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LOXL2 Program Targets Fibrosis of Liver, Lung, Kidney and Heart

The LOXL2 enzyme is fundamental to the fibrotic cascade that follows chronic inflammation in the liver disease NASH, cardiac fibrosis, kidney fibrosis, and idiopathic pulmonary fibrosis (IPF), and it also plays a role in some cancers.

The Pharmaxis drug discovery group has developed two selective small molecule inhibitors to the LOXL2 enzyme from its amine oxidase chemistry platform. Extensive pre‐clinical showed the compounds displayed all the characteristics of a successful oral drug showing excellent efficacy in several different in vivo fibrosis models including fibrosis of the liver, lung, kidney and heart. Over the course of 2019 Pharmaxis scientists and collaborators demonstrated the link between LOXL2 inhibition in diseased organs, a reduction in collagen crosslinking in fibrotic tissue and clinical effect as measured by the area of fibrosis. The LOXL2 inhibitors have subsequently completed 3 month toxicology studies.

In phase 1 studies completed in 2019, doses of the drugs that resulted in 85% or greater inhibition over 24 hours of the target enzyme were significantly below the Human Equivalent No Observed Adverse Effect Level doses in all toxicity studies, demonstrating an adequate safety margin to start phase 2 studies of at least 3 months in length. Further progressing the program in the first quarter of 2020, Pharmaxis completed a small phase 1 study that demonstrated an improved pharmacokinetic profile in a number of different dosing regimens.

Pharmaxis is currently pursuing a number of different partnering options to enable the drug to enter the clinic in phase 2 trials. While the process has taken longer than originally expected, and much of the industry focus has been on the Covid-19 pandemic, the Company continues to have discussions with a number of potential partners. Pharmaxis will provide more information when the process concludes.

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Pharmaxis Targets Myelofibrosis in New Clinical Trial

Pharmaxis is advancing a Phase 2 clinical trial of a new drug (PXS5505A) targeting the rare bone cancer myelofibrosis (MF).

This follows positive results for the anti‐fibrotic Lysyl Oxidase (LOX) inhibitor in phase 1b and long-term toxicity studies. The multiple ascending dose stage of Phase 1 trial demonstrated a well-tolerated drug that effectively inhibits all enzymes in the lysyl oxidase family that are involved in fibrosis.

Pharmaxis CEO Gary Phillips: “With the successful completion of the phase 1b study, 6-month toxicity studies, support from clinical key opinion leaders and preliminary regulatory feedback, Pharmaxis is moving confidently into a 6-month phase 2 study in myelofibrosis with meaningful clinical efficacy and safety endpoints.

“Myelofibrosis is a cancer with a poor prognosis and limited therapeutic options. Pharmaxis believes that the current treatments can be augmented by use of a pan-LOX inhibitor and be disease modifying in a market that is conservatively worth US$1 billion per annum.”

PXS-5505 has been granted Orphan Drug Designation by the US Food and Drug Administration. Read the media release.

In August 2020 the US Food and Drug Administration (FDA) completed a safety review of the company’s Investigational New Drug (IND) application for the pan-LOX inhibitor PXS-5505 and gave Pharmaxis permission to proceed with a phase 1/2 clinical trial for the treatment of myelofibrosis in adults.  The clinical trial protocol incorporates a one-month dose escalation phase followed by six months’ treatment in an open label study of patients who are not on a JAK inhibitor. The company is well advanced in its preparations to start this study including production of the drug product, assigning a contract research organisation to manage the study and completing feasibility in a number of countries. We can therefore progress to initiate patient recruitment in Q4 2020 and respond as needed to the rapidly changing availability of trial sites caused by Covid-19 outbreaks. The study is expected to conclude in 2022. Read the media release.

Gary Phillips CEO Pharmaxis

Recent News

Boehringer Ingelheim Discontinues Development of BI 1467335 for Diabetic Retinopathy

Pharmaxis CEO, Gary Phillips: “We understand Boehringer Ingelheim’s decision to stop development of BI 1467335 in NPDR based on the risk of dose dependent drug interactions at the dose level that was tested in the Phase IIa trial. Based on recent publications AOC3 remains an important clinical target. We will review the data collected in more detail to evaluate potential opportunities in other indications that already have supportive pre-clinical data and where the risk of drug interactions are of less concern. In the meantime, we look forward to the upcoming FDA decision on granting a marketing authorisation for Bronchitol in the US cystic fibrosis market and our focus remains on advancing our anti-cancer pan-LOX inhibitor program into a phase 2 myelofibrosis study following the recent IND approval.”

Read the media release

Pharmaxis Awarded $1m Australian Government Funding to Progress Duchenne Muscular Dystrophy Drug into the Clinic

Pharmaxis CEO, Mr Gary Phillips: “Over recent years Pharmaxis investment in drug discovery has progressed three pipeline drugs through pre-clinical testing to the commencement of human clinical trials and beyond.  Non-dilutive funding sources, such as this one provided by the Australian Government’s BTB grant program, will allow us to similarly progress PXS-4699 in an orphan disease with high unmet need whilst not detracting from the focused investments we are making in a myelofibrosis treatment and as we await the upcoming FDA decision to grant a marketing authorisation of our cystic fibrosis treatment for patients in the United States.” 

Read the media release