APOLLO: Patisiran Reduces Polyneuropathy in hATTR Amyloidosis

Susan Jeffrey

April 26, 2018

LOS ANGELES — Results of a new study show encouraging results with patisiran (Alnylam Pharmaceuticals), an investigational agent for the treatment of hereditary ATTR (hATTR) amyloidosis, in improving polyneuropathy symptoms and a variety of other endpoints, with an "encouraging" safety and tolerability profile, researchers report.

"hATTR amyloidosis is a multisystem, progressive, life-threatening disease with very high morbidity and mortality, and very limited therapeutic options," said lead author, David D Adams, MD, PhD, Department of Neurology at Bicêtre Hospital, Greater Paris University Hospitals, France, principal investigator of the phase 3 APOLLO trial.

"Patisiran treatment resulted in significant improvement in polyneuropathy from baseline relative to placebo," Adams said. "This is the first time in the amyloid story."

There were also significant improvement in quality of life, reduction in disease symptoms and disability, and improvement especially in ambulation with treatment vs placebo, he noted. Favorable changes in exploratory cardiac measures were also seen in the subpopulation of patients with good safety and tolerability.

In a post hoc analysis, there were an approximately 50% reduction in the composite rate of all-cause hospitalization and mortality and a 45% reduction in the composite rate of cardiac hospitalization and all-cause mortality, Adams said.

The results were presented here at the American Academy of Neurology (AAN) 2018 Annual Meeting.

Patisiran is an investigational lipid nanoparticle formulated RNA1, given by intravenous infusion, targeting hepatic production of mutant and wild-type transthyretin (TTR). TTR protein is primarily produced in the liver and is normally a carrier of vitamin A, the company noted in a statement. Mutations in the TTR gene cause abnormal amyloid proteins to accumulate in organs and tissue, including the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations.

Patisiran is under priority review as a breakthrough therapy by the US Food and Drug Administration (FDA), a company release said, and is under accelerated assessment by the European Medicines Agency for the treatment of patients with hATTR amyloidosis. The FDA has set a Prescription Drug User Fee Act date of August 11, 2018, the company noted.

The APOLLO trial was a randomized, double-blind, placebo-controlled study looking at the efficacy and safety of patisiran in patients with hATTR who have polyneuropathy. A total of 225 patients from 44 sites in 19 countries were randomly assigned in a 2:1 ratio to patisiran or placebo. Patisiran was given at a dose of 0.3 mg/kg once every 3 weeks for 18 months.

Most patients in the treated group (93.2%) completed the study, but 29% of placebo patients were withdrawn because of objective disease progression, Adams noted.

Mean patient age was 63 and 62 years in the patisiran and placebo groups, respectively, and about 75% of patients in both groups were male. The populations were balanced on the basis of years since diagnosis, TTR genotype, and disability and severity of the disease.

Treatment with patisiran resulted in a rapid and sustained serum TTR reduction of more than 80% within 2 days of treatment, Adams said. 

The primary endpoint of the study was the change from baseline in the modified Neurologic Impairment Score + 7 (mNIS+7) compared with placebo at 18 months.

At both 9 and 18 months, patients receiving placebo had increases in the mNIS+7 score of about 14 or 28 points, he reported, indicating increasing impairment.

"Conversely — and this is fantastic — you can see the blue line, patients receiving patisiran, you have a decrease of mNIS+7 as early as early as 9 months, confirmed at 18 months, showing improvement of the neuropathy, suggesting reversal of the disease," Adams said (P = 9.26 × 10–24).


Table. Change in mNIS+7 With Patisiran vs Placebo at 9 and 18 Months

Endpoint Baseline: Patisiran Baseline: Placebo 9 Months: Patisiran 9 Months: Placebo 18 Months: Patisiran 18 Months: Placebo
mNIS+7 80.93 (8.0 - 165.0) 74.61 (11.0 - 153.5) –2.04 ± 1.50 13.95 ± 2.10 –6.03 ± 1.74 27.96 ± 2.60
Values in parentheses are ranges; values expressed with plus/minus sign are mean ± standard error of the mean.


