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IAS 2015: Switching to Tenofovir Alafenamide Keeps HIV Suppressed, Helps Kidneys and Bones

People who switch from the current version of tenofovir (TDF) to tenofovir alafenamide (TAF) -- a new formulation that reaches higher levels in HIV-infected cells -- maintained undetectable viral load and saw improvements in kidney function biomarkers and bone density, according to a pair of studies presented at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention last week in Vancouver.

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IAS 2015: New NNRTI Doravirine Suppresses HIV as Well as Efavirenz But with Fewer CNS Side Effects

Merck's next-generation NNRTI doravirine (formerly known as MK-1439) was found to be as effective as efavirenz at suppressing HIV replication, but half as many study participants taking doravirine experienced drug-related adverse events -- in particular central nervous system (CNS) side effects -- and were less likely to stop treatment prematurely, according to study findings reported this week at the at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention this week in Vancouver.

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Gilead Requests FDA Approval of Tenofovir Alafenamide Single-Tablet Regimen

Gilead Sciences has requested U.S. Food and Drug Administration approval of a 1-pill-once-daily coformulation containing tenofovir alafenamide (TAF) -- a new formulation that is easier on the kidneys and bones -- plus emtricitabine and Jansen's NNRTI rilpivirine (Edurant), the company announced this week.

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IAS 2015: Maturation Inhibitor BMS-955176 Shows Good Antiviral Activity with Atazanavir

The next-generation HIV maturation inhibitor BMS-955176 was well-tolerated and suppressed HIV viral load as well as standard antiretroviral therapy (ART) when used in a combination with atazanavir (Reyataz) in a 28-day study, according to late-breaking results from a small study presented at the 8th International AIDS Society Conference this week in Vancouver.

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Combination ART consists of agents that target different steps of the HIV lifecycle, but none of the currently approved drugs inhibit viral assembly, maturation, and release from host cells. If larger studies confirm its safety and efficacy, BMS-955176 could be the first drug in a new class of antiretrovirals that may offer an important treatment option for people with HIV who have developed extensive resistance to existing drug classes.

HIV uses an infected cell's machinery to produce complex polyproteins that are then cut up by protease enzymes and assembled into new virus particles. The final steps include forming a capsid around new viral genetic material and "budding" out through the cell's membrane, resulting in a mature infectious virion. Maturation inhibitors like BMS-955176 interfere with protease cleavage between the viral p24 capsid protein and a smaller peptide in the Gag polyprotein, leading to the release of immature virus that cannot infect other cells.

An older maturation inhibitor candidate, bevirimat (PA-457), initially showed promising antiviral activity, but it was hampered by formulation problems. Worse, more than half of study participants had reduced susceptibility to bevirimat due to naturally occurring HIV Gag variations.

In early studies the newer maturation inhibitor BMS-955176 showed activity against HIV that was not susceptible to bevirimat, as well as virus with resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), NNRTIs, protease inhibitors, and integrase inhibitors.

BMS-955176 has a long half-life in the body, allowing for once-daily dosing, and no significant safety issues have been identified so far. In a proof-of-concept study presented at this year's Conference on Retroviruses and Opportunistic Infections, BMS-955176 reduced HIV RNA by about 1.6 log when used as monotherapy for 10 days.

Carey Hwang from the Bristol-Myers Squibb HIV Global Development Team and colleagues conducted a Phase 2a study to evaluate BMS-955176 used in conjunction with atazanavir for 28 days.

Due to the proximity of their sites of inhibition in the viral lifecycle, the drugs may have synergistic activity, the researchers noted as background. This combination could potentially offer a NRTI-sparing regimen for people who cannot tolerate or are resistant to NRTIs.

Study AI468002 (NCT01803074) enrolled 28 adults with HIV subtype B. Participants could be either treatment-naive or previously treated with drugs other than HIV protease inhibitors or maturation inhibitor candidates. All were men and most were white. At baseline the median CD4 T-cell count was approximately 500 cells/mm3 and the median viral load was about 4.2 log.

