Zotatifin

SOLANA BEACH, Calif. and REDWOOD CITY, Calif., May 20, 2024 (GLOBE NEWSWIRE) -- eFFECTOR Therapeutics, Inc. (NASDAQ: EFTR), a leader in the development of selective translation regulator inhibitors (STRIs) for the treatment of cancer, today announced a collaboration to conduct an investigator-sponsored trial (IST) evaluating zotatifin in combination with abemaciclib and letrozole in patients with estrogen receptor-positive (ER+) endometrial cancer and low grade serous ovarian cancer at the Dana-Farber Cancer Institute (DFCI) under the direction of Panagiotis Konstantinopoulos, M.D., Ph.D., Director of Translational Research and attending oncologist in the Division of Gynecologic Oncology at DFCI, and an Associate Professor of Medicine at Harvard Medical School. “Endometrial cancer is the most prevalent cancer affecting the female reproductive organs in the United States,” said Dr. Konstantinopoulos. “While early detection offers hope for successful treatment, patients with recurrent or metastatic disease have limited treatment options. Recent studies of the abemaciclib and letrozole combo in ER+ endometrial cancer patients have shown promising activity, however, most patients either fail to respond or eventually develop resistance to CDK4/6 inhibition, a critical aspect of treatment. Similarly, low grade serous ovarian cancer has shown sensitivity to combined treatment with aromatase inhibitors and CDK4/6 inhibition, but responding patients eventually develop disease progression. By targeting eIF4A, which subsequently downregulates the key factors implicated in CDK4/6 inhibition resistance, we believe that integrating zotatifin with abemaciclib and letrozole treatment regimen represents a compelling strategy for combating recurrent endometrial cancer and low grade serous ovarian cancer.” Doug Warner, M.D., chief medical officer of eFFECTOR Therapeutics added, “We are thrilled to embark on this investigator-sponsored Phase 2 trial in collaboration with Dr. Konstantinopoulos and his team at the DFCI. This trial represents a significant step forward in our collective efforts to address the complexities of endometrial cancer and low grade serous ovarian cancer. By exploring the potential of zotatifin as a combination treatment and its unique mechanism of action, we aim to redefine the treatment landscape and improve outcomes for these patients. With this comprehensive approach which simultaneously targets tumor cell cycle progression while reducing estrogen levels, we hope to overcome resistance mechanisms and enhance treatment efficacy which we believe could be applied in various malignancies beyond breast and endometrial cancers. In parallel, we continue to advance development of zotatifin in ER+ metastatic breast cancer and anticipate determination of the Phase 2 dose (RP2D) of zotatifin in combination with fulvestrant and abemaciclib, in the second half of 2024.” About Zotatifin Zotatifin is a potent and sequence-selective small molecule inhibitor of the RNA helicase eIF4A that is designed to suppress the overproduction of cell cycle proteins and oncogenes, including Cyclins D and E, CDKs 4 and 6, ERα, KRAS, HER2, and other RTKs. Zotatifin is currently being evaluated in a Phase 2a expansion cohort in combination with fulvestrant and abemaciclib in ER+ breast cancer. Efficacy data presented at 2023 ASCO and SABCS showed a 26% response rate and mPFS of 7.4 months as a triplet in heavily pretreated patients. About eFFECTOR Therapeutics eFFECTOR is a clinical-stage biopharmaceutical company pioneering the development of a new class of oncology drugs referred to as STRIs. eFFECTOR’s STRI product candidates target the eIF4F complex and its activating kinase, mitogen-activated protein kinase interacting kinase (MNK). The eIF4F complex is a central node where two of the most frequently mutated signaling pathways in cancer, the PI3K-AKT and RAS-MEK pathways, converge to activate the translation of select mRNA into proteins that are frequent culprits in key disease-driving processes. Each of eFFECTOR’s product candidates is designed to act on a single protein that drives the expression of a network of functionally related proteins, including oncoproteins and immunosuppressive proteins in T cells, that together control tumor growth, survival, and immune evasion. Zotatifin, eFFECTOR’s inhibitor of eIF4A, is currently being evaluated in a Phase 2a expansion cohort in combination with fulvestrant and abemaciclib in ER+ breast cancer and in Phase 2 IST in combination with abemaciclib and letrozole in ER+ endometrial cancer. Tomivosertib, eFFECTOR’s MNK inhibitor, is currently being evaluated in an investigator-sponsored trial in AML. eFFECTOR has a global collaboration with Pfizer to develop inhibitors of a third target, eIF4E. Forward-Looking Statements eFFECTOR cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: the future clinical development of our product candidates, including expectations on enrollment and the timing of reporting data from ongoing clinical trials; the potential therapeutic benefits of our product candidates; and the timing and potential benefits of the IST evaluating zotatifin in combination with abemaciclib and letrozole in patients with ER+ endometrial cancer and low grade serous ovarian cancer. