2020-03-04| Trials & Approvals

GIVLAARI to Enter European Market Following EMA Approval

by Ruchi Jhonsa
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By Ruchi Jhonsa, Ph.D.

A potentially life-threatening condition of the liver, Acute hepatic porphyria (AHP) is a rare, genetic disease caused by the accumulation of toxic porphyrin levels in the body. The disease-causing genetic mutation lies in the gene catalyzing the final step in the heme synthesis pathway. This reduces heme production but simultaneously up-regulates the levels of intermediate products like porphyrins as feedback inhibition on the pathway is lost. This results in the accumulation of intermediary porphyrins that causes symptoms like abdominal pain, vomiting, and nervous system disorders. Given the symptoms are so common and associated with a variety of other diseases, AHP is hard to diagnose. So far, the only specific therapy for the disease approved under the Orphan Drug Act of 1983 is Panhematin- human blood-derived heme formulation.


GIVLAARI, Alnylam’s Second RNAi Drug

With no therapy for almost three decades, Alnylam started working on AHP from 2017. The company’s extensive experience in the field of RNA interference led to the designing of an RNAi drug that targets the very first enzyme in the heme synthesis pathway causing an immediate shutdown of the porphyrin synthesis. Exciting as it sounds, the drug also showed positive results in a pivotal ENVISION trial. GIVLAARI, the second RNAi product of Alnylam, significantly reduced the rate of porphyria attacks by 74%, diminished the frequency of attack in 50% of the patients, decreased urgent healthcare visits or panhematin treatment at home in comparison to placebo.

This data brought a breakthrough therapy designation for the drug followed by FDA approval in late 2019. Meanwhile, the drug was also being reviewed by the European Medicine Agency (EMA) as they have no approved treatment for the disease so far. Reviewed under EMA’s PRIME scheme that allows rapid approval for drugs with major public health interest, Alnylam today announced the approval of GIVLAARI by the European Commission for treatment of acute hepatic porphyria in adult and adolescent patients aged 12 years and older. Before the approval, the drug was already granted Orphan Designation in the European Union.

“Today’s approval of GIVLAARI marks a historic moment for patients and families living with this devastating genetic disease, as there are currently no approved medicines in Europe proven to decrease the frequency of attacks and reduce the chronic pain that many patients suffer,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. Excited on the approval, Dr. Barry Green, President, Alnylam said, “We are committed to bringing GIVLAARI to patients in Europe as rapidly as possible, and plan to build on our experience in the U.S. by proactively engaging with national authorities in Europe around a value-based agreement framework which we hope will accelerate patient and provider access to GIVLAARI.



GIVLAARI is not without its share of challenges. Firstly, the drug comes with a hefty price tag. The annual cost of the drug in the US is $575,000 per patient based on a list price of $39,000 per vial. But it might be possible to get some rebate on the price with Alnylam’s highly innovative reimbursement strategy, which will offer discounts to the payer if the prevalence of AHP on a given plan is higher than current estimates.

Besides, the drug also has safety concerns. The drug’s safety profile was worse than expected with serious side effects affecting the patient at nearly double the rate of the placebo group. Looking at these problems, critics question whether this RNAi based drug would succeed in the market? Only time will tell.

Despite the speculations, Givlaari is the only one of a kind drug in the market for AHP patients that targets the gene directly and it brings hope to many suffering from the disease. Dr. Eliane Sardh, Head of the Porphyria Centre Sweden, Karolinska University Hospital, Sweden expressed her thoughts on the approval and said, “The fear of not knowing when an attack will strike, combined with ongoing symptoms between attacks, affects every aspect of patients’ lives, limiting their ability to work and maintain a social life. In our experience, life is very different for patients since they have been treated with givosiran. In addition to a reduction in the number of porphyria attacks which require hospitalization and urgent healthcare visits, we have seen improvements in how patients report their overall health status and quality of life, so this approval is truly meaningful for patients, their families and the healthcare professionals who treat them. Some of our patients have been able to achieve significant personal and professional milestones that would not have been possible before” she added.

Related Article: GSK Wins EMA Approval to Market Multiple Myeloma Treatment



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