Core Insights - The FDA granted Fast Track designation to tamibarotene for treating acute myeloid leukemia (AML) in April 2024 [1] - Initial data from the SELECT-AML-1 study indicated a 100% complete response (CR) rate for patients treated with tamibarotene, Venclexta, and azacitidine, compared to a 70% CR rate for those receiving Venclexta and azacitidine alone [2][5] - Syros Pharmaceuticals is developing tamibarotene as a frontline treatment for AML and higher-risk myelodysplastic syndrome (HR-MDS) [3] Company Performance - Syros Pharmaceuticals' stock has increased by 38.1% over the past three months, outperforming the industry average increase of 10.8% [4] - The company is preparing a new drug application for tamibarotene in HR-MDS, aiming to establish it as the new frontline standard of care for patients with RARA overexpression [7] - Syros currently holds a Zacks Rank of 3 (Hold) [15] Clinical Trials and Data - The SELECT-AML-1 study is evaluating tamibarotene in combination with Venclexta and azacitidine in newly diagnosed AML patients with RARA gene overexpression, with pivotal data expected in the third quarter of 2024 [5][6] - The phase III SELECT-MDS-1 study is assessing tamibarotene with azacitidine in newly diagnosed HR-MDS patients, with key complete response data anticipated by mid-fourth quarter of 2024 [13][14] Regulatory Designations - The FDA has previously granted Fast Track designation to tamibarotene in combination with azacitidine for treating adults with HR-MDS and RARA overexpression [11] - The combination of tamibarotene, azacitidine, and Venclexta has received Fast Track designation for treating newly diagnosed AML in adults over 75 or those with comorbidities that prevent intensive chemotherapy [10]

Financial Data and Key Metrics Changes - The company reported a net loss of $3.7 million, or $0.10 per share, for Q1 2024, compared to a net loss of $23.8 million, or $0.85 per share, for the same period in 2023, indicating a significant improvement in financial performance [19][48] - General and administrative (G&A) expenses decreased to $6.3 million in Q1 2024 from $7.4 million in the same quarter last year, primarily due to reductions in headcount and related expenses [19] - Research and development (R&D) expenses were $24.7 million in Q1 2024, down from $28.8 million in Q1 2023, reflecting a focus on advancing tamibarotene [36] Business Line Data and Key Metrics Changes - The company did not recognize any revenue in Q1 2024, compared to $3 million in Q1 2023, due to the termination of a collaboration agreement with Pfizer [48] - The ongoing SELECT-MDS-1 trial is a pivotal study evaluating tamibarotene in combination with azacitidine for higher-risk MDS patients, with a focus on complete response rates [32][52] Market Data and Key Metrics Changes - The FDA granted fast-track designation for tamibarotene in combination with venetoclax and azacitidine for newly diagnosed Unfit AML patients, highlighting the unmet medical need in this market [44][51] - The competitive landscape in higher-risk MDS has narrowed, with many compounds failing interim analyses, which positions tamibarotene favorably [47] Company Strategy and Development Direction - The company is focused on executing clinical development programs and pre-commercial activities for tamibarotene, aiming to establish it as a new standard of care for hematologic malignancies [9][45] - The company plans to report pivotal data from the SELECT-MDS-1 trial by mid-Q4 2024 and additional data from the SELECT-AML-1 trial in Q3 2024, indicating a strategic emphasis on timely data readouts [17][45] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the recent progress in clinical trials, particularly the successful interim futility analysis for the SELECT-MDS-1 trial, which allows the trial to continue without modifications [30][41] - The company believes its current cash position of $108.3 million will be sufficient to fund operations into Q3 2025, supporting ongoing clinical trials and potential product launches [37][38] Other Important Information - The company amended its loan agreement to increase financial flexibility, extending the interest-only period and allowing for additional term loans upon achieving certain milestones [20][38] - A webcast event is scheduled for June 25 to discuss MDS disease biology and treatment landscape, indicating the company's commitment to stakeholder engagement [15] Q&A Session Summary Question: Can you provide details on the interim analysis of SELECT-MDS-1? - Management confirmed that the interim analysis was based on 50% of the patients and passed without any safety concerns, allowing the trial to continue [23][24] Question: Will there be enough information post-Q3 update to make a go/no-go decision on pivotal development in AML? - Management indicated that it is difficult to project when a go/no-go decision would be made, but updates will be provided in the future [49][54]