Results showed that 56.1% of patients in the patisiran group had improvement in neuropathy compared with only 3.9% of those receiving placebo (odds ratio [OR], 39.9; P = 1.82 × 1015). Improvement was defined as a less than 0-point increase from baseline to 18 months on the mNIS+7.

"Regardless of the stage of the disease, and the severity of the NIS at baseline, you have the same effect in early stage as late stage," Adams noted, although he added that "surely" earlier treatment would be better than later treatment.

Secondary endpoints included the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score, NI-weakness, Rasch-built Overall Disability Scale, the timed 10-meter walk, modified body mass index, and composite autonomic symptoms score-31 (COMPASS-31).

All secondary endpoints showed highly statistically significant differences in favor of patisiran treatment, he said. In particular, 51.4% of patients in the patisiran group improved on the Norfolk QOL-DN vs 10.4% in the placebo group (OR, 10.0; P = 1.95 × 10–10).

All other secondary endpoints also improved, he added. "Some of them were better than baseline score; for example, gait speed, which is a major problem in these patients, or autonomic dysfunction with the COMPASS-31 questionnaire," Adams said.

Exploratory cardiac assessments included measurement of N-terminal pro-brain natriuretic peptide (NT-ProBNP) levels and echocardiography.

Patisiran resulted in favorable improvement in mean left ventricular (LV) wall thickness, global longitudinal strain, and NT-proBNP compared with placebo at 18 months, he said. Improvement was also seen in LV end-diastolic volume, interventricular septum thickness, posterior wall thickness, LV relative wall thickness, cardiac output, and LV mass. 

Thirteen patients died during the trial; none of these deaths were judged to be related to treatment, Adams said. The death rate trended higher in the placebo group (7.8% vs 4.7%). Most adverse events (AEs) were mild and moderate, mainly peripheral edema and infusion-related reactions.

"Interestingly, we had no safety signals regarding liver function tests, hematology including thrombocytopenia, and renal dysfunction" related to patisiran, Adams said. Some AEs were more frequent in the placebo group, including falls, urinary tract infection, and syncope, which reflect the burden of disability in the disease, he noted.

In a post hoc analysis presented here, recurrent hospitalization and death were reduced with patisiran treatment, including a 50% reduction in the composite rate of all-cause hospitalization and mortality and a 45% reduction in the composite rate of cardiac hospitalization and all-cause mortality.

All patients who completed the APOLLO trial were eligible for the Global Open Label Extension study, and 99% of the patients are participating, Adams noted.

Cautious Optimism

Natalia Rost, MD, MPH, director of the Acute Stroke Service at Massachusetts General Hospital, associate professor of neurology at Harvard Medical School, Boston, and chair of the AAN Science Committee, was co-moderator of the Clinical Trials Plenary Session where this paper was presented.

"The condition is quite rare, but just like many rare diseases, when they affect segments of population that are predisposed to it, they are quite devastating, and because they are rare, it's most likely that there's not a medication or a therapeutic option available to these patients," she told Medscape Medical News.

"This was really a disease of 'diagnose and adios,' and here we have an opportunity to at least alter the course of disease."

Still, she said, "we need to be cautiously optimistic. It did seem to have some benefits, at least for the patients in the trial, but I think we need to be as always thinking about the big picture and what's next and seeing how we can make it a reality."

Another question with this and some of the other new treatments discussed at this meeting is cost, Rost noted. "It takes an investment to develop these drugs, so obviously, somebody is going to try and recoup on their investment, and I think the cost of these medications is going to be tremendous again."

"So this is going to be the theme of our discussion at all of these neurology annual meetings," she said. "We're excited to see the treatments, but we need to think urgently with regard to how we're going to address the high cost of these drugs."

The study was funded by Alnylam Pharmaceuticals. Adams reports he has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities with Alnylam Pharmaceuticals.

American Academy of Neurology (AAN) 2018 Annual Meeting. Clinical Trials Plenary Session. Abstract S31.003. Presented April 24, 2018.

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