Pharmaxis’ LOXL2 Inhibitor Shows Positive Results in Phase 1 Trial in Healthy Volunteers

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by Patricia Inácio, PhD |

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LOXL2 inhibitor

Pharmaxis’ first small molecule inhibitor of LOXL2 (lysyl oxidase like 2), an enzyme that promotes fibrosis in the lungs of idiopathic pulmonary fibrosis (IPF) patients, was found safe and well-tolerated in healthy volunteers participating in a Phase 1 trial, the company announced.

Additionally, treatment with the LOXL2 inhibitor, called PXS-5338K, either in single or multiple oral dosing, resulted in a robust inhibition — by more than 80 percent — of LOXL2.

LOXL2 belongs to a family of proteins important to the extracellular matrix, a non-cell component that provides structural and biochemical support to tissues and organs. The protein was found to play a key role in the development of IPF by helping to promote lung tissue scarring.

Australia-based pharmaceutical company Pharmaxis has been developing highly selective small molecule inhibitors of LOXL2 that can be taken orally to treat fibrotic diseases, such as pulmonary fibrosis.

In this randomized, double-blind, placebo-controlled, dose-escalating Phase 1 trial (ACTRN12617001444370), the company tested oral PXS-5338K in healthy volunteers. The study was divided into two parts: a single ascending dose stage and a multiple ascending dose stage.

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In the single-dose stage, 48 participants, divided into six groups, received a placebo or single ascending doses of PXS-5338K, ranging from 10-400 mg. In the following multiple ascending dose stage, 24 volunteers were enrolled and divided into three groups, each receiving a single daily dose of PXS-5338K — from 100-400 mg — or a placebo for 14 days.

The study primary’s objective was to assess the safety and tolerability of single and repeated ascending oral doses of PXS-5338K.

As previously shown in preclinical studies, PXS-5338K showed no adverse effects in either the single or multiple treatment doses. Moreover, researchers observed that PXS-5338K led to a significant inhibition of LOXL2 — single doses kept LOXL2 inhibited for 24 hours, and the daily 400 mg dose over 14 days inhibited LOXL2 by more than 80 percent.

“I’m delighted that the excellent pharmacokinetic parameters and the significant and long lasting inhibition of the target LOXL2 enzyme demonstrated in the single dose stage of the study earlier this year completely translated into the profile we have seen in the multiple dosing study,” Gary Phillips, Pharmaxis’ CEO, said in a press release.

“This drug profile has led to increased interest from major pharmaceutical companies looking for good anti fibrotic programs to acquire. Today’s announcement that enzyme inhibition is further enhanced after daily dosing over 14 days goes a long way to completing the data package on which we will base continuing scientific and commercial discussions with potential partners during the current quarter,” he added.

Pharmaxis is also conducting another Phase 1 trial testing a second LOXL2 inhibitor, PXS-5382A, and results are expected by the end of 2018.

The company will be looking for partners to further develop its LOXL2 program after completion of these Phase 1 trials.

“We believe that the best in class LOXL2 inhibition and the availability of two compounds with differentiated pharmacokinetic profiles make this program very attractive and we look forward to concluding a licensing deal with a partner committed to develop the compounds in indications where there remain a lack of treatment options and significant commercial opportunities,” Phillips concluded.

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