Tamibarotene

After flunking a mid-stage study in front-line acute myeloid leukaemia three months back, Syros Pharmaceuticals’ oral retinoic acid receptor alpha (RARα) agonist, tamibarotene, has hit yet another and a potentially terminal roadblock. This time, the investigational therapy in combination with azacitidine failed to meet the primary endpoint of a late-stage study involving patients with newly diagnosed higher-risk myelodysplastic syndrome (HR-MDS) harbouring RARA gene overexpression – triggering a loan default for the company with Oxford Finance LLC.“We are deeply disappointed by this outcome, particularly for the HR-MDS patients who are seeking a new treatment option for this challenging disease,” said CEO Conley Chee, adding that while Syros will terminate the trial, it will continue to review exisiting data and chart out a further course of action.The Phase III SELECT-MDS-1 study assessed the efficacy and safety of tamibarotene plus azacitidine versus placebo plus azacitidine in RARA-overexpressed patients with HR-MDS, the main goal being the complete response (CR) rate in the first 190 participants. Results showed the tamibarotene plus azacitidine arm demonstrated a CR rate of 23.8% in the initial 190 patients, compared with the placebo plus azacitidine arm’s 18.8%, with no statistically significant difference between the groups. Meanwhile, the safety analysis of all enrolled 245 patients showed the tamibarotene combination was generally well-tolerated, with an adverse event profile comparable to previous studies.Facing financial troubles in the wake of failed deals with Incyte and Pfizer in 2023, the company cut 35% of its workforce last October and discontinued most clinical programmes, including SY-2101 for acute promyelocytic leukaemia, to focus on its lead asset, tamibarotene.

Syros noted that SELCT-MDS-1 Phase III trial’s failure to meet its endpoint constituted a default event under its secured loan facility with Oxford Finance. Image credit: MeshCube / Shutterstock. Syros Pharmaceuticals ’ stock has declined sharply for the second time in the past three months as a Phase III trial with its lead cancer therapy, tamibarotene, failed to meet its primary endpoint. The SELECT-MDS-1 Phase III trial (NCT04797780) evaluating the combination therapy of tamibarotene and azacitidine, a chemotherapy, was focused on newly diagnosed higher-risk myelodysplastic syndrome (HR-MDS) patients with RARA gene overexpression. The Massachusetts-based company’s CEO Conley Chee noted that the company plans to discontinue the study with plans to review the results “thoroughly” and evaluate next steps. The news comes three months after the company reported that a Phase II SELECT-AML-1 trial (NCT04905407) evaluating the combination treatment in patients with acute myeloid leukaemia (AML) was unlikely to meet primary endpoint . The futility analysis concluded that the study had “low probability of success”, based on the data analysis of first 40 randomised patients enrolled in the trial. Following the news, the company’s stock was down by over 76% in premarket trading today (13 November). Syros’s stock was showing an upward trend after the value drastically declined in August after the news of a potential Phase II SELECT-AML-1 trial failure broke. Syros also noted that the SELECT-MDS-1 Phase III trial’s failure to meet its endpoint constituted a default event under its secured loan facility with Oxford Finance. The company secured a $60m senior secure loan facility from Oxford Finance in 2022. Syros made monthly interest-only payments on each tranche prior to the amortization date of 1 March 2023, with the debt facility expected to mature on 1 February 2025. The placebo-controlled Phase III study enrolled 190 patients. The complete response rate, the study’s primary endpoint, was similar in both treatment and placebo groups, 23.8% and 18.8% respectively. The company noted that therapy was well tolerated. Tamibarotene is a specific agonist of retinoic acid receptor alpha/beta with possible binding to retinoid X receptors (RXR). The RXR receptors regulate the transcription of signalling pathways that impact numerous hallmarks of cancer by controlling both inflammation and immune responses that modulate the tumour microenvironment.