LONDON – Convert Pharmaceuticals SA has raised €13.6 million (US$16.9 million) in a first funding round, to take a fresh attempt at developing a hypoxia-activated prodrug (HAP) for treating solid tumors.

The Liege, Belgium-based company said it has built on past experience to optimize the clinical structure of its lead product, CP-506, fine-tuning the activity and specificity, and improving safety in comparison to older HAPs.

In parallel, Convert is developing biomarkers that will enable it to select likely responders and side step toxic side effects that have contributed to previous failures, including two HAPs that completed phase III trials.

CP-506 is a new chemical entity that has been designed to avoid off-target effects seen with earlier HAPs, said Janwillem Naesens, acting CEO of Convert and managing partner of the company's lead VC investor, Droia Oncology Ventures.

In addition to a hypoxic environment, the prodrug requires the presence of specific reductase enzymes, meaning it is not activated in other low-oxygen tissues, such as bone marrow. The aim is to avoid dose-limiting toxicities that have undermined previous HAPs, most notably Threshold Pharmaceuticals Inc.'s evofosfamide (TH-302). The prodrug failed in two phase III trials in pancreatic cancer and soft tissue sarcoma at the end of 2015. (See BioWorld Today, Dec. 8, 2015.)

"We went to speak to people involved in the Threshold trial," Naesens said. "They said the compound worked but it was too toxic, so they had to lower the dose," he told BioWorld.

In addition to designing in greater selectivity and specificity, Convert finds itself in a position to take advantage of greater knowledge of the tumor microenvironment. "Hypoxia turns out to be a very dynamic aspect of tumor development; it comes and goes and there is a huge variability in the sensitivity of tumors," Naesens said.

It recently became possible to image hypoxic regions using magnetic resonance imaging and there are potential biomarkers from tumor gene signatures and enzymatic profiling to identify tumors that are likely to respond to CP-506.

Naesens noted Threshold's phase III in pancreatic cancer came close to reaching statistical significance, despite taking all-comers. With patient stratification, the outcome may have been different, he said.

That highlights a further development – the arrival of personalized medicine and tools for molecular profiling – which could give Convert an advantage over the companies that developed earlier generation HAPs.

While its dynamic nature makes hypoxia awkward to address, increased understanding of how low oxygen levels promote resistance to chemo- and radiotherapy and – as has recently become clear – checkpoint inhibitors, means it is a key target.

Indeed, the discovery of the link between hypoxia and checkpoint inhibition gave Threshold one more throw of the dice following its phase III failures, when it tested evofosfamide in a phase I/II trial in combination with checkpoint antibodies. (See BioWorld Today, Oct. 3, 2016.)

The funding for Convert comes from Droia, Meusinvest and Spinventure, with nondilutive funding amounting to almost half the total from two public backers, the Walloon regional fund and the EU's Eurostars program.

Naesens, who will stand down from the helm once a permanent CEO is appointed, said the funding will take Convert to 2020 and the completion of phase I/II development of CP-506. The company also is assessing a couple of other HAPs for in-licensing.

CP-506 was discovered at the faculty of Medical and Health Sciences at Auckland University, New Zealand, one of the world's leading groups in hypoxia selective prodrugs. The university was the source of the technology for HAP specialist, Proacta Inc., developer of PRO-104, another HAP compound to have been discontinued.

Alongside evofosfamide and PR-104, at least five other HAPs have been axed, including tirapazamine, which failed in a phase III trial in head and neck cancer.

The formation of Convert was prompted by Philippe Lambin, a clinical oncologist and specialist in hypoxia at Maastricht University in the Netherlands, who is a collaboration partner of the Auckland scientists. Lambin knows Naesens because he is the scientist behind another Droia-funded startup.

"He approached me and said [CP-506] was a very interesting compound that checks all the boxes and improves on every dimension of previous HAPs," Naesens said. "We've done a year of due diligence and validated all the academic data. The preclinical research looks really impressive."