Profile Of Viiv’s Unboosted Dolutegravir Emerges With First Phase III Results

Viiv Healthcare/Shionogi’s once-daily, unboosted integrase inhibitor dolutegravir is efficacious and well-tolerated in the first of four Phase III HIV trials to report, a study of treatment-naïve patients. Drug poses a competitive threat to Merck’s blockbuster Isentress and Gilead’s elvitegravir, part of the four-in-one “Quad” pill.

ViiV Healthcare/Shionogi Inc.’s eagerly awaited once-daily dolutegravir was efficacious and well-tolerated in the large Phase III SPRING-2 non-inferiority trial in treatment-naïve HIV patients – the first of four late-stage studies to report – setting the stage for a commercial battle against rival integrase inhibitors down the line.

In the randomized study of 822 patients taking two non-nucleoside reverse transcriptase inhibitors (NNRTIs), the drug was as efficacious as Merck & Co. Inc.’s twice-daily Isentress (raltegravir) over a 48-week treatment period, with 88% vs. 85% achieving viral suppression targets, Shionogi and ViiV Healthcare , a joint venture formed in 2009 between GlaxoSmithKline Inc. and Pfizer Inc., announced April 2 (Also see "GSK And Pfizer Join Forces In New HIV-Focused Venture" - Pink Sheet, 3 Nov, 2009.). The candidate’s tolerability was also on par with Isentress, satisfying the safety component of the trial. It did not appear to offer an advantage in this patient population in terms of the drug-related nausea rate, which was 10% in both arms. No other adverse events occurring in over 5% of participants were reported. The rate of events leading to withdrawal was also the same, at 2% in both arms.

Integrase inhibitors represent a fertile area of development and commercialization in HIV (Also see "With Isentress Sales Booming, New Integrase Inhibitors Step Up To The Plate" - Pink Sheet, 1 Mar, 2010.). Approved in 2007, Isentress had sales of $1.4 billion in 2011, up 25% from the previous year. Gilead Sciences Inc. has developed its own once-daily integrase inhibitor called elvitegravir, which is pending FDA review as part of the four-in-one “Quad” pill (Also see "Gilead Quad’s Side Effects Profile, Novel Agents To Get Advisory Committee Review" - Pink Sheet, 23 Mar, 2012.).

The profile of dolutegravir (formerly called S/GSK 1349572) has caught the attention of clinicians for a number of reasons. The drug has an advantage in terms of low milligram dosing, which could make it easier to include in a fixed-dose combination pill and has potential to minimize side effects. In the SPRING-2 study, the drug was given at 50 mg once daily, compared to raltegravir twice a day at 400 mg. Elvitegravir is given once daily at 150 mg.

Once-daily dosing is an obvious attraction and, importantly, the drug does not require a booster, which is used to inhibit an enzyme that would otherwise break down the drug. By giving a booster, it’s possible to reduce the dosage of the original drug to make it available longer or at a higher concentration. But boosters themselves have side effects. Abbott Laboratories Inc.’s commonly used Norvir (ritonavir)causes gastrointestinal distress. There is also a higher risk for resistance with boosters. Gilead has developed its own booster called cobicistat, which is part of the Quad pill, along with elvitegravir and the components of Truvada (emtricitabine and tenofovir).

Data from Phase II studies suggest dolutegravir has a higher genetic barrier to resistance, with activity in patients who had failed on Isentress and were resistant to at least three anti-retroviral drugs (Also see "ViiV Preps Once-Daily Integrase Inhibitor '572 For Phase III" - Pink Sheet, 22 Jul, 2010.). In addition to the treatment-naïve population, the Phase III program for dolutegravir includes studies in treatment-experienced patients who have and have not been exposed to another integrase inhibitor. Results from three other Phase III studies – SINGLE, VIKING-3 and SAILING – will be released throughout the year, according to Viiv and Shionogi (see table). All but one, the single arm VIKING-3 study in 200 patients who have failed on an integrase inhibitor containing regimen, have fully recruited.

Phase III Program For Viiv’s Integrase Inhibitor Dolutegravir
Trial	Description
SPRING-2	Non-inferiority trial in 822 treatment-naïve patients, comparing dolutegravir once daily vs. raltegravir twice daily. All receive background therapy of two NNRTIs chosen by investigator, either abacavir/lamivudine (Viiv’s Epzicom) or tenofovir/emtricitabine (Gilead’s Truvada).
SINGLE	Non-inferiority study in 788 treatment-naïve patients, comparing dolutegravir plus abacavir/lamivudine (Viiv’s Epzicom) vs. dolutegravir plus efavirenz/emtricitabine/tenofovir (Gilead/Bristol’s Atripla).
SAILING	Non-inferiority study in 688 treatment-experienced patients naïve to integrase inhibitors and resistant to at least two antiretroviral drug classes, comparing dolutegravir to raltegravir. Background therapy of investigator’s choice.
VIKING-3	Single-arm study of dolutegravir in 200 patients who failed an integrase inhibitor-containing regimen. Dolutegravir plus background antiretroviral therapy.

The results from the Phase III studies will shed more light on how the new integrase inhibitor will stack up against rivals and on the most appropriate combinations.

In the newly reported SPRING-2 study, investigators had the option of giving either abacavir and lamivudine (Viiv’s Epzicom) or tenofovir and emtricitabine (Gilead’s Truvada) as NNRTI therapy. The companies did not provide breakdowns of how many patients used each regimen, which makes it difficult to assess the efficacy of combinations containing dolutegravir versus boosted elvitegravir, commented analyst Alex To of Cross Current Research in an April 2 note.

“The ultimate question is how does dolutegravir in combination with Epzicom compare to Quad. Both combinations could eventually be once-a-day single pills,” he wrote.

If it turns out that the best regimen is actually dolutegravir with Truvada (tenofovir/emtricitabine), doctors are likely to use that regimen, even if it means patients need to take two pills, he wrote. When Truvada goes generic, Viiv would have the option of making a fixed-dose combination pill with dolutegravir, he observed.