Delstrigo

DELSTRIGO^® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg:

• with no prior antiretroviral treatment history,
  OR
• to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO
  [see

  14 CLINICAL STUDIES

  14.1 Clinical Trial Results in Adults with No Antiretroviral Treatment History

  The efficacy of DELSTRIGO is based on the analyses of 96-week data from a randomized, multicenter, double-blind, active controlled Phase 3 trial (DRIVE-AHEAD, NCT02403674) in participants living with HIV with no antiretroviral treatment history (n=728).

  Participants were randomized and received at least 1 dose of either DELSTRIGO or EFV 600 mg/FTC 200 mg/TDF 300 mg once daily. At baseline, the median age of participants was 31 years, 15% were female, 52% were Non-White, 3% had hepatitis B or C coinfection, 14% had a history of AIDS, 21% had HIV-1 RNA greater than 100,000 copies/mL, and 88% had CD4+ T-cell count greater than 200 cells/mm³; these characteristics were similar between treatment groups. Week 96 outcomes for DRIVE-AHEAD are provided in Table 10.

  Mean CD4+ T-cell counts in the DELSTRIGO and EFV/FTC/TDF groups increased from baseline by 238 and 223 cells/mm³, respectively.

  Table 10: Virologic Outcome in DRIVE-AHEAD at Week 96 in HIV-1 Adult Participants with No Antiretroviral Treatment History

  Outcome	DELSTRIGO Once Daily N=364	EFV/FTC/TDF Once Daily N=364
  HIV-1 RNA <50 copies/mL	77%	74%
  Treatment Difference (95% CI)The 95% CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method.	3.8% (-2.4%, 10.0%)
  HIV-1 RNA ≥ 50 copies/mL Includes participants who discontinued study drug or study before Week 96 for lack or loss of efficacy and participants with HIV-1 RNA equal to or above 50 copies/mL in the Week 96 window.	15%	12%
  No Virologic Data at Week 96 Window	7%	14%
  Discontinued study due to AE or DeathIncludes participants who discontinued because of adverse event (AE) or death if this resulted in no virologic data in the Week 96 window.	3%	8%
  Discontinued study for Other ReasonsOther reasons include: lost to follow-up, non-compliance with study drug, physician decision, pregnancy, protocol deviation, screen failure, withdrawal by participant.	4%	5%
  On study but missing data in window	1%	1%
  Proportion (%) of Participants With HIV-1 RNA <50 copies/mL at Week 96 by Baseline and Demographic Category
  Gender
  Male	78% (N = 305)	73% (N = 311)
  Female	75% (N = 59)	75% (N = 53)
  Race
  White	80% (N = 176)	74% (N = 170)
  Non-White	76% (N = 188)	74% (N = 194)
  EthnicityDoes not include participants whose ethnicity or viral subtypes were unknown.
  Hispanic or Latino	81% (N = 126)	77% (N = 119)
  Not Hispanic or Latino	76% (N = 238)	72% (N = 239)
  Baseline HIV-1 RNA (copies/mL)
  ≤100,000 copies/mL	80% (N = 291)	77% (N = 282)
  >100,000 copies/mL	67% (N = 73)	62% (N = 82)
  CD4+ T-cell Count (cells/mm3)
  ≤200 cells/mm3	59% (N = 44)	70% (N = 46)
  >200 cells/mm3	80% (N = 320)	74% (N = 318)
  Viral Subtype
  Subtype B	80% (N = 232)	72% (N = 253)
  Subtype Non-B	73% (N = 130)	77% (N = 111)

  14.2 Clinical Trial Results in Virologically-Suppressed Adults

  The efficacy of switching from a baseline regimen consisting of two NRTIs in combination with a PI plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI to DELSTRIGO was evaluated in a randomized, open-label trial (DRIVE-SHIFT, NCT02397096), in virologically-suppressed adults living with HIV. Participants must have been virologically-suppressed (HIV-1 RNA <50 copies/mL) on their baseline regimen for at least 6 months prior to trial entry, with no history of virologic failure. Participants were randomized to either switch to DELSTRIGO at baseline [n = 447, Immediate Switch Group (ISG)], or stay on their baseline regimen until Week 24, at which point they switched to DELSTRIGO [n = 223, Delayed Switch Group (DSG)].

  At baseline, the median age of participants was 43 years, 16% were female, and 24% were Non-White, 21% were of Hispanic or Latino ethnicity, 3% had hepatitis B and/or C virus co-infection, 17% had a history of AIDS, 96% had CD4+ T-cell count greater than or equal to 200 cells/mm³, 70% were on a regimen containing a PI plus ritonavir, 24% were on a regimen containing an NNRTI, 6% were on a regimen containing elvitegravir plus cobicistat, and 1% were on a regimen containing a PI plus cobicistat; these characteristics were similar between treatment groups.

  Virologic outcome results are shown in Table 11.

