Syros Pharmaceuticals shares (NASDAQ:SYRS) lost nearly a third of their value Monday after investors learned that, by the end of October, just one out of 48 evaluable patients enrolled in an ongoing study of the company's lead gene control therapy, SY-1425 (tamibarotene), had achieved a complete response. The ongoing trial is evaluating SY-1425 for the treatment of genomically defined subsets of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). No patients with lower-risk MDS had achieved transfusion independence, another endpoint of the study, by the cut-off for reporting.

Syros shares ended the day at $8.45, down $3.92, or 31.7 percent, after briefly touching a 52-week low. The closing price was almost $10 lower than at the end of the company's first day on Nasdaq, June 30.

The data, first released Sunday, cover the experience of patients enrolled in two of the study's five cohorts that received SY-1425 alone. In light of the experience so far, the company has decided to set the idea of monotherapy aside, focusing instead on combining the drug with other already-approved medicines.

To that end, the company is continuing to enroll patients in a cohort evaluating SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy. It also recently added a cohort in R/R AML and higher-risk MDS patients to evaluate SY-1425 in combination with Darzalex (daratumumab, Janssen Biotech Inc.) and expects to begin enrolling patients in that cohort in early 2018. Data from the combination cohorts are expected to be presented later that year.

All patients enrolled in the trial are prospectively selected using the company's retinoic acid receptor alpha (RARA) or IRF8 biomarkers, which in preclinical studies, were shown to be predictive of response to treatment with SY-1425, allowing it to inhibit the growth of cancer cells and prolong survival in preclinical models of AML with high RARA expression.

SY-1425, a RARA agonist, already has a fairly substantial track record of use for the treatment of acute promyelocytic leukemia (APL) in Japan, where it was first approved for that indication in April 2005. It is marketed there by Nippon Shinyaku Co. Ltd., which, like Syros, has a license for the medicine from Toko Pharmaceuticals Ind. Co. Ltd.

Speaking to investors during an investor event held to discuss the initial data, Syros' chief medical officer, David Roth, highlighted hematological improvements seen by investigators. Ten of the 23, or 43 percent, of evaluable relapsed or refractory AML and higher-risk MDS patients and two of the 25, or 8 percent, of evaluable transfusion-dependent lower-risk MDS patients had evidence of clinical activity. Among them, nine patients had improvements in hematological parameters. Of those, four achieved hematological improvement lasting at least eight weeks, as defined by Revised International Working Group (IWG) criteria, including five with reductions in bone marrow blasts.

One relapsed or refractory higher-risk MDS patient achieved a marrow complete response as defined by IWG criteria. The patient had been on treatment 238 days and remained on treatment as of the data cut-off. Thirteen of the 23, or 57 percent, of evaluable R/R AML and higher-risk MDS patients had stable disease. Eleven of 13, or 85 percent of patients with pre- and post-treatment immunophenotyping samples showed increased expression of CD38, a marker of cell differentiation, on bone marrow blasts after one 28-day cycle of treatment.

Chronic daily dosing of SY-1425 was generally well tolerated during the study. The most common adverse events were hypertriglyceridemia, fatigue and dermatologic effects.

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