Complement Therapeutics closes $79M A round for gene therapy in geographic atrophy 

The company is now legally headquartered in Munich, a function of its European investor syndicate, but it is a creation of the U.K. innovation ecosystem. Complement Therapeutics (CTx) was spun out of the University of Manchester to take forward research on the complement system conducted by its founders Simon Clark, Paul Bishop, and Richard Unwin. It closed a €5 million seed round over two years ago. It currently operates from London, but it is setting up laboratories in Stevenage, while it also has a foothold in the U.S., where its chief science officer is located.

There is a wealth of genetic evidence linking many – but not all – cases of dry AMD and its most advanced stage, geographic atrophy, to dysregulation of the complement system. Multiple programs that seek to latch onto this aspect of the disease biology are in the pipeline. “It’s a very, very active space,” CEO Rafiq Hasan told BioWorld. “There’s now a lot of excitement around geographic atrophy.

That wasn’t always the case. For long the area has been the poor relation of wet AMD, which has been a significant market for antibody developers for almost two decades. Vascular endothelial growth factor (VEGF) inhibitors and human epidermal growth factor receptor 2 (Her2) inhibitors have been therapeutic mainstays. More recently, a bispecific inhibitor of VEGF-A and angiopoietin 2 gained approval.

There was no approved therapy for wet AMD or geographic atrophy until February, when Waltham, Mass.-based Apellis Pharmaceuticals Inc., gained U.S. FDA approval with Syfovre (pegcetocoplan), a synthetic cyclic peptide which inhibits complement C3 cleavage. The medical need is substantial, given the high prevalence of the condition. So, too, is the opportunity for successful therapies. “In terms of market potential, this is on a par with the likes of Eylea and Lucentis,” Hasan said.

CTx is taking a novel route to dampening excessive complement activity with its lead program, CTx-001. It comprises an adeno-associated virus (AAV) vector expressing a substantially truncated but biologically active form of complement receptor 1 (CR1; also called CD35 or C3b/C4b receptor), a large protein that down regulates complement activation through both the classical and alternative pathways.

The company has a development candidate in place and is currently commencing manufacturing activities. Preclinical toxicity studies will follow later this year, and the company aims to start a phase Ib trial in patients toward the back end of next year.

A natural history study in patients with geographic atrophy is ongoing, and eligible participants – those with evidence of excessive complement activity – will be invited to enroll in the clinical study.

CTx can, with a mass-spectrometry-based analytical method developed by its founders, quantify the levels of over 30 different complement proteins from a single blood draw. The company is using this capability to evaluate potential biomarkers that may help in identifying potential responders. “Wet AMD is fairly homogeneous,” Hasan said. “Geographic atrophy is more multifactorial, so patient selection is really important.”

It is operating in a highly competitive space. Syfovre has set an initial benchmark for other developers. Across two phase III trials in geographic atrophy, it slowed annual growth of lesions, as compared with placebo, by 12% to 26%, depending on the dose schedule employed. There is likely to be room for improvement. “It’s not really knocking it out of the park,” Hasan said.

What’s more, it requires monthly intravitreal injections. “My own experience has taught me this is very challenging for elderly patients,” said Hasan, who previously held senior commercial roles in ophthalmology with both Basel, Switzerland-based Novartis AG and Leverkusen, Germany-based Bayer AG. As a ‘one-and-done’ gene therapy, CTx-001 will act as a ‘biofactory’, and its gene product will not be confined to the area of the eye to which it is administered.

Several other clinical-stage programs are ahead of it, however. Iveric Bio Inc., of Parsippany, N.J., is developing Zimura (avacincaptad pegol), a pegylated RNA aptamer that inhibits complement C5. It is undergoing priority review at the FDA and has an Aug. 19 PDUFA date. Allegro Ophthalmics LLC, of San Juan Capistrano, Calif., recently disclosed it has received Special Protocol Assistance from the FDA for the design of a phase IIb/III trial in intermediate AMD of risuteganib, a peptide inhibitor of several integrins associated with ocular disease. Lineage Cell Therapeutics Inc., of Carlsbad, Calif., and the Genentech arm of Roche Holding AG, of Basel, Switzerland, are collaborating on a retinal pigment epithelial cell therapy, Opregen, which is in a phase IIa trial.

Johnson & Johnson Co., of New Brunswick, N.J., has completed a phase I study of JNJ-81201887 (formerly AAVCAGsCD59), an AAV-based gene therapy that boosts expression of a soluble form of CD59, a protein that prevents formation of the complement membrane attack complex. It has recently opened recruitment into a phase IIb study, which has a recruitment target of 300 patients. It acquired rights to the program from Waltham, Mass.-based Hemera Biosciences LLC several years ago.

Gimv led CTx’s series A round. Seed investor Forbion participated as co-lead. Other participants included another seed investor, Biogeneration Ventures, as well as Panakès Partners, Cambridge Innovation Capital, Hadean Ventures and Seroba Life Sciences.