This article is part of an ongoing blog series profiling the 12 new, game-changing drugs predicted to achieve blockbuster status by 2022 in the 2018 edition of Drugs to Watch, the annual industry forecast and analysis from Clarivate Analytics. Read the full Drugs to Watch report here or follow the series for the latest updates.
FDA approval of Alnylam’s RNA interference (RNAi) therapeutic Onpattro (patisiran), a potential blockbuster for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis, was anticipated in the 2018 Drugs to Watch, the annual industry forecast and analysis from Clarivate Analytics. The FDA gave the nod as expected on the August 10 PDUFA date under Priority Review with Fast Track, Orphan Drug and Breakthrough Therapy designations. This approval makes Onpattro not only the first and only FDA-approved RNAi therapeutic, thereby paving the way for other RNAi therapeutics, but also the first and only therapeutic approved for this indication in the U.S.1 EU approval is expected in September 2018 following a positive CHMP opinion in late July.2
This approval makes Onpattro not only the first and only FDA-approved RNAi therapeutic, thereby paving the way for other RNAi therapeutics, but also the first and only therapeutic approved for this indication in the U.S.”
Transthyretin (TTR) amyloidosis is a slowly progressive condition characterized by the buildup of abnormal TTR deposits throughout the body due to abnormal formation and aggregation of TTR protein.1 It is a rare disease with an estimated 50,000 patients affected worldwide, and in most cases, the condition is inherited and often fatal with limited treatment options.3 Onpattro is designed to target and silence specific messenger RNA, thereby blocking production of the TTR protein and reducing its deposition to tissues.1
The current standard of care for this disease has been liver transplantation but the risks of surgery, acute liver rejection and infection have made it an option only for patients in good clinical condition. Vyndaqel (tafamidis, Pfizer), a first-in-class anti-amyloid therapy, was until recently the only approved anti-amyloid treatment for TTR familial amyloid polyneuropathy, but it is limited to use in early-stage disease only and not yet approved in the U.S.4
Following its approval, Onpattro is on track to becoming the standard of care for polyneuropathy of hATTR amyloidosis. It will be competing closely with Akcea/Ionis’s Tegsedi (inotersen), an antisense drug that inhibits TTR production, which became the world’s first RNA-targeted therapeutic approved for polyneuropathy of hATTR amyloidosis following EU approval in July.5 In the U.S., the FDA has extended the Tegsedi review period and assigned a new PDUFA date of October 6; Tegsedi’s launch in both the EU and U.S. is expected before the end of 2018.6,7
Both Onpattro and Tegsedi are efficacious and disease-modifying medicines that bring in a new era for treating this debilitating disease, with Onpattro anticipated to reap the greatest benefit. In the APOLLO phase III trial in patients with TTR familial amyloid polyneuropathy (including those with cardiac symptoms), Onpattro showed significant improvement of neurological impairment (with a 34-point difference in the mNIS+7 scale [a composite measure of neurological impairment] at 18 months), improved quality of life and reduced disease symptoms and disability.8 Treatment benefit was better than with Tegsedi, which showed a 19.7-point treatment benefit compared with placebo at month 15 in the phase III NEURO-TTR study.9
Both Onpattro and Tegsedi are efficacious and disease-modifying medicines that bring in a new era for treating this debilitating disease, with Onpattro anticipated to reap the greatest benefit.”
While Tegsedi has a more convenient subcutaneous delivery (once weekly) compared with Onpattro’s intravenous administration (every three weeks), Tegsedi is associated with safety signals, including the risk of thrombocytopenia and glomerulonephritis, while Onpattro has an encouraging safety profile with infusion-related reactions the most common.8,9
Nevertheless, approval of Onpattro fell short of expectations with the indication limited to TTR patients with polyneuropathy (the nerve damage component) despite the APOLLO trial also showing efficacy in patients with cardiac complications. While competitor Tegsedi is also limited to polyneuropathy, Vyndaqel showed significant reductions in the combination of all-cause mortality and frequency of cardiovascular-related hospitalizations in TTR patients with cardiomyopathy in the ATTR-ACT study in March 2018. With Fast Track status for this indication, Vyndaqel could become the first treatment approved for TTR cardiomyopathy, which could limit the commercial opportunity for Onpattro.10
At the time of writing the Drugs to Watch report, Onpattro Cortellis Consensus Forecast data (source Thomson Reuters I/B/E/S) for 2022 were $1.212 billion; although current forecasts for 2022 are short of blockbuster status at $844 million, possibly a result of the FDA label being narrower than expected as well as experienced marketer Sanofi returning rights to Alnylam in early 201811, the $1 billion mark is set to be reached in 2023 (with forecasts of $1.017 billion), rising further thereafter. Tegsedi, in contrast, which had 2022 forecasts of $533 million at the time of writing the Drugs to Watch report, currently has 2022 and 2023 forecasts of $420 million and $543 million, respectively, while Vyndaqel sales forecasts, which earlier in the year were $170 million for 2022, are now $650 million for 2022 and $850 million for 2023. (See Figure 1.)
Figure 1. At the time of writing the 2018 Drugs to Watch report, Onpattro Cortellis Consensus Forecast data (source Thomson Reuters I/B/E/S) for 2022 were $1.212 billion.