Alnylam Pharmaceuticals, together with its partner Sanofi Genzyme, has now released the full results from the Phase 3 trial of patisiran — a drug intended to treat hereditary ATTR amyloidosis with polyneuropathy, also called familial amyloid polyneuropathy (FAP).
The study’s findings — presented at last week’s First European ATTR Amyloidosis Meeting for Patients and Doctors in Paris — provide a compelling case that patisiran robustly improves symptoms and quality of life for FAP patients.
If approved, the treatment may be available in the United States and Europe sometime in the second half of 2018.
“We are very pleased for patients and families living with hATTR amyloidosis as we believe these results from APOLLO offer new hope for the treatment of this devastating disease,” Dr. Akshay Vaishnaw, Alnylam’s executive vice president of research and development, said in a press release. “Indeed, patisiran holds the potential to halt or improve neurological impairment and broader disease features in patients with hATTR amyloidosis.”
The two companies announced earlier that the APOLLO trial (NCT01960348), met its primary goal of improving symptoms, but now offer an insight into the results details. The study was the largest study to date in FAP patients, the company said in a conference call, adding it would seek U.S. regulatory approval by year’s end and in Europe early next year.
Improvements across the board
The APOLLO Phase 3 study of patisiran — a so-called RNAi drug given by infusion — included 225 FAP patients, 148 of whom received the active treatment and 77 a placebo.
The trial’s main outcome measure was change on the Modified Neuropathy Impairment Score +7 (mNIS+7), measuring various aspects of impairment caused by amyloidosis.
Patisiran improved average scores by six points over the 18 month-long study. During this time, patients on placebo worsened by 28 points, meaning the difference between the groups was 34 points. Improvements were seen across all types of impairment.
Analyses also showed that 56 percent of patisiran-treated patients improved, compared to 4 percent on placebo. Among those who did not improve, some were seen to stabilize.
Importantly, patients of different genders, ages, ethnicities and geographical regions benefitted equally well. Researchers also showed that the type of mutation (patients with 39 different mutations were included in the trial), the degree of impairment at the beginning of the study, FAP stage, or earlier use of TTR stabilizing drugs did not affect outcomes.
The improvements mirrored robustly reduced TTR protein levels — about 87 percent — in patients’ blood after 18 months, researchers said in the conference call. Even people with heart problems benefitted to a similar degree, researchers said.
“Patients with hATTR amyloidosis are afflicted with an aggressive, rapidly progressing, debilitating and fatal disease, and have a profound need for effective and safe treatment options,” said Dr. David Adams of Bicetre Hospital in Paris, and principal investigator for the APOLLO trial. “The exciting APOLLO data that were released today demonstrate the potential of patisiran to alleviate the multiple neurological, cardiac, and autonomic manifestations of the disease.”
Added Vaishnaw: “We also view these results as a landmark achievement for the field of RNAi therapeutics, as we believe they demonstrate the transformational potential of this novel class of innovative medicines.”
Patisiran also improved quality of life among treated patients, the trial showed. Again, actively treated patients were largely seen to improve while those on placebo deteriorated during the study. Patisiran treatment triggered quality-of-life improvements in 51 percent of patients, compared to 10 percent in the placebo group.
Patisiran’s impact was broad. Secondary analyses revealed that factors such as daily living activities, nutritional status, motor strength and walking ability all improved with treatment. And researchers observed these improvements after nine months of treatment.
“The positive results in the R-ODS disability score [used to measure disability in the trial] indicates that patisiran improved patients’ ability to perform activities of daily living, specifically … run, walk, go shopping, bathe, turn the key in a lock, use the toilet, or read a newspaper or book,” Vaishnaw said.
The APOLLO trial also included patients who had amyloidosis in the heart at the beginning of the study — ”a very common, and often the deadliest feature of the disease,” according to Vaishnaw. Besides measures of symptoms, disability and quality of life all patients went through, this group also had extensive assessments of their heart function.
Results show that patisiran treatment lowered the levels of NT-proBNP — a marker of heart failure — and reduced the thickness of the left lower heart chamber wall. Increased thickness of this part of the heart is a key sign of heart failure.
Other measures, including left ventricular ejection fraction — the volume of blood leaving the lower left heart chamber in each heartbeat — were not statistically significant.
The improvement in heart function with patisiran treatment was also noted in how well patients performed on a 10-meter walk test.
“If approved, I believe that patisiran could have a tremendous impact for patients and physicians in the amyloidosis community,” said Adams. “As a clinician, it has been deeply rewarding to see the potential impact patisiran may have on the lives of hATTR patients.”
As with any medication, patisiran treatment brings with it the risk of side effects. But analyses showed that the most common adverse events in patisiran-treated patients during the trial were mostly mild or moderate. These included body swelling and infusion-related reactions.
Only one patient quit patisiran due to an infusion-related event. Fewer patients on patisiran stopped the treatment early — only 4.7 percent — compared to 14.3 percent in the placebo group. Likewise, fewer patients in the patisiran group quit the study early due to adverse events.
“The safety results are encouraging, and in many cases, the lower incidence of many adverse events in the patisiran arm, such as falls, syncope [fainting], cardiac arrhythmias, infection and kidney injury, may potentially speak to progression of multisystem disease in the placebo arm,” Alnylam CEO John Maraganore said during the conference call.
Researchers also studied the rates of severe adverse events, noting they were similar in the two treatment groups —36.5 percent of patisiran-treated patients and 40.3 percent in the placebo group experienced them. Such events can be related to the disease itself or to the treatment. Researchers noted one case of severe diarrhea linked to patisiran. Other events, including heart failure, postural blood pressure drops, pneumonia and heart block were not related to the treatment, researchers said.
Meanwhile, 4.7 percent of patients in the patisiran group and 7.8 percent in the placebo group died during the study. No deaths were, however, related to the treatment.
Importantly, the safety profile held up also in the group of patients with heart involvement. Severe adverse events were numerically lower in the actively treated group — 34.4 percent compared to 50 percent among placebo-treated patients. Other adverse events were similar in the two groups. There were also no signs of kidney toxicity or lowering of blood platelets, researchers said.
“The APOLLO data presented in Paris provide robust evidence supporting the potential of RNAi as a novel therapeutic approach for patients with hATTR amyloidosis,” said Dr. Elias Zerhouni, president of global research and development at Sanofi.
“In this study, patisiran’s effect in helping to alleviate neurological impairment and improve the quality of life for people living with this debilitating rare disease is a remarkable accomplishment. Sanofi looks forward to coordinating global regulatory submissions with Alnylam on an expedited basis,” he added.
Patisiran intends to silence the faulty TTR gene using a technology called RNAi. In this way, the medication prevents both natural and faulty TTR from being produced and accumulate in tissues in the form of amyloid deposits.
In addition to the Phase 3 data, the two companies provided an update from the long-term extension of a Phase 2 trial (NCT01961921) of the treatment. All patients in the study received patisiran, and researchers said patisiran’s effects were maintained over 36 months of treatment, with no new safety issues identified.
“Alnylam is indebted to all the patients, investigators, and study staff who took part in the APOLLO study, making this important and notable milestone possible. We’re also grateful to the caregivers and family members whose support of APOLLO patients was such an important contribution,” said Vaishnaw. “With these promising APOLLO data in hand, we intend to start filing our results with regulatory authorities in late 2017 with the goal of achieving approval in mid-2018.”