With the Phase III failure, Syros will discontinue the study of tamibarotene for myelodysplastic syndrome and will default on its loan from Oxford Finance LLC.
Syros Pharmaceuticals on Tuesday reported that its oral drug candidate tamibarotene failed the Phase III SELECT-MDS-1 trial, as it did not significantly improve complete response rates in certain patients with myelodysplastic syndrome compared to the approved drug azacitidine plus placebo. The failure “constitutes an event of default under its secured loan facility with Oxford Finance LLC,” the biotech said. Syros’ stock price fell precipitously after the news was announced.
Topline data from the Phase III study showed that tamibarotene combined with azacitidine hit a complete response (CR) rate of 23.8% in newly diagnosed patients with higher-risk myelodysplastic syndrome (HR-MDS) with an overexpression of the RARA gene. In comparison, patients given placebo plus azacitidine hit an 18.8% CR rate.
The treatment effect of tamibarotene was not statistically significant, with a p-value of 0.2084, according to Syros’ news release. The biotech’s shares fell as much as 92% in post-market trading Tuesday, according to SeekingAlpha.
CEO Conley Chee in a statement said that the biotech is “deeply disappointed by this outcome.” Syros will discontinue SELECT-MDS-1 and “evaluate the next steps” as it completes its review of the late-stage data.
Designed to be orally available, tamibarotene is a selective agonist of the retinoic acid receptor alpha (RARA), which when overexpressed can prevent the differentiation of bone marrow cells into healthy myeloid cells. Around half of MDS patients show RARA overexpression, according to Syros’ website. By binding to excess RARA, tamibarotene helps restore myeloid differentiation.
In December 2023, Syros announced encouraging Phase II data that seemed to validate tamibarotene’s mechanism of action. When combined with azacitidine and venetoclax, tamibarotene achieved 100% complete response or complete response with incomplete hematologic recovery in all nine patients who were evaluable at the time.
Syros’ late-stage stumble on Tuesday illustrates the difficulty of developing an effective therapy for MDS, an indication that has tripped up several other biopharma companies.
In April 2024, for instance, Gilead announced that it would no longer invest in development of the anti-CD47 antibody magrolimab, which it was trialing for MDS and acute myeloid leukemia, following several clinical and regulatory setbacks. A few months later, in June 2024, the pharma completed its analysis of the Phase III ENHANCE study—which had been discontinued a year earlier—showing that magrolimab aggravated the risk of death by 20% in HR-MDS patients.
In February 2024, Roivant shuttered its subsidiary Hemavant after a disappointing Phase I/II readout for the MDS candidate RVT-2001.
Not all the news is bleak for MDS patients, though. In June 2024, the FDA signed off on Geron’s first-in-class telomerase blocker Rytelo (imetelstat) for the treatment of patients with lower- to intermediate-risk MDS. In October 2023, the regulator expanded the label of Servier’s Tibsovo (ivosidenib tablets) to include relapsed or refractory MDS with susceptible IDH1 mutations.