Revenue and Financial Performance - The company has not generated any revenue from product sales and does not expect to do so for the foreseeable future, with no revenue recognized in Q1 2024 and $3.0 million in Q1 2023 from a collaboration that has since terminated[132] - Revenue for the three months ended March 31, 2024, was $0, a decrease of 100% compared to $2.954 million in the same period of 2023[145][146] - Net loss for the three months ended March 31, 2024, was $3.708 million, a significant improvement of 84% compared to a net loss of $23.789 million in Q1 2023[145] - Interest income decreased by 13% from $1.775 million in Q1 2023 to $1.546 million in Q1 2024 due to a lower average cash balance[145][151] - Interest expense increased by 7% from $1.217 million in Q1 2023 to $1.307 million in Q1 2024 due to higher interest rates[145][152] - Change in fair value of warrant liabilities increased by 204% from $8.865 million in Q1 2023 to $26.974 million in Q1 2024[145][153] - As of March 31, 2024, the company had cash, cash equivalents, and marketable securities of approximately $108.3 million[161] - Net cash used in operating activities for Q1 2024 was $31.098 million, compared to $36.901 million in Q1 2023[162] - Net cash used in operating activities decreased to $31.1 million for the three months ended March 31, 2024, from $36.9 million in the same period of 2023, primarily due to a $2.3 million decrease in net loss from operations[164] - Net cash used in investing activities was $24.6 million for the three months ended March 31, 2024, compared to $25.7 million in the same period of 2023, mainly due to the purchase of marketable securities totaling $24.7 million[165] - Net cash used in financing activities was $0.3 million for the three months ended March 31, 2024, compared to net cash provided of $0.1 million in the same period of 2023, primarily due to payments related to issuance costs[166] - The company raised approximately $45.0 million through an underwritten offering of common stock and pre-funded warrants in December 2023[131] - The company has $203.6 million of securities available for future issuance under the 2023 Registration Statement as of March 31, 2024[160] Research and Development - Research and development expenses for Q1 2024 totaled $24.7 million, a decrease from $28.8 million in Q1 2023, with external costs for the tamibarotene program increasing to $16.5 million from $13.4 million[135] - The SELECT-MDS-1 trial for tamibarotene in combination with azacitidine is designed to include approximately 550 patients, with a primary endpoint focused on complete response rates and a key secondary endpoint on overall survival[127] - The SELECT-AML-1 trial reported a 100% complete response/complete response with incomplete blood count recovery (CR/CRi) rate among evaluable patients treated with tamibarotene, venetoclax, and azacitidine, compared to 70% in the control arm[129] - The company completed enrollment of 190 patients for the SELECT-MDS-1 trial in Q1 2024 and expects to report pivotal complete response data by mid-Q4 2024[127] - The SELECT-AML-1 trial is expected to report clinical activity and tolerability data from over 40 patients in Q3 2024[130] - The company is focused on advancing clinical trials and developing companion diagnostic tests for tamibarotene, which are critical for future commercialization efforts[167] Market Outlook - The company expects the global market for acute myeloid leukemia (AML) patients to grow to approximately $7.5 billion by 2028, with around 25,000 patients diagnosed annually in the U.S. and Europe[125] - The global market for myelodysplastic syndrome (MDS) patients is projected to reach approximately $4.7 billion by 2028, with an estimated 18,500 HR-MDS patients diagnosed annually in the U.S. and Europe[126] - The FDA granted Fast Track Designation to tamibarotene in combination with azacitidine for newly diagnosed HR-MDS patients with RARA overexpression in January 2023[127] Financial Risks and Funding - The company expects to incur significant expenses for clinical trials and commercialization of tamibarotene, necessitating substantial additional funding[167] - As of March 31, 2024, the company believes its cash, cash equivalents, and marketable securities will fund operations into the third quarter of 2025[168] - The company may need to rely on equity offerings, debt financings, and collaborations to finance its cash needs until substantial product revenues are generated[170] - If additional funding is not secured, the company may have to delay or reduce its product development efforts[171] - The company is exposed to market risks related to interest rates and foreign currency exchange rates, but does not currently hedge against foreign currency risks[172][173] - Inflation has not materially affected the company's business or financial condition during the three months ended March 31, 2024[174]

Financial Data and Key Metrics Changes - For Q4 2023, revenues were $400,000, compared to negative $800,000 in Q4 2022, indicating a significant improvement [43] - The net loss for Q4 2023 was $64.4 million or $2.18 per share, compared to a net loss of $4.8 million or $0.17 per share in Q4 2022 [20] - For the full year 2023, the net loss was $164.6 million or $5.81 per share, compared to a net loss of $94.7 million or $7.49 per share in 2022 [20] - Cash and cash equivalents as of December 31, 2023, were $139.5 million, down from $202.3 million at the end of 2022 [45] Business Line Data and Key Metrics Changes - R&D expenses for Q4 2023 were $21.5 million, down from $27.9 million in Q4 2022, while full-year R&D expenses were $108.2 million compared to $111.9 million in 2022 [19] - G&A expenses for Q4 2023 were $5.9 million, down from $7.3 million in Q4 2022, and full-year G&A expenses were $28.3 million compared to $29.3 million in 2022 [44] Market Data and Key Metrics Changes - The company is focusing on the U.S. market for the launch of tamibarotene, targeting approximately 50% of higher-risk