Imara Left Reassessing After Sickle Cell and Beta-Thalassemia Trials Disappoint

Failed Endpoint

Imara stock plunged 40% after announcing the failure of Phase II sickle cell and beta-thalassemia trials and plans to discontinue development. Specifically, the company announced results from interim analyses of its Ardent Phase IIb trial of tovinontrine in sickle cell disease (SCD) and the Forte Phase IIb trial of the same drug in beta-thalassemia.

Tovinontrine is a highly selective and potent small molecule phosphodiesterase-9 (PDE9) inhibitor. Its multimodal mechanism of action acts on red blood cells, white blood cells, adhesion molecules and blood vessels. PDE9 degrades cyclic guanosine monophosphate (cGMP), an active signaling molecule associated with vascular biology.

For the Forte Phase IIb trial in beta-thalassemia, the interim analysis looked at safety and biomarker data for both transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) cohorts, in addition to data on transfusion burden reduction in the TDT cohort. The drug was well-tolerated in both cohorts, although one NTDT and eight TDT participants discontinued treatment because of side effects. The analysis found no meaningful benefit in transfusion burden in either tovinontrine group compared to placebo, or in most disease-related biomarkers, including total hemoglobin (Hb).

In the Ardent Phase IIb sickle cell study, interim analysis was performed when all participants completed the 24-week assessment or left the trial early. Again, it was generally well-tolerated, with 3.6% of participants discontinuing before week 24 because of side effects. The primary efficacy analysis was a comparison of the median annualized vaso-occlusive crisis (VOC) rate between the high dose tovinontrine group, once-daily oral dose of 300mg or 400 mg based on patient weight and the placebo group.

The median annualized rate for the placebo group was 2.02 VOCs per year. For the high-dose tovinontrine group, it was 1.89 VOCs per year or about 6.4%. The company indicated that “Based on the minimal decrease observed in VOCs with the high dose and low VOC rate in the placebo arm, Imara enacted an addendum to the statistical analysis plan for the trial and noted trends of VOC benefit with Tovinontrine.”

The median annualized rate of VOCs in the low dose tovinontrine group was zero compared to 2.02 in the placebo group. There were positive numerical trends for benefit, but none were statistically significant.

“We are disappointed in the outcomes of the interim analyses in our Phase IIb studies for sickle cell disease and beta-thalassemia, and particularly that the Ardent trial interim analysis did not replicate our previously observed positive vaso-occlusive crisis data,” stated Rahul Ballal, Ph.D., president and chief executive officer of Imara. “We plan to discontinue both studies during the second quarter.”

He added that “Moving forward, we plan to consider our strategic options, including development of tovinontrine in heart failure with preserved ejection fraction (HFpEF) as well as IMR-261 clinical development plans.”

It wasn’t long ago, at the company’s March 15 full-year financial report that Ballal noted, “While our trials of tovinontrine as a treatment for SCD and beta-thalassemia remain foundational, I am excited about tovinontrine’s potential in HFpEF. In January 2022, the FDA cleared our investigational new drug application for tovinontrine in HFpEF and we expect to dose the first subject in our SP9IN Phase 2 clinical trial of tovinontrine in HFpEF in the second quarter of 2022.”

Now, a whole lot more of the company’s fortunes depends upon that trial. Imara also recently added IMR-261 to their pipeline. The drug is an oral, clinic-ready activator of the nuclear factor erythroid 2-related factor 2 (Nrf2), which it has validated in preclinical models for SCD and beta-thalassemia. It may also have applications for hemoglobin disorders such as iron overload.

As of December 31, 2021, the company had $90.3 million in cash, cash equivalents and investment.

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