As the number of first-line HIV treatment options has greatly expanded over the last several years, research on the other end of the spectrum -- on antiretrovirals for people with extensive drug resistance -- has felt more stagnant. Last year's demise of vicriviroc cast a shadow over drug development in "deep salvage" situations, and left many in the field concerned that the small-but-growing number of people with dwindling treatment options may increasingly be up the creek without a paddle.
It's for that reason, as much as any, that ibalizumab raises so many feelings of hope: Though still relatively early in its development, ibalizumab is a potential oasis in the desert for HIV treatment-experienced people and the clinicians who treat them. Here at ICAAC 2011, new data maintain the vision of that oasis; whether it turns out to be the real thing or just a mirage will be borne out in future studies.
Ibalizumab is by no means a new kid on the HIV-treatment-research block: It's been in an assortment of early-phase studies for the better part of a decade, formerly under the name TNX-355, which has now been changed to TMB-355. It aims to eventually become the first HIV drug approved in the "monoclonal antibody" class -- a group of entry inhibitors that works differently from all the other types of entry inhibitors, though its exact mechanism currently remains a mystery even to the scientists who are developing it. Previous research has offered tantalizing signs that ibalizumab may be effective in highly treatment-resistant patients and -- perhaps almost as exciting -- may also buck the tradition of antiretrovirals that must be taken at least once per day in order to retain their efficacy.
The phase 2b study results presented here by Stanley Lewis, M.D., M.P.H., of TaiMed Biologics USA, the latest company to take on the mantle of developing ibalizumab, reaffirm the drug's potential. The double-blind (but not placebo-controlled) study involved 113 highly treatment-experienced patients -- we're talking people who had resistance to all three major HIV drug classes (NNRTIs, NRTIs and protease inhibitors) and were failing their current regimen (with a viral load of 1,000 or higher; mean viral load at baseline was actually well over 100,000), though there was still at least one antiretroviral in an optimized background regimen (OBR) that their HIV would be susceptible to. On average, study volunteers had been living with HIV for 17 years (and were in their late 40s); most patients were men and a majority were white. The vast majority of study participants entered with a CD4 count below 200.
These volunteers were randomized to receive an OBR plus ibalizumab in one of two doses: 800 mg once every two weeks or 2,000 mg every four weeks. You read right: a monthly dose. The catch is that the medication was administered via infusion, which isn't the most patient-friendly way to take a drug.
Twenty-four week data were presented. They show similar efficacy between both arms of the study, with the 800-mg-per-two-weeks dose trending slightly better in the primary endpoint: undetectable viral load.
The results were not stunning, but they were encouraging, particularly considering these volunteers' treatment history and baseline viral load: Forty-four percent of people on the 800-mg arm and 28% of people on the 2,000-mg arm reached a viral load below 50 (P = .160), while 58% of people on the 800-mg arm and 46% of people on the 2,000-mg arm reached a viral load below 400 (P = .321).
Other data similarly showed modest (in absolute terms), but noteworthy, gains: a median viral load drop from baseline of 1.6 log among patients on the 800-mg arm, versus 1.5 log among patients on the 2,000-mg arm; a median CD4+ cell count gain of 37 among patients on the 800-mg arm, versus 40 for the 2,000-mg arm; and the percentage of patients with a CD4+ cell count below 20 dropped from 26% at baseline to 12% after 24 weeks on treatment.
Importantly, though, this was not a controlled trial (there was no OBR-only or OBR-plus-placebo arm), so it's difficult to gauge how much of this success is due to ibalizumab and how much is thanks to the OBR. In a Q & A following the presentation, clinician-researcher Cal Cohen, M.D., contended that these efficacy findings were similar to that seen for OBRs in some previous clinical trials. So there is certainly skepticism among some researchers regarding the drug's true efficacy in highly treatment-experienced patients.
Moving on to adverse events: They were relatively common, with rash and diarrhea leading the way, closely followed by headache, upper respiratory tract infections, nausea, fatigue, cough, vomiting, nasopharyngitis and oral candidiasis (with some of these perhaps suggesting that immune reconstitution syndrome came into play as suppressed immune systems began to recover). Grade 3/4 lab abnormalities were also noted in several areas, including absolute neutrophil count, total cholesterol, creatinine, glucose, phosphorus and urine protein. In almost all cases, the 2,000-mg dose was more frequently associated with these adverse events and lab abnormalities than the 800-mg dose -- although, again, a lack of a control arm makes it difficult to determine which adverse effects are ibalizumab-related.
Worth noting after that laundry list of potential problems, however, is this: No volunteers reported reactions at the drug-infusion site; there were no reports of immunogenicity, which is a theoretical concern for an entry inhibitor with an as-yet-unknown mechanism of action; and none of the drug-related adverse events were severe.
And so, this intriguing and unique antiretroviral moves onward, albeit slowly. A small, phase 1 study going by the name TMB-108 is now recruiting. It will assess the safety and pharmacokinetics (in HIV-uninfected volunteers) of a subcutaneous administration for ibalizumab, which is still no walk in the park for patients, but is a leap and/or bound better than infusion (and the no-more-than-weekly dosing schedule would hopefully make injection site reactions more rare than they were for enfuvirtide [T-20, Fuzeon], that other not-so-popular subcutaneously injected antiretroviral). The study is being conducted in concert with the Aaron Diamond AIDS Research Center and the Bill and Melinda Gates Foundation. Lewis also noted that an AIDS Clinical Trials Group (ACTG) trial, study A5299, would also study subcutaneous ibalizumab in HIV-infected volunteers, with a similar design to TMB-108.
In questions after his presentation, Lewis noted that the drug was most likely to continue its development using either a once-every-two-weeks dose, or even a once-weekly dose, to minimize the risk of adverse events and lab abnormalities that appeared more frequent with the higher-but-less-frequent dose.
While we wait for drugs such as ibalizumab to hopefully yield new treatment options for those who sorely need it, there are -- well, there are those who sorely need it. I urge any of you who are currently treating multidrug-resistant patients who are failing their current therapy to read Nelson Vergel's recent blog post on "single-patient Investigational New Drug" access and do what you can to hook your patients up.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.