Merck's lead HIV play hits the mark in first phase 3 challenge

Merck has taken a big step toward getting its lead HIV candidate doravirine to market, setting up a showdown with Johnson & Johnson's big-selling Prezista.

Doravirine has shown its value in a first phase 3 trial, matching the efficacy of a ritonavir-boosted Prezista (darunavir) regimen over 48 weeks in previously untreated adults with HIV when given on top of standard two-drug antiretroviral regimens.

As a bonus, doravirine was also less likely to cause elevations in blood low-density lipoprotein cholesterol (LDL-c) levels, a marker for the metabolic side effects linked to some antiretroviral drugs, said Merck, which presented the data at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington, this week.

It's a good result for doravirine, particularly as HIV protease inhibitor Prezista has become a preferred component for first-line HIV treatment because it is one of the antiretroviral drugs least likely to stimulate resistance in HIV, helping it reach $1.85 billion in sales last year.

Merck's drug is new member of the older non-nucleoside reverse transcriptase inhibitor (NNRTI) class that includes drugs such as Bristol-Myers Squibb's Sustiva (efavirenz) and J&J's Edurant (rilpivirine), also a component of HIV cocktails but now showing their age and no longer first-line choices.

Merck's R&D head Roger Perlmutter told delegates at the Morgan Stanley Healthcare conference last year that doravirine has properties "very much like efavirenz, but a substantially better safety profile which could lead it to be one of the dominant agents used in HIV treatment."

Although HIV can generally be managed with available antiretroviral drugs, there is still a need for new agents that overcome the limitations of earlier drugs, such as improved potency, dosing and tolerability, as well as effectiveness against drug-resistant strains of the virus. 

Experimental data suggest that doravirine works against HIV strains that are resistant to other NNRTIs, so could potentially reinvigorate the class if approved. Analysts at Credit Suisse have suggested the drug could make $250 million in sales by 2020, assuming it gets approved in the U.S. and other world markets in 2018.

"Improved understanding of the biology of HIV and growing clinical evidence from current therapies are advancing the management of HIV infection,” said Dr. Kathleen Squires, professor and director of infectious diseases at Thomas Jefferson University.

"The results of this study provide solid evidence of the efficacy and safety profile of doravirine as a potential treatment option for treatment-naïve HIV-1 patients," she added.

Merck has been something of a second-tier player to date in a market currently dominated by Gilead Sciences and GlaxoSmithKline's ViiV joint venture with just one approved HIV therapy—the integrase inhibitor Isentress (raltegravir).

Isentress has performed well since its launch in 2007, nudging $1.4 billion in sales last year thanks to a good toxicity and drug-drug interactivity profile, but is facing tough competition from newer integrase inhibitors from Gilead and ViiV, particularly after a once-daily version of the drug flunked clinical trials.

Meanwhile, Merck's Perlmutter says the company has a "pretty large and exciting" HIV program with some candidates that could really disrupt the market.

For instance, there is a lot of anticipation about another of Merck's HIV drugs—MK-8591—among clinicians because it has a slightly different mechanism of action and an extended duration of action compared to its predecessors, controlling viral replication for up to 10 days from a single oral dose in phase 1 trials. A parenteral formulation could provide 6 months cover from a single injection.

It is estimated there are currently around 37 million people worldwide living with HIV, with new infections occurring at a rate of about 2 million a year.