HTB

FDA approves doravirine (Pifeltro) and new FDC with TDF/3TC (Delstrigo) in the US

Simon Collins, HIV i-Base

On 30 August 2018, the US FDA approved doravirine as a separate formulation for use with ART and in a fixed dose combination (FDA) 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 for adults (18 years and older) 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 contraindicated with drugs that are strong cytochrome P450 CYP3A enzyme inducers, because of the potential to reduce doravirine levels.

These drugs include, but are not limited to, the following:

•    Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin.

•    Androgen receptor inhibitor: enzalutamide

•    Antimycobacterials: rifampin, rifapentine.

•    Mitotane

•    St. John’s wort (Hypericum perforatum)

Doravirine is marketed in the US with the trade name Pifeltro and the doravirine/TDF/3TC FDC is marketed as Delstrigo. Both formulations were developed by Merck (MSD).

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The submission for EU approval is already underway, with the CHMP opinion due by 20 September and final decision expected late November.

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.

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]

The DRIVE-AHEAD study is now published as an open-access paper in CID. [3]

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).
    https://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 
  3. Orkin C et al. Doravirine/lamivudine/tenofovir disoproxil fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults with HIV–1 infection: week 48 results of the DRIVE-AHEAD trial. Clinical Infectious Diseases, ciy540. (August 2018).
    https://doi.org/10.1093/cid/ciy540

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