Lampalizumab

Looking to scuffle with rare disease giant and now AstraZeneca subsidiary Alexion, little Apellis scored a breakthrough win earlier this summer for its own complement factor inhibitor drug. Apellis, though, always had its eyes on bigger fish, but a first glimpse at pivotal data for a major indication has muddied the waters. In two Phase III studies testing pegcetacoplan in patients with geographic atrophy, Apellis’ drug nailed the primary endpoints in one test but flopped the same checkpoints in a “carbon copy” study, according to topline data released Thursday. Geographic atrophy is an advanced form of dry age-related macular degeneration with no approved therapies that affects around 5 million patients worldwide — including around 1 million in the US — and is a leading cause of blindness. An approval here could spell blockbuster sales for pegcetacoplan, a complement C3 inhibitor now marketed as Empaveli for paroxysmal nocturnal hemoglobinuria (PNH) — which is exactly why analysts and investors have kept such a close eye on these studies. In June, Evaluate Pharma pegged the drug’s potential market in GA at $1.2 billion in 2026. In the Phase III OAKS trial, pegcetacoplan injected in the eye reduced the rate of GA lesion growth by 22% (p=0.0003) and 16% (p=0.0052) compared with pooled sham injection in patients administered a monthly and once-every-other-month dose of the drug, respectively, after a year, Apellis said. Taken alone, that’s great news for Apellis. But the second trial toplined Thursday — the Phase III DERBY study — painted a murkier picture of the drug’s efficacy. In that trial, pegcetacoplan failed to significantly cut lesion growth rate compared with sham in both cohorts, posting rates of 12% (p=0.0528, just over the standard benchmark of p=0.05) and 11% (p=0.075), respectively. That’s a concern since the studies were mirror images of one another and offered contradicting pictures of whether Apellis’ drug works in this indication. In an attempt to bridge the gap between the two studies, Apellis offered results from a prespecified analysis combining the primary endpoints from both studies to determine overall significance. The biotech said monthly doses of the drug in both studies cut lesion growth by 17% overall (p=<0.0001) and a once-every-other-month dose cut lesion growth by 14% (p=0.0012) compared with sham. A failed study is a black mark on any drug’s record, but CEO Cedric Francois said the totality of pegcetacoplan’s efficacy and safety data — which includes results from the Phase II FILLY trial — could offer a compelling case for regulators. The company expects to file for approval as soon as the first half of 2022. “You have to look at these data in terms of the totality of data that we have assembled,” he told Endpoints News . “The entire data package that we have presents a very strong case for approval.” In terms of why the studies diverged so greatly, Francois didn’t have much to offer, saying: “If you run the same trial 20 times, you’ll get 20 different results.” Francois highlighted the safety data for pegcetacoplan in DERBY and OAKS, with just 6% of patients reporting exudations from the eye in the monthly dose cohorts and 4.1% in the every-other-month cohorts. There were two confirmed cases of infectious endophthalmitis and another suspected case among 6,331 injections administered during the studies. Meanwhile, there were 13 cases of intraocular inflammation reported and no retinal vasculitis or retinal vein occlusion reported. “We came into this program with a drug that we believed would have to be given every month to patients, where there was concern that we may have an increased rate of exudation that was going to be a problem,” Francois said. “The safety here is so good that this is a drug that you’ll want to give to all patients with GA.” Another potential boon to the drug’s case was its effect on what are called extrafoveal lesions, which are early signs of the disease prior to central vision being affected. In a combined exploratory analysis, pegceptacoplan cut the rate of growth for those lesions by 26% (p=<0.0001) for the once-monthly cohorts and 23% (p=0.0002) for the once-every-month cohorts. So that leaves the ball in the FDA’s court, and it’s unclear exactly how regulators will absorb these conflicting results. It wouldn’t be the first time that missing a primary endpoint hasn’t torpedoed a drug’s chances, and the unmet clinical need and strong safety data could be enough to push the drug over the finish line. If the FDA does cooperate, it would be the culmination of Apellis’ yearslong drive for GA, a disease Francois described as a “forest fire” in the eye that has so far confounded drug developers. Way back in 2017, Roche saw its own chances in GA collapse after its antibody lampalizumab flopped a key test in GA patients. But Apellis believes complement factor inhibition could be key, which explains why Alexion — now a part of AstraZeneca — has been dabbling here with its own C5 inhibitor franchise. Empavelis’ approval in PNH in May marked the first major challenge to Alexion’s Soliris, a blockbuster drug for which PNH is the single largest indication. Prior to its acquisition, Alexion was busy switching most of its patients over to follow-up drug Ultomiris, which sports a matching PNH approval and is working to quickly expand its label to match the older drug.