MDS patients with RARA overexpression [12] - The SELECT-MDS-1 trial is a key focus, with pivotal data expected by mid-Q4 2024 [8][62] Company Strategy and Development Direction - The strategy includes launching tamibarotene with its own specialty sales force and focusing on key opinion leader engagement [12][27] - The company aims to deliver a new standard of care for higher-risk MDS and AML patients, emphasizing the importance of RARA overexpression [36][58] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the potential of tamibarotene to transform treatment options for patients with higher-risk MDS and AML [36] - The company remains well-capitalized to fund ongoing development, with cash runway projected into Q2 2025 [18][35] Other Important Information - The company completed an equity financing of approximately $45 million in December 2023, reinforcing its cash position [17][42] - The SELECT-AML-1 trial has shown promising initial data, with a 100% complete response rate in the triplet regimen compared to 70% in the doublet regimen [38][39] Q&A Session Summary Question: Discussion on complete response endpoint and regulatory agency interactions - Management confirmed that complete response (CR) can support regulatory decisions for approval, having had discussions with the FDA regarding this endpoint [23][24] Question: Insights on cash runway and future expenses - Management indicated that Q4 2023 expenses in R&D and SG&A are a reasonable run rate for future quarters, with some variability due to vendor payables [26][50] Question: Focus on medical affairs and commercial preparation - The company is prioritizing education on RARA overexpression and preparing for the launch of tamibarotene, focusing on key opinion leader engagement [27][58]

Financial Performance - The company incurred net losses of $164.6 million and $94.7 million for the years ended December 31, 2023 and 2022, respectively, with an accumulated deficit of $722.8 million as of December 31, 2023[216]. - The company expects to continue incurring significant net operating losses for at least the next several years and has not generated any revenues from product sales[216]. - Future funding requirements will increase substantially as the company continues clinical development activities for tamibarotene and seeks regulatory approvals[217]. - The company believes its cash and cash equivalents as of December 31, 2023 will fund operations into the second quarter of 2025, but may need additional funds sooner than planned[220]. Product Development and Clinical Trials - The company is dependent on the successful clinical development and commercialization of tamibarotene, with no products currently approved for sale[231]. - Clinical trials for tamibarotene are subject to delays and uncertainties, including site activation and patient enrollment challenges[233]. - The company is conducting SELECT-MDS-1 and SELECT-AML-1 clinical trials in foreign countries, relying on third parties for execution, which may introduce additional risks and delays[237]. - The new Clinical Trials Regulation (EU) No 536/2014 aims to streamline clinical trial processes in the EU, but the company has not yet secured authorization under this regulation, posing a risk of delays[238]. - Adverse events associated with tamibarotene include mild to moderate dry skin, skin rash, headache, and severe cases of retinoic acid syndrome, which could impact marketing approval[241]. - The company is focused on developing tamibarotene for patients with RARA overexpression, but the actual patient population may be lower than expected, affecting clinical trial feasibility[240]. - The company entered a Master Collaboration Agreement with Qiagen to develop a companion diagnostic for RARA biomarker, which is critical for the commercialization of tamibarotene[243]. - Companion diagnostics require separate regulatory approval, which could lead to delays in the approval process for tamibarotene if not successfully developed[246]. - Delays in patient enrollment for clinical trials could significantly increase development costs and jeopardize the ability to generate revenue from product candidates[251]. - Variability in safety or efficacy results between different clinical trials may occur, impacting the development timeline and regulatory approval prospects for tamibarotene[253]. - The company faces competition for patient enrollment in clinical trials for AML, which may hinder the recruitment of eligible patients[251]. - The company acknowledges that results from preclinical studies may not predict outcomes in later-stage clinical trials, posing a risk to the development of tamibarotene[252]. - The company has never obtained marketing approval for any product candidate, including tamibarotene, which may delay commercialization and revenue generation[254]. - If marketing approvals are delayed or not obtained, the company may have to abandon development efforts, significantly harming its business[255]. - Even with marketing approval, the product may not achieve necessary market acceptance, impacting revenue and profitability[257]. - The company plans to build a specialized sales and marketing organization in the U.S. for tamibarotene, but lacks existing sales or distribution infrastructure[262]. - The company intends to seek partnerships for the commercialization of tamibarotene outside the U.S., which may lower product revenues[263]. Competition and Market Risks - The company faces substantial competition