KENILWORTH, N.J.) Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved Pifeltro (doravirine, 100 mg), a new non-nucleoside reverse transcriptase inhibitor (NNRTI) to be administered in combination with other antiretroviral medicines. Pifeltro is indicated for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience, and is administered orally once daily with or without food. Pifeltro does not cure HIV-1 infection or AIDS.
The FDA also approved Delstrigo, a once-daily fixed-dose combination tablet of doravirine (100 mg), lamivudine (3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg).
Pifeltro is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of Pifeltro.
Data Supporting the Approval of Pifeltro (doravirine)
The FDA approvals of Delstrigo and Pifeltro are based on findings from the pivotal, randomized, multicenter, double-blind, active controlled Phase 3 trials, DRIVE-AHEAD and DRIVE-FORWARD, evaluating the efficacy and safety of Delstrigo and Pifeltro, respectively, in participants infected with HIV-1 with no antiretroviral treatment history.
The DRIVE-FORWARD Clinical Trial
In DRIVE-FORWARD, 766 participants with no antiretroviral treatment history were randomized and received at least one dose of either Pifeltro once daily or darunavir 800 mg + ritonavir 100 mg (DRV+r) once daily, each in combination with emtricitabine (FTC)/TDF or abacavir (ABC)/3TC selected by the investigator. Pifeltro demonstrated sustained viral suppression through 48 weeks, meeting its primary endpoint of non-inferior efficacy compared to DRV+r, each in combination with FTC/TDF or ABC/3TC (84% in the Pifeltro group achieved viral suppression of HIV-1 RNA <50 copies/mL vs. 80% in the DRV+r group; treatment difference: 3.9%, [95% CI:] -1.6%, 9.4%). Of the 20 percent of study participants with a high viral load at baseline (HIV-1 RNA >100,000 copies/mL), 77 percent in the Pifeltro group and 74 percent in the DRV+r group achieved HIV-1 RNA <50 copies/mL at Week 48.
At Week 48, Pifeltro-treated participants showed statistically significant superior lipid profiles as measured by changes from baseline in LDL-cholesterol and non-HDL-cholesterol (LDL-C: -4.6 mg/dL in the Pifeltro group vs. 9.5 mg/dL in the DRV+r group; treatment difference: -14.4 mg/dL, [95% CI:] -18.0, -10.8, p<0.0001; non-HDL-C: -5.4 mg/DL in the Pifeltro group vs. 13.7 mg/dL in the DRV+r group, treatment difference: -19.4 mg/dL, [95% CI:] -23.4, -15.4, p<0.0001). However, the clinical benefit of these findings has not been demonstrated.
The rate of discontinuation of therapy due to adverse events in either treatment group was low (2% in the Pifeltro group and 3% in the DRV+r group). Clinical adverse reactions of all grades occurring in ≥5 percent of participants in the Pifeltro treatment group included nausea (7%), headache (6%), fatigue (6%), diarrhea (5%) and abdominal pain (5%). No adverse reactions of Grade 2 or higher (moderate or severe) occurred in ≥2 percent of participants treated with Pifeltro.
Pifeltro can be co-administered with a wide range of antiretroviral agents and non-antiretroviral agents. Pifeltro cannot be co-administered with enzalutamide, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, mitotane or St. John’s wort. If Pifeltro is co-administered with rifabutin, patients need to increase the Pifeltro dosage to one tablet twice daily approximately 12 hours apart. Use of Pifeltro with efavirenz, etravirine, or nevirapine is not recommended.
No clinically significant changes in concentration have been observed following the co-administration of doravirine and the following drugs: dolutegravir, ritonavir, TDF, 3TC, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam.
Overall Viral Resistance Profile
In the Delstrigo and Pifeltro treatment arms of the DRIVE-AHEAD and DRIVE-FORWARD trials (n=747), a total of 11 participants showed the emergence of doravirine-associated resistance substitutions, among the 28 participants in the resistance analysis subset (participants with HIV-1 RNA >400 copies per mL at virologic failure or early study discontinuation and having resistance data). Of these 11 participants, seven showed both genotypic and phenotypic resistance to doravirine, with at least a 100-fold reduction in susceptibility to doravirine. The other four participants had substitutions that were associated with less than twofold reduction in susceptibility to doravirine.
In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364), 12 participants showed the emergence of efavirenz-associated resistance substitutions among 20 participants in the resistance analysis subset. In the DRV+r treatment arm of the DRIVE-FORWARD trial (n=383), no participants showed the emergence of DRV+r associated resistance substitutions among the nine participants with resistance data.
Cross-resistance has been observed among NNRTIs, including doravirine. Treatment-emergent doravirine resistance-associated substitutions can confer cross-resistance to efavirenz, rilpivirine, nevirapine and etravirine. No significant cross-resistance has been demonstrated between doravirine-resistant HIV-1 variants and 3TC, FTC or tenofovir or between 3TC or tenofovir-resistant variants and doravirine.
Pifeltro (doravirine) Availability and Access
The approval of Pifeltro comes ahead of the original FDA target action date of Oct. 23, 2018. Merck anticipates that Pifeltro will be stocked through wholesalers within one month. Merck is working to obtain access for patients in government-sponsored programs, including Medicare Part D, Medicaid and AIDS Drug Assistance Programs. Upon approval, Pifeltro will be covered under the Merck Patient Assistance Program and will be available to eligible patients when the medicine is available. Doravirine is also under regulatory review by the European Medicines Agency (EMA).
Selected Safety Information about Pifeltro (doravirine)
Pifeltro is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers (including the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the androgen receptor inhibitor enzalutamide; the antimycobacterials rifampin and rifapentine; the cytotoxic agent mitotane; and the herbal product St. John’s wort (Hypericum perforatum)), as significant decreases in Pifeltro plasma concentrations may occur, which may decrease the effectiveness of Pifeltro. Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment. Co-administration of Pifeltro with efavirenz, etravirine or nevirapine is not recommended. If co-administered with rifabutin, increase Pifeltro dosage to one tablet twice daily (approximately 12 hours apart).
Consult the full Prescribing Information prior to and during treatment for important potential drug-drug interactions. The safety of Pifeltro is based on two studies, DRIVE-FORWARD and DRIVE-AHEAD. In DRIVE-FORWARD, the most common adverse reactions (incidence ≥5%, all intensities) were nausea (7%), headache (6%), fatigue (6%), diarrhea (5%) and abdominal pain (5%). In DRIVE-AHEAD, the most common adverse reactions (incidence ≥5%, all intensities) were dizziness (7%), abnormal dreams (5%) and nausea (5%).
There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to Pifeltro during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Mothers infected with HIV-1 should be instructed not to breastfeed if they are receiving Pifeltro due to the potential for HIV transmission.
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