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News from the AAN Annual Meeting
In an Open-Label Study, Patisiran is Found Safe for Familial Amyloid Polyneuropathy, Stabilizing Symptoms at 18 Months


Patisiran, an investigational RNAi therapeutic that targets mutant transthyretin, showed in an open label trial that it was safe for patients with familial amyloid polyneuropathy.

VANCOUVER—Results from a phase 2 open-label study of patisiran, an experimental drug for familial amyloid polyneuropathy (FAP), suggest that patients on the infused therapy did not experience any drug-related serious adverse effects, and their clinical symptoms remained stable over an 18-month follow-up period. The findings were reported here on April 20 at the AAN Annual Meeting.

Patisiran is a small interfering RNA molecule (siRNA) that targets transthyretin (TTR), a protein produced by the liver. Mutations in the TTR gene cause misfolding of the protein and the formation of amyloid fibrils in nerve cells in FAP patients, leading to progressive neuropathy and eventual death.

Following uptake by hepatocytes, the siRNA in patisiran is able to suppress the production of TTR protein by lowering the amount of TTR mRNA. This suppression in turn results in the substantial reduction of TTR levels in the blood, which has the potential to benefit patients with FAP.

In the new study, patisiran, which is being developed and tested by Alnylam Pharmaceuticals, reduced the production of both mutant and wild type TTR measured in serum by more than 80 percent. The study investigators have been conducting repeated tests over the length of the two-year study, and reported that patients stabilized and, for some measures, improved over the first 18 months.

“We think that we can have a big impact on this disease by lowering levels of both mutant and wild-type TTR with patisiran,” said the study's lead investigator, David Adams, MD, a neurologist at the Bicêtre Hospital in Le Kremlin-Bicêtre in France. Dr. Adams is also head of the neurology department and coordinator of the French Reference Center for FAP and other rare peripheral neuropathies.

“Of course, it is an open-label study, and these findings have to be confirmed in the phase 3 study, which is ongoing. But it gives us a window into what the drug is doing to alter the disease course.”


Twenty-seven patients, between the ages of 29 and 77, were enrolled in the phase 2 open-label extension study of patisiran, beginning in 2013. The main objective of the study was to assess safety of the drug, which was delivered intravenously every three weeks (0.3 mg/kg) for two years. Among the secondary outcome measures, the investigators assessed TTR levels, disability progression through the modified Neuropathy Impairment Score (mNIS+7) and Neuropathy Impairment Score (NIS), walking speed, hand strength, and quality of life.

Serum was collected for TTR levels approximately every three months. Throughout the 18 months, the mean serum TTR was lowered by approximately 80 percent, with mean maximal knockdown of 92 percent. Neuropathy impairment scores were stable at 18 months with a mean change in mNIS+7 and NIS of -0.8 and +2.6 points, respectively. Dr. Adams said “this compares favorably to the 17- to 26-point increase in neurologic impairment scores estimated at 18 months from prior FAP studies in a patient population with similar baseline NIS scores. The quality-of-life measures on the EQ-5D QOL were unchanged from the baseline to the 18-month testing period.”

“It looks like we can stabilize the disease and the neuropathy,” said Dr. Adams. “And we have seen improvements on some global composite measures, as well.”

Dr. Adams said that the medication was generally well tolerated. There were reports of flushing in 22 percent of patients and infusion-related reactions in 18.5 percent of the patients, but these effects were mild and did not lead to anyone dropping out of the study. Five patients experienced serious adverse events that were not drug-related, and one of the 27 dropped out after 20 months following a diagnosis of a gastrointestinal cancer that was also unrelated to the drug, the investigators reported at the meeting. “The study patients have received more than 900 infusions, and there have been no serious adverse events related to the drug,” Dr. Adams added.

The scientists also collected skin biopsies to assess nerve fibers around the sweat glands. They reported at the AAN meeting that they found an increased density of nerve fibers in the distal thigh at 18 months compared to baseline measurements. “This suggests that there may be regeneration of the nerve fibers,” said Dr. Adams.