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: potential delays in the commencement, enrollment and completion of clinical trials, including the IST conducted by DFCI; the success of our clinical trials and preclinical studies for our product candidates is uncertain; we are dependent on DFCI to conduct the IST trial and we may not realize any benefits from the collaboration with DFCI; our dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; the results of preclinical studies and early clinical trials are not necessarily predictive of future results; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; and other risks described in our prior filings with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Contacts: Investors: Christopher M. Calabrese Managing Director LifeSci Advisors 917-680-5608 ccalabrese@lifesciadvisors.com Kevin Gardner Managing Director LifeSci Advisors 617-283-2856 kgardner@lifesciadvisors.com Media: Michael Fitzhugh Vice President, Chief of Media Strategy LifeSci Communications mfitzhugh@lifescicomms.com

Dose escalation of zotatifin in the ZFA triplet ongoing at 0.14 mg/kg, with RP2D expected in H2 2024 Raised $15.0 million in gross proceeds from registered direct financing, extending cash runway into first quarter of 2025 SOLANA BEACH, Calif. and REDWOOD CITY, Calif., May 09, 2024 (GLOBE NEWSWIRE) -- eFFECTOR Therapeutics, Inc. (NASDAQ: EFTR), a leader in the development of selective translation regulator inhibitors (STRIs) for the treatment of cancer, today reported financial results for the first quarter ended March 31, 2024, and provided a corporate update. “We had a productive first quarter marked by continued progress in the zotatifin program, including successful completion of the ZF doublet dose escalation, and ongoing assessment of increasing doses in the ZFA triplet,” said Steve Worland, Ph.D., president and chief executive officer of eFFECTOR. “We are highly encouraged with the safety profile and activity already reported for the ZFA triplet, in particular the 7.4 month mPFS in heavily pre-treated patients, and look forward to finalizing the dose and schedule in the second half of 2024. We believe the zotatifin program is well positioned to move into a randomized trial later this year.” Dr. Worland continued: “While we were disappointed in the results from the KICKSTART trial, our commitment to maximizing the value of all assets in our pipeline remains unchanged. Our focus is now further sharpened towards advancing zotatifin through development as efficiently as possible. As part of our strategy to leverage external interest in our clinical programs to conserve capital, we will continue investigator-sponsored trials of zotatifin in ER+ breast cancer in a pre-operative setting and tomivosertib in acute myeloid leukemia (AML). Additionally, with the completion of the registered direct financing in January 2024, extending our cash runway into the first quarter of 2025, we can continue progressing with these planned zotatifin development activities and the initiated ISTs.” Pipeline Highlights Zotatifin (eFT226): eFFECTOR’s wholly-owned potent and selective inhibitor of mRNA helicase eIF4A designed to downregulate the expression of key oncoproteins and cell cycle proteins that drive tumor growth and resistance: Dose escalation now focused on the ZFA triplet. Based on favorable safety and tolerability results observed in more than 50 patients who received zotatifin at the initial RP2D of 0.07 mg/kg on Days 1 and 8 of a 21-day cycle, as monotherapy, combined with fulvestrant (ZF doublet) or combined with fulvestrant and abemaciclib (ZFA triplet), dose escalation was resumed using a more convenient schedule of zotatifin dosed every other week (Q2W). In the first quarter of 2024, dose escalation of the ZF doublet concluded with the determination of 0.2 mg/kg zotatifin Q2W as the new RP2D for the doublet, which is projected to provide approximately twice the overall zotatifin exposure compared to the initial RP2D. Determination of the RP2D for the ZFA triplet is ongoing, with dosing currently at 0.14 mg/kg and determination of the RP2D anticipated in the second half of 2024. The company looks forward to finalizing the dose and schedule for zotatifin in the ZFA triplet and interacting with the FDA prior to initiating a randomized, potentially registrational, trial in ER+ breast cancer. Positive interim Phase 2 data including mPFS of 7.4 months in the ZFA triplet expansion cohort reported at the 2023 San Antonio Breast Cancer Symposium (SABCS®). In the ZFA triplet cohort, wherein patients with a median of four prior lines of therapy for metastatic disease received 0.07 mg/kg zotatifin dosed on Days 1 and 8 of a 21-day cycle, combined with fulvestrant and abemaciclib, the mPFS was 7.4 months (95% confidence intervals 2.8 to non-estimable). As previously reported, five of 19 (26%) RECIST-evaluable patients had partial responses, including four confirmed and one