. Selected Financial Data This section summarizes consolidated financial data from 2014-2018, including operations and balance sheet information Consolidated Statement of Operations Data (2014-2018) | (In thousands, except share and per share data) | 2018 | 2017 | 2016 | 2015 | 2014 | | :-------------------------------------------- | :--- | :--- | :--- | :--- | :--- | | Revenue | $1,517 | $2,108 | $1,220 | $627 | $— | | Research and development | 60,106 | 48,201 | 31,665 | 9,549 | 10,175 | | General and administrative | 17,287 | 15,861 | 13,321 | 11,591 | 11,157 | | Total operating expenses | 77,393 | 64,062 | 44,986 | 21,140 | 21,332 | | Loss from operations | (75,876) | (61,954) | (43,766) | (20,513) | (21,332) | | Net loss | $(73,961) | $(60,802) | $(44,472) | $(24,119) | $(19,828) | | Net loss per share (basic and diluted) | $(2.92) | $(2.90) | $(3.22) | $(1,519.27) | $(453.02) | | Weighted-average common shares outstanding | 25,371,511 | 20,997,211 | 14,619,716 | 68,352 | 58,181 | Consolidated Balance Sheet Data (2014-2018) | (In thousands) | 2018 | 2017 | 2016 | 2015 | 2014 | | :-------------------------------------------- | :--- | :--- | :--- | :--- | :--- | | Cash, cash equivalents, short-term and long term investments | $80,911 | $133,220 | $105,330 | $86,489 | $12,901 | | Working capital | 67,241 | 117,644 | 98,144 | 83,160 | 2,181 | | Total assets | 83,938 | 137,186 | 109,013 | 89,903 | 12,525 | | Accumulated deficit | (439,423) | (366,111) | (305,293) | (259,675) | (159,801) | | Total stockholders' equity (deficit) | 53,047 | 104,319 | 84,139 | (252,415) | (152,569) | Item 7. Management's Discussion and Analysis of Financial Condition and Results of Operations Management discusses the company's financial condition, results of operations, liquidity, and capital resources Overview - Syndax is a clinical-stage biopharmaceutical company developing an innovative pipeline of cancer therapies, including entinostat, SNDX-6352, and SNDX-5613[341] - The company has no products approved for commercial sale and has incurred significant net losses since inception, reporting a net loss of $74.0 million for 2018 and an accumulated deficit of $439.4 million as of December 31, 2018[342] - As of December 31, 2018, cash, cash equivalents, and short-term investments totaled $80.9 million[342] Pipeline Updates - The next interim overall survival (OS) analysis for E2112 (entinostat plus exemestane in HR+, HER2- breast cancer) is anticipated in Q2 2019, with a positive OS assessment potentially enabling full regulatory approval[344] - Phase 2 portions of ENCORE 603 (entinostat + Bavencio for ovarian cancer) and ENCORE 602 (entinostat + Tecentriq for triple-negative breast cancer) did not meet their primary endpoints of statistically significant improvement in PFS[344][347] - Preclinical data supporting the Menin-Mixed Lineage Leukemia (MLL) inhibitor program (SNDX-5613) were presented in December 2018, with an IND filing expected in Q2 2019 and initiation of a Phase 1 clinical trial soon after[347] - Initial results from the Phase 1 dose escalation trial of SNDX-6352 in chronic graft versus host disease (cGVHD) are anticipated in the second half of 2019, and a recommended Phase 2 dose and schedule for SNDX-6352 monotherapy and in combination with Imfinzi are expected in Q2 2019[347] Financial Overview - Revenue to date has been solely derived from the license agreement with Kyowa Hakko Kirin Co., Ltd. (KHK) for entinostat in Japan and Korea, with a $17.3 million license fee recognized ratably through 2029 and a $5.0 million milestone payment received in 2017[346][348] - Research and development expenses are central to the business model and are expected to increase for the foreseeable future as product candidates advance, with external spending growing faster than internal[349][350] - From inception through December 31, 2018, the company incurred $211.7 million in research and development expenses[350] - General and administrative expenses are anticipated to increase in the future due to increased headcount and preparation for commercial operations, particularly sales and marketing[354] - Interest income increased primarily due to increased yield on cash, cash equivalents, and short-term investment balances, despite a lower average cash and investment balance[355] Results of Operations Comparison of Years Ended December 31, 2018 and 2017 (in thousands) | Metric | 2018 | 2017 | Change ($) | Change (%) | | :-------------------------- | :----- | :----- | :--------- | :--------- | | License fees | $1,517 | $2,108 | $(591) | (28)% | | Research and development | 60,106 | 48,201 | 11,905 | 25% | | General and administrative | 17,287 | 15,861 | 1,426 | 9% | | Total operating expenses | 77,393 | 64,062 | 13,331 | 21% | | Loss from operations | (75,876) | (61,954) | 13,922 | 22% | | Net loss | $(73,961) | $(60,802) | $13,159 | 22% | - License fees decreased by $0.6 million (28%) in 2018, primarily due to the partial recognition of a $5.0 million milestone payment from KHK in 2017[365] - Research and development expenses increased by $11.9 million (25%) in 2018, driven by increases in clinical trial activities ($5.4 million, including CMC for SNDX-6352 and the Menin program), employee compensation ($4.4 million), and legal and consultant expenses ($1.8 million)[366] - General and administrative expenses increased by $1.4 million (9%) in 2018, mainly due to pre-commercialization work ($1.1 million) and employee compensation ($0.4 million)[369] Comparison of Years Ended December 31, 2017 and 2016 (in thousands) | Metric | 2017 | 2016 | Change ($) | Change (%) | | :-------------------------- | :----- | :----- | :--------- | :--------- | | License fees | $2,108 | $1,220 | $888 | 73% | | Research and development | 48,201 | 31,665 | 16,536 | 52% | | General and administrative | 15,861 | 13,321 | 2,540 | 19% | | Total operating expenses | 64,062 | 44,986 | 19,076 | 42% | | Loss from operations | (61,954) | (43,766) | 18,188 | 42% | | Net loss | $(60,802) | $(44,472) | $16,330 | 37% | - License fees increased by $0.9 million (73%) in 2017, primarily due to the recognition of $0.9 million from a $5.0 million milestone payment received from KHK[372] - Research and development expenses increased by $16.5 million (52%) in 2017, driven by increases in clinical trial activities ($9.1 million), employee compensation ($3.6 million), and legal and consultant expenses ($3.1 million), including a $5.0 million upfront payment for the Menin Assets[373] - General and administrative expenses increased by $2.5 million (19%) in 2017, mainly due to increases in employee compensation ($1.3 million) and pre-commercialization work ($0.7 million)[375] Liquidity and Capital Resources - As of December 31, 2018, Syndax had cash, cash equivalents, and short-term investments totaling $80.9 million, which management believes will fund projected operating expenses and capital expenditure requirements for at least the next 12 months[379] - Primary funding sources include net proceeds from the IPO ($50.5 million in March 2016), a follow-on public offering ($48.7 million in May 2017), a direct stock placement ($24.9 million in October 2017), and "at-the-market" (ATM) offerings ($15.5 million net in 2018 and $0.9 million net in Q1 2019)[380][381][382] - As of March 6, 2019, $31.2 million of common stock remained available for sale under the ATM program[381] - Future capital requirements are substantial and depend on factors such as the initiation, progress, timing, and costs of clinical trials, regulatory approvals, intellectual property costs, market acceptance, manufacturing capabilities, and reimbursement policies[385] - The company anticipates continued significant losses and will require additional capital, which may be raised through equity offerings, debt financings, or collaboration arrangements, potentially leading to stockholder dilution or relinquishing valuable rights[386] Summary of Cash Flows (in thousands) | (in thousands) | 2018 | 2017 | 2016 | | :------------------------------------ | :----- | :----- | :----- | | Net cash used in operating activities | $(68,531) | $(47,371) | $(35,157) | | Net cash provided by (used in) investing activities | 51,398 | (17,072) | (18,283) | | Net cash provided by financing activities | 15,729 | 75,722 | 54,202 | | Net (decrease) increase in cash and cash equivalents | $(1,404) | $11,279 | $762 | | Cash, cash equivalents and restricted cash—end of year | $33,985 | $35,389 | $24,110 | - Net cash used in operating activities increased to $68.5 million in 2018 (from $47.4 million in 2017), primarily due to the net loss adjusted for non-cash items and changes in operating assets and liabilities[389][390][391] - Net cash provided by investing activities was $51.4 million in 2018 (compared to $17.1 million used in 2017), mainly driven by proceeds from maturities of available-for-sale marketable securities offsetting purchases[392][393][394] - Net cash provided by financing activities was $15.7 million in 2018 (compared to $75.7 million in 2017), primarily from net proceeds from "at-the-market" offerings and stock option exercises[396][397][398] Contractual Obligations as of December 31, 2018 (in thousands) | (in thousands) | Total | Less