On January 9, 2023 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in advancing new standards of care for the frontline treatment of hematologic malignancies, reported an update on its clinical development programs and outlined its strategic priorities for 2023 (Press release, Syros Pharmaceuticals, JAN 9, 2023, View Source [SID1234626113]).

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"We are entering 2023 with a singular focus on developing and delivering new standards of care for the frontline treatment of hematologic malignancies," said Nancy Simonian, M.D., Chief Executive Officer of Syros Pharmaceuticals. "We recently shared encouraging data from the safety lead-in portion of SELECT-AML-1, demonstrating that tamibarotene can combine with existing treatments with the goal of delivering better outcomes to newly diagnosed unfit AML patients positive for RARA gene overexpression, including those with a disease phenotype that may be resistant to venetoclax. These results support our advancement into the randomized portion of SELECT-AML-1, which we expect to initiate in the first quarter of 2023, and give us growing confidence in the potential for tamibarotene to provide clinical benefit to AML and MDS patients with RARA overexpression. We are on track to report initial data from this study in the fourth quarter of 2023."

Dr. Simonian added, "In addition, we continue to open clinical sites and enroll newly diagnosed HR-MDS patients positive for RARA gene overexpression in our Phase 3 SELECT-MDS-1 trial. While we are encouraged by physician and patient enthusiasm at open clinical sites, we have experienced slower-than-anticipated site activations as we expanded the study global footprint and now expect data from the SELECT-MDS-1 trial in the third quarter of 2024."

Program Updates and Upcoming Milestones

Tamibarotene: Higher-Risk Myelodysplastic Syndrome (HR-MDS)

Syros is evaluating tamibarotene in combination with azacitidine in newly diagnosed HR-MDS patients with RARA overexpression in the ongoing SELECT MDS-1 Phase 3 trial, which the company believes is the only Phase 3 trial currently recruiting in frontline HR-MDS. This randomized, double-blind, placebo-controlled study is intended to enroll 190 patients. Syros currently has over 75 clinical sites open for recruitment in 12 countries. Syros expects to complete patient enrollment in SELECT-MDS-1 in the fourth quarter of 2023, with data to follow in the third quarter of 2024.

Tamibarotene: Acute Myeloid Leukemia (AML)

Syros is evaluating tamibarotene in combination with venetoclax and azacitidine in newly diagnosed unfit AML patients with RARA overexpression. At the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2022, Syros presented data from six response-evaluable patients from the safety lead-in portion of the ongoing SELECT-AML-1 Phase 2 trial, in which treatment with the triplet combination of tamibarotene, venetoclax and azacitidine demonstrated an 83 percent composite complete response rate and rapid onset of action, with no evidence of increased toxicity relative to historical data of the venetoclax and azacitidine doublet combination. Based on these data, Syros plans to initiate the randomized portion of the SELECT-AML-1 Phase 2 trial in the first quarter of 2023, directly comparing the triplet of tamibarotene, venetoclax and azacitidine to the doublet of venetoclax and azacitidine with initial randomized data expected in the fourth quarter of 2023 and additional data in 2024.

SY-2101: Acute Promyelocytic Leukemia (APL)

Syros is developing SY-2101, a novel oral form of arsenic trioxide (ATO) for the treatment of newly diagnosed APL patients. In August 2022, Syros reported promising preliminary data from its dose confirmation study of SY-2101, which showed that SY-2101 administered at 15 mg achieved comparable pharmacokinetic (AUC and Cmax) exposures to the approved intravenous (IV) dose of ATO administered at 0.15 mg/kg, with high oral bioavailability of approximately 80 percent and a favorable tolerability profile. Syros is encouraged by this initial data and, if additional data are supportive, intends to leverage these results to explore an alternative, more efficient registration strategy for SY-2101. Syros plans to provide an update on the dose confirmation study, as well as the development path and timing for further evaluation of SY-2101 in a registration enabling study in APL, in the second half of 2023.

CDK Inhibitor Portfolio and Discovery-Stage Oncology Programs

In November 2022, Syros announced initial data from the safety lead-in portion of its Phase 1 trial evaluating SY-5609 in combination with chemotherapy in patients with relapsed/refractory metastatic pancreatic cancer as well as an update from the single agent portion in advanced solid tumor patients. The data demonstrated encouraging safety and clinical activity in pancreatic cancer patients, including a partial response and an emerging exposure response relationship. Syros is continuing dose escalation of SY-5609 as a single agent and as a doublet with gemcitabine while seeking partnership opportunities for the program.