from major pharmaceutical and biotechnology companies, which may impact its market position[265]. - Competitors may develop more effective or cost-efficient products, potentially rendering the company's candidates obsolete[268]. - The commercial success of tamibarotene will depend on third-party payor coverage and reimbursement, which is uncertain and varies widely[270]. - Delays in obtaining coverage and reimbursement for newly approved drugs may negatively impact revenue generation[273]. - The company faces challenges from third-party payors requiring higher evidence of benefits and clinical outcomes for new technologies, which may affect pricing and reimbursement rates[274]. - Product liability lawsuits could divert resources and limit commercialization of products, with potential substantial liabilities arising from claims related to clinical testing and product safety[275]. - The company maintains clinical trial liability insurance coverage of up to $10 million, but this may not fully cover potential liabilities, and increasing insurance costs could impact product development[276]. - The FDA's approval of generic versions of products could adversely affect sales, as generic products are typically offered at lower prices, leading to significant revenue loss for branded products[277]. Manufacturing and Supply Chain Risks - The company relies on third-party manufacturers for clinical and commercial supplies, which poses risks related to compliance with manufacturing practices and potential disruptions from external events[283]. - The company does not have long-term supply agreements with third-party manufacturers, which could lead to challenges in securing reliable production[284]. - The company faces risks from potential competition and market dynamics that could impact the commercialization and profitability of its product candidates[279]. Intellectual Property and Regulatory Risks - The company lacks composition of matter patent protection for tamibarotene and SY-2101, which may limit its ability to enforce patent rights against competitors[299]. - The company may face challenges in maintaining necessary intellectual property rights, which could hinder the development and commercialization of its product candidates[302]. - The company’s success is contingent on obtaining and maintaining patent protection, as competitors may develop similar products if patent rights are insufficient[305]. - The patent landscape is uncertain, and the company may face challenges in enforcing its patents or may not secure meaningful protection against competitors[310]. - The company may need to defend its patents against challenges, which could result in loss of exclusivity or invalidation of patent claims[313]. - The company may face challenges in enforcing its licensed patents due to reliance on third-party licensors, which could adversely affect its competitive position and financial condition[316]. - The company seeks to protect its trade secrets through non-disclosure agreements, but breaches could lead to significant harm to its business and technology value[317]. - Intellectual property litigation could be costly and time-consuming, potentially diverting management's attention and resources from core business activities[318]. - There is a risk that courts may invalidate the company's patents or determine they are unenforceable, limiting the ability to exclude competitors from the market[319]. - The company may not have sufficient resources to pursue infringement claims, which could last for years and may not yield adequate remedies[320]. - If the company is found to infringe third-party intellectual property rights, it could face costly litigation and be forced to cease development of its product candidates[321]. - Changes in U.S. patent law, such as the America Invents Act, could increase uncertainties and costs associated with obtaining and enforcing patents[325]. - The company may struggle to enforce its intellectual property rights globally due to varying patent laws and potential compulsory licensing in certain jurisdictions[330]. - A Russian decree allows local companies to exploit U.S. patents without consent, further complicating the company's ability to protect its inventions in that market[331]. - Patent terms may not provide adequate protection for the company's products, as patents could expire before commercialization, allowing competitors to launch similar products[334]. Regulatory Environment - The company has obtained orphan drug designation for tamibarotene for the treatment of MDS and AML in the United States and Europe[350]. - The exclusivity period for orphan drugs is seven years in the United States and ten years in Europe, which can be reduced to six years under certain conditions[349]. - The regulatory approval process for marketing products is lengthy, expensive, and uncertain, potentially delaying revenue generation[341]. - The company has limited experience in conducting and managing clinical trials necessary for obtaining marketing approvals[338]. - Changes in regulatory policies and requirements may cause delays in the approval process for product candidates[340]. - The company may face heightened risks in obtaining marketing authorization in the U.K. post-Brexit, with new regulatory responsibilities assigned to the MHRA[344]. - Foreign regulatory authorities may change their approval policies, impacting the company's ability to market products internationally[345]. - The company is conducting