Merck Announces Positive Results From Phase 2b HIV Combo Therapy Study

By Ed Miseta, Chief Editor, Clinical Leader

Merck has announced data from a 48-week Phase 2b clinical trial that evaluated the safety and efficacy of once daily oral doravirine plus tenofovir/emtricitabine (TDF/FTC). Doravirine is an investigational next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI). The study compared doravirine plus TDF/FTC to efavirenz plus TDF/FTC, in previously untreated patients with HIV-1 infection.  

The treatment of HIV has changed considerably since the early days of the epidemic. Initially there were no therapies, which eventually gave way to single therapies. Today multiple classes of therapies are available which target different parts of the virus lifecycle are available. It has now become clear to researchers that combination therapies are key to battling the disease. With combination therapies, patients are able to live lives much closer to normal without the HIV complications that would often be fatal. 

“While those earlier therapies showed they could successfully suppress the virus, they also had a number of shortcomings, such as toxicity and drug interaction issues,” says Dr. Hedy Teppler, Executive Director of Infectious Diseases Clinical Research at Merck Research Laboratories. “In more recent years we have not only been looking for more efficacious drugs, but drugs that are better tolerated, have better safety profiles, and are easier to use with other medications. As people live longer lives they need to be treated for other ailments and those medicines would have to be compatible with any HIV treatments they are also receiving.”

Teppler notes the hope for the doravirine compound is that it will join the already established class of other NNRTI therapies but have a better profile than agents already available in that class. The study noted above was the first Phase 2b study of doravirine in HIV infected patients. Two of the major goals of the study were to look at a range of doses and compare them against one of the most commonly used therapies in that class. For the first 24 weeks of the study, four doses of doravirine were compared against efavirenz, both used in combination with tenofovir/emtricitabine.

“We have already presented data showing 24-week results from a study of 210 patients looking at both the safety and efficacy of doravirine,” says Teppler. “Each of the doses fared well against efavirenz and one of the doses (100 mg) was chosen for further study. All of the patients in the study who were started at a different dose were eventually transferred to the 100 mg dose. In addition, we enrolled more patients at the selected 100 mg dose versus efavirenz to allow for a more robust statistical comparison when looking at neuro psychiatric tolerability because of neuro toxicity issues that exist with efavirenz.”

Teppler is encouraged by the anti-viral activity and the overall tolerability profile of doravirine and notes the company is looking forward to initiating Phase 3 studies on the combination treatment. The results of the study showed the 100 mg dose of doravirine compared favorably with efavirenz and had a superior neuro psychiatric tolerability profile.  

Additionally, patients who have been on the treatment for 48 weeks are also faring well and the anti-viral responses were good and comparable with efavirenz. The tolerability profile held up and looked good when compared with efavirenz. Teppler notes fewer toxicities were also noted. “The data looks as we had hoped and we will continue to work on developing the compound,” adds Teppler.

The primary safety analysis from the expansion phase of the study compared the incidence of specific central nervous system (CNS) adverse events by week 8. The results showed a significantly lower incidence of one or more specific CNS adverse events (all causality) among the doravirine100mg treated group compared to the efavirenz-treated group (22.2 % vs. 43.5 %, respectively). The most common (occurring in more than 5 percent of patients) CNS adverse events in the doravirine- and efavirenz-treated groups, respectively, were dizziness (9.3 % vs. 27.8 %), insomnia (6.5 % vs. 2.8 %), abnormal dreams (5.6 % vs. 16.7 %), and nightmares (5.6 % vs. 8.3 %).

Additional follow-up data through 48 weeks of treatment showed a 76 percent overall virologic response rate for all doravirine doses that is comparable to 71 percent reported for patients administered efavirenz (600 mg). In addition, all treatment groups showed increased CD4 cell counts relative to baseline, consistent with the 24-week findings. 

Merck plans to initiate the first Phase 3 clinical trial of doravirine by the end of 2014. The study will enroll treatment-naïve patients and compare the efficacy, safety and tolerability of doravirine and ritonavir-boosted darunavir, both in combination with other anti-retroviral therapy.