FDA approves second RNAi based drug

By Rajaneesh K. Gopinath, Ph.D.

Alnylam Pharmaceutical’s GIVLAARI™ (givosiran) became the second-ever RNA interference-based drug to bag the FDA nod.

The RNA interference (RNAi) phenomenon discovered by Andrew Fire and Craig Mello in 1998 was a watershed moment in Biology that led to a Nobel Prize in 2006. It is a cellular mechanism through which small, non-coding RNAs such as siRNAs and miRNAs control gene expression through transcriptional or post-transcriptional gene silencing. Although initial research was confined to nematodes, flies, and plants, interest in the phenomenon surged rapidly post 2001, when Thomas Tuschl and colleagues at the Max Planck Institute for Biophysical Chemistry demonstrated specific RNAi silencing in vitro using mammalian cells. This led to the founding of Alnylam Pharmaceuticals in the year 2002. This Cambridge based biopharma is one of the first companies that focused on developing RNAi therapies. Following a number of clinical trials and optimizations, it’s Onpattro® (patisiran) became the first-ever FDA approved RNAi based drug last year.

Givlaari, the Second Ever RNAi Drug

Today, the U.S. Food and Drug Administration announced its approval to GIVLAARI™ (givosiran) for the treatment of adults with acute hepatic porphyria (AHP), a rare inherited genetic disorder. Hepatic porphyria is characterized by the accumulation of organic compounds called porphyrins, the precursors of heme protein. The disease is a result of mutations in the enzymes that are involved in heme production in the liver. The accumulation can cause neurological attacks including seizures, psychosis, severe abdominal and back pain, and acute polyneuropathy.

“These attacks occur suddenly and can produce permanent neurological damage and death,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Prior to today’s approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks. The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients.”

Positive Clinical Trial Data from the ENVISION Study

GIVLAARI functions by targeting and silencing the aminolevulinic acid synthase 1 (ALAS1) enzyme thereby reducing its levels and in turn the toxic heme intermediates. The approval was based on ENVISION, a phase III clinical trial involving 94 patients with AHP. Those who received Givlaari experienced 70% fewer porphyria attacks compared to patients subjected to placebo treatment. Common adverse effects included nausea and reactions at the injection site. Other adverse reactions include rash, serum creatinine increase, transaminase elevations, and fatigue. Health care professionals are advised to monitor patients for anaphylactic (allergic) reaction and renal (kidney) function.

In spite of the safety issues, the drug has received FDA approval in less than four months following its New Drug Application (NDA) filing acceptance. Earlier, it had received FDA’s Breakthrough Therapy designation, Priority Review designation and also the Orphan Drug designation. It also received similar designations from the European Medicines Agency (EMA) and is currently awaiting approval from the body.

“We believe the approval of GIVLAARI represents a landmark event for the advancement of precision genetic medicines, providing new hope for patients and their caregivers living with the debilitating manifestations of AHP and unpredictable nature of AHP attacks, as well as for the doctors who diagnose and treat these patients. We are grateful to the investigators, patients and families who have helped make this new treatment option a reality for the AHP community. We also commend the FDA for recognizing the immense medical need and granting this approval so quickly,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam.

References

1. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-inherited-rare-disease
2. http://investors.alnylam.com/news-releases/news-release-details/alnylam-announces-approval-givlaaritm-givosiran-us-food-and-drug

Author

Rajaneesh K. Gopinath