LOXL2 inhibitor combats fibrosis

NEW SOUTH WALES, Australia—Pharmaceutical company Pharmaxis announced positive results in mid-November from the Phase 1 clinical trial for the second of its lysyl oxidase-like 2 (LOXL2) inhibitor compounds, which are being developed to treat fibrotic diseases such as non‐alcoholic steatohepatitis (NASH) and idiopathic pulmonary fibrosis (IPF).

As Gary J. Phillips, CEO of Pharmaxis, tells DDNews, “The LOXL2 enzyme is involved in the cross-linking of collagen and elastin fibers in the body and increased levels found in organs such as the lungs, liver, kidney and heart are strongly associated with fibrotic disease. A LOXL2 inhibitor blocks the enzyme and stops cross-linking happening. The cross-linking of collagen and elastin driven by LOXL2 are the final stages in the fibrotic process that often starts with chronic inflammation that is driven by metabolic diseases such as diabetes.”

“There are a number of drugs in development to dampen the metabolic and inflammatory drivers of fibrosis, but there are very few effective options to treat fibrosis itself,” Phillips continues. “Many of these treatments may cause a slowing of disease progression, but many researchers believe that combining one or more of these approaches with a drug that tackles the fibrotic process directly will be necessary to effect a real improvement in treatment of diseases like NASH and IPF.”

The Pharmaxis LOXL2 program compounds are highly selective small-molecule inhibitors of LOXL2 that can be administered orally, and the company’s preclinical development program supports the potential of both compounds to treat fibrotic disease in one or more organs, Phillips says, adding: “Pharmaxis believes that it has a best-in-class program, with no other LOXL2 inhibitors under development that can produce 24-hour reduction in LOXL2 from a single daily dose.”

The double-blind, placebo-controlled study consisted of two stages; the first single ascending dose stage was conducted in 48 healthy subjects divided into six groups, with each taking a single dose ranging from 5 mg to 200 mg, or placebo. The second multiple ascending dose stage was conducted in 24 healthy subjects divided into three groups. Each received a single daily dose of either 50 mg, 100 mg, 200 mg or placebo for 14 days.

Repeating the positive results seen in the Phase 1 trial of the first inhibitor compound announced on Oct. 10, the reportedly excellent drug-like properties demonstrated in earlier preclinical testing were confirmed. There were no adverse safety findings, and the pharmacokinetic profile showed the expected dose-related increases in exposure.

“The targeted inhibition of greater than 80 percent of the LOXL2 enzyme has now been demonstrated in blood serum by both compounds for a full 24 hours from a single dose over a 14-day period. The second compound achieved more than 85-percent inhibition over 24 hours from a 100mg daily dose compared to the 400mg dose required to reach this level for the first compound,” notes Phillips. “Both compounds have met our objectives for safety and enzyme inhibition in the Phase 1 studies, but the different pharmacokinetic properties of the two compounds may also usefully lend themselves to application in different disease indications.”

“Several large pharma companies are interested in the Pharmaxis program, where both of our LOXL2 inhibitors have now successfully completed Phase 1 studies and demonstrated a best-in-class profile with 24-hour inhibition of the target enzyme from a single daily dose,” Phillips says. “In a further significant scientific advancement, we have also managed to underline the relevance of the program to potential partners by using our proprietary research tools to confirm that our compounds directly inhibit the activity of the raised levels of LOXL2 seen in diseased tissue from NASH and IPF animal models.

“The compounds are undergoing three-month toxicity studies which are due to report in the current quarter. Pharmaxis is working on a partner licensing deal for this asset and a number of companies are reviewing our scientific data package. Following the completion of the data package, Pharmaxis intends to conduct a final series of scientific briefings to potential partners before moving to commercial partnering discussions to secure a comprehensive licensing agreement in 2019.”

Arix Bioscience, a global healthcare and life-sciences company supporting medical innovation, was pleased to note the positive results from the Phase 1 clinical trial. Arix Bioscience led the A$24 million (about $17.7 million in U.S. dollars) financing for Pharmaxis in August, acquiring an 11.1-percent equity stake. Arix’s Ed Rayner also joined the Pharmaxis board of directors in September 2018.

Pharmaxis hosted an investor research briefing on Nov. 20, providing an overview of the Pharmaxis drug discovery pipeline, including: an anti-inflammatory drug currently being developed with Boehringer Ingelheim; work in collaboration with the Garvan Institute of Medical Research on an antifibrotic LOX inhibitor targeting pancreatic cancer; and an antifibrotic LOXL2 inhibitor program currently completing Phase 1 trials and extended toxicity studies.

“Pharmaxis is also developing other compounds to inhibit all lysyl oxidase family members (LOX, LOXL1, 2, 3 and 4) and is making good progress in this area, which will focus initially on pancreatic cancer,” mentions Phillips. According to a news release also from Nov. 20, Pharmaxis has completed the preclinical package on its antifibrotic lysyl oxidase program focused on pancreatic cancer and filed an ethics submission to enable a Phase 1 clinical trial in healthy volunteers. The trial is planned to commence in the first quarter of 2019.

Pharmaxis is collaborating with the Garvan Institute of Medical Research to investigate the therapeutic potential of LOX inhibition in pancreatic cancer. Researchers at the Institute have evidence in mouse models that inhibition of the LOX family alters the tumor microenvironment, rendering tumors more susceptible to existing therapies. The team has also generated positive results in in-vitro and in-vivo models of pancreatic cancer using the Pharmaxis LOX inhibitor. The Garvan Institute’s research on the role of LOX enzymes in pancreatic cancer and the potential of Pharmaxis compounds in this disease will be the subject of presentations at upcoming international scientific symposia in 2019.