than 1 Year | 1 to 3 Years | 3 to 5 Years | More than 5 Years | | :-------------------------------- | :---- | :--------------- | :----------- | :----------- | :---------------- | | Operating leases for office space | $1,604 | $566 | $979 | $59 | $— | | Operating lease for office equipment | 7 | 3 | 4 | — | — | | Capital lease for office equipment | 13 | 4 | 8 | 1 | — | | Total | $1,624 | $573 | $991 | $60 | $— | - As of December 31, 2018, federal net operating loss (NOL) carryforwards were approximately $51.7 million (expiring from 2025, indefinite for 2018+), and state NOLs were $27.9 million. Federal R&D credits were $2.3 million, and state R&D credits were $1.4 million (expiring from 2021)[401] - A full valuation allowance is recorded on all deferred tax assets, and the utilization of NOLs and credits may be subject to limitations due to ownership changes[402] - The company did not have any off-balance sheet arrangements during the periods presented[403] Item 7A. Quantitative and Qualitative Disclosures about Market Risk The company's primary market risk is interest rate sensitivity on its cash and short-term investments - The primary market risk is interest rate sensitivity, affecting cash and cash equivalents ($33.8 million) and short-term investments ($47.1 million) as of December 31, 2018[405] - Investment activities prioritize liquidity and preservation of principal while maximizing income, with established guidelines for approved investments and maturities[405] - Due to the short-term maturities and low-risk profile of cash equivalents and short-term investments, an immediate 100 basis point change in interest rates would not have a material effect on their fair market value[405] Item 8. Financial Statements and Supplementary Data This item refers to the consolidated financial statements and supplementary data included in the report - The consolidated financial statements and supplementary data are presented starting on page F-1 of this Annual Report on Form 10-K[407] Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosure There have been no changes in or disagreements with accountants on accounting and financial disclosure - There have been no changes in and disagreements with accountants on accounting and financial disclosure[408] Item 9A. Controls and Procedures Management concluded that disclosure controls and internal control over financial reporting were effective as of December 31, 2018 - Management, with the participation of the principal executive officer and principal financial officer, concluded that disclosure controls and procedures were effective at the reasonable assurance level as of December 31, 2018[409] - Management concluded that the company's internal control over financial reporting was effective as of December 31, 2018[410] - An attestation report of the independent registered public accounting firm on the effectiveness of internal control over financial reporting is not included due to an exemption for "emerging growth companies" under the JOBS Act[411] - There was no change in internal control over financial reporting during the most recent fiscal quarter that materially affected, or is reasonably likely to materially affect, internal control over financial reporting[411] Item 9B. Other Information No other information is required to be reported under this item - No other information is required to be reported under this item[412] PART III Item 10. Directors, Executive Officers and Corporate Governance Information regarding directors, executive officers, and corporate governance is incorporated by reference from the 2019 Proxy Statement - Information required by this item is incorporated by reference from the sections titled "Information About Our Board of Directors," "Executive Officers," "The Board of Directors and Its Committees," and "Section 16(a) Beneficial Ownership Reporting Compliance" in the 2019 Proxy Statement[415] Item 11. Executive Compensation Information regarding executive compensation is incorporated by reference from the 2019 Proxy Statement - Information required by this item is incorporated by reference from the section titled "Executive Officer and Director Compensation" in the 2019 Proxy Statement[416] Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters Information regarding security ownership is incorporated by reference from the 2019 Proxy Statement - Information required by this item is incorporated by reference from the section titled "Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters" in the 2019 Proxy Statement[417] Item 13. Certain Relationships and Related Transactions, and Director