PIFELTRO™ (doravirine 100 mg) tablets and DELSTRIGO™ (doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg) tablets

 

Resistance profile of PIFELTRO

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DRIVE-SHIFT: In a 48-week study, a doravirine-based fixed-dose combination (FDC)a demonstrated:

Zero cases of doravirine resistance in two subjects in the Immediate Switch Group (ISG)

DRIVE-SHIFT: In a 48-week study, a doravirine-based fixed-dose combination (FDC)^a demonstrated: Zero cases of doravirine resistance in two subjects in the Immediate Switch Group (ISG). Among the 656 subjects, 8 met protocol defined virologic failure (PDVF) criteria.^b In the Immediate Switch Group (ISG) (n=447), 6 subjects met PDVF criteria, there were 2 subjects with resistance data, and there were 0 cases of resistance to doravirine in the two subjects in the ISG. In the Delayed Switch Group (DSG) (n=209), 2 subjects met PDVF criteria and 1 subject failed on baseline regimen before switching to a doravirine-based FDC.^c Among the 656 subjects, 8 met protocol defined virologic failure (PDVF) criteriaImmediate Switch Group (n=447)bDelayed Switch Group(n=209)subjects met PDVF criteriasubjects met PDVF criteriasubjects with resistance datasubject failed on baseline regimen before switching to a doravirine-based FDCCcases of resistance to doravirine in the two subjects in the ISGZERO
  • aDoravirine-based FDC (DELSTRIGO) = doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg tablets.
  • bConfirmed HIV-1 RNA ≥50 copies/mL.
  • cThis subject developed the RT M184M/I substitution and phenotypic resistance to FTC and 3TC during treatment with their baseline regimen.

DRIVE-FORWARD (PIFELTRO + 2 NRTIs) and DRIVE-AHEAD (doravirine-based FDC): In two 96-week studies, doravirine demonstrated:

Low rate of resistance in treatment-naïve adults

DRIVE-FORWARD and DRIVE-AHEAD: Combined rates of resistance. 13 in the DOR treatment arms showed DOR resistance-associated substitutions.^d 8 subjects showed DOR phenotypic resistance^e and 5 subjects showed DOR phenotypic fold-changesof less than 2-fold.^f There was a 1.7% (13/747) combined rate of resistance with PIFELTRO + 2 NRTIs (DRIVE-FORWARD) and a doravirine-based FDC (DRIVE-AHEAD). Among the 747 subjects studied, 13 in the DOR treatment arms showed DOR resistance-associated substitutionssubjects showed DOR phenotypic resistanceesubjects showed DOR phenotypic fold-changesof <2-foldfcombined rate of resistance with PIFELTRO + 2 NRTIs (DRIVE-FORWARD) and a doravirine-based FDC (DRIVE-AHEAD)(13/747)81.7%5d
  • dThere were 36 subjects in the resistance analysis subset (HIV-1 RNA >400 copies per mL at virologic failure or early study discontinuation and having post-baseline resistance samples) from the doravirine treatment arms of 2 clinical trials evaluating a doravirine-based FDC (N=747) through week 96.
  • eMost subjects had at least a 100-fold reduction in doravirine susceptibility.
  • fSubjects had only amino acid mixtures of NNRTI resistance substitutions.

Of the 36 subjects in the resistance analysis subset, 10 subjects (28%) developed genotypic and/or phenotypic resistance to the other drugs (abacavir, emtricitabine, lamivudine, or tenofovir) in the regimens of the DRIVE-FORWARD and DRIVE-AHEAD trials.

In the DRV+r treatment arm of DRIVE-FORWARD (n=383) through week 96, no subjects showed the emergence of darunavir resistance-associated substitutions among 15 subjects with resistance data and 2 of the subjects had emergent genotypic or phenotypic resistance to lamivudine or tenofovir.

In the EFV/FTC/TDF treatment arm of DRIVE-AHEAD (n=364) through week 96, 15 subjects showed the emergence of efavirenz resistance-associated substitutions among 25 (60%) subjects in the resistance analysis subset and genotypic resistance to emtricitabine or tenofovir developed in 5 evaluable subjects; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), M184I or V (n=5), and K219K/E (n=1).

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Study design

DRIVE-SHIFT study design

A randomized, international, multicenter, open-label study of adults with virologically suppressed HIV-1 for ≥6 months on 2 NRTIs with a PI plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI, with no history of virologic failure. Patients either immediately switched to a doravirine-based FDC on Day 1 of the study for 48 weeks (ISG [n=447]) or continued on their baseline regimen and switched after 24 weeks to a doravirine-based FDC (DSG [n=223]).