Dr. Adams started collaborating with Alnylam, the drug's manufacturer and a sponsor of the trial, in 2010 on a phase 1 safety study in FAP patients using an earlier generation lipid nanoparticle formulation of an siRNA targeting TTR (ALN-TTR01). That study, along with a subsequent phase 1 study of patisiran in healthy volunteers, provided the first proof of concept for an RNA interference therapeutic in humans. The results of that study were published in The New England Journal of Medicine in 2013.

Dr. Adams and colleagues in Italy, Portugal, and the US recently published the results of a natural history study in 300 untreated FAP patients that provides insights into how the disease progresses over time. He and others have treated FAP patients with liver transplantation, which removes the mutant form of TTR. While FAP patients with early disease can benefit from this treatment, more advanced patients often progress following the liver transplant due to the continued production of wild-type TTR by the transplanted liver.

Patisiran has a potential advantage over liver transplantation since it lowers both mutant and wild-type TTR, Dr. Adams said.


Commenting on the study, Michael J. Polydefkis, MD, FAAN, a professor of neurology at Johns Hopkins University and director of the Johns Hopkins Bayview EMG Laboratory and Cutaneous Nerve Laboratory, said: “There doesn't seem to be any deleterious consequences of reducing TTR by 80 to 90 percent, and it is pretty exciting that at 18 months the patients are stable, not just in one test but in every measurement they looked at.”

Still, he said, the results come from an open-label study, which is subject to bias. “If only one measure was improving, I would be less enthusiastic,” he said. However, he added, “the findings hold more weight with everything going in the right direction. The fact that patients are stable and even improving is terrific.”

“These are intriguing drugs,” said P. James B. Dyck, MD, FAAN, a professor of neuropathology and head of the peripheral nerve section at the Mayo Clinic in Rochester, MN. “The drugs get rid of TTR and may be more powerful than anything we have had to treat familial amyloid polyneuropathy.”

His father, Peter J. Dyck, MD, FAAN, director of the Peripheral Nerve Research Laboratory at the Mayo Clinic, developed the composite neurologic impairment scores that are being used in clinical trials in familial amyloid polyneuropathy. “The outcomes of the trial will depend not only on the efficacy of the trial drug but also on the adequacy of the assessment of severity of polyneuropathy,” said the senior Dr. Dyck, whose center is involved in training investigators to perform the key neurologic assessments included in the Alnylam and Ionis phase 3 trials.

The Mayo Clinic Peripheral Nerve Laboratory also provides not only training of investigators, but also quality control and reference values for the assessed neuropathic signs and neurophysiologic tests. “The importance of the trial will be at the endpoints,” said Dr. Dyck.

Alnylam Pharmaceuticals is also sponsoring a multinational phase 3 double-blind study of pastisiran (called APOLLO) with 225 patients. Two-thirds of patients are being randomized to receive patisiran and one-third to receive placebo. The primary outcome measure of the APOLLO study is the change from baseline to 18-months in the mNIS+7. The researchers are also collecting quality-of-life data, and following additional measures of motor and autonomic function. The study completed enrollment in January 2016 and results are expected in the second half of 2017.



DR. MICHAEL J. POLYDEFKIS: “There doesnt seem to be any deleterious consequences of reducing TTR by 80 to 90 percent, and it is pretty exciting that at 18 months the patients are stable, not just in one test but in every measurement they looked at.”


DR. P. JAMES B. DYCK: “These are intriguing drugs.The drugs get rid of TTR and may be more powerful than anything we have had to treat familial amyloid polyneuropathy.”


DR. PETER J. DYCK: “The outcomes of the trial will depend not only on the efficacy of the trial drug but also on the adequacy of the assessment of severity of polyneuropathy.”


•. AAN Annual Meeting Abstract S38.003: Phase 2 open label extension study (OLE) of patisiran, an investigational RNAi therapeutic for familial amyloid polyneuropathy (FAP).
    •. Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis N Engl J Med 2013; 369: 819–829.