Study participants were randomly assigned to receive once-daily oral BMS-955176 at doses of either 40 mg or 80 mg plus either 300 mg atazanavir boosted with 100 mg ritonavir, or 400 mg unboosted atazanvir. A control group received standard therapy using tenofovir/emtricitabine (the drugs in Truvada) plus boosted atazanavir. Treatment continued for 28 days, with follow-up through day 42.

Results

  • Viral load rapidly declined in all treatment arms. Median declines in HIV RNA the day after the last dose ranged from -1.66 to -2.18 log in the 3 BMS-955176 arms, comparable to the -2.22 logdrop seen in the standard therapy arm.
  • Maximum median viral load declines were -2.02 logfor people taking 40 mg BMS-955176 with boosted atazanavir, -1.86 logfor those taking 40 mg BMS-955176 with unboosted atazanavir, and -2.23 logfor those taking 80 mg BMS-955176 with unboosted atazanavir, compared with -2.39 logusing standard therapy.
  • Short-term treatment with BMS-955176 was generally safe and well-tolerated, with no serious adverse events or study discontinuations due to adverse events. One person in the 80 mg arm developed transient neutropenia (low white blood cells).
  • A majority of people who used ritonavir-boosted atazanavir, either with 40 mg BMS-955176 or in the standard-of-care regimen, experienced grade 3-4 bilirubin elevations -- a known side-effect of atazanavir; however, this occurred in just 2 of the 16 people using unboosted atazanavir.
  • Bilirubin increased by a median of 60.0 mcmol/L in the 40 mg BMS-955176 plus boosted atazanavir arm and 41.8 in the standard therapy arm, compared with 11.8 and 7.7 mcmol/L, respectively, in the 40 mg and 80 mg BMS-955176 arms with unboosted atazanavir.

BMS-955176 80 mg plus atazanavir or BMS-955176 40 mg plus atazanavir and ritonavir "demonstrated similar antiviral activity compared to the standard of care control over the 28-day treatment period," the researchers concluded. "BMS-955176 plus unboosted atazanavir was associated with lower median changes from baseline in bilirubin levels compared to the arms with boosted atazanavir."

Bristol-Myers Squibb announced in a press release that a pair of Phase 2b studies of BMS-955176 have started this year: a traditional dose-finding study (NCT02415595) for treatment-naive people and a study evaluating a NRTI- and booster-sparing regimen for treatment-experienced patients.

7/21/15

Reference

C Hwang, D Schürmann, C Soboths, et al. Second-generation HIV-1 maturation inhibitor BMS- 955176: antiviral activity and safety with atazanavir +/- ritonavir. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Abstract TUAB0106LB.

Bristol-Myers Squibb. Second-Generation Investigational HIV-1 Maturation Inhibitor Demonstrates Positive New Phase IIa Results, Supporting Continued Development. Press release. July 21, 2015.

Gilead Requests Approval of Tenofovir Alafenamide Dual Combination Pill

Gilead Sciences has requested U.S. Food and Drug Administration approval of a combination pill containing emtricitabine plus tenofovir alafenamide (TAF), a new formulation that is easier on the kidneys and bones, according to a company press release. If approved, the new coformulation could take the place of Truvada for HIV treatment, though its effectiveness for pre-exposure prophylaxis, or PrEP, is not yet known.

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Tenofovir disoproxil fumarate or TDF (Viread, also in Truvada, Atripla, and other Gilead single-tablet regimens) is one of the most widely used antiretroviral drugs. TAF is a pro-drug that delivers the active agent to HIV-infected cells more efficiently than TDF. TAF produces adequate intracellular drug levels with lower doses, which means lower concentrations in the blood plasma and less drug exposure for organs and tissues.