In addition, Roche continues to enroll patients in the arm of its ongoing Phase 1/1b INTRINSIC trial evaluating SY-5609 in combination with atezolizumab, its PD-L1 inhibitor, in BRAF-mutant colorectal cancer patients. Under the terms of the collaboration, Roche is the sponsor of the trial and Syros is supplying SY-5609.

As previously disclosed, Syros is also exploring partnership opportunities for its oncology discovery programs.

Financial Guidance

Based on its current operating plans, including the deferral of the SY-2101 registration enabling study, Syros expects that its existing cash, cash equivalents, and marketable securities will be sufficient to fund its anticipated operating expenses and capital expenditure requirements into the second quarter of 2025, beyond the Phase 3 data from the SELECT-MDS-1 trial and the initial data from the randomized portion of SELECT-AML-1 trial.

On January 9, 2023 Sutro Biopharma, Inc. (Sutro or the Company) (NASDAQ: STRO), a clinical-stage oncology company pioneering site-specific and novel-format antibody drug conjugates (ADCs), reported its results from a Phase 1 dose-expansion study of STRO-002 (luvelta), a novel Folate receptor alpha (FolRα)-targeting ADC and interim safety data from exploratory cohort C, a cohort of 15 patients with advanced ovarian cancer treated at the higher dose of luvelta, (5.2mg/kg), along with prophylactic pegfilgrastim. Additionally, the company provided details on the design of the registration-directed Phase 2/3 study, REFRaME, to start in the second quarter of 2023 (Press release, Sutro Biopharma, JAN 9, 2023, View Source [SID1234626112]).

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Results demonstrated that luvelta provided substantial clinical benefit in FolRα-selected patients, defined by Tumor Proportion Score (TPS) of >25%, with a 37.5% overall response rate (ORR), median duration of response (median DOR) of 5.5 months, and median progression free survival (median PFS) of 6.1 months, regardless of starting dose. Results also demonstrated the higher starting dose of 5.2 mg/kg providing greater patient benefit compared to the lower dose of 4.3mg/kg. FolRα-selected patients account for approximately 80% of the patient population in advanced ovarian cancer, as represented in the patient stratification in the Phase 1 study.

Consistent with prior luvelta data, the primary adverse event from the dose-expansion cohort was predominantly asymptomatic neutropenia, with no meaningful ocular toxicity signals or complications reported.

In cohort C, an additional 15 patients with advanced ovarian cancer were enrolled and treated with prophylactic pegfilgrastim on Day 8 after each 5.2 mg/kg administration of luvelta. Initial data on neutropenia and dose delays were available on the first 10 patients, which showed that patients in cohort C experienced substantial decreases in neutropenia and potential increases in dose intensity, due to decreased dose delays.

"Today, patients with this form of heavily pre-treated ovarian cancer have extremely limited treatment options available to them, and unfortunately, experience poor outcomes," said Dr. R. Wendel Naumann, Professor and Director of Gynecologic Oncology Research and Associate Medical Director of Clinical Trials at the Levine Cancer Institute, Atrium Health in Charlotte, North Carolina, and a co-lead principal investigator in the STRO-002-GM1 studies. "To date, luvelta continues to demonstrate encouraging efficacy data, which was further supported by results from the dose-expansion cohort. The safety profile was shown to be manageable and notably devoid of ocular complications across a broad spectrum of patients with FolRα-selected ovarian cancer."

Commented Bill Newell, Chief Executive Officer of Sutro: "We are pleased with our Phase 1 dose-expansion efficacy data, which are generally consistent with previously reported results and demonstrate luvelta’s potential in a difficult-to-treat patient population. Through the addition of cohort C, we were able to evaluate patients at the higher dose of luvelta at 5.2mg/kg with the use of prophylactic pegfilgrastim and determined that the rates of asymptomatic neutropenia and dose delays could be diminished. Our meeting with the FDA in 2022 provided a framework for our path forward on the registration-directed Phase 2/3 trial for platinum resistant ovarian cancer patients, called REFRaME, which we plan to initiate in the second quarter of 2023."

