A self-injectable monoclonal antibody vies to become a monotherapy
by Chael Needle
[dropcap]A[/dropcap]nti-HIV agents currently being researched these days seem split between (1) improving regimens to improve a patient’s quality of life and range of treatment options for those who might become drug-resistant or need a more efficacious regimen, and (2) focusing on vaccine potential. Some agents attempt to straddle both. PRO 140, a fully humanized IgG4 monoclonal antibody delivered through a subcutaneous injection, is one such candidate.
An entry inhibitor from CytoDyn, PRO 140 works to block CCR5, a co-receptor needed for HIV to enter a cell and continue its replication process. Active against HIV (R5) subtype, PRO 140 so far does not seem to interrupt the immune-response function of CCR5, while remaining active against CCL5, which activates the R5 coreceptor. Researchers are also looking at the potential of PRO 140 as a treatment for other diseases beyond HIV.
Across seven clinical trials, PRO 140 has been shown to be safe, well-tolerated, and efficacious in significantly reducing or controlling viral loads in individuals living with CCR5-tropic HIV. As a candidate, it has earned fast-track status from the FDA. It should be noted that recent study results have not been published yet in any peer-reviewed journal, so we do not have the benefit of other scientists publicly weighing in on the credibility of the data.
Researchers are currently studying PRO 140 as part of an optimized HAART therapy as well as a monotherapy, in patients who have become stable on combination therapy. With PRO 140’s expected commercialization in 2017 as an adjunct therapy with the appropriate green lights, its candidacy as a monotherapy, a treatment substitution for HAART, has received special focus. After the first group of participants in the CDI-01 Phase 2b monotherapy study passed one year of viral load suppression, an extension study was set up and some of those participants substituting PRO 140 for HAART have continued to show virologic control. Ten out of the fourteen participants enrolled have achieved complete suppression of the virus for at least eighteen months, and, for several, even longer. (One other participant had achieved viral suppression through seventeen months, but has since dropped out.) All have indicated an improved quality of life.
Offering treatment-experienced HIV patients relief from the possibility of the long-term toxicity, sleep disruptions, and lower energy levels associated with some of the current antiretrovirals is what makes PRO 140 a hopeful candidate as a monotherapy, says Nader Pourhassan, PhD, CEO of CytoDyn Inc. Its development as a monotherapy candidate is a response to current patient needs rather than future ones, when it could prove useful as part of a combination regimen. “Twenty years ago [HIV/AIDS] was a deadly disease; now it’s a chronic disease. So you need to be able to give patients something that’s very much needed, which is to allow them to get off their pills for at least a period of time, which they’re not able to do now,” explains Dr. Pourhassan. “They’re sentenced to a life of taking pills every day, one, two, or three or up to seven or ten pills a day.” As mentioned, PRO 140 is concurrently being studied as a substitution, with the candidate alternating with HAART, and now as a monotherapy. Tolerability was shown to be good and “every patient reported a higher quality of life,” he notes.
The data from the ongoing studies indicated to the research team members that they were looking at long-term monotherapy, not short-term.
He points to candidates like PRO 140 as playing a part in reaching higher treatment as prevention (TasP) goals. “Only twenty-five percent of HIV patients in the United States have a suppressed viral load which means zero rate of transmission, [but] that’s not acceptable. Seventy-five percent do not have a suppressed viral load, which means that [regimens featuring] all pills is not the solution to this problem of getting everybody suppressed,” he theorizes.
He agrees that adherence to the candidate might be easier as well, due to the fact that PRO 140 could become a self-injectable requiring less frequent dosing. “We started testing these antibodies by using an IV, one infusion, to see how far we could go. At a higher dose we can actually go once a month. But ideally the way to go is a self-injectable, at home and very convenient, like patients with diabetes, who inject themselves every day, two times. This, however, is going to be once a week, and we believe we are going to make it once a month, once we get to post-launch,” he says. Researchers have established proof-of-principle for one injection every two weeks, he adds, but the company voted to first obtain approval for once a week to be safe and conservative. The research team will continue to study less frequent dosing afforded by the subcutaneous injections in relation to efficacy.
CytoDyn is currently enrolling patients in its CDI-14 pivotal Phase III trial, for PRO 140 as a combination therapy with HAART, and plans to begin patient enrollment during the second quarter of 2016 in its CDI-18 Phase III trial, for PRO 140 as a long-term monotherapy.
If PRO 14o comes of age as a monotherpay “[i]t would change the HIV paradigm. It would change how every expert thinks about HIV,” says Dr. Pourhassan. “And it would change patients’ quality of life in a tremendous fashion.”
Chael Needle wrote about the Women’s HIV Program at UCSF in the April issue.