In the absence of a cure, advances in HIV treatment have centred on limiting resistance and reducing side effects. French biotech Abivax (OTC:AAVXF) is hoping its novel approach disrupting viral RNA splicing can not only reduce viral load but also reduce cellular reservoirs.
Backed by the largest ever biotech initial public offering on the French Euronext exchange, Abivax has launched a phase IIa trial of ABX464 that hopes to duplicate the findings of a study in mice that detected lower viral rebound in those treated with the experimental drug when compared to standard therapy. “It means that something must have happened at the reservoir level,” Chief Medical Officer Jean-Marc Steens tells EP Vantage. “That was very intriguing”.
The drug’s effect is built around inhibition of Rev, which is involved in the export of unspliced viral RNA from cell nuclei. Without Rev, aberrant viral RNAs are created, preventing the expression of viral structural proteins and replication.
To determine whether it is as effective in humans, ABX464 is being offered in addition to antiretroviral therapy in a 28-patient placebo-controlled trial. After 28 days of treatment, all HIV therapies will be interrupted, and enrollees will have their viral loads measured, with time to viral rebound being an efficacy endpoint. Patients will resume antiretroviral therapy if viral rebound is detected.
The hypothesis is that if the drug is effective in reducing replication at the reservoir level, it can suppress the virus to a point where the patient's immune system can take over. Presumably, this would remove the need for antivirals. Top-line results of this trial, ABX464-004, are expected by the end of 2016.
A phase IIa dose-ranging trial, data from which were presented at CROI earlier this year, found that as a monotherapy, four of six patients receiving a 150mg once-daily dose achieved a 0.5 log10 reduction in viral load at 14 days.
This dosage was associated with a high number of adverse events, mostly headache, nausea and vomiting, although all were judged mild or moderate, and subsided after the first day – investigators said it was related to peak serum concentrations. The dose being tested in the placebo-controlled phase IIa trial now underway – on top of Prezista plus Norvir, or Prezcobix – is 50mg once-daily.
Viral control without antiretroviral treatment would be a step forward for HIV patients, who now must expect to take drugs for the rest of their lives – and risk side effects – in order to prevent disease progression.
“It’s the next logical step of therapy. We don’t know if we will be able to completely eliminate the virus,” says chief executive Hartmut Ehrlich. “But what we are aiming for is to get the patient into a situation where the human immune system takes over the control of the virus as we have seen in the ‘elite controllers’”.
These rare elite controllers are infected with HIV but have undetectable viral loads using conventional assays. Abivax points to reduced inflammation in that population as an explanation for their ability to control the disease without drug therapy, and adds that ABX464 patients experience 50-fold increases in their expression of the anti-inflammatory cytokine interleukin-22.
“We are now sort of looking at our compound from this point of view and actually are seeing that it is able to function in a strong anti-inflammatory mode,” he says.
If the current phase IIa trial returns positive results, a single phase IIb trial in around 200 patients will begin in the first half of 2017 in combination with existing treatments, trying to achieve long-lasting effects using endpoints to which the US FDA and European Medicines Agency will agree. The company expects that two pivotal trials will be necessary, one in the US and one in Europe, with regulatory submissions targeted for 2019 and approval decisions in 2020.
The group has €28m ($31m) in cash, giving it a runway to the end of 2017, according to Finance Chief Alain Chevallier. On the current schedule, it should be able to deliver phase IIb proof-of-concept data to take into partnering discussions by then.
Mr. Ehrlich says Abivax is hoping for a partner for the US, Europe and Japan, but likely as a licensing deal. With 25 employees, he says building a commercial organization to support global marketing would be difficult.
Obviously, big companies with a stake in HIV like Gilead Sciences (NASDAQ:GILD), GlaxoSmithKline (NYSE:GSK), Merck & Co (NYSE:MRK) and Johnson & Johnson (NYSE:JNJ) would be interested in a pill that can have sustained effect on viral loads even after treatment has been ceased. But the company’s executives are being careful not to oversell the notion that ABX464 can be a cure, but rather letting the data tell the story.
“It’s a functional cure, but it will all depend on the outcome of the trial,” Mr. Steens says. “Whether it’s remission or whether it’s a cure, it’s too early to say”.