clinical trials globally, but acceptance of foreign data by the FDA is not guaranteed[347]. - The company may not be able to obtain orphan drug exclusivity for future product candidates, even if designations are secured[351]. - The FDA's reevaluation of the Orphan Drug Act could impact the company's business and orphan drug exclusivity[352]. - The company may face substantial penalties if it fails to comply with regulatory requirements for marketing approvals, which could adversely affect profitability[353]. - Non-compliance with EU safety monitoring and personal information protection requirements can lead to significant financial penalties[355]. Legislative and Economic Factors - The corporate tax rate has been reduced from 35% to 21% under the TCJA, which could impact the company's financial condition[371]. - The Consolidated Appropriations Act delays the 4% Medicare sequester until the end of 2024, affecting potential revenue from Medicare[367]. - The FDA's ability to review and approve new products can be hindered by inadequate funding and government shutdowns, impacting the company's operations[362]. - Future government shutdowns could significantly impact the FDA's ability to process regulatory submissions, adversely affecting the company's business[364]. - Current legislation may affect the prices for tamibarotene and future product candidates due to efforts to reduce prescription drug costs in the U.S.[372]. - The Inflation Reduction Act (IRA) requires manufacturers to negotiate prices for certain drugs starting in 2026, with a cap on negotiated prices[375]. - Medicare will negotiate prices for ten high-cost drugs in 2026, increasing to 20 drugs by 2029 and beyond[376]. - The IRA imposes penalties for manufacturers that do not comply with negotiated prices or exceed inflation-based price increases[377]. - The FDA approved Florida's plan for Canadian drug importation on January 5, 2024, allowing states to import certain prescription drugs from Canada[373]. - The removal of safe harbor protections for price reductions under Medicare Part D is delayed until January 1, 2032[374]. - States are increasingly passing legislation to control pharmaceutical pricing, which may reduce demand for products once approved[379]. - Pricing negotiations in the EU can take considerable time post-marketing approval, potentially impacting reimbursement and pricing[380]. Compliance and Operational Risks - Compliance with healthcare laws and regulations may expose the company to significant penalties and operational disruptions[381]. - The California Privacy Rights Act (CPRA) went into effect on January 1, 2023, imposing additional compliance requirements that may impact business operations[388]. - Eleven states in the U.S. have passed comprehensive privacy laws similar to CCPA and CPRA, impacting business activities related to personal information processing[389]. - GDPR imposes fines of up to €20 million or 4% of total worldwide annual turnover for non-compliance, whichever is higher[391]. - The invalidation of the EU-U.S. Privacy Shield in July 2020 raises compliance costs and scrutiny for data transfers from the EEA to the U.S.[392]. - The EU-U.S. Data Privacy Framework was adopted in July 2023, allowing U.S. companies to self-certify for data transfers, but challenges from privacy advocacy groups may arise[393]. - The U.K. Data Protection Act 2018 parallels GDPR, and both jurisdictions have agreed on data transfer adequacy decisions[394]. - Non-compliance with anti-corruption laws, such as the FCPA, could lead to significant fines, reputational harm, and operational disruptions[397][398]. - Export control laws may impair the ability to compete internationally and result in substantial penalties for non-compliance[399]. - Environmental, health, and safety regulations could lead to fines and significant costs if not adhered to, impacting business operations[401][403]. Operational and Management Challenges - Global economic downturns could weaken demand for products and hinder capital raising efforts, affecting overall business performance[404]. - Cybersecurity threats pose risks to data integrity and could result in significant costs and operational disruptions if breaches occur[405][406]. - The company is highly dependent on key personnel, including its CEO and CFO, which poses a risk if any of them leave[409]. - The company anticipates significant growth in operations and employee count if it receives marketing approval for tamibarotene, necessitating improvements in managerial and operational systems[411]. - The company may engage in acquisitions, which could dilute stockholder equity and disrupt business operations[412]. - Public health crises, such as COVID-19, have adversely impacted the company's operations and may continue to do so in the future[408]. - The company faces intense competition for qualified personnel, which could hinder its ability to develop and commercialize products[410]. - The company is exposed to risks of misconduct by employees and contractors, which could lead to regulatory sanctions and reputational harm[407]. - The company may encounter difficulties in managing growth, potentially leading to operational mistakes and reduced productivity[411]. - Catastrophic events, including natural disasters and geopolitical tensions, could significantly disrupt the company's operations and financial performance[413]. - The company's stock price is likely to be highly volatile, posing risks for stockholders[414].

