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FDA Approves Doravirine (Pifeltro) and New FDC With TDF/3TC (Delstrigo) in the U.S.

August 31, 2018

On 30 August 2018, the U.S. FDA approved doravirine as a separate formulation for use with ART and in a fixed-dose combination (FDC) with generic tenofovir DF and lamivudine (3TC).1

Doravirine is a once daily NNRTI that was initially developed as MK-1439. The standard adult dose is 100 mg once-daily, with or without food.

Approval is based on results from two large international randomised phase 3 studies in treatment-naive participants with control arms using darunavir (in DRIVE-FORWARD) and efavirenz (in DRIVE-AHEAD).

Each study reported primary endpoint results of viral suppression <50 copies/mL at 48 weeks in 84% vs approximately 81% (doravirine vs control respectively), with 95% confidence intervals that confirmed non-inferiority.

Although discontinuation rates were low in all study arms, tolerability advantages favoured doravirine from fewer darunavir/ritonavir-associated or efavirenz-associated side effects.

Doravirine is marketed in the U.S. with the trade name Pifeltro and the FDC is marketed as Delstrigo. Both formulations were developed by Merck (MSD).


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Comment

Although most treatment guidelines now recommend integrase inhibitor-based first line treatment, drug-pricing is also increasingly important.

Doravirine has a better tolerability profile compared to efavirenz (which is still widely-used despite the guidelines).

The FDA indication is only for people who are treatment-naive. However, in vitro, doravirine retains sensitivity to common NNRTI resistance mutations (K103N, Y181C, G190A, E101K, E138K, and K103N/Y181C), with a profile that suggests limited cross-resistance to rilpivirine and etravirine. In vivo, doravirine selects for distinct mutations (V106A and F227L) that remain sensitive to rilpivirine and efavirenz (with possible increased sensitivity to the NRTI MK-8591).

Several studies in treatment-experienced participants are ongoing, but only as switch options in people with current viral suppression.

Development of a paediatric granule formulation has been delayed by a waiver on the grounds that doravirine does not represent a significant therapeutic benefit over existing treatments. The timeline for completing the paediatric plan is 2024.

Doravirine is also included in an FDC with 3TC plus the investigational NRTI EFdA (MK-8591), with phase 2 results expected in mid-2019.2


References

  1. Merck (MSD) press release. FDA approves Merck's Delstrigo (doravirine/lamivudine/tenofovir disoproxil fumarate), a once-daily fixed-dose combination tablet as a complete regimen and Pifeltrotm (doravirine), an NNRTI, both for the treatment of HIV-1 in appropriate patients. (30 August 2018).
    www.mrknewsroom.com
  2. ClinicalTrials.gov. MK-8591 with doravirine and lamivudine in participants infected with HIV type 1 (MK-8591-011) (DRIVE2Simplify). NCT03272347.
    https://clinicaltrials.gov/ct2/show/NCT03272347

[Note from TheBodyPRO: This article was originally published by HIV i-Base on Aug. 31, 2018. We have cross-posted it with their permission.]


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