FDA Drug Approvals: Primary Care — Year in Review 2018

Mary L Windle, PharmD


January 15, 2019

New HIV Antiretrovirals

Trogarzo (ibalizumab)

The first-in-class CD4-directed postattachment inhibitor, ibalizumab, is indicated for HIV-1 infection in heavily treated adults with multidrug-resistant infection failing their current antiretroviral therapy (ART) regimen. It is used in combination with the patient's current ART regimen. Ibalizumab is a humanized monoclonal antibody that binds to extracellular domain 2 of the CD4 receptor. Ibalizumab does not inhibit HIV gp120 attachment to CD4; however, its postbinding conformational effects block the gp120-CD4 complex from interacting with CCR5 or CXCR4 and thus prevents viral entry and fusion.

Approval was based on the MB-301 phase 3 trial. MB-301 was a single-arm, 24-week study of ibalizumab plus optimized background regimen (OBR) in treatment-experienced patients infected with multidrug-resistant HIV-1. The primary objective was to demonstrate the antiviral activity of ibalizumab 7 days after the first dose. Patients receiving their current failing ART, or no therapy, were monitored during a 7-day control period. Thereafter, a single loading dose of ibalizumab 2000 mg IV was the only ART added to their regimen. The primary efficacy endpoint was the proportion of patients achieving a 0.510 or greater decrease in HIV-1 RNA 7 days after initiating ibalizumab therapy (ie, study day 14). Ibalizumab was continued at doses of 800 mg IV every 2 weeks through 24 weeks on study treatment.

The following study results were observed at 24 weeks:

  • Forty-three percent of study participants achieved viral suppression to fewer than 50 copies/µL and half to fewer than 200 copies/µL.

  • While 60% of those with a baseline CD4 count of greater than 50 cells/µL achieved undetectable viral load, this fell to less than 20% for those with lower CD4 counts.

  • Fifty-five percent of participants had at least a 1-log decrease, and 48% had at least a 2-log decrease in HIV RNA; the average reduction from baseline was 1.6 log.

  • The overall average CD4 cell gain was 48 cells/µL, but this differed according to baseline level; people who started with at least 50 cells/µL saw a mean gain of about 75 cells/µL, while those with lower baseline levels gained an average of 9 cells/µL.

(N Engl J Med. 2018 Aug 16;379(7):645-654)

Pifeltro (doravirine)

Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated in combination with other antiretroviral agents for treatment of HIV-1 infection in treatment-naive adults. It was also approved as the complete regimen combination product Delstrigo (doravirine/lamivudine/tenofovir DF).

Approval for doravirine was based on the DRIVE-FORWARD clinical trial, which showed noninferiority between doravirine and darunavir plus ritonavir (DRV+r), each in combination with FTC/TDF or ABC/3TC. (Lancet HIV. 2018 May;5(5):e211-e220)

Noninferiority was also demonstrated in the DRIVE-AHEAD study, which randomly assigned patients to once-daily treatment with doravirine/3TC/TDF or efavirenz/emtricitabine/TDF. (Clin Infect Dis. 2018 Aug 31)

Biktarvy (bictegravir/emtricitabine/tenofovir AF)

Bictegravir is an integrase strand transfer inhibitor (INSTI) that was FDA approved as a once-daily, fixed-dose combination tablet with emtricitabine/tenofovir AF in February 2018. This combination is indicated for the treatment of antiretroviral-naive patients or as a replacement for existing antiretroviral therapy in patients with viral suppression below 50 copies/µL for at least 3 months and no history of prior treatment failure or underlying resistance.

FDA approval of bictegravir was based in part on two phase 3, randomized, double-blind, noninferiority studies comparing the fixed-dose combination of bictegravir/emtricitabine/tenofovir AF with dolutegravir and lamivudine/abacavir administered either as separate components or as a coformulation in antiretroviral-naive patients. At 48 weeks, 89-92% and 93% of patients achieved viral suppression below 50 copies/µL in the bictegravir and dolutegravir treatment arms, respectively. (Lancet. 2017 Nov 4. 390(10107):2063-72; Lancet. 2017 Nov 4. 390(10107):2073-82)


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