Phase 3 Trial Results Supporting Benefits of Patisiran in FAP Published in NEJM

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by Patricia Inacio PhD |

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A Phase 3 trial testing patisiran as a therapy for hereditary ATTR amyloidosis with polyneuropathy (also called familial amyloid polyneuropathy, or FAP), showed treatment with patisiran safely improved many symptoms as well as patients’ quality of life.

The full results have been published in The New England Journal of Medicine (NEJM), according to Alnylam Pharmaceuticals.

The study, “Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis,” is now available in the NEJM online edition.

“The publication of the APOLLO study results in NEJM underscores the potential for clinical benefit and the encouraging safety profile of patisiran, and reinforces the strong therapeutic potential of this investigational medicine for people living with hATTR amyloidosis,” David Adams, an MD and PhD, and principal investigator for the APOLLO trial, said in a press release.

Patisiran is an RNAi therapy, meaning it blocks the production of messenger RNA — the intermediate molecule in the process of translating genetic information (DNA) to a protein. Patisiran silences the messenger RNA of the disease-causing TTR (transthyretin) protein.

The APOLLO Phase 3 study (NCT01960348) randomized 225 FAP patients to receive patisiran (148 patients) or a placebo (77 patients). Both active treatment and placebo were administered intravenously (directly into the blood)  once every three weeks.

The trial’s main outcome measured the changes on the Modified Neuropathy Impairment Score +7 (mNIS+7), developed specifically to improve quantification and monitoring of neuropathy in FAP, from the beginning of the trial (baseline) up to 18 months. Secondary objectives included changes in patients’ quality of life, among others.

The results confirmed previous initial analyses and showed that treatment with patisiran resulted in a wide range of improvements not only in measures of polyneuropathy and quality of life (measured by the Norfolk Quality of Life–Diabetic Neuropathy questionannaire), but also in daily living activities, patients’ ambulation, nutritional status, and symptoms compared to those treated with a placebo.

As previously reported, the average scores of patients in the mNIS+7 improved by six points over the 18-month-long study when treated with patisiran.

During this period, control patients worsened by 28 points, leading to a gap of 34 points between both groups (patisiran vs. placebo).

Patisiran improved patients’ gait speed and contributed to weight stabilization, measured by changes in body mass index (BMI).

The therapy also improved heart function in patients that, at the beginning of the trial, showed cardiac amyloid involvement.

Most importantly, since the trial included patients with different types of disease-causing mutations (a total of 39 mutations were included), as well as patients from  different genders, ages, ethnicities, and geographical regions, these findings support the wide-ranging benefits of patisiran.

The improvements seen in the trial correlated with a reduction in the TTR protein levels in patients’ blood after 18 months.

“The broad, international patient population recruited to APOLLO is characteristic of the wide disease spectrum seen in clinical practice, supporting the relevance of the potential beneficial effects of patisiran for patients worldwide afflicted with this progressive and generally fatal disease,” Adams said.

“We are extremely pleased with the publication of this landmark manuscript, the first-ever pivotal RNAi clinical trial to be published in a top-tier, peer-reviewed medical journal,” said Akshay Vaishnaw, and MD and PhD, and president of research and development at Alnylam.

“Publication of the APOLLO study results in NEJM is a testament to Alnylam’s decade-long effort and unwavering commitment to patients with hATTR amyloidosis, and to the goal of advancing an innovative new class of medicines that harnesses the natural RNAi mechanism of action to silence production of disease-causing proteins,” he added.

“Further, publication of these comprehensive efficacy and safety results highlights our commitment to scientific and clinical excellence, and the importance we place on data transparency,” Vaishnaw wrote. “This work would not have been possible without all the patients and investigators who participated in APOLLO, and we are deeply indebted to them.”

The publication of the full results of APOLLO trial will help Alnylam seek regulatory approval for patisiran.