  • Primary end point: Proportion of patients with HIV-1 ≥50 copies/mL: 2% for a doravirine-based FDC (ISG at week 48) vs 1% for baseline regimen (DSG at week 24). Difference (95% CI): 0.7 (-1.3, 2.6)
  • Additional efficacy end point: Proportion of patients with HIV-1 RNA <50 copies/mL in the Immediate Switch Group (ISG) at week 48 vs the Delayed Switch Group (DSG) at week 24: 91% for a doravirine-based FDC (ISG, n=447) vs 95% for a baseline regimen (DSG, n=223)

DRIVE-FORWARD study design

A randomized, multicenter, double-blind, active-controlled, non-inferior, phase 3 study comparing PIFELTRO 100 mg once daily (n=383) vs DRV 800 mg + ritonavir 100 mg once daily (n=383), each in combination with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator, in treatment-naïve adult patients with HIV-1 RNA ≥1000 copies/mL.1

  • Primary end point: Proportion of participants who had plasma HIV-1 RNA <50 copies/mL at week 48: 84% for PIFELTRO + 2 NRTIs (n=383) vs 80% DRV/r + 2 NRTIs (n=383). Difference (95% CI): 3.9 (-1.6, 9.4)1
  • Additional efficacy outcome: Proportion of participants who had plasma HIV-1 RNA <50 copies/mL at week 96: 72% for PIFELTRO + 2 NRTIs (n=383) vs 65% DRV/r + 2 NRTIs (n=383). Difference (95% CI): 7.5 (1.0, 14.1)

DRIVE-AHEAD study design

A randomized, multicenter, double-blind, active-controlled, non-inferior, phase 3 study comparing DOR 100 mg + 3TC 300 mg + TDF 300 mg once daily (n=364) vs EFV 600 mg + FTC 200 mg + TDF 300 mg once daily (n=364) in treatment-naïve adult patients with HIV-1 RNA ≥1000 copies/mL.2

Primary end points:

  • Proportion of participants who had plasma HIV-1 RNA <50 copies/mL at week 48: 84% for DELSTRIGO (n=364) vs. 81% EFV/FTC/TDF (n=364). Difference (95% CI): 3.5 (-2.0, 9.0)2
  • The proportion of participants with three pre-specified neuropsychiatric events (dizziness, sleep disorders/disturbances, and altered sensorium)2 at week 48.g Dizziness: 9% for DELSTRIGO vs 37% for EFV/FTC/TDF. Difference (95% CI): -28.3 (-34.0, -22.5); P<0.001.h Sleep disorders and disturbancesi: 12% for DELSTRIGO vs 26% for EFV/FTC/TDF. Difference (95% CI): -13.5 (-19.1, -7.9); P<0.001.h Altered sensoriumj: 4% for DELSTRIGO vs 8% for EFV/FTC/TDF. Difference (95% CI): -3.8 (-7.6, -0.3); P=0.033h

Additional efficacy end point: Proportion of participants who had plasma HIV-1 RNA <50 copies/mL at week 96: 77% for DELSTRIGO (n=364) vs. 74% EFV/FTC/TDF (n=364). Difference (95% CI): 3.8 (-2.4, 10.0).

  • gn=364 for each treatment group.
  • hThe 95% CIs were calculated using Miettinen and Nurminen's method.
  • iPredefined using MedDRA preferred terms, including: abnormal dreams, hyposomnia, initial insomnia, insomnia, nightmare, sleep disorder, and somnambulism.
  • jPredefined using MedDRA preferred terms, including: altered state of consciousness, lethargy, somnolence, and syncope.

Definitions

  • 3TC, lamivudine; ABC, abacavir; DOR, doravirine; DRV+r, darunavir/ritonavir; EFV, efavirenz; FDC, fixed-dose combination; FTC, emtricitabine; MedDRA, Medical Dictionary for Regulatory Activities; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RT, reverse transcriptase; TDF, tenofovir disoproxil fumarate.

References

  1. 1. Molina JM, Squires K, Sax PE, et al; for the DRIVE-FORWARD Study Group. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5(5):e211-e220. doi:10.1016/S2352-3018(18)30021-3. Epub 2018 March 25.
  2. 2. Orkin C, Squires KE, Molina JM, et al; for the DRIVE-AHEAD Study Group. Doravirine/lamivudine/tenofovir disoproxil fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results of the DRIVE-AHEAD trial. Clin Infect Dis. 2019;68(4):535-544. doi: 10.1093/cid/ciy540
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Indications

PIFELTRO is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine.

DELSTRIGO is indicated as a complete regimen for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO.