Financial Data and Key Metrics Changes - The company recognized $3.8 million in revenue for Q3 2023, a decrease from $3.9 million in Q3 2022, primarily due to the conclusion of a collaboration with Pfizer [6] - The net loss for Q3 2023 was $40.1 million, or $1.43 per share, compared to a net loss of $30.3 million, or $3.21 per share, for the same period in 2022 [46] - Cash, cash equivalents, and marketable securities as of September 30, 2023, were $112 million, down from $144 million on June 30, 2023 [7] Business Line Data and Key Metrics Changes - R&D expenses increased to $28.3 million in Q3 2023 from $25.8 million in Q3 2022, focusing primarily on the advancement of tamibarotene [31] - G&A expenses slightly decreased to $7.8 million in Q3 2023 from $8.1 million in Q3 2022 [31] Market Data and Key Metrics Changes - The market opportunity for tamibarotene is significant, with approximately 21,000 people diagnosed with higher-risk MDS and nearly 25,000 diagnosed with unfit AML annually in the U.S. and Europe [41] - The existing standard of care for unfit AML patients has a composite CR rate of 66% and a median overall survival of less than 15 months [4][59] Company Strategy and Development Direction - The company is focused on advancing tamibarotene as a potential standard of care for higher-risk MDS and unfit AML patients with RARA overexpression [22][26] - The company plans to report pivotal data from the SELECT-MDS-1 trial next year and initial data from the SELECT-AML-1 trial in early December [23][42] - The leadership transition to Conley Chee is aimed at building a robust commercial business for tamibarotene [24][40] Management's Comments on Operating Environment and Future Outlook - Management highlighted the significant unmet medical need in the treatment of higher-risk MDS and unfit AML, emphasizing the importance of developing well-tolerated therapies [65][66] - The company remains optimistic about the potential of tamibarotene to improve patient outcomes, particularly in the context of evolving treatment landscapes [11][59] Other Important Information - Restructuring costs for Q3 2023 amounted to $2.4 million, including severance and asset impairment charges [63] - The company believes its current cash position will be sufficient to fund operations into 2025, covering anticipated expenses related to ongoing trials [32] Q&A Session Summary Question: Changes in the AML and MDS landscape since designing the SELECT studies - Management acknowledged the evolution of treatment standards and the ongoing unmet needs in these areas, expressing hope for tamibarotene's distinct mechanism to address these challenges [50][66] Question: Efficacy of adding tamibarotene to the combination therapy - Management indicated that the expected composite CR rate for the ven/aza control arm is 66%, and they are looking for a response rate above that in the triplet regimen [67] Question: Enrollment completion timeline for SELECT-MDS - Management updated the expected completion of enrollment for SELECT-MDS to Q1 2024, citing improved accuracy in projections as enrollment nears completion [69]

Revenue and Collaboration - For the three and nine months ended September 30, 2023, the company recognized revenue of $3.8 million and $9.6 million, respectively, related to its collaboration with GBT[178]. - The collaboration with GBT terminated effective October 16, 2023, and the company does not expect to recognize collaboration revenue from GBT following that date[179]. - Revenue for the three months ended September 30, 2023, was $3.8 million, a decrease of 3% from $3.9 million in the same period of 2022[194]. - Revenue for the nine months ended September 30, 2023, was $9.6 million, a decrease of 39% from $15.6 million in the same period of 2022[204]. Clinical Trials and Development - The company is advancing tamibarotene in combination with azacitidine in a Phase 3 clinical trial (SELECT-MDS-1) for higher-risk myelodysplastic syndrome (HR-MDS), with an expected total addressable market of approximately $3.3 billion by 2026[170]. - The SELECT-MDS-1 trial is designed to include approximately 550 patients to assess overall survival as a key secondary endpoint, with pivotal complete response data expected by mid-Q4 2024[170]. - The ongoing Phase 2 clinical trial (SELECT-AML-1) for tamibarotene in combination with venetoclax and azacitidine reported a composite complete response rate of 83% in a small cohort of newly diagnosed unfit AML patients[171]. - The company has stopped further investment in the clinical development of SY-2101 to prioritize the ongoing development of tamibarotene[167]. - The total addressable market opportunity for all AML patients is expected to grow to approximately $6.6 billion by 2025[169]. - The company is exploring out-licensing opportunities for SY-5609, a selective inhibitor of CDK7, after completing a Phase 1/1b clinical trial[174]. - The company is focused on the clinical trials of tamibarotene and associated companion diagnostic tests, with ongoing development efforts for future product candidates[230]. Financial Performance - Research and development expenses increased by approximately $2.5 million, or 10%, from $25.8 million in Q3 2022 to $28.3 million in Q3 2023[195]. - External research and development costs rose by approximately $3.9 million, or 31%, primarily due to increased costs associated with clinical trials of tamibarotene[199]. - General and administrative expenses decreased by approximately $0.3 million, or 4%, from $8.1 million in Q3 2022 to $7.8 million in Q3 2023[196]. - Interest income increased by approximately $1.2 million, or 317%, due to higher interest rates in Q3 2023 compared to Q3 2022[193]. - Interest expense increased due to higher interest rates on credit facilities and equipment financing arrangements[201]. - The net loss for the three months ended September 30, 2023, was $40.1 million, an increase of 33% from a net loss of $30.3 million in Q3 2022[193]. - Total operating expenses decreased by 11% from $43.3 million in Q3 2022 to $38.4 million in Q3 2023[193]. - Research and development expenses increased by approximately $2.6 million, from $84.0 million in 2022 to $86.7 million in 2023, representing a 3% increase[205][206]. - General and administrative expenses rose by approximately $0.4 million, or 2%, from $22.0 million in 2022 to $22.4 million in 2023[207]. - Interest income surged to $5.5 million in 2023, a 927% increase from $0.5 million in 2022, due to higher average cash balances and interest rates[210]. - Net loss for the nine months ended September 30, 2023, was $100.2 million, an 11% increase from a net loss of $89.9 million in 2022[221]. Cash Flow and Funding - Cash and cash equivalents as of September 30, 2023, were approximately $112.2 million, which is expected to fund operations into 2025[219][227]. - Net cash used in operating activities was $91.1 million in 2023, a slight decrease from $92.0 million in 2022[223]. - Net cash provided by investing activities was $35.8 million in 2023, compared to $29.5 million in 2022, primarily due to the maturity of marketable securities[224]. - The company expects to incur significant expenses related to advancing clinical trials and commercialization efforts for tamibarotene, necessitating additional funding[226][228]. - As of September 30, 2023, $250.0 million of securities remained available for future issuance under the 2023 Registration Statement[218]. - The company may need to relinquish valuable rights to technologies or future revenue streams if additional funds are raised through collaborations or licensing arrangements[229]. Market Risks and Economic Factors - The company is exposed to market risk related to changes in interest rates, but a 10% change in market interest rates is not expected to materially impact the investment portfolio[231]. - The company contracts with vendors in Asia and Europe, exposing it to foreign currency exchange rate fluctuations, but currently does not hedge this risk[232]. - Inflation has increased labor and clinical trial costs, but it did not have a material effect on the company's financial condition during the nine months ended September 30, 2023[233].

