BARCELONA, Spain – What may well be Europe's least known cell therapy company has just begun a phase III trial of its lead program in a notoriously challenging indication. Rexgenero Ltd. began recruiting diabetic patients with critical limb ischemia (CLI) last week, CEO Joe Dupere told BioWorld Today. He expects the first patient to receive treatment by the end of this month.
In all, the trial will recruit 150 patients across 35 centers in nine European countries. Participants will be randomized, in a 4:1 ratio, to receive either REX-001 (Rexmyelocel-T), Rexgenero's autologous, bone-marrow-derived cell therapy, or standard of care.
"We think we can recruit in nine to 12 months in Europe," Dupere said. With a one-year follow-up, that puts the company on track to file for European approval by the end of 2018. It aims to add further centers in the U.S. once it receives IND clearance and special protocol agreement from the FDA.
Crucially, the company has already obtained agreement from the EMA to employ new endpoints. Instead of measuring amputation-free survival, an efficacy threshold no developer has yet managed to clear, the company will evaluate the ability of REX-001 to resolve completely resting pain and to heal ischemic ulcers, two of the major complications of CLI.
The EMA has indicated that the therapy would be approvable on the basis of a single pivotal trial that hit these two endpoints, Dupere said.
"You really need a strong signal in amputation-free survival – otherwise it just falls over," he said. The condition, which arises from peripheral arterial disease, is characterized by arterial obstruction in the extremities, which leads to severe constant pain, ulcers and gangrene. About 25 percent to 30 percent of CLI patients undergo amputation or die each year, but medical and cultural attitudes to amputation vary in different regions, which can be another confounding factor in clinical trials.
Endpoints alone are not the cause of so many failures in CLI, however. Dupere identified several issues with previous attempts. The composition of the therapy, the dose level employed and the route of administration are all significant factors. Intravenous dosing or direct injection of cells into either leg muscle or into ischemic ulcers can result in a significant dilutive effect, as the cells are unable to traffic in sufficient numbers to areas where they can promote revascularization.
"It needs a real kick to get it going," he said. Rexgenero is employing a catheter to enable intra-arterial delivery of the cells to the lower leg – which offers a 10-fold dose improvement over administration directly into the femoral artery, Dupere said. Moreover, the company is administering a dose of about 1 billion cells, whereas most other approaches involve about 100 million, he said. The bone marrow fraction it administers contains endothelial progenitor cells, endothelial cells as well as growth factors that help to promote blood vessel growth.
Rexgenero has purposely maintained a relatively low-profile until now, but it set out its stall at BIO-Europe Spring this week, befitting the Andalusian origins of its stem cell technology. Although formally headquartered in London, its main operational base is in Seville. Rexgenero has negotiated an exclusive option license agreement with Andalusia's innovation, economic, and health ministries covering the region's combined effort in cell and gene therapies and tissue engineering. This extends to over 20 programs in all, Dupere said.
REX-001 has a 10-year clinical history, originally as an in-hospital procedure. Rexgenero was formed to translate this into a pharma-standard therapy – an advanced therapy medical product in European parlance. It has received backing from two family offices, one each in Spain and the U.K. It has completed open-label phase II studies in both diabetic and non-diabetic CLI patients. In patients who are classified at stage 4 on the 6-point Rutherford classification scale – meaning they have severe pain but no ulceration – the therapy has a response rate of about 80 percent. In those at stage 5, who have ulceration as well, the response rate is about 75 percent, Dupere said. Response rates of 60 percent and 55 percent in these two respective categories would allow the phase III trial to achieve statistical significance, he said. "This is not an area where you get a big placebo response. Blood vessels do not resolve just because you're in a clinical trial."
Rexgenero has some company in phase III in CLI, including Pluristem Therapeutics Inc., of Haifa, Israel, which is developing placenta-derived cells, and Emeryville, Calif.-based Mercator Medsystems Inc., which is employing the Bullfrog micro-infusion device for arterial delivery of the anti-inflammatory drug dexamethasone.
Notable late-stage clinical trial casualties include Ann Arbor, Mich.-based Aastrom Biosciences Inc., which had developed an autologous cell therapy, and Paris-based Sanofi SA and San Diego-based Vical Inc., which had tested a gene therapy treatment, Temusi (riferminogene pecaplasmid), based on the expression of fibroblast growth factor. Another Vical partner, Anges MD, of Osaka, Japan, has terminated a phase III trial of AMG0001, a plasmid encoding hepatocyte growth factor. Slow recruitment was pushing up both costs and anticipated timelines – some time ago it disclosed plans to revamp its development strategy in order to reduce both.
Rexgenero also plans to conduct a phase III trial of REX-001 in non-diabetic CLI patients. Even if its clinical development strategy does not require as many patients as rival developers have recruited, the studies do not come cheap, and it is seeking additional external investment. Its EMA agreement on a novel set of endpoints could be an enticing proposition for some.
The conference closed Wednesday.