In March of this year, Roche pressed the pause button for the Phase III trial of Huntington's disease drug tominersen. At present, Roche is reviewing the test in order to find out the cause of the problem, but it has not yet received a satisfactory answer.

On Tuesday, Roche announced tominersen follow-up trial data, aiming to provide some clues as to why the drugmaker stopped its phase III trial. But Stifel analysts wrote in a report to customers on Wednesday that the real situation may be more complicated. Roche said that after the independent data committee "has questioned the benefits and safety risks of subjects receiving tominersen therapy," Roche decided to stop late-stage clinical trials of the antisense drug tominersen for huntingtin and mutants.

In 2017, Roche obtained the rights to tominersen's drug assets by paying a license fee of US$45 million to Ionis Pharmaceuticals. Up to now, Roche has recruited 791 subjects in 18 countries around the world to participate in the GENERATION HD1 Phase III clinical trial of Huntington's disease. The trial is a double-blind, placebo-controlled clinical study. Patients with Huntington’s disease history of more than 25 months were randomly divided into 3 groups, each taking 120 mg tominersen every 2 months and 120 mg every 4 months. Milligram dose tominersen, or placebo treatment.

The results of the test showed that in terms of improving the symptoms of patients, tominersen showed a treatment effect worse than that of the placebo group, and especially in the high-dose patient group, the efficacy performance was particularly inferior. Stifel analysts said that although the specific reasons for the need to suspend dosing are unclear, the underlying reason why higher doses of tominersen has worse efficacy is not yet clear. Stifel analysts believe that there are 4 possible hypotheses about the factors that may lead to the suspension of the tominersen trial, such as the inability of the drug to be effectively dispersed in the body, the drug attacking the "benign" huntingtin protein, or the specific toxicity of tominersen , Making it unsuitable for higher dose administration.

Stifel wrote that the data released by Roche on Tuesday did not really link any of the above reasons to the performance of the drug, so Stifel speculated that the reason for the trial failure is more likely to be the result of a combination of multiple factors. . Taking biodistribution as an example, "If only the biodistribution of tominersen in the patient's body is the culprit of failure, then it is difficult to explain that tominersen has a worsening trend in all test endpoints. On the contrary, tominersen may be in some cognitive tests. Trends towards better curative results."

The drug is an anti-nucleic acid drug. After binding to Huntington's mRNA, it can reduce the expression of toxic proteins by degrading the mRNA and change the course of chorea. In a phase I/II clinical trial, tominersen significantly reduced the level of variant huntingtin in spinal fluid, but the results of the late trial showed that the results of the early trial did not translate into a real therapeutic effect. Since no safety issues seem to have been found, so far, the shortcomings of this therapy should be the inaccurate efficacy.

Roche pointed out that the committee's decision did not involve new security risks. However, in March last year, Roche suspended the study called GEN-PEAK because researchers found two cases of intrathecal catheter-related infections that were not related to the drug. Similar to Spinraza, another blockbuster ASO and SMA drug discovered by Ionis, tominersen also requires spinal administration, so the above-mentioned infection may be related to the way of administration.

Stifel also put forward a noteworthy market point of view, that is, if the problem of tominersen is discontinued, it also exists in other ASO drugs, which will be a huge challenge for Ionis. On the contrary, it is a huge market opportunity for uniQure and its gene therapy AMT-130 for Huntington's disease. Previously, the clinical shelving of uniQure gene therapy AMT-130 has been lifted by the FDA.

Reference source: What caused Roche's Huntington's drug tominersen to hit the skids in late-stage test? It's complicated, analysts say