  Table 11: Virologic Outcomes in DRIVE-SHIFT in HIV-1 Virologically-Suppressed Participants Who Switched to DELSTRIGO

  Outcome	DELSTRIGO Once Daily ISG Week 48 N=447	Baseline Regimen DSG Week 24 N=223
  HIV-1 RNA ≥ 50 copies/mL Includes participants who discontinued study drug or study before Week 48 for ISG or before Week 24 for DSG for lack or loss of efficacy and participants with HIV-1 RNA ≥50 copies/mL in the Week 48 window for ISG and in the Week 24 window for DSG	2%	1%
  ISG-DSG, Difference (95% CI)The 95% CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method.,Assessed using a non-inferiority margin of 4%.	0.7% (-1.3%, 2.6%)
  HIV-1 RNA <50 copies/mL	91%	95%
  No Virologic Data Within the Time Window	8%	4%
  Discontinued study due to AE or DeathIncludes participants who discontinued because of adverse event (AE) or death if this resulted in no virologic data on treatment during the specified window.	3%	<1%
  Discontinued study for Other ReasonsOther reasons include: lost to follow-up, non-compliance with study drug, physician decision, protocol deviation, withdrawal by participant.	4%	4%
  On study but missing data in window	0	0
  Proportion (%) of Participants With HIV-1 RNA <50 copies/mL by Baseline and Demographic Category
  Age (years)
  <50	90% (N = 320)	95% (N = 157)
  ≥50	94% (N = 127)	94% (N = 66)
  Gender
  Male	91% (N = 372)	94% (N = 194)
  Female	91% (N = 75)	100% (N = 29)
  Race
  White	90% (N = 344)	95% (N = 168)
  Non-White	93% (N = 103)	93% (N = 55)
  Ethnicity
  Hispanic or Latino	88% (N = 99)	91% (N = 45)
  Not Hispanic or Latino	91% (N = 341)	95% (N = 175)
  CD4+ T-cell Count (cells/mm3)
  <200 cells/mm3	85% (N = 13)	75% (N = 4)
  ≥200 cells/mm3	91% (N = 426)	95% (N = 216)
  Baseline Regimen Baseline Regimen = PI plus either ritonavir or cobicistat (specifically atazanavir, darunavir, or lopinavir), or elvitegravir plus cobicistat, or NNRTI (specifically efavirenz, nevirapine, or rilpivirine), each administered with two NRTIs.
  PI plus either ritonavir or cobicistat	90% (N = 316)	94% (N = 156)
  elvitegravir plus cobicistat or NNRTI	93% (N = 131)	96% (N = 67)

  14.3 Clinical Trial Results in Pediatric Participants

  The efficacy of DELSTRIGO was evaluated in cohort 2 of an open-label, single-arm 2-cohort trial in pediatric participants 12 to less than 18 years of age living with HIV (IMPAACT 2014 (Protocol 027), NCT03332095). In cohort 1, virologically-suppressed participants (n=9) received a single 100 mg dose of doravirine followed by intensive PK sampling. In cohort 2, virologically-suppressed participants (n=43) were switched to DELSTRIGO and treatment-naïve participants (n=2) were started on DELSTRIGO.

  In cohort 2, at baseline the median age of participants was 15 years (range: 12 to 17), the median weight was 52 kg (range: 45 to 80), 58% were female, 78% were Asian and 22% were Black, and the median CD4+ T-cell count was 713 cells per mm³(range 84 to 1397). After switching to DELSTRIGO, 95% (41/43) of virologically-suppressed participants remained suppressed (HIV-1 RNA <50 copies/mL) at Week 24. One of the two treatment-naïve participants achieved HIV-1 RNA <50 copies/mL at Week 24. The other treatment-naïve participant met the protocol-defined virologic failure criteria (defined as 2 consecutive plasma HIV-1 RNA test results ≥200 copies/mL at or after Week 24) and was evaluated for the development of resistance; no emergence of genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir was detected.

  ]
  .

• Testing: Prior to or when initiating DELSTRIGO, test for HBV infection. Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus
  .
  (
  2.1 Testing When Initiating and During Treatment with DELSTRIGO

  Prior to or when initiating DELSTRIGO, test patients for HBV infection

  [see Warnings and Precautions (5.2)].

  Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus

  [see Warnings and Precautions (5.3)].
  )
• Recommended dosage: One tablet taken orally once daily with or without food in adults and pediatric patients weighing at least 35 kg. (
  2.2 Recommended Dosage

  DELSTRIGO is a fixed-dose combination product containing 100 mg of doravirine (DOR), 300 mg of lamivudine (3TC), and 300 mg of TDF. The recommended dosage of DELSTRIGO in adults and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with or without food

  [see Clinical Pharmacology (12.3)]

  .
  )
• Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL per minute. (
  2.3 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

  [see Warnings and Precautions (5.3)and Use in Specific Populations (8.6)]

  .
  )
• Dosage adjustment with rifabutin: Take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine 100 mg (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO. (
  2.4 Dosage Adjustment with Rifabutin

  If DELSTRIGO is co-administered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine 100 mg (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO for the duration of rifabutin co-administration

  [see Drug Interactions (7.2)and Clinical Pharmacology (12.3)].
  )

DELSTRIGO film-coated tablets are yellow, oval-shaped tablets, debossed with the corporate logo and 776 on one side and plain on the other side. Each tablet contains 100 mg doravirine, 300 mg lamivudine, and 300 mg tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil).

• Pediatrics: Not recommended for patients weighing less than 35 kg. (
  8.4 Pediatric Use

  The safety and efficacy of DELSTRIGO for the treatment of HIV-1 infection have been established in pediatric patients weighing at least 35 kg

  [see Indications and Usage (1)and Dosage and Administration (2.2)]

  .

  Use of DELSTRIGO in this group is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, safety, and efficacy data from an open-label trial in virologically-suppressed or treatment-naïve pediatric participants 12 to less than 18 years of age. The safety and efficacy of DELSTRIGO in these pediatric participants were similar to that in adults, and there was no clinically significant difference in exposure for the components of DELSTRIGO.

  [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)].

  Safety and efficacy of DELSTRIGO in pediatric patients weighing less than 35 kg have not been established.
  )