Developing Doravirine

[Treatment Horizons]

Running Into Options
An NNRTI candidate seeks to keep on track to expand therapies
by Chael Needle


In this next-generation era of anti-HIV meds, research and development has turned to candidates with alternative functions, like reducing HIV reservoirs; candidates with better side effect profiles; candidates with simplified dosing—in short, better therapeutic options.

Better therapeutic options allow patient-centered treatment to come to the fore as the range of decisions to be made increase and as individuals living with HIV and on treatment become attuned to how their own particular body responds to treatment. It’s almost as if the treatment-empowerment days of the early epidemic—when those affected by AIDS took their health into their own hands and became on-the-fly health experts—has come full circle. Now, however, patient-centered treatment can begin with more answers than questions, more particulars than generalizations, more context about what works and what doesn’t.

One pharmaceutical company that has taken this to heart is Merck, with its I Design campaign, which, through guided worksheets and apps, encourages individuals with HIV and on treatment to pursue with their physicians dialogues about current treatment goals, health-related lifestyle choices, and family medical history, among other concerns, all in an effort to tailor their own health and well being. This strategy is important in our community’s efforts to improve adherence and achieve viral suppression. But Merck is also dedicated to expanding those options for tailoring, as well.

For example, Merck is currently studying doravirine (MK-1439), a next-generation candidate of the non-nucleoside reverse transcriptase (NNRTI) class. At ICAAC 2012, researchers presented findings that doravirine looks to have solid efficacy against NNRTI-resistant viruses (comparable to or better than other standard-of-care NNRTIs) in cell studies. The resistance profile of NNRTIs has often meant that patients have had to curtail treatment with established drugs in this class.

In this case, the “resistance profile would need to be borne out in further clinical study,” notes Dr. Hedy Teppler, executive director, Infectious Diseases, Merck Research Laboratories. However, researchers do have human-based data about how doravirine might improve upon other limitations of the class.

“There can be a lot of variations and attributes within any particular class, whether it’s toxicity profile, whether it’s the activity profile,” says Dr. Teppler, “and so I think that we know that there are limitations of some of the currently approved NNRTIs, for example, the neurotoxicity associated with efavirenz. We know that one of the newer approved NNRTIs, rilpivirine, has efficacy issues; in fact it’s only labeled for use in patients who have a viral load below 100,000 copies, and that’s essentially an efficacy limitation, as some patients need to start treatment with much higher values of viral load at baselines. We feel this compound, doravirine, has the potential to have a better safety profile than efavirenz and a better efficacy profile than rilpivirine.”

At the 12th International Congress on HIV Drug Therapy held in Glasgow in early November, researchers presented interim results of an ongoing Phase 2b clinical trial that compared once daily oral doravirine (25, 50, 100 and 200 mg), plus tenofovir/emtricitabine (TDF/FTC), with efavirenz (600 mg) plus TDF/FTC in treatment-naive patients with HIV-1 infection. The presentation, led by Dr. Josep M. Gatell, head, Infectious Diseases and AIDS Units-IDIBAPS, Hospital Clinic, Barcelona, outlined safety, efficacy, and tolerability data of the randomized, double blind, dose-ranging clinical trial, whose treatment end-point is ninety-six weeks.

Doravirine was found to have good tolerability and efficacy overall when compared to efavirenz at forty-eight weeks of dosing, says Dr. Teppler. Doravirine, at all doses, showed a seventy-six percent overall virologic response rate, which is comparable to that of efavirenz, at seventy-one percent. Increased CD4 cell counts relative to baseline were noted in all treatment groups.

“It also can be taken without regard to food and has a low propensity for causing drug-drug interaction,” she adds.

When it came to comparing the incidence of central nervous system (CNS) adverse events between doravirine 100 mg plus TDF/FTC and efavirenz with TDF/FTC, patients in the doravirine arm showed a significantly lower incidence of one or more of reported CNS adverse events than those in the efavirenz arm by Week 8. (The doravirine dose—100 mg—was selected based on safety and efficacy data through twenty-four weeks, and was given to all participants in the arm, which enrolled an additional 132 patients, for the expansion phase of the fairly large trial.) In the doravirine-treated group, the incidence of CNS adverse events was 22.2 percent compared to 43.5 percent in the efavirenz-treated arm. Additionally, doravirine has been shown to have minimal central nervous system toxicity.

Patients in the dose-ranging part of the study and received doravirine were found to have a lower overall incidence of drug-related adverse events—not just CNS-related adverse events—when compared to patients who received efavirenz (36.7 percent vs. 57.1 percent, respectively), after forty-eight weeks of treatment.

Next up is a Phase 3 clinical trial that will compare doravirine and ritonavir-boosted darunavir, both in combination with other antiretroviral therapy, for efficacy, safety, and tolerability in treatment-naive patients.

Chael Needle wrote about a Harris Interactive/ViiV Healthcare survey exploring attitudes toward HIV care among positive individuals for the August issue.