unconfirmed. The ZFA triplet continued to be generally well tolerated, with the majority of zotatifin-related treatment-emergent adverse events (TEAEs) being Grade 1 or 2. The most common zotatifin-related TEAEs were nausea, vomiting, and fatigue, all of which were Grade 1 or 2. The most common Grade 3 or higher zotatifin-related TEAEs were anemia and blood creatinine phosphokinase increase, each in two of 20 (10%) patients. Four of 20 (20%) patients discontinued treatment due to adverse events of any cause. Ongoing patient enrollment in randomized Phase 2 investigator sponsored trial (IST) in ER+ breast cancer. The study is being conducted as part of a collaboration with Stanford Medicine in which zotatifin is being tested in specific genomically-defined subgroups, including standard-risk patients as well as high-risk patients carrying specific markers predictive of relapse. The trial is led by Jennifer Caswell-Jin, M.D., Assistant Professor of Medicine at Stanford Medicine, and brings to the clinic the science of integrative subgroups of breast cancer, building on work done by Christian Curtis, Ph.D., Professor of Medicine, Genetics, and Biomedical Data Science, and Director of Artificial Intelligence and Cancer Genomics at Stanford Medicine. Tomivosertib (eFT508): eFFECTOR’s wholly-owned, highly selective MNK inhibitor designed to enhance anti-tumor immune activity by activating T cells, delaying their exhaustion, and expanding the pool of central memory T cells: Phase 1 investigator-initiated dose escalation trial in patients with relapsed/refractory Acute Myeloid Leukemia (AML) in collaboration with Northwestern University. Currently enrolling patients, the trial is designed to capitalize on previously published results that showed preclinical activity of tomivosertib in AML models. Once the appropriate dose for tomivosertib in AML is identified, the company hopes to expand the trial to test tomivosertib in combination with venetoclax and azacytidine. The study is led by Shira Dinner, M.D., Associate Professor of Medicine (Hematology and Oncology) at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Topline results from Phase 2b KICKSTART trial in NSCLC reported in April 2024. The hazard ratio for progression free survival, based on 36 events, was 0.62 (95% confidence intervals 0.3 and 1.3) using a stratified COX proportional hazards model, with a two-sided p-value for PFS of 0.21, which did not meet the pre-specified threshold of 0.2. Based on the totality of the data available as of the primary analysis, the company does not see an obvious path forward to continue developing tomivosertib in frontline NSCLC. Business Highlights $15.0 million in gross proceeds raised from registered direct financing, extending cash runway into the first quarter of 2025. The Company completed a registered direct financing that closed on January 29, 2024, which included the sale of an aggregate of 1,488,834 shares of common stock (or common stock equivalents in lieu thereof), at a purchase price of $10.075 per share (or common stock equivalent in lieu thereof) and warrants to purchase up to an aggregate of 1,488,834 shares of common stock with an exercise price of $9.95 per share. First Quarter 2024 Financial Results Cash Position and Guidance: The company had cash, cash equivalents, and short-term investments totaling $25.4 million as of March 31, 2024, compared to $18.4 million as of December 31, 2023. The company anticipates that its current cash, cash equivalents, and short-term investments will be sufficient to fund operations into the first quarter of 2025. Research and Development (R&D) Expenses: R&D expenses were $5.3 million for the quarter ended March 31, 2024, compared to $6.6 million for the same quarter of 2023. This decrease for the quarter was due to lower external development expenses primarily associated with the timing of clinical trial activities for both the tomivosertib and zotatifin programs along with lower drug product manufacturing. R&D expenses included approximately $0.4 million and $0.5 million of non-cash stock compensation expense in the quarters ended March 31, 2024, and 2023, respectively. General and Administrative (G&A) Expenses: G&A expenses were $3.1 million for the quarter ended March 31, 2024, compared to $2.9 million for the same quarter of 2023. This increase for the quarter was primarily due to increased personnel related costs along with increased legal and consultant costs for the period, partially offset by a decrease in premiums paid on directors and officers insurance. G&A expenses included approximately $0.6 million and $0.7 million of non-cash stock compensation expense in the quarters ended March 31, 2024, and 2023, respectively. Other Expense: Other expense was $0.4 million and $0.5 million for the quarters ended March 31, 2024, and 2023, respectively. Other expense in the quarters ended March 31, 2024, and 2023 consisted primarily of interest expense associated with the company’s term loans, partially offset by interest income earned on the company’s cash, cash equivalents, and short-term investments. Net Loss: Net loss