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Syros Pharmaceuticals Sets Ambitious Timeline for Tamibarotene Regulatory Submission in MDS

AML cells illustration

This article has been updated to reflect that Syros will not necessarily file a new drug application with the FDA by Q4 2024, but as soon as possible after a positive Phase III readout from SELECT-MDS-I and the correct endpoint in SELECT-AML-1.

NEW YORK – After undergoing restructuring due to limited cash flow in 2023, Syros Pharmaceuticals is laser focused on bringing its late-stage asset tamibarotene to market as quickly as possible and generating revenue.

Last fall, the company reported $3.8 million in revenue in Q3 2023, entirely from a sickle cell disease research collaboration with Pfizer, compared to $3.9 million in collaboration revenue during the same period in 2022. The Cambridge, Massachusetts-based firm's net loss grew to $40.1 million in Q3 2023 from $30.3 million over the same period in 2022, and it had $112 million in cash, cash equivalents, and marketable securities as of Sept. 30, 2023.

After evaluating its financial position, Syros laid off 35 percent of its workforce in October and reorganized the company around the retinoid acid receptor alpha (RARα) agonist tamibarotene, which it is developing as a treatment for patients with higher-risk myelodysplastic syndrome and newly diagnosed acute myeloid leukemia characterized by RARA gene overexpression.

As part of the reorganization announced in October, Syros also paused development of its oral arsenic trioxide SY-2101, which it was studying as a treatment for AML caused by a RARA and PML fusion and licensed out some of its discovery-stage programs. Later in 2023, it also paused development of the CDK7 inhibitor SY-5609 in pancreatic cancer.

"Both of those programs, we stopped in a good place … and particularly for SY-2101, we're ready to move into Phase III, potentially," Syros CEO Conley Chee said, adding that this Phase III program could start any time after tamibarotene begins generating revenue.

Chee attributed the cash crunch to a generally tough fundraising environment in 2023 in which investors were reluctant to put money into early-stage assets. "With all of the biotechs, it's very difficult to raise money these days, particularly when investors are looking for later-stage assets," Chee said.

However, Syros' decision to pivot to tamibarotene development seems to have struck a positive chord with investors. The firm raised $45 million in an underwritten stock offering in December 2023.

Syros decided to focus on tamibarotene based on encouraging data from a Phase II trial in AML. MDS and AML are related in that about 30 percent to 40 percent of MDS patients progress to AML. In the SELECT-AML-1 Phase II trial comparing a cocktail of tamibarotene, AbbVie and Genentech's BCL-2 inhibitor Venclexta (venetoclax), and azacitidine against Venclexta and azacitidine in newly diagnosed patients with RARA-overexpressing AML, investigators saw a 100 percent rate of complete response or complete response with incomplete hematologic recovery (CR/CRi) in the tamibarotene arm and a 70 percent CR/CRi rate in the control arm.

In addition to the promising efficacy seen in SELECT-AML-1, patients in the trial appeared to tolerate tamibarotene well, since its addition didn't increase adverse events compared to those who received just Venclexta and azacitidine. "Where we've seen a lot of MDS trials fail in the past is that the drugs are intolerable to patients," Chee said.

In fact, he noted that the researchers saw a slight decrease in some of the hematological side effects in the tamibarotene arm. Chee speculated this might happen because Venclexta is a myelosuppressor, whereas tamibarotene promotes cell differentiation and increases blood cell counts, potentially neutralizing the effects of Venclexta.

Because MDS can progress to become AML, Chee explained that researchers identified patients in the trial who were on the borderline between MDS and AML. In those patients, the complete response rate to the tamibarotene regimen was 67 percent, which Chee said gave the company confidence to move into MDS first, where there is a greater unmet need for effective treatments. He noted that patients with MDS have not seen a new therapy in 20 years, and only 17 percent of patients respond to currently available therapies.

Syros estimates that about 21,000 patients are diagnosed with higher-risk MDS in the US and Europe annually, and the total global market for therapies for MDS patients across all risks groups is expected to grow to about $4.7 billion by 2028. Moreover, a greater proportion of MDS patients, about 50 percent, overexpress RARA, compared to around 30 percent of AML patients.

According to Chee, the cash from the financing last December will support Syros' upcoming tamibarotene R&D and carry the company through Q2 2025, with a new drug application submission to the US Food and Drug Administration for tamibarotene in MDS as quickly as possible following a Phase III pivotal data readout from the SELECT-MDS-1 clinical trial in Q4 2024.

To hit those milestones, Syros is prioritizing analysis of a 190-patient cohort in the SELECT-MDS-1, which will generate a complete response rate for tamibarotene-azacitidine compared to azacitidine alone. Based on guidance from the FDA, this is the primary endpoint the firm is focusing on for a regulatory submission seeking either full or accelerated approval.

The firm announced this week that it had completed enrolling the 190 RARA-overexpressing, previously untreated MDS patients needed for this analysis, though the goal is to enroll 550 patients in total and assess overall survival as a secondary endpoint. According to Chee, the FDA has said "on multiple occasions" that overall survival data supported by data on durability of response would be sufficient to validate conversion of accelerated approval to full approval. Other secondary endpoints in the trial include duration of complete response, time to complete remission, time to initial response, duration of event-free survival, safety, and quality of life.

Researchers will gauge patients' RARA expression status using an investigational assay. Syros is working with Qiagen to develop and commercialize a messenger RNA-based blood test to determine RARA expression level in newly diagnosed higher-risk MDS patients.

Chee noted that tamibarotene is unusual for a biomarker-directed therapy because rather than targeting a mutation in a particular gene, it is targeting a gene that regulates expression of other genes. "If there's overexpression of [RARA]," Chee said, "it seems to drive AML and higher-risk MDS." As a RARα agonist, tamibarotene is designed to bind to the receptor and normalize its function.

While it is pursuing a pivotal trial in MDS, Syros is still evaluating tamibarotene in SELECT-AML-1, where it hopes to also establish the treatment as an option for newly diagnosed AML patients, particularly the one-third of patients who do not respond to existing standard-of-care therapies. Syros also expects to report additional data from the AML trial this year.