Having secured a fresh source of funds last month Noxxon is hoping to follow with some data to please its new investors. These will emerge later next week from its lead asset, NOX-A12, a chemokine-targeted agent that is being tested in combination with Merck & Co’s Keytruda.
A small phase II trial in very late-stage microsatellite-stable, metastatic colorectal or pancreatic cancer patients will read out at Esmo’s Immuno-Oncology Congress. Because Keytruda is known not to work in patients with microsatellite stable tumours, any responses seen can be attributed to NOX-A12, Noxxon’s chief executive Aram Mangasarian told Vantage. After years of struggling to make headway with this asset, the stakes could not be much higher for the German biotech.
NOX-A12 targets CXCL12, also known as SFD-1, a chemokine ligand involved in tumour proliferation and new blood vessel formation, among other roles. Chemokine targeting has been fairly widely explored over the years with limited success. An anti-CCL 2 antibody called CNTO-888 from Johnson & Johnson was studied fairly extensively in phase II before being abandoned, while ulocuplumab looks to have been sidelined by Bristol-Myers Squibb; this project hits CXCR4, the chemokine receptor though which the CXCL12 ligand signals (Bristol failure makes small dent in CXCR4-blocking approach, 23 March 2017).
Mr Mangasarian suggested that failure to find a therapeutic window has frequently been a stumbling block.
“It looked like they couldn’t neutralise the chemokine for very long. Our drug has shorter half-life than antibodies but we have shown in the clinic that we can chronically inhibit the chemokine for three months,” he told Vantage, at the recent Esmo conference in Munich.
Finding a partner
NOX-A12 is a RNA aptamer, pegylated for a longer half-life; Noxxon’s platform generates candidates as RNA mirror images, making them resistant to RNA degradation. This approach has failed to find a place so far, however: NOX-A12 first entered the clinic back in 2009 and its role in leukaemia, multiple myeloma and stem cell transplant settings have previously been explored.
Mr Mangasarian said that finding a potent enough combination partner is key, and he hopes that checkpoint inhibition could finally unlock the potential. This is based on CXCL12’s role as a repulsive for effector T cells in certain cancers, causing them to be excluded from the tumour microenvironment.
“The idea is that we lower the concentration [of CXCL12] at the tumour invasive margins, and then T cells can infiltrate. Once they get in, the checkpoint inhibitor can do its job, and that’s what we’re trying to show in this study,” Mr Mangasarian said.
The 20 patient Opera study recruited 11 colorectal and nine pancreatic cancer patients, all of whom had failed three to five lines of prior treatment. Only one of the 20 responded to their previous therapy, developing stable disease. The company is hoping to show an improvement on that response rate, and demonstrate that the combination can stabilise disease for a meaningful length of time.
“These are very sick patients. Progression-free survival for pancreatic patients at this stage is around two months… colorectal is a bit longer,” Mr Mangasarian said. “If we see any significant percentage of patients where we can bend the curve down and achieve stable disease, I think that’s going to be a big deal.”
Noxxon is arguably running out of chances to push on with NOX-A12. However a recent financing bought it a second shot on goal. A trial in combination with radiotherapy in patients with glioblastoma is slated to start in the second quarter, which could read out in 2020.
The November €6.2m ($7m) cash injection was mostly provided by Acuitas Capital, a US family office. New investors bought into Noxxon at a 10% discount to its current share price, while existing bond holders also swapped debt for equity at the same rate. This resulted in a significant dilution to existing shareholders – to the tune of 52% – but left the company debt-free and funded until at least the end of 2019.
Still, with a valuation of €14m, close to all-time lows, much still needs to be done to tempt investors to return to Noxxon. Encouraging data next week would be a start, and others still pursuing the chemokine approach, like Biolinerx and X4 Pharmaceuticals, will be watching the readout with interest.
Given that microsatellite stable tumours have proven to be stubbornly unresponsive to immunotherapy, and that this field remains a huge untapped area for immuno-oncology, Merck & Co will also be keeping an eye on the results.