was $8.8 million, or $2.16 per basic and diluted share, for the quarter ended March 31, 2024, as compared to net loss of $10.0 million, or $5.96 per basic and diluted share for the same quarter of 2023. About eFFECTOR TherapeuticseFFECTOR is a clinical-stage biopharmaceutical company pioneering the development of a new class of oncology drugs referred to as STRIs. eFFECTOR’s STRI product candidates target the eIF4F complex and its activating kinase, mitogen-activated protein kinase interacting kinase (MNK). The eIF4F complex is a central node where two of the most frequently mutated signaling pathways in cancer, the PI3K-AKT and RAS-MEK pathways, converge to activate the translation of select mRNA into proteins that are frequent culprits in key disease-driving processes. Each of eFFECTOR’s product candidates is designed to act on a single protein that drives the expression of a network of functionally related proteins, including oncoproteins and immunosuppressive proteins in T cells, that together control tumor growth, survival and immune evasion. Zotatifin, eFFECTOR’s inhibitor of eIF4A, is currently being evaluated in a Phase 2a expansion cohort in combination with fulvestrant and abemaciclib in ER+ breast cancer. Tomivosertib, eFFECTOR’s MNK inhibitor, is currently being evaluated in an investigator-sponsored trial in AML. eFFECTOR has a global collaboration with Pfizer to develop inhibitors of a third target, eIF4E. Forward-Looking StatementseFFECTOR cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: the future clinical development of our product candidates, including expectations on enrollment and the timing of reporting data from ongoing clinical trials; the potential therapeutic benefits of our product candidates, including potential lines of therapy and in multiple patient segments; and the sufficiency of our capital resources to fund operations into the first quarter of 2025. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: interim results of a clinical trial are not necessarily indicative of final results and one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data and more patient data become available; potential delays in the commencement, enrollment, data readouts and completion of clinical trials; our dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; the results of preclinical studies and early clinical trials are not necessarily predictive of future results; the success of our clinical trials and preclinical studies for our product candidates is uncertain; we may use our capital resources sooner than expected and they may be insufficient to allow clinical trial readouts; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; our ability to obtain and maintain intellectual property protection for our product candidates; any future impacts to our business resulting from inflation or other geopolitical developments outside our control; and other risks described in our prior filings with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. eFFECTOR Therapeutics, Inc.Condensed Consolidated Balance Sheets(in thousands) March 31, 2024 December 31, 2023 Assets(Unaudited) Current assets: Cash and cash equivalents$15,508 $14,875 Short-term investments 9,875 3,495 Prepaid expenses and other current assets 867 1,468 Total current assets 26,250 19,838 Property and equipment, net 190 140 Operating lease right-of-use assets 225 53 Other assets 466 513 Total assets$27,131 $20,544 Liabilities and stockholders' equity (deficit) Current liabilities: Accounts payable$1,713 $2,330 Accrued expenses 3,787 2,921 Current term loans, net 18,916 19,385 Accrued final payment on term loans, current 1,100 1,100 Lease liabilities, current portion 53 60 Total current liabilities 25,569 25,796 Other accrued liabilities, non-current 516 503 Non-current warrant liability 40 40 Non-current lease liabilities 179 — Total liabilities 26,304 26,339 Stockholders' equity (deficit): Preferred stock — — Common stock — — Additional paid-in capital 189,038 173,582 Accumulated other comprehensive income (loss) — — Accumulated deficit (188,211) (179,377) Total stockholders' equity (deficit) 827 (5,795) Total liabilities and stockholders' equity (deficit)$27,131 $20,544 eFFECTOR Therapeutics, Inc.Condensed Consolidated Statement of Operations and Comprehensive Loss(Unaudited)(in thousands, except share and per share data) Three Months Ended March 31, 2024 2023 Operating expenses: Research and development 5,306 6,609 General and administrative 3,090 2,927 Total operating expenses 8,396 9,536 Operating loss (8,396) (9,536)Other income (expense) (438) (478)Net loss (8,834) (10,014)Other comprehensive income — 19 Comprehensive loss$(8,834) $(9,995) Net loss per share, basic and diluted$(2.16) $(5.96)Weighted-average common shares outstanding, basic and diluted 4,081,580 1,680,032 Contacts: Investors: Media:Christopher M. Calabrese Managing Director LifeSci Advisors917-680-5608ccalabrese@lifesciadvisors.comKevin GardnerManaging DirectorLifeSci Advisors617-283-2856kgardner@lifesciadvisors.comMike TattoryAccount SupervisorLifeSci Communications609-802-6265mtattory@lifescicomms.com