Syros Pharmaceuticals said it will pursue development of its lead candidate SY-1425 (tamibarotene) in a combination therapy after acknowledging that only one of 48 evaluable patients achieved complete response to the treatment alone in an ongoing Phase II trial.

The results—presented during the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta—disappointed investors, touching off a selloff that sent the price of Syros shares falling about 50% in premarket trading this morning. As of 8:51 a.m., shares of Syros had fallen to $6.34, down 48.75% from Friday’s closing price of $12.37.

SY-1425 is an oral first-in-class selective retinoic acid receptor alpha (RARα) agonist under study in genomically defined subsets of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients.

According to Syros, subsets of AML and MDS patients have “superenhancers”—highly specialized regulatory regions of DNA associated with the RARA and IRF8 genes—that have been shown in earlier preclinical studies to predict response to treatment with SY-1425, promoting differentiation of AML cells with high RARA or IRF8 expression, but not in AML cells with normal RARA and IRF8 expression.

Preclinical results also showed promise for SY-1425 in combinations with the chemotherapy drug azacitidine and with Darzalex® (daratumumab), marketed by Janssen Biotech (Johnson & Johnson).

Today in reporting initial clinical data from the ongoing Phase II trial (NCT02807558), Syros played up data showing initial clinical activity associated with SY-1425 in the 48 patients who were evaluable for clinical response. The 48 consisted of 23 patients in the relapsed or refractory AML and higher-risk MDS cohort and 25 patients in the lower-risk transfusion-dependent MDS cohort.

According to Syros, 10 of 23 (43%) evaluable relapsed or refractory AML and higher-risk MDS patients and two of 25 (8%) evaluable transfusion-dependent lower-risk MDS patients had evidence of clinical activity.


One Complete Response

Overall, nine patients showed improvements in hematological parameters. Of those, four achieved hematological improvement lasting at least eight weeks, while the other five showed reductions in bone marrow blasts.

And of those five, one relapsed or refractory higher-risk MDS patient achieved a marrow complete response following treatment 238 days; that patient remained on treatment as of the data cutoff.

The trial’s primary outcome measures, all within 20 months of treatment, included: overall response rate (ORR) in relapsed/refractory AML or higher-risk MDS patients treated with SY-1425 as a monotherapy; ORR in newly diagnosed treatment-naïve AML patients treated with SY-1425 as a monotherapy; transfusion independence rate for lower-risk MDS patients treated with SY-1425 as a monotherapy; and ORR in newly diagnosed treatment-naïve AML patients treated with SY-1425 in combination with azacytidine.

Other clinical results:

  • No patients with lower-risk MDS showed transfusion independence.
  • 13 of the 23 (57%) evaluable relapsed or refractory AML and higher-risk MDS patients showed stable disease.
  • 11 of 13 (85%) patients with pre- and post-treatment immunophenotyping samples showed increased expression of CD38 on bone marrow blasts after one 28-day cycle of treatment.

Syros said the induction of CD38 observed in bone marrow blasts from patients treated with SY-1425 also supported a combination cohort with daratumumab, which had been recently added to the Phase II trial.

“The biologic and clinical activity seen in patients selected by our proprietary RARA and IRF8 biomarkers provide validation of our platform’s ability to enrich for patients most likely to respond to gene control therapies. These data support continued development of SY-1425 in combination, which will be our focus going forward,” Syros CEO Nancy Simonian, M.D., said in a statement.

“Our preclinical data showing the tumor-killing activity of SY-1425 in combination with azacitidine and with daratumumab support the ongoing development of SY-1425 in combination with these therapies, and we plan to present initial clinical data on these two combinations in 2018,” Dr. Simonian added.

Syros also reported positive initial safety data, showing in part that chronic daily dosing of SY-1425 administered at 6 mg/m2 orally divided in two doses to be generally well tolerated, with a median treatment duration of 80 days and patients treated up to eight months and remaining on study. The most commonly reported adverse events included hypertriglyceridemia (36%), fatigue (31%), and dermatologic effects (28%).







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