| --- | |----------------------------------------------------------------------------------------------------------------------------------| | Novel oral form of arsenic trioxide (ATO) with opportunity to replace standard of care for APL patients | | Orally bioavailable with exposures consistent with IV ATO | | Clear development path to approval in frontline APL with potential to leverage emerging data for a more efficient pivotal study | | Potential for rapid adoption in frontline APL, benefitting from a s ...

Financial Data and Key Metrics Changes - The company recognized $2.8 million in revenue for Q2 2023, entirely from its collaboration with Pfizer, compared to $6.3 million in Q2 2022 [38][44] - R&D expenses decreased to $29.6 million in Q2 2023 from $33.1 million in Q2 2022, focusing on late-stage clinical programs [39] - General and administrative expenses increased to $7.2 million in Q2 2023 from $6.9 million in Q2 2022 [45] - The net loss for Q2 2023 was $36.3 million, or $1.30 per share, compared to a net loss of $34.5 million, or $5.40 per share, in the same period of 2022 [45] - Cash, cash equivalents, and marketable securities as of June 30, 2023, were $144 million, down from $166 million on March 31, 2023, with sufficient funds projected to last into 2025 [46] Business Line Data and Key Metrics Changes - The SELECT-MDS-1 Phase III trial is evaluating tamibarotene plus azacitidine in newly diagnosed high-risk MDS patients, with a primary endpoint of complete response rate [29] - Enrollment in SELECT-AML-1 and SELECT-MDS-1 trials is ongoing, with initial data from SELECT-AML-1 expected in Q4 2023 and pivotal CR data from SELECT-MDS-1 anticipated in Q3 2024 [23][14] Market Data and Key Metrics Changes - Approximately 50% of patients with higher-risk MDS and 30% of AML patients are positive for RARA overexpression, aligning with expectations [24] - The existing standard-of-care for high-risk MDS has a complete response rate of 17% and a median overall survival of 18.6 months, indicating a significant unmet need [18][27] Company Strategy and Development Direction - The company remains focused on clinical trial execution and aims to achieve upcoming milestones, including data readouts from its Phase II study of tamibarotene [14] - The strategy includes addressing unmet needs in hematologic malignancies and establishing new standards of care for patients with RARA gene overexpression [15][28] - The company is exploring out-licensing opportunities for its 5609 program to support further development [37] Management's Comments on Operating Environment and Future Outlook - Management expressed optimism about the ongoing momentum in clinical trials and precommercial activities, indicating a productive first half of the year [6][7] - The management team highlighted the potential of tamibarotene to improve outcomes for high-risk MDS and unfit AML patients, emphasizing the differentiated profile of their biologically targeted programs [9][26] Other Important Information - The company plans to report initial data from the SELECT-AML-1 trial in Q4 2023, which will be the first direct comparison of the triplet regimen versus the doublet in AML [20] - The SELECT-MDS-1 trial is designed to enroll a total of 550 patients, with the initial 190 patients supporting the primary endpoint [31] Q&A Session Summary Question: Update on SELECT program and potential partnerships - The company is in discussions regarding partnerships for the 5609 program and will provide updates as they arise [41][42] Question: Go/no-go decision timeline for tamibarotene in AML - Initial data from the randomized portion of the trial in Q4 2023 will inform the go/no-go decision, with further insights expected in 2024 [51][55] Question: Futility analysis timing - A futility analysis is planned before the primary efficacy analysis, focusing on safety and risk/benefit ratios [58] Question: Updates on 2101 and FDA meetings - The company is analyzing PK data from the dose confirmation trial and will provide updates in the second half of the year regarding development plans and timelines [59]

