Tovinotrine Shows No Benefit in Trials; Imara Will Stop Development
Imara is discontinuing the clinical development of tovinontrine (IMR-687), its experimental oral therapy for sickle cell disease (SCD) and beta-thalassemia, based on interim data from two Phase 2b clinical trials.
While the therapy was generally safe and well tolerated in adults with both inherited blood disorders, it resulted in no significant clinical benefit compared with a placebo.
Both Phase 2b trials — Ardent NCT04474314) in adults with SCD and Forte (NCT04411082) in beta-thalassemia patients— will be discontinued in the coming months. An ongoing open-label extension study (NCT04053803) of a previous Phase 2a trial in SCD will likely be stopped as well.
“We are disappointed in the outcome of both of the interim analyses in our Phase 2b 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,” Rahul Ballal, PhD, Imara’s president and CEO, said in a press release.
“We remain deeply grateful to the patients, investigators and their teams for their participation in these trials and to the extended Imara team for their role and dedication in generating the comprehensive interim results,” Ballal said.
Imara will now consider its strategic options, including advancing the development of IMR-261, an investigative oral therapy that showed promise in mouse models of SCD and beta-thalassemia, into clinical trials.
SCD and beta-thalassemia are inherited blood diseases associated with abnormalities in hemoglobin, the molecule in red blood cells responsible for oxygen transport throughout the body.
Tovinontrine is an orally available molecule that blocks phosphodiesterase 9 (PDE9), an enzyme in red blood cells that destroys a signaling molecule called cyclic guanosine monophosphate (cGMP). Low cGMP levels are often detected in people with SCD and beta-thalassemia and are associated with impaired blood flow, increased inflammation, greater cell adhesion, and impaired blood vessel widening.
By blocking PDE9 and increasing cGMP levels, tovinontrine is thought to reactivate the production of fetal hemoglobin, a form of hemoglobin produced during fetal development that is more effective at transporting oxygen than its adult counterpart. That, in turn, would ease SCD and beta-thalassemia’s symptoms and reduce complications.
Tovinontrine received orphan drug, fast track, and rare pediatric disease designations in the U.S., and orphan drug status in Europe for treating SCD. These designations are meant to accelerate the therapy’s clinical development and regulatory review.
Data from a previous Phase 2a trial (NCT03401112), involving 93 adults with SCD, showed that daily treatment with tovinontrine for six months lowered the number of painful vaso-occlusive crises (VOCs) by 40% relative to a placebo. VOCs are a common painful complication of SCD caused by blood vessel blockage.
These and other positive findings supported the launch of the Phase 2b Ardent trial to confirm the therapy’s benefits in a larger patient population. The study completed enrollment in August.
A total of 112 adult SCD patients were randomly assigned to receive either a low (200 mg or 300 mg) or high (300 mg or 400 mg) weight-based dose of tovinontrine, or a placebo, once a day, for a year.
The study’s main goals were to assess changes in annualized VOC rates between the high-dose group and the placebo group, along with rates of side effects and serious side effects.
Key secondary goals included the time to first VOC and the proportion of patients with a meaningful increase (of at least 3%) in fetal hemoglobin levels in the high-dose group versus the placebo group.
Newly announced, interim, six-month data showed that tovinontrine was generally safe and well tolerated across both doses. The most common side effects that were considered possibly related to treatment included nausea, headache, dizziness, and vomiting. Four (3.6%) participants left the trial due to side effects.
Tovinontrine was not significantly superior to a placebo at any measure of effectiveness, suggesting a lack of clinical benefit.
Specifically, the median annualized VOC rate was 2.02 for patients on a placebo and 1.89 for those given the therapy’s high dose, reflecting a 6.4% reduction, which was not statistically significant.
Compared with the placebo group, the low-dose group showed a markedly lower median annualized VOC rate (of zero), a greater median time to first VOC, and a higher proportion of patients without VOCs.
Also, patients in both treatment groups who were not receiving hydroxyurea — an approved therapy to reduce VOCs — showed a trend toward a lower VOC rate relative to those given a placebo.
All of these differences failed to reach statistical significance, however. Moreover, the proportion of patients showing meaningful increases in fetal hemoglobin was similar between all three groups.
“Collectively, the overall additional data did not materially increase the likelihood of success for this trial,” Imara stated in its release.
Similar results were observed for the placebo-controlled Forte trial, which involved 74 adults with beta-thalassemia. The therapy was found to be generally well tolerated, but was not associated with significant or meaningful clinical benefits over a placebo.