As reported at the recent 2015 Conference on Retroviruses and Opportunistic infections, Phase 3 studies have shownthat a single-tablet regimen containing TAF, emtricitabine, elvitegravir, and cobicistat was equally effective at suppressing HIV but hadless detrimental effects on the kidneys and bones than the existing Stribild coformulation containing TDF.

Below is an edited excerpt from a Gilead press release describing the TAF/emtricitabine new drug application. The company has also requested approval of the 4-drug single-tablet regimen described above, and stand-alone TAF is being developed as a treatment for hepatitis B.

Gilead Submits New Drug Application to U.S. Food and Drug Administration for Fixed-dose Combination of Emtricitabine/Tenofovir Alafenamide for HIV Treatment

Potential New Backbone for Future HIV Therapy Combinations

Foster City, Calif. -- April 7, 2015 -- Gilead Sciences, Inc. (NASDAQ: GILD) today announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for two doses of an investigational fixed-dose combination of emtricitabine and tenofovir alafenamide (200/10 mg and 200/25 mg) (F/TAF) for the treatment of HIV-1 infection in adults and pediatric patients age 12 years and older, in combination with other HIV antiretroviral agents.

TAF is a novel nucleotide reverse transcriptase inhibitor(NRTI) that has demonstrated high antiviral efficacy at a dose less than one-tenth that of Gilead’s Viread (tenofovir disoproxil fumarate, TDF), as well as improved renal and bone laboratory parameters as compared to TDF in clinical trials.

"Gilead has a long history of innovating HIV treatments, and with F/TAF we have the potential to further optimize therapies for HIV patients who face a lifetime of antiretroviral treatment," said Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer, Gilead Sciences. "With its high antiviral efficacy and favorable safety profile, F/TAF may offer an improved backbone for a new generation of HIV regimens."

Today’s filing is Gilead’s second F/TAF-based NDA submitted to the FDA for review.  In November 2014, Gilead filed an NDA for an investigational once-daily single tablet regimen containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and TAF 10 mg (E/C/F/TAF). Under the Prescription Drug User Fee Act, the FDA has set a target action date of November 5, 2015. Additionally, a Marketing Authorization Application in the European Union for E/C/F/TAF was fully validated on December 23, 2014.

The F/TAF NDA is supported by data from Phase 3 clinical studies evaluating the safety and efficacy of E/C/F/TAF for the treatment of HIV-1 infection among treatment-naive adults, in which the F/TAF-based regimen (administered as E/C/F/TAF) resulted in non-inferior efficacy and improved renal and bone laboratory parameters as compared to F/TDF-based therapy (administered as E/C/F/TDF or Stribild).The NDA is also supported by data from additional Phase 3 studies evaluating the F/TAF-based regimen (administered as E/C/F/TAF) among treatment-naive adolescents, virologically suppressed adults who switched regimens, and adults with mild-to-moderate renal impairment. Lastly,bioequivalence studies demonstrated that the formulation of the fixed-dose combinations of F/TAF achieved the samedruglevelsin the blood as in E/C/F/TAF.

The recommended dose of F/TAF is 200/25 mg; if it is used in combination with a protease inhibitor that is administered with either ritonavir or cobicistat, the recommended dose is 200/10 mg.

Additional F/TAF-based regimens for HIV treatment are currently in development. In December 2014, Gilead announced the expansion of its existing agreements with Janssen Sciences Ireland UC for the development and commercialization of two new investigational once-daily single tablet regimens containing F/TAF. One combines F/TAF with Janssen’s rilpivirine. The other regimen contains F/TAF, cobicistat and Janssen’s darunavir.

Gilead plans to submit a regulatory application for F/TAF in the European Union in the second quarter of 2015.

F/TAF-based regimens are investigational products and have not been determined to be safe or efficacious.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need.  The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

4/8/15

Source

Gilead Sciences. Gilead Submits New Drug Application to U.S. Food and Drug Administration for Fixed-dose Combination of Emtricitabine/Tenofovir Alafenamide for HIV Treatment. Press release. April 7, 2014.