FDA Approves Quad in U.S.: Price May Prohibit UK Access

On 27 August 2012, both the US Food and Drug Administration (FDA) and Gilead Sciences issued news releases confirming the approval for a single pill boosted integrase inhibitor fixed dose combination for adult HIV treatment.

Developed under the name Quad and with a new tradename Stribild, the combination contains elvitegravir, a new pharmacokinetic booster called cobicistat, FTC and tenofovir. The indication is for treatment-naive patients with estimated creatinine clearance (CrCl) of >70 mL/min.^1,2

The two large phase 3 studies on which approval was based compared Quad to Atripla (efavirenz/FTC/tenofovir) and to atazanavir/ritonavir plus separate FTC/tenofovir. Both studies concluded that Stribild was non-inferior to the comparitor arms with 88-90% rates of undetectable viral load at week 48 compared to 84% with Atripla and 87% with boosted atazanavir.

The press release summarised nausea and diarrhoea as common side effects and new or worsening kidney problems, decreased bone mineral density, fat redistribution and changes in the immune system (immune reconstitution syndrome) as serious side effects.  Stribild's label gives advice to health care providers on how to monitor patients for kidney or bone side effects.

Stribild needs to be taken with food. This is based on increased mean exposure of elvitegravir and tenofovir by 34% and 24% respectively with a light meal (373 kcal, 20% fat) and by 83% and 23% respectively with a higher fat meal (~800 kcal, 50% fat).³

Of note, the US DHHS guidelines have already issued an update that recommends Stribild as an alternative rather than preferred option for first-line therapy. This decision was based on "a significant potential for drug-drug interactions, the availability of only 48 weeks of safety data, usage limited to individuals with pre-treatment CrCl >70 mL/min, a possible increased risk of proximal renal tubulopathy, limited data in patients with advanced HIV disease and in women, and the need for the drug to be taken with food".⁴

Comment

This decision was expected after the FDA advisory panel voted 13:1 in May 2012⁵ based on the 200-page briefing document summary of preclinical and clinical studies.⁶

But the expected welcome for an important new option for treatment is tempered by a US price more than a third higher than Atripla (approximately $28,500 vs $21,000 for the US annual wholesale list price). Although the European decision on approval is not expected until later this year, and drug pricing is complex, a similar differential in the UK would severely restrict prescribing.⁷

While Quad offers potential advantages to some current options, these were not demonstrated in the clinical trials that led to approval based on finding it is "not likely to be worse" than current treatment, based on a non significant 4% difference in the percentage of patients with undetectable viral load after 48 weeks of treatment.

Unless Stribild is a cost neutral option compared to Atripla, this potentially important new drug is likely to be rarely used in the UK. Without a cost-neutral price compared to boosted atazanavir or boosted darunavir, it is likely to be rarely used in second-line therapy, or as a switch option based on a better side effect profile compared to efavirenz. If the price is not cost-neutral compared to raltegravir, it is unlikely to be widely used in patients with multidrug resistance.

The cost differences are likely to widen further when efavirenz comes off patent in 2013, with costs savings from generic formulations expected to be sufficient to routinely switch patients from Atripla to efavirenz and separate tenofovir/FTC.

While switching between brand and generic formulations is a basic tenet of NHS healthcare, switching between classes is not.

Gilead have stated that this is a competitive price for the US market and that they have set up patient access programme. Gilead in the UK do not want to comment on European pricing prior to EU licensing.

References

1. Gilead press release: FDA Approves Gilead's Stribild, a Complete Once-Daily Single Tablet Regimen for Treatment-Naive Adults with HIV-1 Infection. (27 August 2012). www.gilead.com/pr_1728981
2. FDA press release: FDA approves new combination pill for HIV treatment for some patients. (27 August 2012). www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm317004.htm
3. Gilead. US Product information label for Stribild. Section 12.3 Pharmacokinetics, page 25. (August 2012). www.gilead.com/pdf/stribild_pi.pdf
4. HHS Panel Statement. HHS panel on antiretroviral guidelines for adults and adolescents recommends a fixed-dose combination product of elvitegravir/cobicistat/tenofovir/emtricitabine as an alternative regimen in antiretroviral treatment-naive Individuals with HIV-1 infection. (18 September, 2012). http://aidsinfo.nih.gov/contentfiles/AdultARVStatementOnEVG_COBI_TDF_FTC.pdf
5. FDA advisory panel vote 13:1 for approval of Quad. HTB, June 2012. http://i-base.info/htb/16640
6. Elvitegravir/Cobicistat/emtricitabine/tenofovir disoproxil fumerate single-tablet regimen (EVG/COBI/FTC/TDF, QUAD STR) for treatment of HIV-1 infection in adults. Antiviral Drugs Advisory Committee Meeting Briefing Document. (11 May 2012). www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM303397.pdf
7. Quad approved in US: cost may limit use in Europe. Online comment. http://i-base.info/gilead-price-quad/