A month and a half later, Gyroscope Therapeutics’ Phase I/II win for its dry-AMD gene therapy is already paying off. On Friday, the biotech took the wraps off a $148 million Series C round to advance the candidate through two Phase II trials in patients with a debilitating eye disorder that causes gradual and permanent blindness. Syncona — which founded Gyroscope with Cambridge Enterprise — contributed $42.3 million to the Series C round, and now maintains a 54% stake in the London-based biotech. Spark’s costly Luxturna made waves when it became the first gene therapy approved for inherited blindness back in 2017. Since then, other gene therapies for rare eye disorders have advanced in development — but none have been approved for dry, age-related macular degeneration (AMD), a leading cause of blindness in people over 50 years old. About 85% to 90% of people with AMD have the dry type, according to Gyroscope. Gyroscope’s lead candidate, GT005, is currently in two Phase IIs for patients with geographic atrophy, an irreversible degeneration of retinal cells caused by dry-AMD. The candidate is injected under the retina to increase production of the Complement Factor I protein, which Gyroscope believes could dampen an overactive complement system that’s been tied to worsening atrophy in AMD patients. “We recently announced encouraging Phase I/II clinical trial data with our lead investigational gene therapy, GT005, that give us confidence in its potential as a treatment for geographic atrophy and are continuing to advance our Phase II clinical programme,” CEO Khurem Farooq said in a statement. Farooq, a Genentech vet, oversaw commercial activities for the wet-AMD drug Lucentis and pre-launch work for Roche’s lampalizumab, a dry-AMD candidate that was dropped after failing two Phase III trials in 2017. In a Phase I/II dose-escalation trial, patients who responded to GT005 saw a 146% increase in their vitreous Complement Factor I levels as well as a decrease in downstream biomarkers tied to geographic atrophy for patients with dry AMD, according to data released in mid-February. Nadia Waheed At an interim check-in, nine out of 10 patients across four cohort groups saw increased CFI levels after receiving the therapy, and eight of those nine maintained elevated levels of CFI after six months, Gyroscope said. “Consistently we’re hitting the targets we want to hit in the downstream amplification loop,” CMO Nadia Waheed told Endpoints News last month. “Everything so far looks like it’s pointing in the right direction.” The Series C funds will also be used to advance Gyroscope’s early-stage pipeline and delivery tech, according to a statement. The round was led by Forbion’s Growth Opportunities Fund, with a hand from Sofinnova Investments, funds and accounts advised by T. Rowe Price Associates, Tetragon Financial Group Limited, an undisclosed healthcare-focused fund, Fosun Pharma and Cambridge Innovation Capital. Wouter Joustra and Maha Katabi, general partners at Forbion and Sofinnova, respectively, are joining the board. And director Dominic Schmidt is on his way out. “With the expansion of the Board it is the right time for Dominic (Schmidt) to step down from his position as Director. We thank Dominic for his key role in the launch and growth of Gyroscope and his support of the Company,” chief investment officer Chris Hollowood wrote in a statement. Last month, Waheed told us the Phase I/II FOCUS trial would finish enrollment by the end of 2021, and that the team was “on track” to fill out enrollment in the two Phase II efficacy trials. A correction has been made to reflect that Luxturna is the only ocular gene therapy currently approved.