Summary of Results from Phase 1 Dose-Expansion Study

Based on the results, luvelta has demonstrated the potential to provide meaningful clinical benefit to a substantially broader patient population than the on-label patient population of the approved FolRα-targeting agent

Patients who were FolRα-selected, defined by TPS>25%, regardless of starting dose, demonstrated an ORR of 37.5% (n=32) with a median DOR of 5.5 months (n=12) and a median PFS of 6.1 months (n=35)

Targeted luvelta patient population is approximately 80% of advanced ovarian cancer patients based on pooled Phase 1 biomarker data

Luvelta demonstrated a FolRα-dependent response, with patients who were unselected for FolRα (TPS≤25%) demonstrating an 11.1% ORR (n=9) with a median DOR of 2.9 months (n=1) and a median PFS of 3.8 months (n=9)

Luvelta, when given to patients at a starting dose of 5.2 mg/kg, provided greater patient benefit than a starting dose of 4.3 mg/kg

FolRα-selected patients given the higher dose of luvelta (5.2 mg/kg) demonstrated higher response rates

ORR of 43.8% (n=16)

Median DOR of 5.4 months (n=7)

Median PFS of 6.6 months (n=16)

FolRα-selected patients given the lower dose of luvelta (4.3 mg/kg) demonstrated

ORR of 31.3% (n=16)

Median DOR of 13 months (n=5)

Median PFS of 6.1 months (n=19)

Consistent with earlier reported data, the primary adverse event from the dose-expansion cohort was asymptomatic, transient neutropenia

Cohort C was initiated to explore the use of prophylactic pegfilgrastim for patients treated with the higher dose of luvelta (5.2mg/kg). Early results in the initial 10 patients in cohort C, when compared to patients who were not given prophylactic pegfilgrastim in the dose-expansion cohort at the higher dose (5.2mg/kg), showed substantial reductions in Grade 3+ neutropenia and in instances of dose delays

Grade 3+ neutropenia was reduced from 66.7% to 10.0%, resulting in an 85.0% decrease in Grade 3+ neutropenia rates at the first cycle of luvelta (p=0.006)

Instances of dose delays at the second cycle of luvelta were reduced by 60.6% (p=0.021)

Planned Phase 2/3 Study Details

As discussed with the U.S. Food and Drug Administration (FDA), the Phase 2/3 REFRaME study is planned to begin with a randomized, run-in dose confirmation phase. In this phase of the trial, 25 patients will be evaluated at the 5.2 mg/kg dose with pegfilgrastim delivered prophylactically for two cycles followed by a step-down dose to 4.3 mg/kg. The other 25 patients will be evaluated from the start at the 4.3 mg/kg dose without prophylactic pegfilgrastim. Following this 50-patient phase of the study, additional patients will be randomized between these two luvelta dose levels, and standard of care (chemotherapy). Upon agreement with FDA on the go-forward dose versus standard of care, the dose level of luvelta not chosen will be dropped. Upon having data on approximately 110 patients in the selected dose of luvelta arm, Sutro will look to apply for accelerated approval based on ORR as the primary endpoint. At the end of the Phase 3 portion of the trial, full approval can be sought based on PFS as the primary endpoint comparing the luvelta arm (n=160) and the standard of care arm (n=160).

Webcast Details

The data will be presented by members of the Sutro management team and Dr. R. Wendel Naumann, a co-lead principal investigator in the STRO-002-GM1 studies. Dr. Naumann is a Professor and Director of Gynecologic Oncology Research and Associate Medical Director of Clinical Trials at the Levine Cancer Institute, Atrium Health in Charlotte, North Carolina. Dr. Naumann is also a member of Sutro’s Clinical Advisory Board.

Monday, January 9, 2023 at 1:30 pm PT, or 4:30 pm ET

To access and register for the live audio webcast, please go to View Source

The webcast information will also be available through the News & Events section of the Investors portion of the Company’s website at www.sutrobio.com. An archived replay will be available for at least 30 days after the event.

On January 9, 2023 United therapeutics presented its corporate presentation (Presentation, United Therapeutics, JAN 9, 2023, View Source [SID1234626115]).

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On January 9, 2023 Syros Pharmaceuticals presented its corporate presentation (Presentation, Syros Pharmaceuticals, JAN 9, 2023, View Source [SID1234626114]).

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On January 9, 2023 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, will present today at the 41st Annual J.P. Morgan Healthcare Conference at 7:30 a.m. PT (10:30 a.m. ET), and a live webcast will be available at ir.springworkstx.com. Ahead of the presentation, the Company highlighted its 2022 accomplishments and reported its anticipated key milestones for 2023 (Press release, SpringWorks Therapeutics, JAN 9, 2023, View Source [SID1234626110]).

