LONDON – Redx Pharma plc is in the process of handing its RXC-006 program over to Astrazeneca plc, after signing a potential $377 million development and commercialization deal for the porcupine inhibitor in the treatment of fibrotic disease.
For starters, Redx will get several milestones worth $17 million, up to the start of phase I, with Astrazeneca initially targeting idiopathic pulmonary fibrosis (IPF). A large body of preclinical work is completed and IND-enabling studies are underway, so those milestones should be triggered quite quickly, with RXC-006 expected to enter the clinic in 2021.
The remaining $360 million will come in development, regulatory and commercial milestones leading to approval, with Redx in line for mid-single-digit royalties on sales of a marketed product.
“It’s a typical structure, as with biotech and pharma agreements,” said Redx CEO Lisa Anson. “It’s an important deal for us, [and] it’s exciting to make sure the molecule is taken forward in IPF because of the patient need,” she told BioWorld.
RXC-006 aims to prevent the aberrant activation of Wnt signaling, which drives several processes contributing to fibrosis, through blocking porcupine, a key enzyme in the pathway.
Inhibition of Wnt has been shown to suppress inflammation, reduce apoptosis, block the epithelial mesenchymal transition and inhibit fibroblast activation.
Redx has demonstrated RXC-006 can achieve those effects, potently inhibiting Wnt, and resulting in antifibrotic effects in in vivo models and human lung fibroblasts. The molecule works in a dose-dependent manner, suppressing pro-fibrotic gene expression and collagen deposition.
“We feel, and Astrazeneca obviously feels, it is an exciting, potentially novel way to target fibrosis,” Anson said. “There are a number of drugs in development [for fibrosis], but not much in the way of treatment.”
Wnt is a complex, multifaceted pathway, with feedback loops and diversions that bypass drug effects. At the same time, the pathway has multiple roles, meaning drugs may have the intended effect but interfere with other processes.
From that perspective, the Astrazeneca deal is a flattering validation of Redx’s medicinal chemistry skills. While Wnt signaling has always been interesting, Anson said, the question was how to drug it. “Wnt is an area of deep expertise for us. [We have] understanding of the pathway and what you need to do to hit the therapeutic window.”
RXC-006 is being lined up for treating IPF, but it also has been shown to be effective in liver fibrosis and diabetic nephropathy in preclinical research. Astrazeneca may expand into those areas, said Anson. “We will have to see where it goes.”
Redx was founded in 2007 around technology that originated in Astrazeneca’s labs. In that sense, licensing a program to the pharma company brings things full circle. But it is also a turning point, in being the first deal since Redx was rescued by Redmile Group LLC and Sofinnova Partners, which between them invested $33.6 million, in March this year.
That ended more than two years of uncertainty, after Alderley Park, U.K.-based Redx was forced into bankruptcy in November 2017.
Work on RXC-006 was held back during that time, due to the funding constraints and the need to focus elsewhere. To now be out-licensing the program is an important juncture, said Anson. “We’ve restructured and relaunched since 2017, and the [AZ deal] shows the progression of the strategy,” she said.
Getting back on track
After closing the RXC-006 deal, Redx is working on advancing another fibrosis program, RXC-007, which it selected as the next in-house project in January this year. The compound is a selective Rho-associated coiled-coil containing protein kinase 2 (ROCK 2) inhibitor.
ROCK 2 is involved in regulating cell morphology, growth, migration and apoptosis. Redx has preclinical data showing RXC-007 has antifibrotic effects in animal models of liver and lung fibrosis. Anson said the compound will enter the clinic in 2021.
Also next year, Redx hopes to start a phase II trial of its lead program, RXC-004, another porcupine inhibitor. That compound has broad-spectrum effects on Wnt, preventing secretion of all 19 Wnt proteins and stopping all signaling through the pathway.
The compound is being tested in a third phase I dose-escalation cohort in advance solid tumors, but has been held up because of the COVID-19-enforced suspension of clinical trials.
“We managed to be operational and carry on with business development and research, but the biggest challenge has been to get cancer patients into the phase I. The big U.K. centers had to stop recruiting,” Anson said.
Things are getting back on track and pending the results, Anson said she is hopeful of getting the phase II off the ground in 2021. Here the company will recruit patients with either colorectal cancer or pancreatic tumors that carry a high level of mutations showing they are Wnt-dependent.
In addition to showing effectiveness as a monotherapy through direct tumor targeting, Redx intends to develop RXC-004 as an immune modulator for use in combination with checkpoint inhibitors.