GlaxoSmithKline  marketed the first HIV drug Retrovir in 1987 before losing out to Gilead Sciences Inc. (GILD) as the world’s biggest maker of AIDS medicines. The virus became resistant to Retrovir when given on its own, leading to the development of therapeutic cocktails.

The new once-daily drug Dolutegravir, which belongs to a novel class known as integrase inhibitors that block the virus causing AIDS from entering cells, is owned by ViiV Healthcare, a joint venture focused on HIV in which GSK is the largest shareholder.

Raltegravir (brand name Isentress) received approval by the U.S. Food and Drug Administration (FDA) on 12 October 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval. it is a potent and well tolerated antiviral agent.  However, it has the limitations of twice-daily dosing and a relatively modest genetic barrier to the development of resistance, prompting the search for agents with once-daily dosing.

Elvitegravir, approved by the FDA on August 27, 2012 as part of theelvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine fixed-dose combination pill (Quad pill, brand name Stribild) has the benefit of being part of a one-pill, once-daily regimen, but suffers from extensive cross-resistance with raltegravir.

Gilead’s Atripla (Emtricitabine/Tenofovir/efavirenz), approved in 2006 with loss of patent protection in 20121, is the top-selling HIV treatment. The $3.2 billion medicine combines three drugs in one pill, two compounds that make up Gilead’s Truvada (Emtricitabine/Tenofovir) and Bristol- Myers Squibb Co.’s Sustiva (Efavirenz).

A three-drug combination containing dolutegravir and ViiV’s older two-in-one treatment Epzicom(Abacavir/Lamivudine, marketed outside US as Kivexa) proved better than Gilead’s market-leading Atripla  in a clinical trial released in July, 2012 (See the Full Conference Report Here), suggesting it may supplant the world’s best-selling AIDS medicine as the preferred front-line therapy. In the latest Phase III study, after 48 weeks of treatment, 88% of patients taking the dolutegravir-based regimen had reduced viral levels to the goal compared with 81% of patients taking Atripla. More patients taking Atripla dropped out of the study because of adverse events compared with those taking dolutegravir — 10% versus just 2% — which was the main driver of the difference in efficacy. The result was the second positive final-stage clinical read-out for dolutegravir, following encouraging results against U.S. company Merck & Co’s rival Isentress in April, 2012 (See the Conference Abstract Here)..

Dolutegravir is viewed by analysts as a potential multibillion-dollar-a-year seller, as its once-daily dosing is likely to be attractive to patients. The FDA is scheduled to issue a decision on the drug’s approval by August 17。

Sources:

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National Institutes of Health (U.S.). A trial comparing GSK1349572 50 mg plus abacavir/lamivudine once daily to Atripla (also called the SINGLE trial). Available from:http://clinicaltrials.gov/ct2/show/NCT01263015.

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Dolutegravir synthesis (EP2602260, 2013). LiHMDS as the non-nucleophilic strong base pulling compound 1 carbonyl group proton alpha position with an acid chloride after 2 and ring closure reaction to obtain 3 , 3 via primary amine 4 ring opening ring closure to obtain 5 , NBS the bromine under acidic conditions to obtain aldehyde acetal becomes 6 , 6 of the aldehyde and amino alcohols 7 and turn off the condensation reaction obtained by the ring 8 , alkaline hydrolysis 8 of bromine into a hydroxyl group and hydrolyzable ester obtained 9 after the 10 occurred acid condensation Dolutegravir.