When Novartis last week announced positive outcomes from two Phase III trials for new age-related macular degeneration (AMD) drug brolucizumab (RTH258), it seemed the other two major players in the AMD space – Regeneron and Roche – might lose some of their luster.
But Regeneron’s stock kept gaining ground despite the potential threat of four-times-a-year brolucizumab therapy to Regeneron’s six-times-a-year Eylea (aflibercept), and Roche, which owns Genentech and US rights to Lucentis (ranibizumab), broke out with news of encouraging results of the Phase II MAHALO trial of lampalizumab for the treatment of geographic atrophy, an advanced form of AMD for which no cure exists. Novartis holds ex-US rights to Lucentis, for which sales fell about 10% a year over the past two years.
Let’s try to sort all this out.
Novartis Makes a Move
Novartis reported that RTH258 6 mg met the primary and key secondary endpoints in the Phase III HAWK and HARRIER trials. (RTH258 3 mg, evaluated in HAWK, also met these endpoints.) The pivotal studies enrolled more than 1,800 patients with neovascular AMD across 400 centers worldwide. The primary and key secondary efficacy endpoints were non-inferiority of RTH258 to Eylea in mean change in best-corrected visual acuity from baseline to week 48, and average mean change over the period of week 36 to 48, respectively.
RTH258 dosed every 12 weeks demonstrated long-lasting efficacy versus Eylea dosed every eight weeks. A majority of patients in both trials – 57% in HAWK and 52% in HARRIER – were maintained exclusively on intravitreal injections every 12 weeks immediately following the loading phase through week 48. The ocular and systemic adverse event rates of both drugs were comparable.
“These results clearly and convincingly demonstrate RTH258 has the potential to reduce injection burden while providing excellent visual outcomes,” says Vas Narasimhan, MD, Novartis’ CMO. Data analysis is ongoing and Novartis says it will be presented at an “upcoming medical congress.” The American Society of Retina Specialists meeting is in August in Boston, and the annual meeting for the American Academy of Ophthalmology will be in November in New Orleans.
In a research note, Jefferies‘ Jeffrey Holford says, “Given these treatments are dosed via intravitreal injection directly into the eye, the ability to show non-inferiority on efficacy, but with injections given every 12 weeks instead of the more frequent dosing for the competitors … will be a key determinant to RTH258’s likely future success.” He predicts a US launch of RTH258 in 2019 and peak sales of $2 billion if it also gets FDA approval for diabetic macular edema.
Brolucizumab could be a welcome relief for Novartis’ AMD business. Besides its ex-US stake in Lucentis, Novartis took a hit last year when Ophthotech posted disappointing Phase III results for Fovista (pegpleranib) in combination with Lucentis, which sent Opthotech’s stock reeling. Novartis holds foreign rights to Fovista.
Regeneron Holds Its Own
While investment websites portrayed the Novartis news as a threat to Regeneron, its stock actually gained ground since the Novartis announcement, increasing about 5% the day of the announcement and even reaching a 52-week high of $541.70 a few days later before settling in around $510–$520. Regeneron shares have increased 13.3% in the past month and are up about 36% this year.
That activity might have nothing to do with ophthalmology, though. Reuters quotes Leerink Partners analyst Geoffrey Porges as saying the Novartis announcement removed doubt for Regeneron investors who had been on the sidelines and were now looking to take advantage of the positive sales trajectory of Dupixent, the company’s recently approved treatment for severe atopic dermatitis. The potential negative impact of the Novartis data was already fully priced into the Regeneron stock, Porges tells Reuters.
The Fly reports that Piper Jaffray analyst Edward Tenthoff sees the Novartis announcement as a buying opportunity – for Regeneron stock. Novartis will not file until 2018 due to manufacturing issues, Tenthoff tells investors in a research note. He continues to expect Eylea sales growth of 6.1% to $3.52 billion this year and 5% to $3.7 billion in 2018 before brolucizumab hits the market in 2019. Tenthoff raised his price target for Regeneron Pharmaceuticals to $557 from $446 to reflect a higher price-to-earnings. Again, Tenthoff is looking beyond ophthalmology with Regeneron: positive Dupixent Phase III asthma data this fall would dramatically expand the company’s market opportunity, he contends.
Regeneron seems to be on track to hit those numbers. US Eylea sales increased 9% in the first quarter this year to $854 million and global sales jumped 12% to $1.34 billion versus Q1 2016.
Roche Weighs in on GA
Roche’s lampalizumab is a specific inhibitor of complement factor D, a pivotal regulator of the alternative complement pathway, for the treatment of geographic atrophy secondary to AMD. Roche reports the MAHALO Phase II trial, results of which were published last week in Science Translational Medicine, met its primary efficacy endpoint with a 20% reduction in lesion area progression with monthly lampalizumab treatment compared with sham.1
MAHALO was a multicenter, randomized, controlled study that evaluated monthly intravitreal lampalizumab injection (n = 42) and every other month (n = 41) versus sham controls (n = 40) in patients with geographic atrophy secondary to AMD. The primary endpoint was the mean change in lesion area from baseline to month 18 as measured by fundus autofluorescence.
Lampalizumab also showed an acceptable safety profile, and a more substantial monthly treatment benefit of 44% reduction in geographic atrophy progression versus sham in a subgroup of patients who were complement factor I risk-allele carriers.
European Biotechnology reports that Roche announced a week before the publication that it had initiated two Phase III trails (CHROMA and SPECTRI) of lampalizumab, enrolling 936 patients. European Biotechnology cited “rumors” that the FDA could accelerate patient access to the drug by granting breakthrough status to the treatment.
1. Yaspan BL, Williams DF, Holz FG, et al; for MAHALO Study Investigators. Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondaryto age-related macular degeneration. Sci Transl Med. 2017 21;9(395): eaaf1443. doi: 10.1126/scitranslmed.aaf1443.