Rare Daily Staff
Europe’s Committee for Medicinal Products for Human Use recommended marketing authorization of patisiran, Alnylam Pharmaceuticals’ treatment of the rare and potentially fatal hereditary transthyretin-mediated amyloidosis in adults with stage 1 or stage 2 polyneuropathy.
Hereditary transthyretin-mediated amyloidosis is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Mutations in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations.
hATTR amyloidosis represents a major unmet medical need with significant morbidity and mortality, affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival of 3.4 years for patients presenting with cardiomyopathy. In Europe, treatment options that can modify the course of the disease are limited and there remains a need for novel medicines to help treat patients with hATTR amyloidosis.
Patisiran is an investigational, intravenously administered RNAi therapeutic targeting transthyretin in development for the treatment of hATTR amyloidosis. It is designed to target and silence specific messenger RNA, potentially blocking the production of TTR protein before it is made. This may help to reduce the deposition and facilitate the clearance of TTR amyloid in peripheral tissues and potentially restore function to these tissues.
A CHMP positive opinion is one of the final steps before marketing authorization is granted by the European Commission. It was based on the evaluation of the effects of patisiran in patients with hATTR amyloidosis and its safety profile as demonstrated in the APOLLO phase 3 study.
The study showed that patisiran improved measures of polyneuropathy, quality of life, activities of daily living, ambulation, nutritional status and autonomic symptoms relative to placebo in adult patients with hATTR amyloidosis.
The APOLLO study used the modified Neuropathy Impairment Score +7 (mNIS+7) to assess motor strength, reflexes, sensation, nerve conduction and postural blood pressure. Patients treated with patisiran had a mean 6.0-point decrease (improvement) in mNIS+7 score from baseline compared to a 28.0-point mean increase (worsening) for patients in the placebo group, resulting in a 34.0-point mean difference relative to placebo, after 18 months of treatment.
While nearly all patisiran-treated patients experienced a treatment benefit relative to placebo, 56 percent of patisiran-treated patients experienced significant improvement in measures of their polyneuropathy (as assessed by mNIS+7 score) relative to their own baseline with 18 months of treatment, compared to four percent of patients who received placebo.
As measured by the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Score, 51 percent of patients treated with patisiran experienced improvement in quality of life at 18 months relative to their own baseline, compared to 10 percent of the placebo-treated patients.
Over 18 months of treatment, patients treated with patisiran experienced significant benefit versus placebo for all other efficacy endpoints including measures of activities of daily living, walking ability, nutritional status, and autonomic symptoms.
The incidence and severity of adverse events were similar in patients receiving patisiran and placebo. The most common adverse events that occurred more frequently with patisiran than with placebo were peripheral edema and infusion-related reactions.
The European Medicines Agency reviewed patisiran under the accelerated assessment procedure that is granted to medicines that the CHMP believes are of major interest for public health and therapeutic innovation. The European Commission will now review the CHMP recommendation to deliver its final decision, applicable to all 28 EU member states, plus Iceland, Liechtenstein and Norway. Patisiran is currently under priority review as a Breakthrough Therapy with the U.S. Food and Drug Administration (FDA), with an action date of August 11, 2018. Regulatory filings in other markets, including Japan, are planned for mid-2018.
If approved by the European Commission, the company will market the drug under the brand name Onpattro.
“We are ready to launch patisiran following the EC decision, and hope that it will help to meet the pressing need for new treatment options for patients living with hATTR amyloidosis in Europe,” said Theresa Heggie, head of Europe for Alnylam Pharmaceuticals.
August 1, 2018
Photo: Theresa Heggie, head of Europe for Alnylam Pharmaceuticals