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2022 Accomplishments

Presented positive Phase 3 DeFi data of nirogacestat, an investigational oral gamma secretase inhibitor, in adult patients with desmoid tumors at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress.
Submitted a New Drug Application (NDA) to the United States Food and Drug Administration (FDA) for nirogacestat for the treatment of adults with desmoid tumors, which is being reviewed under the FDA’s Real-Time Oncology Review (RTOR) program.

Expanded and strengthened its intellectual property portfolio, including a new patent issued by the United States Patent and Trademark Office in the fourth quarter of 2022 directed to pharmaceutical compositions of nirogacestat (U.S. Patent No. 11,504,354), which expires in 2042 and represents what is expected to be the seventh Orange Book-listable patent for nirogacestat.

Participated in a Type C meeting with the FDA to align on the statistical analysis plan for the Phase 2b ReNeu trial evaluating mirdametinib, an investigational MEK inhibitor, in adult and pediatric patients with NF1-associated plexiform neurofibromas (NF1-PN) and expectations for an anticipated NDA submission in this indication.

Initiated a Phase 2 trial evaluating nirogacestat in patients with ovarian granulosa cell tumors (OvGCT).
Expanded global, non-exclusive license and collaboration agreement with GSK plc (GSK) to evaluate nirogacestat in combination with belantamab mafodotin in patients with multiple myeloma, including in earlier lines of treatment.

Demonstrated clinical proof of concept for BGB-3245, a selective RAF dimer inhibitor being developed by MapKure, LLC, a joint venture between SpringWorks and BeiGene, as well as for the combination of mirdametinib and BeiGene’s RAF dimer inhibitor, lifirafenib.

Advanced BGB-3245 monotherapy into dose expansion cohorts and announced plans for a new Phase 1/2a study evaluating BGB-3245 in combination with mirdametinib.
Nominated TEAD inhibitor development candidate (SW-682).

Strengthened financial position to over $650 million in cash, cash equivalents and marketable securities, as of September 30, 2022, which is expected to provide runway into 2026.

Established commercial infrastructure to support anticipated first U.S. product launch for nirogacestat in patients with desmoid tumors.

Anticipated 2023 Key Milestones

Obtain regulatory approval from the FDA for nirogacestat in adults with desmoid tumors and launch nirogacestat as the first approved therapy for these patients in the second half of 2023.

Highlight publication of Phase 3 DeFi trial data in a peer-reviewed journal and present additional analyses from the study at upcoming medical meetings.

Present topline data from the pediatric and adult cohorts of the Phase 2b ReNeu trial in NF1-PN in the second half of 2023. Pending these data, SpringWorks anticipates submitting an NDA for mirdametinib as a treatment for NF1-PN in the first half of 2024.

Continue enrollment in the Phase 2 trial of nirogacestat in patients with OvGCT.

Expand data set with additional clinical data of nirogacestat in combination with BCMA-directed therapies and initiate additional planned Phase 1 collaborator studies.

Present additional clinical data from the Phase 1 trial evaluating BGB-3245 in adult patients with RAF mutant solid tumors at a medical conference in the first half of 2023.

Present additional data from BeiGene-sponsored Phase 1b/2 trial evaluating mirdametinib in combination with lifirafenib in adult patients with RAS/RAF mutant and other MAPK pathway aberrant solid tumors at a medical conference in the first half of 2023.

Dose first patient in BGB-3245 + mirdametinib combination study in MAPK-mutant solid tumors in the first half of 2023.
File Investigational New Drug Application for TEAD inhibitor SW-682.
"We expect 2023 to not only mark SpringWorks’ transition into a commercial-stage company, but also to be a year of continued development execution and value-creating data readouts across our portfolio," said Saqib Islam, Chief Executive Officer of SpringWorks. "We are very pleased with our progress towards our goal of having two marketed products by 2025, given the overwhelmingly positive Phase 3 DeFi data for nirogacestat in desmoid tumors that were disclosed last year and our expectations for a successful topline readout for the Phase 2b ReNeu trial in children and adults with NF1-PN. Our strong execution in 2022, coupled with a financial position that funds us well into 2026 and durable IP protections for our lead assets, positions us well for continued performance on behalf of patients with devastating diseases."

Presentation at the 41st Annual J.P. Morgan Healthcare Conference
SpringWorks will webcast its presentation from the 41st Annual J.P. Morgan Healthcare Conference today, Monday, January 9, 2023 at 7:30 a.m. PT (10:30 a.m. ET). To access the live webcast, please visit the Events & Presentations page within the Investors & Media section of the company’s website at View Source A replay of the webcast will be available on SpringWorks’ website for a limited time following the conference.