Independence Information regarding related party transactions and director independence is incorporated by reference from the 2019 Proxy Statement - Information required by this item is incorporated by reference from the sections titled "The Board of Directors and Its Committees – Board Independence" and "Certain Relationships and Related Party Transactions" in the 2019 Proxy Statement[418] Item 14. Principal Accountant Fees and Services Information regarding principal accountant fees and services is incorporated by reference from the 2019 Proxy Statement - Information required by this item is incorporated by reference from the section titled "Independent Registered Public Accounting Firm Fees" contained in Proposal 2 in the 2019 Proxy Statement[419] PART IV Item 15. Exhibits and Financial Statement Schedules This section lists the financial statements, schedules, and exhibits filed with the Form 10-K Financial Statements - The response to this portion of Item 15 is set forth under Item 8[422] Financial Statement Schedules - All schedules have been omitted because they are not required or because the required information is given in the Consolidated Financial Statements or Notes thereto[423] Exhibits - A detailed list of exhibits is provided, including corporate documents (e.g., Amended and Restated Certificate of Incorporation, Bylaws), stock plans (e.g., 2007 Stock Plan, 2015 Omnibus Incentive Plan, ESPP), executive employment agreements, and various license and collaboration agreements (e.g., with Bayer, KHK, Genentech, Merck KGaA/Pfizer, UCB, Vitae Pharmaceuticals)[425][426][427][428][429] Item 16. Form 10-K Summary This item is not applicable - This item is not applicable[431] SIGNATURES The report is duly signed by the company's executive officers and directors as of March 7, 2019 - The report was signed on March 7, 2019, by Briggs W. Morrison, M.D., Chief Executive Officer (Principal Executive Officer), and Richard P. Shea, Chief Financial Officer and Treasurer (Principal Financial Officer and Principal Accounting Officer), along with other directors[435][438] Index to Consolidated Financial Statements This section provides an index to the company's consolidated financial statements and related notes - The index lists the Report of Independent Registered Public Accounting Firm, Consolidated Balance Sheets, Consolidated Statements of Operations, Consolidated Statements of Comprehensive Loss, Consolidated Statements of Convertible Preferred Stock and Stockholders' Equity (Deficit), Consolidated Statements of Cash Flows, and Notes to Consolidated Financial Statements, starting from page F-2[440] Report of Independent Registered Public Accounting Firm Deloitte & Touche LLP issued an unqualified opinion on the company's consolidated financial statements for 2016-2018 - Deloitte & Touche LLP issued an unqualified opinion on the consolidated financial statements of Syndax Pharmaceuticals, Inc. for the three years ended December 31, 2018[442] - The financial statements present fairly, in all material respects, the financial position and results of operations in conformity with accounting principles generally accepted in the United States of America (U.S. GAAP)[442] - Deloitte & Touche LLP has served as the company's auditor since 2008[446] SYNDAX PHARMACEUTICALS, INC. CONSOLIDATED BALANCE SHEETS The balance sheets show a decrease in cash and investments and a growing accumulated deficit from 2017 to 2018 Consolidated Balance Sheets (Selected Data, in thousands) | Metric | Dec 31, 2018 | Dec 31, 2017 | | :------------------------------------ | :----------- | :----------- | | Cash and cash equivalents | $33,769 | $35,168 | | Restricted cash | 101 | 106 | | Short-term investments | 47,142 | 94,806 | | Prepaid expenses and other current assets | 2,334 | 3,362 | | Total current assets | 83,346 | 133,442 | | Long-term investments | — | 3,246 | | Property and equipment, net | 373 | 267 | | Other assets | 219 | 231 | | Total assets | $83,938 | $137,186 | | Accounts payable | $1,439 | $2,232 | | Accrued expenses and other current liabilities | 13,149 | 11,993 | | Current portion of deferred revenue | 1,517 | 1,573 | | Total current liabilities | 16,105 | 15,798 | | Deferred revenue, less current portion | 14,650 | 16,759 | | Other long-term liabilities | 136 | 310 | | Total long-term liabilities | 14,786 | 17,069 | | Total liabilities | 30,891 | 32,867 | | Common stock | 2 | 2 | | Additional paid-in capital | 492,493 | 470,571 | | Accumulated other comprehensive loss | (25) | (143) | | Accumulated deficit | (439,423) | (366,111) | | Total stockholders' equity | 53,047 | 104,319 | | Total liabilities and stockholders' equity | $83,938 | $137,186 | SYNDAX PHARMACEUTICALS, INC. CONSOLIDATED STATEMENTS OF OPERATIONS The company reported increasing net losses from 2016 to 2018, driven by rising research and development expenses Consolidated Statements of Operations (in thousands, except per share data) | Metric | 2018 | 2017 | 2016 | | :-------------------------------------------- | :----- | :----- | :----- | | License fees | $1,517 | $2,108 | $1,220 | | Total revenues | 1,517 | 2,108 | 1,220 | | Research and development | 60,106 | 48,201 | 31,665 | | General and administrative | 17,287 | 15,861 | 13,321 | | Total operating expenses | 77,393 | 64,062 | 44,986 | | Loss from operations | (75,876) | (61,954) | (43,766) | | Interest income (expense), net | 1,942 | 1,421 | 956 | | Change in fair value of common stock warrant liability | — | — | (1,703) | | Other (expense) income, net | (27) | (269) | 41 | | Total other income (expense) | 1,915 | 1,152 | (706) | | Net loss | $(73,961) | $(60,802) | $(44,472) | | Net loss attributable to common stockholders | $(73,961) | $(60,802) | $(47,070) | | Net loss per share (basic and diluted) | $(2.92) | $(2.90) | $(3.22) | | Weighted-average common shares outstanding | 25,371,511 | 20,997,211 | 14,619,716 | SYNDAX PHARMACEUTICALS, INC. CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS Comprehensive loss was primarily driven by net losses for the years ended December 31, 2016, 2017, and 2018 Consolidated Statements of Comprehensive Loss (in thousands) | Metric | 2018 | 2017 | 2016 | | :------------------------------------ | :----- | :----- | :----- | | Net loss | $(73,961) | $(60,802) | $(44,472) | | Other comprehensive loss: | | Unrealized (losses) gains on marketable securities, net of tax | 118 | (199) | 28 | | Comprehensive loss | $(73,843) | $(61,001) | $(44,444) | SYNDAX PHARMACEUTICALS, INC. CONSOLIDATED STATEMENTS OF CONVERTIBLE PREFERRED STOCK AND STOCKHOLDERS' EQUITY (DEFICIT) This statement details changes in stockholders' equity, reflecting equity offerings and the growing accumulated deficit - The statement reflects the conversion of all outstanding convertible preferred stock into common stock upon the closing of the IPO in March 2016[456] - Additional paid-in capital increased significantly due to proceeds from the initial public offering, follow-on offerings, and direct stock placements[456] - The accumulated deficit increased from $(305,293) thousand at December 31, 2016, to $(439,423) thousand at December 31, 2018, reflecting ongoing net losses[456] - Total stockholders' equity decreased from $104,319 thousand at December 31, 2017, to $53,047 thousand at December 31, 2018[456] SYNDAX PHARMACEUTICALS, INC. CONSOLIDATED STATEMENTS OF CASH FLOWS Operating activities consistently used cash, while financing activities provided significant cash to fund operations Consolidated Statements of Cash Flows (in thousands) | (in thousands) | 2018 | 2017 | 2016 | | :------------------------------------ | :----- | :----- | :----- | | Net cash used in operating activities | $(68,531) | $(47,371) | $(35,157) | | Net cash provided by (used in) investing activities | 51,398 | (17,072) | (18,283) | | Net cash provided by financing activities | 15,729 | 75,722 | 54,202 | | Net (decrease) increase in cash and cash equivalents | $(1,404) | $11,279 | $762 | | Cash, cash equivalents and restricted cash—end of year | $33,985 | $35,389 | $24,110 | Notes to Consolidated Financial Statements This section provides detailed notes explaining the company's accounting policies and specific financial statement items 1. Nature of Business - Syndax Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company focused on developing an innovative pipeline of cancer therapies, including entinostat, SNDX-6352, and SNDX-5613[462] - The company completed its initial public offering (IPO) in March 2016, raising $50.5 million in net proceeds[463] - An "at-the-market" (ATM) equity offering program was established in April 2017 for up to $50.0 million in common stock; $32.1 million remained available as of December 31, 2018, and $31.2 million as of March 6, 2019[464] - A follow-on public offering in May 2017 generated approximately $48.7 million in net proceeds[465] - In October 2017, the company entered a license agreement with Vitae Pharmaceuticals (Allergan) for Menin Assets, making a nonrefundable upfront payment of $5.0 million, which was recorded as research and development expense[466][515] - The company issued 2,021,018 shares of common stock to Biotech Value Fund, L.P. (BVF) in October 2017, generating approximately **