Study Explains Phase 3 Clinical Trial Evaluating Alnylam’s Patisiran as Potential FAP Therapy

A new study outlines the design and rationale for APOLLO, a Phase 3 clinical trial (NCT02510261) to evaluate the effect of patisiran (ALN-TTR02) in patients with hATTR (hereditary ATTR) amyloidosis with polyneuropathy.

The study, “Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy,” appeared in the journal BMC Neurology.

Familial amyloid polyneuropathy (FAP) — also known as hATTR amyloidosis — is caused by misfolded protein transthyretin (TTR), which leads to the formation of insoluble amyloid fibrils that accumulate in the heart, nerves and gastrointestinal tract. It is a complex disease whose symptoms encompass the sensory, motor and cardiac systems; more than 120 TTR gene mutations are associated with hATTR.

One way to treat hATTR amyloidosis is via orthotopic liver transplant (OLT), since the liver produces TTR . However, OLT is expensive and advisable only for a certain subset of patients. It is further limited by and is limited by donor availability and toxicity.

New medicines such as Vyndaqel (tafamidis) and diflunisal are known to stabilize TTR protein complexes and prevent protein misfolding. Both of those drugs slow progression of nerve disease, and patients appear to tolerate them well, according to clinical studies. But some patients get neuropathy symptoms anyway, promoting the need for more therapeutic options.

Patisiran, developed by Alnylam Pharmaceuticals, is a clinical-stage RNA interference (RNAi) therapy designed to recognize certain sequences of mRNA molecules and degrade them. Given that mRNAs are the intermediary molecules between DNA sequences and protein expression, patisiran targets the part of TTR mRNA that is the same across regular and mutated protein. The drug should effectively eliminate mutated TTR and subsequently reduce fibril levels.

The Phase 2 study (NCT01617967) showed that Patisiran slashed mean TTR by about 80 percent, leading to stabilizing or even reversing nerve disease in hATTR amyloidosis patients.

The Phase 3 APOLLO study, a double-blind, placebo-controlled, global trial, aimed to determine patisiran’s efficacy and safety. The trial lasted from December 2013 to January 2016 and included 225 hATTR amyloidosis patients ranging in age from 18 to 85. Researchers randomly assigned them to receive either intravenous patisiran at a dose of 0.3 mg/kg or placebo once every three weeks.

Researchers used the mNIS+7 test to determine patisiran’s effectiveness. The mNIS+7 is a 304-point composite measure of neurologic deficits through examination of lower limbs, upper limbs and cranial nerves; measurement of small and large nerve fiber function; quantitative sensory testing (touch pressure and heat pain) at specific body surface locations; and autonomic function (postural hypotension). Patients were tested 21 days before starting patisiran, at baseline again at nine and 18 months. Higher mNIS+7 scores indicate  worsening impairment.

Researchers also tested patisiran’s effect on the Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status, motor function (NIS-weakness test and 10-m walk test), and autonomic symptoms (Composite Autonomic Symptom Score-31 questionnaire). They examined cardiac function, assessment of nerve fiber innervation and amyloid burden as well as safety.

The global open-label extension study began in July 2015 and will provide the long-term data on safety and efficacy of patisiran.