www.hivandhepatitis.com

FDA Approves Gilead's Genvoya Single-tablet Regimen with Tenofovir Alafenamide

The U.S. Food and Drug Administration (FDA) announced on November 5 the approval of Gilead Sciences' Genvoya, a new once-daily single-tablet regimen containing the integrase inhibitor elvitegravir, the booster cobicistat, emtricitabine, and tenofovir alafenamide (TAF) -- a new formulation that is easier on the kidneys and bones than the older tenofovir disoproxil fumarate (TDF).

"Today’s approval of a fixed-dose combination containing a new form of tenofovir provides another effective, once-daily complete regimen for patients with HIV-1 infection," Edward Cox, director of the FDA's Office of Antimicrobial Products, said in an FDA press release.

Genvoya is the first approved product containing TAF, a pro-drug that delivers the active agent, tenofovir diphosphate, to HIV-infected cells more efficiently than the current TDF formulation (Viread, also in Truvada, Atripla, Complera, and Stribild). The new coformulation is similar to Stribild, but with 10mg of TAF replacing 300mg of TDF.

One of the most widely used antiretroviral drugs, TDF is considered generally safe and well-tolerated, but it can cause a small amount of bone loss soon after starting therapy and can lead to kidney problems in susceptible individuals. TAF produces adequate intracellular drug levels with smaller doses, which means lower concentrations in the blood and less drug exposure for the kidneys, bones, and other organs and tissues.

FDA approval of Genvoya was based on data from Phase 3 randomized clinical trials enrolling more than 3000 participants, which showed that TAF-containing regimens work as well as TDF-containing regimens at suppressing HIV replication, but with less kidney and bone toxicity. Nausea was the most common side effect seen in these studies.

Genvoya was approved for use by previously untreated HIV-positive adults and children ages 12 years and older and weighing at least 35 kilograms (about 77 pounds), and for adults switching from a stable suppressive antiretroviral regimen who have no prior history of treatment failure.

Genvoya is not recommended for people with severe kidney function impairment (eGFR 30 mL/min), but it can be used by those with moderate impairment. In clinical trials of Genvoya there were no cases of Fanconi syndrome or proximal renal tubulopathy, 2 types of serious kidney disease, among people with normal kidney function at baseline (eGFR >50 mL/minute). While TAF is active against hepatitis B virus (HBV), Genvoya is not approved as a treatment for hepatitis B and stopping it could lead to sudden worsening of hepatitis B.

U.S. Full Prescribing Information, including a BOXED WARNING, for Genvoya is available at www.gilead.com.

First-Line Genvoya

Two international studies (Study 104 and Study 111) did a head-to-headcomparison of first-line treatment using either Genvoya or Stribild. Together they enrolled 1733 treatment-naive participants with near-normal kidney function.

As described at this year's Conference on Retroviruses and Opportunistic Infections (CROI), after 48 weeks of treatment 92% of people taking Genvoya and 90% taking Stribild had undetectable viral load. As reported at the recent European AIDS Conference in Barcelona,at 96 weeks response rates were 87% and 85%, respectively. Virological outcomes did not differ by age, sex, race/ethnicity, geographic region, baseline viral load, or CD4 count.

Treatment was generally safe and well-tolerated, with low rates of serious adverse events and discontinuation due to adverse events, but TAF had less detrimental effects on the kidneys and bones. Various laboratory tests of kidney function favored the TAF regimen. People taking Genvoya had significantly smaller mean decrease in spine and hip bone mineral density at 96 weeks. Total, LDL, and HDL cholesterol increases were larger in the TAF arm (a known side effect of tenofovir), but the total-to-HDL cholesterol ratio remained stable.

Other studies showed that Genvoya was safe and effective for previously untreated people with pre-existing kidney impairment (eGFR 30-69 mL/min) (Study 112) and for treatment-naive adolescents with HIV (Study 106).

Switching to Genvoya

Another Phase 3 trial (Study 109) showed that people who switched from a combination regimen containing TDF to Genvoya maintained viral suppression while seeing improvement in kidney and bone markers.

As described at the International AIDS Society Conference this summer in Vancouver, Tony Mills from the Southern California Men’s Medical Group and colleagues studied 1436 treatment-experienced people with normal kidney function who at study entry had stable viral suppression while taking Stribild; the efavirenz/TDF/emtricitabine coformulation (Atripla); or atazanavir (Reyataz), boosted with either ritonavir or cobicistat, plus TDF/emtricitabine (Truvada). They were randomly assigned to either stay on their current TDF-containing regimen or switch to Genvoya.

After48 weeks, virological response rates were high in both groups -- 97% with Genvoya and 93% with existing regimen -- showing that switching to Genvoya was non-inferior to staying on a TDF-containing regimen. People who switched from Atripla or atazanavir had significantly better responses, while those who switched from Stribild did about the same.

Overall safety and tolerability were good in both treatment groups, with few discontinuations due to adverse events. People who switched to Genvoya experienced improvements in kidney function markers, while those who stayed on TDF-containing regimens worsened. Spine and hip bone density rose in the Genvoya arm while falling among those who stayed on their existing regimens, and people who switched saw significant improvements in osteoporosis. Again, blood lipid changes were larger with the TAF-containing regimen and more people taking Genvoya started lipid-modifying medication.

TAF Going Forward

Gilead set the wholesale price for Genvoya at about the same level as Stribild, approximately $31,000 annually. The Fair Pricing Coalition welcomed this move, but urged the company to negotiate discounts for cash-strapped public insurance programs such as Medicaid.

In addition to Genvoya, Gilead has also requested approval of another TAF-containing single-tablet regimen containing NNRTI rilpivirine (which would be a successor to Complera) anda dual coformulation of TAF and emtricitabine (a successor to Truvada). Stand-alone TAF is being developed as a treatment for hepatitis B.

Importantly, tenofovir alafenamide has not yet been adequately studied for pre-exposure prophylaxis (PrEP), and it potentially may not work as well as TDF because it does not build up as much in body tissues. Asked about the role of TAF for HIV prevention at CROI, Marshall Fordyce from Gilead said the company is collaborating with the Centers for Disease Control and Prevention on a study of TAF and emtricitabine PrEP in monkeys.

"As the HIV patient population ages there is an increased risk for development of age- and treatment-related comorbidities, including low bone mineral density and renal impairment. This is due to the combination of HIV infection, antiretroviral treatments, and the natural aging process," Study 104/111 lead investigator David Wohl from the University of North Carolina at Chapel Hill said in a Gilead press release. "Given its demonstrated efficacy and safety profile, Genvoya represents an important new treatment option for a range of patients who are either new to therapy or who choose to switch treatments."

11/5/15

Sources

U.S. Food and Drug Administration. FDA approves new treatment for HIV. Press release. November 5, 2015.

R Klein, K Struble, and S Morin, U.S. Food and Drug Administration. FDA approved GENVOYA as a complete regimen for the treatment of HIV-1 infection. FDA alert. November 5, 2015.

Gilead Sciences. U.S. Food and Drug Administration Approves Gilead’s Single Tablet Regimen Genvoya (Elvitegravir, Cobicistat, Emtricitabine and Tenofovir Alafenamide) for Treatment of HIV-1 Infection. Press release. November 5, 2015.

Fair Pricing Coalition. Fair Pricing Coalition welcomes Gilead Sciences’ pricing of its new single- tablet regimen Genvoya in parity with Stribild, urges controlled costs across U.S. payer landscape. Press release. November 9, 2015.