Pharmaxis Ltd (ASX:PXS), a clinical-stage drug development company, has received positive results from data analysis of a phase 1c clinical trial (MF-101) studying its drug PXS-5505 in patients with the bone marrow cancer myelofibrosis.
This phase 1c trial was centred on dose escalation and involved giving patients with the bone marrow cancer myelofibrosis PXS’ LOX-inhibiting drug PXS-5505 for 28 days at three dosage levels.
Assessment with Pharmaxis’ proprietary assays of the highest dose has shown inhibition of the target enzymes, LOX and LOXL2, at greater than 90% over a 24-hour period at day 7 and day 28.
Myelofibrosis is an uncommon type of bone marrow cancer that disrupts the body’s normal production of blood cells. The disease can cause extensive scarring in bone marrow, leading to severe anaemia that can result in weakness and fatigue. The average survival rate is between five and seven years.
Lysyl oxidase (LOX) has been identified with independent, peer-reviewed research as a contributor to the progression of myelofibrosis and thus a potential novel therapeutic target for the treatment of myelofibrosis.
"Clear and positive findings"
PXS-5505 is an oral pan-LOX inhibitor designed to inhibit all lysyl oxidase family members with significant potential to reduce fibrosis in in-vivo models of kidney fibrosis, lung fibrosis, myelofibrosis and pancreatic cancer.
“We are very pleased to have completed the dose-escalation phase of this study with such clear and positive findings,” Pharmaxis CEO Gary Phillips said.
“We will now immediately progress to the phase 2 dose-expansion study where we aim to show PXS-5505 is safe to be taken longer-term with the disease-modifying effects that we have seen in the pre-clinical models. The trial infrastructure and funding is in place and we are on track to complete the study by the end of 2022.”
Exceeds disease modifying levels
The trial safety committee has reviewed the results and having found no safety signals, has cleared the study to progress to phase 2 dose expansion where 24 patients will be treated at the highest dose twice a day for six months.
The level of inhibition of LOX achieved in the current study at all three doses exceeds levels that caused disease modifying effects with PXS-5505 in pre-clinical models of myelofibrosis with improvements in blood cell count, diminished spleen size and reduced bone marrow fibrosis.
LOXL2 was inhibited to a similar degree and based on pre-clinical work such high inhibition is likely replicated for other LOX family members (LOXL1, 3 and 4).
PXS-5505 very well tolerated
Pharmaxis’ phase 1c/2a trial 'MF-101', cleared by the FDA under the Investigational New Drug scheme, intends to demonstrate that PXS-5505 – currently the lead asset in PXS’s drug discovery pipeline – is safe and effective as a monotherapy in myelofibrosis patients who are intolerant, unresponsive, or ineligible for treatment with approved JAK inhibitor drugs.
“Despite improvements in the treatment of myelofibrosis, the only curative therapy remains an allogeneic stem cell transplantation, a therapy that many patients are not eligible for due to its morbidity and mortality,” Dr Gabriela Hobbs, assistant professor of Medicine at Harvard Medical School and clinical director of Leukaemia at Massachusetts General Hospital, said.
“None of the drugs approved to date consistently or meaningfully alter the fibrosis that defines this disease. PXS-5505 has a novel mechanism of action by fully inhibiting all LOX enzymes.
“An attractive aspect of this drug is that so far in healthy controls and in this phase 1c study in myelofibrosis patients, the drug appears to be very well tolerated. This is meaningful as approved drugs and those that are undergoing study, are associated with abnormal low blood cell counts.
"Preliminary data thus far, demonstrate that PXS-5505 leads to a dramatic, over 90% inhibition of LOX and LOXL2 at one week and 28 days.
“This confirms what’s been shown in healthy controls as well as mouse models, that this drug can inhibit the LOX enzymes in patients. Inhibiting these enzymes is a novel approach to the treatment of myelofibrosis by preventing the deposition of fibrosis and ultimately reversing the fibrosis that characterizes this disease.”
Potential billion-dollar market
An effective pan-LOX inhibitor for myelofibrosis would open a market that is conservatively estimated at US$1 billion per annum. Trail sites will now open to recruit myelofibrosis patients into a six-month phase 2 study in Australia, South Korea, Taiwan and the US.
The drug also has potential in other fibrotic tissue cancers such as liver and pancreatic cancer, where it has potential to break down fibrotic tissue in the tumour and enhance the effect of chemotherapy.
Pharmaxis’ CEO Gary Phillips spoke to Proactive following the news they've been cleared to progress to a phase 2 dose-expansion phase:
