Merck halts study of once-daily raltegravir

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Merck & Co announced today that it has halted a phase III study comparing once-daily dosing of the company’s HIV integrase inhibitor raltegravir to the standard twice-daily dose, on the recommendation of the trial's independent Data Safety Monitoring committee.

Although once-daily raltegravir (Isentress) did not prove statistically inferior to twice-daily raltegravir, fewer patients in the once-daily arm had a viral load suppressed below 50 copies/ml after 48 weeks of treatment.

This difference was chiefly driven by poorer viral suppression among people with high baseline viral loads (above 100,000 copies/ml), the company said in a press release.

Glossary

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

immune system

The body's mechanisms for fighting infections and eradicating dysfunctional cells.

first-line therapy

The regimen used when starting treatment for the first time.

The study randomised participants new to HIV treatment to receive 800mg of raltegravir once daily or 400mg of raltegravir twice daily, in combination with Truvada (tenofovir/FTC).

Among all participants (n=770), 83.2% of the once-daily group had viral load below 50 copies/ml at week 48, compared to 88.9% of the once-daily group. This difference (-5.7%) was within the pre-defined 95% confidence intervals (-10.7% - -0.83%).

However, among participants with baseline viral load above 100,000 copies/ml (n=304), the difference was greater. While 84.2% of the twice-daily raltegravir group had a viral load below 50 copies/ml within this viral load stratum by week 48, the proportion with fully suppressed viral load in the once-daily group was 74.3%.

Following an initial analysis of the data the trial’s Independent Data Monitoring Committee recommended that all patients in the once-daily arm should be switched to twice-daily raltegravir, and Merck & Co decided to halt the study.

Raltegravir is the first of a new class of antiretroviral drug, called integrase inhibitors, which block the integration of HIV’s genetic material into immune system cells. Raltegravir is currently licensed for twice-daily dosing in the United States and European Union, and is one of the recommended options for first-line antiretroviral therapy in US treatment guidelines.

A number of other companies are developing once-daily integrase inhibitors.

Gilead is currently testing elvitegravir, a once-daily integrase inhibitor that will be boosted with ritonavir or with Gilead’s own proprietary boosting agent, cobicistat. A phase III clinical trial of a pill combining elvitegravir, cobicistat, tenofovir and FTC is currently underway.

Another once-daily integrase inhibitor is being developed by Viiv Healthcare and Shionogi Pharmaceuticals, and has just entered phase III trials.