IQWiG Pans Gilead’s Stribild For HIV On Missing Data, Safety Concerns

Germany’s reimbursement watchdog IQWiG has panned Gilead’s HIV combination drug Stribild, saying it is inferior to existing therapies.

Gilead Sciences Inc.’s Stribild (tenofovir, emtricitabine, cobicistat and elvitegravir) seems to have taken off in the U.S. – but the HIV drug combination has been brought painfully down to earth in Europe’s biggest drug market by a comprehensive rejection from the German reimbursement watchdog IQWiG.

Also known as Quad, due to its four-drug, fixed-dose combination, Stribild combines the novel HIV integrase inhibitor elvitegravir with a novel “boosting” agent, cobicistat, and Gilead’s dual nucleoside/nucleotide reverse transcriptase inhibitor regimen Truvada (emtricitabine/tenofovir).

FDA approval on Aug. 27, 2012, made Stribild the first fixed-dose combination HIV drug approved before its individual novel components (Also see "The New Quad: FDA Approves Gilead’s 4-In-1 HIV Pill Stribild" - Pink Sheet, 27 Aug, 2012.).

The European authorization came almost a year later, with the European Commission giving it the nod on May 28 this year, for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve or are infected with HIV-1 without known mutations associated with resistance to any of the three antiretroviral agents in Stribild.

Non-Adherence

Despite the Commission’s take on the drug, IQWiG argued in its reimbursement assessment that for patients who already had received a previous treatment, the manufacturer failed to provide any convincing data. And the information submitted to IQWiG suggested that treatment-naïve patients experienced more adverse incidents and AIDS-related illnesses with Stribild than with the appropriate comparators selected by the senior health technology body, the Joint Federal Committee (G-BA).

The G-BA had proposed Bristol-Myers Squibb Co.’s Sustiva (efavirenz) in combination with Gilead’s own Viread (tenofovir) and Emtriva (emtricitabine), or in combination with ViiV Healthcare ’s Ziagen (abacavir) and GlaxoSmithKline PLC’s Epivir (lamivudine) for treatment-native patients. For pre-treated patients, it suggested that the therapy be adapted to the requirements of the patients, with a view to avoiding those treatments against which they had shown resistance or where a serious adverse event had arisen.

IQWiG said that while Gilead had agreed to employ the G-BA’s comparator of choice with regard to therapy naïve patients, the U.S. drug maker had instead provided additional results from a different comparator, namely a boosted protease inhibitor or Merck & Co. Inc.’s Isentress (raltegravir), each in combination with emcitrabine and tenofovir. The explanation offered by Gilead, according to IQWiG, was that the company did not consider these comparators to be in any way inferior to those set out by the G-BA.

In the case of patients who had received prior treatment, before its previous agreement, IQWiG said that Gilead actually had included some therapy-naïve patients because the manufacturer had been unable to identify any relevant study for pre-treated patients. IQWiG added that this presentation was unsuccessful because Gilead had failed to provide adequate scientific evidence that data from clinical studies involving therapy-naïve patients could be transferred across to those who had received prior treatment.

What’s more, although Gilead had agreed to use the comparator appointed by the G-BA for pre-treated patients, it did so in less therapy regimes than the committee had been expecting – EFV/FTC/TDF; ATV/r+FTC/TDF; and RAL+FTC/TDF – on the grounds that these were the most representative treatment combinations.

IQWiG said that restricting the number of combinations was unacceptable, as the G-BA had called for individually suited therapies.

A Lost Cause

Gilead’s case already was in a nose-dive at this point, but more downward pressure was still to come from IQWiG.

Indeed, for therapy-naive patients, Stribild offered a benefit over existing therapies in terms of avoiding non-serious side-effects such as skin rashes and illnesses of the nervous system. But IQWiG concluded that this was only a minor advantage. Stribild also offered minimal benefit to non-Caucasian patients in that they experienced only minor harm when forced to give up using the drug due to adverse events.

There simply were too many negatives for Stribild, with IQWiG citing the drug’s inability in therapy-naive patients to combat AIDS-related illnesses and the significant potential of serious harm from adverse events.

IQWiG concluded that for pre-treated patients, there simply were insufficient data for the reimbursement watchdog to draw a positive conclusion.

If Gilead had been hoping that the more favorable safety profile for Stribild compared to its older, cheaper triple-combination product Atripla (efavirenz/emtricitabine/tenofovir ) – which it had been touting in the U.S. – might hold some meaning for IQWiG, then it was mistaken (Also see "It’s Not Just Dosing: Stribild’s Side Effect Profile Could Give It An Edge In HIV Market" - Pink Sheet, 3 Sep, 2012.). And if its 35% premium price of Atripla in the U.S. is anything to go by, Gilead is going to have a job on its hands to convince the G-BA – which has the ultimate say in reimbursement matters in Germany – of the value of the Quad at a time when Europe is tightening its purse strings.

A spokesperson for Gilead noted that the IQWiG assessment is preliminary and based on clinical data that follow strict evidence-based methodologies. The company said it was ready to provide additional safety and efficacy data for the G-BA to consider in its final assessment.

“Given its potency and tolerability, Gilead believes that Stribild has the potential to become an important treatment option for a wide range of HIV patients in Germany and we will work with the G-BA to ensure it has the information it needs to fully evaluate the benefit of Stribild,” the spokesperson said.

Surprise Reaction?

IQWiG’s decision may raise some eyebrows across Europe, not least with the Medicines Patent Pool, a United Nations-backed health care organization (Also see "HIV Deal Between MPP And ViiV Healthcare Offers Future IP Blueprint" - Pink Sheet, 4 Mar, 2013.).

The Medicines Patent Pool signed its first agreement with a pharmaceutical company – Gilead Sciences – to improve access to HIV and Hepatitis B treatment in developing countries. The agreement allowed for the production of the HIV medicines tenofovir, emtricitabine, cobicistat and elvitegravir as well as a combination of these products, which constitute the Quad.

A spokesperson for the pool said there would be no comment until the organization had scrutinized the IQWiG report.