Onpattro safely eases neurological symptoms of FAP, review finds
Analysis of 11 studies eyes changes with treatment across 503 adult patients
Long-term treatment with Onpattro (patisiran) is generally safe and results in a stabilization or lessening of neurologic impairments in people with familial amyloid polyneuropathy (FAP), according to a meta-analysis of published studies.
Onpattro was used for a mean of 17.4 months (about 1.5 years) among the 503 patients in the 11 studies analyzed by the researchers, while 195 of them were on the treatment for more than 30 months (about 2.5 years).
The study, “Efficacy and safety of patisiran for ATTRv-PN: a systematic review and meta-analysis,” was published in the journal Therapeutic Advances in Neurological Disorders.
Onpattro is designed to lower levels of a damaging transthyretin protein
FAP, also known as hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN), is a rare progressive disease caused by mutations in the TTR gene. These mutations lead to the production of a faulty transthyretin protein, which forms toxic and damaging clumps that accumulate mostly in nerves outside the brain and spinal cord, a condition known as polyneuropathy.
Other organs may also be affected, including the heart and the kidneys. When transthyretin clumps mainly affect the heart, the disease is called hereditary transthyretin amyloid cardiomyopathy.
Given that transthyretin is produced in the liver, a liver transplant was the first treatment given to slow the disease’s course. Since then, other FAP therapies have been developed to halt the production of abnormal transthyretin or stabilize it, each preventing further protein clumping.
Onpattro, by Alnylam Pharmaceuticals, is an RNA interference-based therapy approved for adults with FAP. It works by targeting the TTR gene’s messenger RNA, an intermediate molecule derived from DNA that is used as a template to manufacture protein.
Infused directly into the bloodstream, Onpattro works to reduce the levels of abnormal transthyretin protein, thereby preventing the formation of more toxic aggregates.
Data from the Phase 3 APOLLO trial (NCT01960348) showed that Onpattro outperformed a placebo at lessening polyneuropathy symptoms and improving life quality over 1.5 years of treatment in adults with FAP.
“However, the current findings on the efficacy and safety of [Onpattro] for ATTRv-PN remain understudied,” the researchers wrote.
Slightly more than 50% of patients in 11 analyzed studies had cardiac symptoms
Scientists at Shanghai Medical College in China systematically reviewed studies published up to early June, reporting on the therapy’s safety and efficacy in FAP.
Among the 11 studies included in the meta-analysis, seven were cohort studies, or those that follow patients over time; two were single case reports; one was a case series study; and one focused on the APPOLO trial and its results.
About half of all patients, with a mean age of 61.5, had heart symptoms (50.9%), and 48.5% had undergone a liver transplant prior to starting on Onpattro. The therapy was administered at a dose of 0.3 mg/kg every three weeks over a mean of about 1.5 years for most of the 503 patients involved, while 38.8% were treated for more than 30 months.
Pooled data showed a response rate of 88%. Changes in neurological impairments were assessed in eight studies before and after Onpattro’s use. In five studies, no significant changes were reported in the Neuropathy Impairment Score (NIS), a scale in which higher scores indicate worse neuropathy, or nerve damage.
Three studies used the modified Neuropathy Impairment Score +7 (mNIS+7), considered a more comprehensive scale for disability associated with neuropathy. Pooled results showed that neurological symptoms significantly eased after starting on Onpattro.
The lack of significant differences in NIS scores with treatment may be due to fewer patients being assessed with NIS relative to mNIS+7 (100 vs. 187), and the fact that mNIS+7 “captures more comprehensive and detailed information compared to the traditional NIS,” the researchers wrote. “mNIS + 7 may serve as a more suitable and improved scale.”
Consistent gains seen in 195 adults treated for more than 2.5 years
Seven studies also assessed Onpattro’s efficacy through the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (QoL-DN) score, which assesses patients’ perceptions of polyneuropathy-related symptoms. Pooled data indicated a significant lessening of symptoms.
Across the 195 adults treated for more than 2.5 years, “consistent improvement or stabilization was observed in nearly all efficacy assessments, including the NIS, mNIS + 7, [and] Norfolk QoL-DN,” the researchers wrote.
The therapy was generally safe. A total of 413 adverse events were reported in nine studies, with most being mild to moderate in severity. Those most commonly reported included diarrhea (23%), swelling of the extremities (17.5%), infusion-related reactions (13.8%), a urinary tract infection (12.7%), falls (11.5%), and the common cold (10.1%).
A total of 37 patients died (7.6%), mostly due to cardiovascular events, and no death was deemed to be related to Onpattro.
Overall, these findings suggest that Onpattro is “effective and safe for patients with ATTRv-PN,” the researchers wrote. Additional “large-scale clinical trials and long-term studies are necessary to further validate [Onpattro’s] efficacy and safety.”
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