PERTH, Australia – With the approval of cystic fibrosis treatment Bronchitol (mannitol), Sydney-based Pharmaxis Ltd. joins a small group of elite Australian biotech companies to take their drugs all the way to FDA approval.

The Oct. 30 approval came two days before the Nov. 1 PDUFA date. The FDA approved the drug as an add‐on maintenance therapy to improve pulmonary function in cystic fibrosis (CF) patients 18 years of age and older.

Bronchitol is a spray-dried form of mannitol, delivered to the lungs by a portable inhaler. Bronchitol works by rehydrating the airway/lung surface and promoting a productive cough.

The FDA approval is a transformational step for Pharmaxis, said Pharmaxis CEO Gary Phillips. “We’re very pleased that Bronchitol, an Australian drug discovery, will now be available for patients in the U.S.A. FDA approval is a testament to the capability of our team, [which] conducted the three large‐scale phase III trials that established Bronchitol’s safety and efficacy.”

The approval is based on three phase III trials in 1,020 patients with cystic fibrosis that were completed in 2017. The primary efficacy endpoint in all three studies was improvement in lung function over 26 weeks of treatment.

Bronchitol received an FDA complete response letter in June 2019, which requested a human factor study and revised product packaging and user instructions. The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 9-16 in favor of recommending the drug for approval.

“The NDA was a huge body of work, and we built a lot of in-house experience,” Phillips said during an Oct. 26 conference call with Investment fund Horizon 3 Biotech. He advised Australian biotechs to hire outside help to prepare for FDA advisory committee meetings.

“Don’t underestimate the amount of work to submit an application to the FDA,” he said. “The FDA is a huge organization, and with the amount of submissions they get, they work to a very strict timeline. It’s not the FDA that bends, it’s you that has to bend,” he said.

Bronchitol is manufactured in Pharmaxis’ facility in Sydney and will be distributed in the U.S. by Chiesi Farmaceutici SpA.

Bronchitol is Pharmaxis’ second FDA-approved product from its mannitol platform. Its first FDA approval was for Aridol, a lung function test designed to help doctors diagnose and manage asthma by detecting active airway inflammation through measuring airway hyper‐responsiveness. Aridol is also approved in Europe, Australia and certain Asian countries.

FDA approval clears path for myelofibrosis candidate

The Bronchitol approval puts Pharmaxis in good stead with its partner Chiesi USA, triggering $7 million in development and commercialization milestone payments for Pharmaxis. An additional $3 million is payable when the product launches.

Those milestone payments will bankroll the company to take its PXS‐5505 drug candidate, aimed at myelofibrosis in adults, through its planned phase I/II trials. The aim is to make Pharmaxis a global leader in myelofibrosis, and flowing from that, to develop PXS‐5505’s potential in several other cancers, including liver and pancreatic cancers.

“With the two mannitol products in the marketplace and generating revenue, we can shift the focus to our pipeline of small‐molecule drugs for big diseases. It’s already enabling us to put the most promising of those, PXS‐5505 into phase I/II trials,” Phillips said.

PXS‐5505 inhibits all the lysyl oxidase (LOX) family of enzymes, which play a crucial role in the development of severe fibrosis, as well as cancers to which fibrosis contributes. The drug is being targeted for first-line treatment of myelofibrosis, a rare cancer in which normal bone marrow tissue is gradually replaced with a fibrous scar‐like material. Over time, this leads to progressive bone marrow failure preventing the production of adequate numbers of red cells, white cells and platelets.

Because there is no effective treatment, the FDA granted Pharmaxis orphan drug designation for PXS‐5505 for myelofibrosis.

“All the building blocks are in place now for the phase II trial, and we expect to start recruiting for the study in the first quarter of 2021, and conclude it by the end of 2022,” Phillips said, adding that the development of the drug has been quite fast after just two years.

The phase I study was conducted in Australia, and the phase II study is powered to show safety and efficacy.

“The aim is to show that our drug is disease‐modifying and will make a real difference to patients with myelofibrosis. That is an attractive market, at more than $1 billion a year.

“While our primary focus is the development of PXS‐5505 for myelofibrosis, the drug also has potential in several other cancers including liver and pancreatic cancers, where it aims to breakdown the fibrotic tissue in the tumor and enhance the effect of existing chemotherapy,” Phillips said.

“With the milestone payments that we will get from Chiesi, plus the existing cash in the company, plus ongoing sales revenue from Bronchitol and Aridol, our funding situation for PXS‐5505 is assured,” said Phillips.

“Our long-term supply contracts with Bronchitol and Aridol distribution partners minimizes our exposure to the commercial risks and secures a steady revenue stream. The focus for investors becomes PXS‐5505 and the rest of our anti‐fibrotic LOX program.

Boehringer Ingelheim discontinued development of BI-1467335 in December 2019 for the treatment of nonalcoholic steatohepatitis (NASH) that it acquired from Pharmaxis in 2015. The announcement was a major blow to Pharmaxis, which was counting on nearly AU$600 million (US$411 million) in future milestone payments from the deal.

BI announced in September that it was also discontinuing development of the same drug for diabetic retinopathy due to the lack of a clear efficacy signal. Pharmaxis said it will look at the data to plan its next steps.

Pharmaxis stock on the Australian Securities Exchange (ASX:PXS) jumped 25% on the approval news, with its shares trading at AU11 cents (US7 cents) at market close Nov. 2.