XORTX Pharma Corp. spent four years quietly assembling the patent estate behind XRx-008, a formulation of oxypurinol aimed at the treatment of rare autosomal dominant polycystic kidney disease (ADPKD), before completing a reverse merger in January to become XORTX Therapeutics Inc. The lead program, now in pre-IND, is positioned to move directly into phase II in expectation of a 505(b)(2) filing, with a mechanism targeting the "disease axis" among obesity, blood pressure and insulin resistance, explained Allen Davidoff, president and CEO of the Calgary, Alberta-based firm.

The symptoms that characterize metabolic syndrome often lead consecutively to prediabetes, diabetes and complications of diabetes. The common thread running through them, Davidoff said, is abnormal levels of uric acid.

XRx-008 is a new formulation of the xanthine oxidase inhibitor that was in development in the 1990s by Ilex Oncology Inc. for the treatment of gout. As that company was moving to pivotal trials, Cardiome Pharma Corp. (now Correvio Pharma Corp.), exercised an option to acquire from Ilex rights to the phase II data, which Cardiome intended to apply to its oxypurinol candidate to treat congestive heart disease. That candidate missed the primary and secondary endpoints in a phase II trial, however. Ilex went to then-independent Genzyme Corp. in a billion-dollar deal, Cardiome moved on to other assets and oxypurinol was put on a shelf. (See BioWorld Today, March 1, 2004, and Aug. 16, 2005.)

Davidoff, who served as senior scientist and head of pharmacology at Cardiome, saw an opportunity for the asset, which had an existing package of safety and early proof-of-concept data, not in the broad categories targeted by previous companies but in ADPKD. He founded XORTX in 2013 and began to assemble the intellectual property (IP) package.

A year ago, investor groups in Vancouver, British Columbia, expressed interest in "trying to take a next step" to move XORTX into the public markets, Davidoff said. That goal was accomplished with the reverse merger with Apac Resources Inc., in conjunction with a financing that raised C$2 million (US$1.6 million) in cash and a listing on the Canadian Securities Exchange as XRX.

The fundraising opened the door for XORTX – an acronym for xanthine oxidase reducing technologies – to begin regulatory preparations, including orphan drug and the pre-IND application, both under review by the FDA.

"Those were driven, in part, because we have had outreach from a number of companies around the globe interested in that program, once we've gotten through the phase II clinical trial and produced the results that are already hinted at in some of the pilot trials that have been done to date," Davidoff told BioWorld.

The approach to reposition oxypurinol in ADPKD is "based on a number of phase II clinical trial successes," he added. Though the asset never reached the market, it was previously advanced to an NDA filing in 2004 that resulted in an approvable letter.

"We know the drug is safe and effective, and ideal for repositioning in an orphan program like autosomal dominant polycystic kidney disease," Davidoff said.

XORTX candidate could leapfrog others in pipeline assets

ADPKD is a prevalent monogenic human disorder and the most common inherited cystic kidney disease. More than half of individuals with ADPKD eventually develop end-stage kidney disease. Earlier this year, following an initial rejection in 2013, Jynarque (tolvaptan) from Otsuka Pharmaceutical Co. Ltd. became the first therapy approved by the FDA to slow kidney function decline in individuals with ADPKD, following previous approvals in Japan and Europe. Due to liver injury risks, however, the drug is available only through a restricted distribution program and bears a REMS program requiring patient monitoring for elevations in certain liver enzyme levels. (See BioWorld, April 26, 2018.)

The slim pipeline of clinical assets is topped by bardoxolone methyl from Reata Pharmaceuticals Inc. and partner Kyowa Hakko Kirin Co. Ltd., according to Cortellis Competitive Intelligence. In May, positive interim data from the ADPKD and IgA nephropathy cohorts of the ongoing open-label phase II PHOENIX trial were presented at the European Renal Association and European Dialysis and Transplant Association meeting in Copenhagen. The data showed that bardoxolone improved kidney function in ADPKD patients as measured by their estimated glomerular filtration rate (eGFR), with treated patients showing a mean improvement of 6.6 mL/min/1.73 m2 at week four (n=31; p<0.0001) and increasing to 12 mL/min/1.73 m2 at week 12 (n=8; p<0.0001), compared to mean baseline eGFR of 47.7 mL/min/1.73 m2.

Other phase II efforts include tesevatinib, an oral, reversible inhibitor of epidermal growth factor receptor, from Kadmon Holdings Inc.; and venglustat, a glucosylceramide synthase inhibitor that Sanofi Genzyme is looking to move into phase III this year.

With a 505(b)(2) filing, XRx-008 could potentially leapfrog some of those, and earlier-stage, assets. Brian Mangal, director of business and product development at XORTX, fully understands positioning of the drug candidate; he previously served as director of biostatistics for Cardiome.

The "small and virtual" company plans to conduct the phase II trial in the U.S. and is gearing up for a limited staff expansion in chemistry and manufacturing as well as its clinical trials group.

"We're taking the steps to grow as quickly as possible while positioning the company to grow in a de-risked fashion," Davidoff said.

For the time being, XORTX doesn't expect to seek an additional financing. Davidoff said the January raise was sufficient to see the company through a number of steps that could lead to "key announcements" that could trigger additional cash infusions.

Beyond XRx-008, which XORTX will seek to out-license following a successful phase II program, the company has XRx-221, a small molecule targeting diabetic nephropathy. Nevertheless, the company is in discussions with a number of companies for potential in-licensing of a molecule that might have a superior profile and IP package, Davidoff said.

"We're moving to find a co-development deal that would make sense for the company," using the standard development pathway for a new chemical entity, he explained.

Long term, the company could seek to move additional assets through phase III on its own, Davidoff added.

As the company's name implies, "our focus is on progressive kidney disease and on diabetes treatments, because we think there are a number of opportunities there that are directly influenced by uric acid metabolism that's outside the normal range," he said.

On Monday, the company's shares (XRX.CN) gained C3.5 cents to close at C23.5 cents.