FDA Approves Two New Treatments for HIV

The US Food and Drug Administration (FDA) has approved 2 new HIV-1 medicines produced by Merck, a once daily fixed dose combination tablet of doravirine (100 mg), lamivudine (3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg) (doravirine/3TC/TDF) (DELSTRIGO); and doravirine 100 mg (PIFELTRO) a new non-nucleoside reverse transcriptase inhibitor (NNRTI) to be administered alongside other antiretroviral medicines.

Both drugs are approved for the treatment of HIV-1 infection in adult treatment-naïve patients and are administered orally once daily.

“As part of Merck’s 30-year commitment to the care of people with HIV, we are pleased to now bring forward these two new antiretroviral treatment options, DELSTRIGO and PIFELTRO, which we believe offer a compelling clinical profile for clinicians and people living with HIV,” said George Hanna, MD, vice president and therapeutic area head of infectious diseases, Global Clinical Development, Merck Research Laboratories in a statement. “We are thankful to the researchers as well as those living with HIV and their communities for the collaboration that made today’s approval possible.”

The approvals by the FDA were based on data from the phase 3 trials DRIVE-AHEAD and DRIVE-FORWARD.

In DRIVE-AHEAD, 728 treatment-naïve adults infected with HIV were randomized to receive doravirine/3TC/TDF or efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) once daily. doravirine/3TC/TDF demonstrated viral suppression through 48 weeks and met the primary endpoint of non-inferior efficacy.

Of the 21% of participants with a high viral load at baseline (HIV-1 RNA >100,000 copies/mL), 77% in the doravirine/3TC/TDF group and 72% in the EFV/FTC/TDF group achieved HIV-1 RNA <50 copies/mL at Week 48.

At Week 48, participants treated with doravirine/3TC/TDF showed statistically significant superior lipid profiles which were measured by changes from baseline in LDL-cholesterol and non-HDL-cholesterol (LDL-C: -2.1 mg/dL in the doravirine/3TC/TDF group vs. 8.3 mg/dL in the EFV/FTC/TDF group; treatment difference: -10.2 mg/dL, [95% CI:] -13.8, -6.7, p<0.0001; non-HDL-C: -4.1 mg/dL in the doravirine/3TC/TDF group vs. 12.7 mg/dL in EFV/FTC/TDF; treatment difference: -16.9 mg/dL, [95% CI:] -20.8, -13.0, p<0.0001). However, according to Merck, the clinical benefit of these findings has not been demonstrated.

In addition, fewer neuropsychiatric adverse events were reported in participants treated with doravirine/3TC/TDFcompared to EFV/FTC/TDF-treated participants, including: 3 pre-specified categories of dizziness (9% vs. 37%; treatment difference: -28.3%, [95% CI:] -34.0, -22.5, p <0.001), sleep disorders and disturbances (12% vs. 26%; treatment difference: -13.5%, [95% CI:] -19.1, -7.9, p <0.001), and altered sensorium (4% vs. 8%; treatment difference: -3.8%, [95% CI:] -7.6, -0.3, p=0.033).

Additionally, doravirine/3TC/TDF contains a boxed warning regarding post-treatment acute exacerbation of hepatitis B infection.

In DRIVE-FORWARD, 766 treatment naïve participants were randomized and received at least 1 dose of either doravirine once daily or darunavir 800 mg + ritonavir 100 mg (DRV+r) once daily, each in combination with either emtricitabine (FTC)/TDF or abacavir (ABC)/3TC. doravirine maintained 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. In the doravirine group 84% of participants 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% of study participants with a high viral load at baseline (HIV-1 RNA >100,000 copies/mL), 77% in the doravirine group and 74%in the DRV+r group achieved HIV-1 RNA <50 copies/mL at Week 48.

At Week 48, doravirine -treated participants showed statistically significant superior lipid profiles which were measured by changes from baseline in LDL-cholesterol and non-HDL-cholesterol(LDL-C: -4.6 mg/dL in the doravirine 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 due to adverse events in either treatment group was 2% in the doravirine group and 3% in the DRV+r group.

According to a statement issued by Merck both therapies can be administered in combination with a variety of non-ART agents, according to investigators, and doravirine can also be co-administered with a range of ART agents as well. Both treatments are contraindicated when co-administered with strong cytochrome P450 (CYP) 3A enzyme-inducing therapies. This can cause significant decreases in doravirine plasma concentrations which could then decrease the effectiveness of both drugs.

The approvals of doravirine/3TC/TDF and Doravirine come ahead of the original FDA target action date of Oct. 23, 2018. Merck has indicated the expectation that Doravirine and doravirine/3TC/TDF will be stocked through wholesalers within a month.

Doravirine is also under regulatory review by the European Medicines Agency (EMA).