Acquisition and Mergers - On September 16, 2022, the Company completed the acquisition of Tyme Technologies, Inc., issuing approximately 7.5 million shares and acquiring net cash and marketable securities of approximately $67.1 million[39]. - The Company issued approximately 7.5 million shares of common stock to former Tyme stockholders in connection with the Merger[83]. - As of June 30, 2023, the Company has incurred $3.1 million in transaction costs related to the Merger, which are reflected as a reduction of additional paid-in capital[85]. - The Company incurred $4.5 million in severance payments to former Tyme employees, expensed at the closing of the transaction[85]. - The Company assumed certain Tyme stock options, issuing options to purchase 692,460 shares at the completion of the merger on September 16, 2022[151]. Financial Performance and Revenue - The Company has not generated any revenue from product sales and does not expect to do so in the foreseeable future[61]. - Revenue recognized under the GBT Collaboration Agreement for the three and six months ended June 30, 2023, was $2.8 million and $5.8 million, respectively, compared to $5.7 million and $10.7 million for the same periods in 2022[94]. - The Company did not recognize any revenue under the Incyte Collaboration Agreement during the three and six months ended June 30, 2023, while recognizing $0.6 million and $1.0 million for the same periods in 2022[103]. Cash and Liquidity - As of June 30, 2023, the Company believes it will meet its liquidity requirements for at least 12 months[42]. - Cash, cash equivalents, and marketable securities totaled $143.982 million as of June 30, 2023, down from $202.304 million as of December 31, 2022[106][107]. - The Company has a total cash, cash equivalents, and restricted cash amounting to $118.5 million as of June 30, 2023, compared to $62.2 million in 2022, indicating an increase of 90.5%[116]. - As of June 30, 2023, the Company had deferred revenue of approximately $2.2 million under the GBT Collaboration Agreement, all classified as current[94]. Investments and Securities - The Company filed a universal shelf registration statement to register for sale up to $250.0 million of various securities, declared effective on April 28, 2023[41]. - The fair value of warrant liabilities decreased from $24.472 million as of December 31, 2022, to $18.712 million as of June 30, 2023, reflecting a change in fair value of $(5.760) million[114]. - The average expected volatility for the warrants was 86.95% as of June 30, 2023, compared to 86.79% as of December 31, 2022[113]. Research and Development - Research and development expenses include both internal and external costs, with significant judgments made in estimating accrued liabilities[68][70]. - The Company will recognize revenue associated with the GBT collaboration as research and development services are provided, using an input method based on costs incurred[93]. - The Company completed all target validation activities under the Incyte Collaboration Agreement as of June 30, 2023[100]. Stock-Based Compensation - The Company accounts for stock-based compensation expenses based on grant date fair values, expensed over the vesting period[73]. - The Company recorded a change in fair value of $3.1 million for the 2022 Warrants and $5.8 million for the 2020 Warrants for the six months ended June 30, 2023[139]. - The company granted 1,354,236 restricted stock units during the six months ended June 30, 2023, with an average grant date fair value of $4.00[156]. - The company has $13.2 million of unrecognized stock-based compensation expense related to outstanding restricted stock units and awards, with an expected recognition period of 2.1 years[156]. - Stock-based compensation expense for the three months ended June 30, 2023, was $2,814 million, compared to $2,689 million in 2022, reflecting an increase of 4.6%[158]. Debt and Obligations - The Company has a total minimum loan payment obligation of $40.0 million as of June 30, 2023, with $6.7 million due in 2024 and $20.0 million in 2025[123]. - Interest expense related to the Loan Agreement for the three months ended June 30, 2023, was approximately $1.3 million, compared to $1.0 million for the same period in 2022, reflecting a 30% increase[123]. General Business Operations - The Company operates only in the United States and manages its business as a single operating segment[47]. - The Company has not recognized any impairment losses from inception through June 30, 2023[59]. - The Company’s financial statements are prepared in accordance with U.S. GAAP, with all necessary adjustments made for fair presentation[44]. - The Company’s investment policy prioritizes safety, preservation of principal, and liquidity of investments to meet cash flow requirements[50]. Other Financial Metrics - The Company recorded no realized gains or losses on sales of investments during the six months ended June 30, 2023[107]. - The Company recorded a right-of-use asset and lease liability of $15.8 million for the HQ Lease, with a weighted average discount rate of 9.3%[126]. - The number of authorized shares of the Company's common stock was increased to 700 million before a reverse stock split, which adjusted the number to 70 million shares[133].