Against the odds, the vascular-disrupting strategy refuses to die. Last week saw the stock market debut of Beyondspring Pharmaceuticals, a biotech whose lead asset, plinabulin, targets this tried and failed anticancer mechanism.
But Beyondspring says it has found a niche – positioning plinabulin against neutropenia – as well as suggesting added mechanistic benefits. “Going solely after vascular disruption may not cut it,” the group’s chief medical officer, Ramon Mohanlal, told EP Vantage at December’s Ash meeting. “If that was the only thing plinabulin was doing then I think we should have reason to be concerned.”
Vascular-disrupting agents (VDAs) were once thought to represent a promising oncology drug class, but in the past few years most have fallen by the wayside (Twilight of the vascular disrupting agents, January 16, 2013).
Plinabulin, too, had underwhelmed in a phase I/II trial attempting to show a therapeutic effect against lung cancer, run by its originator, Nereus Pharmaceuticals. However, that study showed plinabulin to be associated with greatly reduced neutropenia – something Nereus “totally overlooked”, merely reporting it as a safety benefit, said Mr Mohanlal.
Nereus ran into financial issues and was sold to Triphase Accelerator, while Beyondspring bought out plinabulin. When Mr Mohanlal joined the newly formed company in 2015 he recognised the reduction in neutropenia as “more than a safety benefit. I viewed it as a true indication in its own right.”
Beyondspring managed to price its Nasdaq IPO at $20 a share, the bottom of its $20-22 range, and the float raised $54m. Mr Mohanlal said Nereus retained no royalty interest in plinabulin, deriving any benefit solely through an equity stake of around 10%.
Of course, plinabulin is not the only VDA to buck the failure trend. Zybrestat, owned by Mateon (a company formerly known as Oxigene), remains in phase III after showing a surprising benefit in ovarian cancer (Oxigene soars on surprisingly positive news from disappointing drug class, March 12, 2014).
Mr Mohanlal said if plinabulin was successful this would be down to its mechanism of action, which went beyond vascular disruption, and included effects on the immune system. These, he said, could be directly responsible for long-lived improvement in cancer patients’ neutropenia.
In particular, the molecule might enhance maturation of dendritic cells, which present antigens, as well as activating and co-stimulating T cells, and increasing cytokine secretion. Some cytokines stimulate neutrophil activation and survival, and others have been associated with reducing neutrophil destruction – effects that might account for neutropenia reduction.
Of course, Beyondspring has not given up on a straight cancer indication, and is running Dublin-3, a phase III NSCLC study measuring plinabulin’s effect on overall survival. But it is neutropenia that could provide the asset with a cheaper and quicker route to market, comprising a pivotal programme of only two 200-patient studies with three months’ follow-up.
The first of these recently got the go-ahead under a US IND. It will recruit patients with various cancers and compare plinabulin’s effect head to head versus Neulasta, a pegylated G-CSF, the standard of care for neutropenia. To circumvent ethical concerns, any patients developing neutropenia on the active arm can switch to Neulasta – the primary endpoint measures duration of neutropenia in the first cycle alone.
Mr Mohanlal said pricing could be a key advantage of plinabulin, which as a synthetic, small molecule would have lower manufacturing cost than G-CSF, a biological. Indeed, he said that owing to cost constraints only about 20% of eligible patients got G-CSF.
And a separate strategy still will see plinabulin tested as an anticancer agent in combination with checkpoint inhibitors. Already two investigator-initiated trials combining it with Opdivo are under way.
With Beyondspring armed with IPO cash to explore these novel theories, it will be interesting to see if companies such as Sanofi, Bionomics and Angiogene are persuaded to dust off their own failed VDAs and tease out novel immune system benefits.