Inflammatory bowel disease might not be an obvious offshoot from HIV research, but this is exactly where Abivax is heading with its lead asset, ABX464. The French biotech unveiled promising early data in ulcerative colitis this week, adding to encouraging signals in HIV that began to emerge last year.
The company's chief executive, Hartmut Ehrlich, tells Vantage that the company wants to have phase IIb trials in both settings up and running next year. Fund raising options are being explored – current reserves will last until the end of 2019 – and Mr Ehrlich hopes to be able to hold out on partnering discussions until more robust evidence of efficacy is in hand.
That will not emerge until 2020, though at least now Abivax has two chances of success. And, while the fields of HIV and inflammatory disease might appear unrelated, there are biological associations. Even HIV patients whose virus is well suppressed by drug therapy will exhibit markers of inflammation, and infected adults are at heightened risk of conditions such as cardiovascular disease and cancer.
Binding and splicing
Unlike standard-of-care HIV antivirals, which hit viral replication mechanisms, ABX464 targets human cells. By targeting cap binding complex (CBC) Abivax reckons it interferes with the process by which viral genes are integrated into host DNA. This should prevent mRNA from leaving a cell and, ultimately, stop viral reproduction.
At the same time, however, it seems that ABX464 is also working through other mechanisms, namely the triggering of two anti-inflammatory molecules, IL-22 and miR124.
“This binding to CBC and the conformational change we are making leads to the acceleration of splicing of two pieces of RNA,” Mr Ehrlich says. “One is non-coding RNA … but it contains the sequence for miR124, which is able to dampen inflammation.”
This explains activity in inflammatory conditions, and could also likely be beneficial in HIV. But Abivax also believes that ABX464 is contributing to the killing of HIV-infected immune cells.
“We have been able to identify a specific of new HIV RNA that is being formed as a consequence of splicing, which is not normally seen. Our leading hypothesis … is that this is a new peptide, which might have the potential to function as an antigen and direct the host immune response to infected cells.”
In phase IIa studies, Abivax has shown that ABX464 can prompt HIV DNA to drop in both peripheral blood mononuclear cells and rectal tissue – two major reservoirs for the virus. Intriguingly, this effect appears to be sustained for a few weeks after antiviral therapy is ceased, though the numbers of patients tested so far are small and not all responded.
A more rigorous trial of around 150 patients is planned, in which Abivax hopes to generate more conclusive evidence of ABX464’s ability to drain the reservoir of infected HIV cells throughout a patient’s body. Exactly where ABX464 will fit within existing therapies remains to be elucidated. But Abivax sees the potential for ABX464 to allow patients to take drug holidays, and possibly even represent something of a “functional cure”.
Data this week in ulcerative colitis demonstrated that this disease could also be a fruitful path of enquiry. A small study reported encouraging signs on measures such as clinical remission rate and clinical response, though only mucosal healing showed a significant difference from placebo.
The trial was only 8 weeks long, and just 32 patient were recruited; a 12-month extension study due to yield data in October will confirm whether ABX464 can maintain its effects safely.
|ABX464-101 trial in ulcerative colitis|
|Clinical remission rate||35%||11.10%|
|Mucosal healing rate*||50%||11.10%|
|Clinical response rate||70%||33%|
|*Statistically significant. Primary endpoint of the trial was safety, which was met. Source: company presentation.|
Mr Ehrlich says a phase IIa trial in Crohn’s disease will start imminently, and insists that the company is committed to pushing on in both ulcerative colitis and HIV – although presumably this will depend on it being able to raise fresh funds.
This will not be easy, at least not from equity investors. After the initial HIV data back in May last year the company’s stock soared to almost €18, but today trades at just €7.3, even after a 9% jump yesterday on the bowel disease data.
Abivax’s market cap stands at €72m ($84m). Expectations of a cash call will not be helping this valuation, and neither will the fact that Truffle Capital holds about 69% of the company’s stock.
All of this meant that Abivax was forced to turn to debt financing: €20m was raised from Kreos Capital in July.
Mr Ehrlich says that partnering, which could also provide funds, is a longer-term goal. “We want to wait until we have data to provide additional support of the validity of our concept. We will take our time," he says.
Still, if funds cannot be found Abivax could be forced to make some difficult decisions. Mr Ehrlich says the board is reviewing its strategy in light of the ulcerative colitis data, and insists that the company is committed to both projects. Realistically, however, the higher-risk HIV research, where ABX464's mechanism of action needs much more exploration, looks most likely to move into the slow lane.