On January 21, 2022, Alnylam Pharmaceuticals announced the results of its HELIOS-A Phase III study of vutrisiran, an investigational RNAi therapeutic for the treatment of transthyretin-mediated amyloidosis (ATTR) neuropathy, which met all secondary endpoints measured at 18 months. Vutrisiran is a second-generation formulation of Alnylam’s Onpattro (patisiran). Both vutrisiran and Onpattro are small interfering RNA that target TTR-producing genes and reduce the production in the liver. Onpattro is currently marketed for ATTR polyneuropathy in the US, the EU and Japan. Onpattro was first launched in the US in 2018 and GlobalData expects Onpattro to be the market leader for the treatment of ATTR polyneuropathy through 2029, however, vutrisiran will provide significant competition if it is approved for reimbursement.

The FDA is currently considering vutrisiran for approval in the treatment of hereditary ATTR polyneuropathy, with a PDUFA date of April 14, 2022. When compared to Onpattro, vutrisiran was found to be non-inferior in terms of serum transthyretin reduction. In ATTR amyloidosis, reduction of TTR serum is a known biomarker of the disease. Vutrisiran was also successful in an exploratory cardiac endpoint in the study, which included a known biomarker of heart failure called NT-proBNP. Safety and tolerability were consistent with data reported at the nine-month mark.

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Vutrisiran’s primary advantage over Onpattro is its dosing regimen. Patients taking Onpattro must undergo an 80-minute infusion every three weeks. Vutrisiran, on the other hand, is a subcutaneous injection that is administered every three months, addressing the unmet need for a treatment with a less onerous dosing schedule.

Onpattro is taking a much larger share of the ATTR polyneuropathy market due to its greater efficacy and safety profile over AKCEA’s Tegsedi (inotersen). This gap in patient share between Tegsedi and Alnylam’s ATTR portfolio is expected to increase. Onpattro is also being trialled for ATTR cardiomyopathy and is expected to provide greater competition to Pfizer’s Vyndaquel (tafamidis). The RNAi therapies act directly at the source of TTR production, reducing it, unlike the TTR stabilisers like Vyndaqel, which act to stabilise circulating TTR. Another benefit of RNAi therapies versus TTR stabilizers is their effect on the neurologic decline: 75% of those taking TTR stabilizers will still experience neurologic decline while RNAi therapies have been found to halt the disease.

Onpattro, however, will face competition from vutrisiran. Alnylam’s development of vutrisiran as a direct competitor for Onpattro will limit the company’s total revenue, as increased patient share for one drug will directly impact and reduce the patient share of the other. But, vutrisiran’s commercial success will be heavily dependent on its ability to achieve an adequate level of reimbursement. Alnylam has stated that Onpattro has confirmed access from 98% of US payers, with 80% of patients having zero co-pay. Onpattro is also covered by the NHS.

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AKCEA’s second-generation RNA-targeted therapy AKCEA-TTR-LRx is still in Phase III development, but vutrisiran is expected to lead competition between the two due to its efficacy results and the success of Onpattro in improving Alnylam’s drug development reputation, in contrast to the clinical obstacles faced by AKCEA’s Tegsedi. Furthermore, vutrisiran is administered every three months, making it more appealing than AKCEA-TTR-LRx, which is administered every four weeks.

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The pipeline for ATTR is growing quickly. Many of the therapies are relatively new to the market and although this brings new hope to the disease area, real-world data and long-term efficacy data are still in progress.