Selected Safety Information

Warning: Posttreatment Acute Exacerbation of Hepatitis B (HBV)

All patients with HIV-1 should be tested for the presence of HBV before initiating ARV therapy. Severe acute exacerbations of HBV have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Patients coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be monitored with both clinical and laboratory follow-up for at least several months after stopping DELSTRIGO. If appropriate, initiation of anti-HBV therapy may be warranted.

Contraindications

PIFELTRO and DELSTRIGO are 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 doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO and PIFELTRO.

DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.

Warnings and Precautions

Renal Impairment: New or Worsening of Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been reported with the use of TDF. DELSTRIGO should be avoided with concurrent or recent use of a nephrotoxic agent (eg, high-dose or multiple NSAIDs). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in patients with risk factors for renal dysfunction who appeared stable on TDF.

Prior to or when initiating DELSTRIGO, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue DELSTRIGO in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Discontinue DELSTRIGO if estimated creatinine clearance declines below 50 mL/min.

Bone Loss and Mineralization Defects

In clinical trials in HIV-1 infected adults, TDF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher. Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of TDF.

Immune Reconstitution Syndrome

Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

Drug Interactions

Because DELSTRIGO is a complete regimen, co-administration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.

Co-administration of PIFELTRO with efavirenz, etravirine, or nevirapine is not recommended.

If DELSTRIGO is co-administered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO.

If PIFELTRO is 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 more information on potential drug-drug interactions.

Dosage and Administration/Special Populations

Renal Impairment

Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min.

Adverse Reactions

The most common adverse reactions with DELSTRIGO (incidence ≥5%, all intensities) were dizziness (7%), nausea (5%), and abnormal dreams (5%). The most common adverse reactions with PIFELTRO (incidence ≥5%, all intensities) were nausea (7%), dizziness (7%), headache (6%), fatigue (6%), diarrhea (6%), abdominal pain (5%), and abnormal dreams (5%).

By Week 96 in DRIVE-FORWARD, 2% of adult subjects in the PIFELTRO group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication.

By Week 96 in DRIVE-AHEAD, 3% of adult subjects in the DELSTRIGO group and 7% in the EFV/FTC/TDF group had adverse events leading to discontinuation of study medication.

In DRIVE-FORWARD, mean changes from baseline at Week 48 in LDL-cholesterol (LDL-C) and non HDL-cholesterol (non-HDL-C) were pre-specified. LDL-C: -4.6 mg/dL in the PIFELTRO group vs 9.5 mg/dL in the DRV+r group. Non-HDL-C: -5.4 mg/dL in the PIFELTRO group vs 13.7 mg/dL in the DRV+r group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-AHEAD, mean changes from baseline at Week 48 in LDL-C and non-HDL-C were prespecified. LDL-C: -2.1 mg/dL in the DELSTRIGO group vs 8.3 mg/dL in the EFV/FTC/TDF group. Non-HDL-C: -4.1 mg/dL in the DELSTRIGO group vs 12.7 mg/dL in the EFV/FTC/TDF group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-SHIFT, mean changes from baseline at Week 48 in LDL-C and non-HDL-C were prespecified. LDL-C: -16.3 mg/dL in the DELSTRIGO group vs -2.6 mg/dL in the PI + ritonavir group. Non-HDL-C: -24.8 mg/dL in the DELSTRIGO group vs -2.1 mg/dL in the PI + ritonavir group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-AHEAD, neuropsychiatric adverse events were reported in the three pre-specified categories of sleep disorders and disturbances, dizziness, and altered sensorium. Twelve percent of adult subjects in the DELSTRIGO group and 26% in the EFV/FTC/TDF group reported neuropsychiatric adverse events of sleep disorders and disturbances; 9% in the DELSTRIGO group and 37% in the EFV/FTC/TDF group reported dizziness; and 4% in the DELSTRIGO group and 8% in the EFV/FTC/TDF group reported altered sensorium.

The safety of DELSTRIGO in virologically-suppressed adults was based on Week 48 data from subjects in the DRIVE-SHIFT trial. Overall, the safety profile in virologically-suppressed adult subjects was similar to that in subjects with no ARV treatment history.

Pregnancy/Breastfeeding

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO or DELSTRIGO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Mothers infected with HIV-1 should be instructed not to breastfeed if they are receiving PIFELTRO or DELSTRIGO due to the potential for HIV-1 transmission.

Before prescribing PIFELTROTM (doravirine), please read the accompanying Prescribing Information. The Patient Information also is available. Before prescribing DELSTRIGOTM (doravirine/lamivudine/tenofovir disoproxil fumarate), please read the accompanying Prescribing Information, including the Boxed Warning about posttreatment acute exacerbation of Hepatitis B. The Patient Information also is available.

US-DOR-0064210/20