complement factor

Ionis Pharmaceuticals disclosed the news it no longer sees a future for one of its assets in geographic atrophy alongside confirmation that ION541, an amyotrophic lateral sclerosis candidate, is no longer part of its plans. Another of Ionis Pharmaceuticals’ key midphase readouts has fallen short of expectations, prompting the biotech to stop studying the Roche-partnered candidate in an advanced form of age-related macular degeneration. Roche exercised its option on the drug candidate, which is variously called IONIS-FB-LRx, RO7434656 and RG6299, in 2022. The Swiss drugmaker took responsibility for global development, with the exception of an open-label phase 2 IgA nephropathy (IgAN) trial and a phase 2 study in geographic atrophy (GA). In June, Ionis identified the GA readout as one of the key value-driving events planned for 2024.The event failed to drive value. Rather, Ionis stopped development of the candidate in GA after seeing the results of the 332-patient phase 2 study that wrapped up in June. Ionis said it saw “favorable safety profiles and good target engagement, but insufficient efficacy to advance into phase 3 development.”Roche is continuing to enroll patients in its phase 3 IgAN study, and data from the open-label trial in the chronic kidney disease remains on Ionis’ road map for the year. But Ionis no longer sees a future for the asset in GA.   Ionis’ interest in testing the drug in the eye disease reflected evidence that the alternative complement pathway is linked to GA. Overproduction of complementing factor B, an activating factor in the pathway, is associated with higher risk. Roche targeted similar biology with complement factor D-binding antibody fragment lampalizumab only to see the candidate fail a phase 3 clinical trial in GA in 2017.Lampalizumab was administered into the eye. With most factor B produced in the liver, Ionis gave its GA drug candidate systemically to try to stop the accumulation of the complement factor and the resulting destruction of the macula. Ionis CEO Brett Monia, Ph.D., acknowledged that rationale may fail to translate into an effective drug at a TD Cowen investor event in June.“It's a significantly risky program. But on the other hand, the upside is enormous, since this drug would not have to be intravitreally administered, it would be injected using a simple auto-injector once per month by the patient themselves,” Monia said. “It could be a real breakthrough, game changer for this indication, but it does not come without risk.”Ionis disclosed the failure of IONIS-FB-LRx to live up to that billing alongside confirmation that ION541 is no longer part of its plans. The biotech and partner Biogen reported the termination of development of the amyotrophic lateral sclerosis candidate, which is also called BIIB105, in May after seeing phase 1/2 data. 

The FDA’s recent approval of Biogen’s Aduhelm has provided a spark plug for neuroscience research across the biopharma spectrum with investors more likely than ever to jump on board. A Chicago biotech now has its own clutch of blue-chip backers to pursue drugs across a range of indications — and it all started from a close colleague’s own diagnosis and search for a cure. OrbiMed startup Vanqua Bio closed an $85 million Series B led by Omega Funds to put its lead candidate targeting the GCase enzyme in the clinic, first in Gaucher disease and then for a rare form of Parkinson’s, the company said Tuesday. The company’s lead drug, a small molecule activator of GCase, targets the mutant GBA1 gene pathway, which can cause Gaucher and is correlated with a form of Parkinson’s known as GBA-PD that affects around 10% of all patients and a form of Lewy body dementia known as GBA-LBD. The biotech launched back in 2019 emboldened by the work of Jonathan Silverstein, a former managing partner at OrbiMed who was diagnosed with GBA-PD some five years ago and kickstarted the Silverstein Foundation to pursue cures for that disease. Funds from the foundation helped pay for pivotal genetics research in the lab of Dimitri Krainc, the chair of neurology at Northwestern University’s Feinberg School of Medicine, which now undergirds Vanqua’s platform. Vanqua relies both on genetics research out of Krainc’s lab and in vitro modeling technology that tests compounds in patient-derived neurons, potentially offering an early sneak peek at the drug’s efficacy for human tests. The neurons are derived from induced pluripotent stem cells, which are in turn derived and converted from patients’ skin cells. It’s an approach that looks to fill in the gap left by inadequate animal modeling for neuroscience, where the chances of success in large indications like Alzheimer’s disease and Parkinson’s have left a slew of failures in its wake. According to Vanqua CSO Kevin Hunt, rodent models simply aren’t good predictors of in vivo human testing in neuroscience, and adding a stable preclinical research tool derived from potential patients could eventually help crack the code for a range of diseases with huge unmet clinical needs. CEO Jim Sullivan, a former VP of research at AbbVie who helped shepherd JAK inhibitor Rinvoq and blood cancer medicine Venclexta into the clinic, and has worked as a venture partner at OrbiMed since 2019, sees Vanqua’s platform as a best of all worlds strategy: combining cutting-edge genetics research and preclinical tools to develop effective molecules with a next-generation modeling approach to up the chances of success. “Our approach builds on breakthroughs in a couple different areas: one, genetics and pinpointing causes of neurodegenerative disease and two, much more enhanced preclinical models,” he said. “We’re really trying to overcome the limitations of neuroscience research for the last decade.” The team expects “meaningful” clinical data from its lead drug to be published within the next two years, Sullivan said. In GBA-PD, which may affect around 800,000 patients worldwide and 100,000 in the US, Vanqua is looking to pair genetic marker researchers pioneered in Krainc’s lab to partner with patient cells and established biology around the GBA1 pathway to tackle Gaucher. But in Alzheimer’s or ALS — or even Parkinson’s, in the case of GBA1 — the genetic correlation is less understood, leaving a big gap where a team like Vanqua could add to the scientific heavy lifting and potentially find a breakthrough along the way. The Vanqua team acknowledges that cracking the code on Alzheimer’s, for instance, despite the recent approval of Biogen’s Aduhelm, will require a great deal more work in understanding the genetic pathways and developing therapeutic modalities to target them. But that doesn’t mean they’re not ready to try. After the GCase lead drug, Vanqua has an undisclosed therapy in the preclinical stage that leverages the complement factor pathway to potentially modulate a range of neurodegenerative disorders. The research is still relatively new, but Sullivan said the program could eventually prove to be a game-changer in other large indications. It’s still early days, but Vanqua has all the trappings of an ambitious platform company and enough scientific cachet to pull in a notable investor syndicate. In addition to round leader Omega, the syndicate is joined by Series A investor OrbiMed and new investors Surveyor Capital, Avoro Ventures, Pontifax, Casdin Capital Management, Eli Lilly, Logos Capital and Osage University Partners. The biotech expects to use the proceeds to advance its two lead programs and add to its team of 15, potentially doubling in size in the coming years. Vanqua has headquarters in Chicago, near Krainc’s lab from which the team is shuttling researchers over to join the clinical effort. Sullivan highlighted the growing Chicago biotech hub as a major draw for Vanqua and a source of untapped potential for the neuroscience field writ large.

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.