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Date: 2018-09-20

Type of information: Positive opinion for the granting of a Market Authorisation in the EU

Product name: Delstrigo™ (doravirine / lamivudine / tenofovir disoproxil fumarate)/Pifeltro™ (doravirine)

Compound: doravirine with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF)

Therapeutic area: Infectious diseases

Action mechanism:

  • non-nucleoside reverse transcriptase inhibitor (NNRTI). Doravirine is an investigational non-nucleoside reverse transcriptase inhibitor being evaluated for the treatment of HIV-1 infection. In early clinical studies, doravirine demonstrated a pharmacokinetic profile supportive of once-daily dosing and the ability to be dosed with or without food.
  • Doravirine is being evaluated in several ongoing clinical trials both as a once-daily single-entity tablet in combination with other antiretroviral agents in a tailored regimen, and as a once-daily fixed-dose combination (DOR/3TC/TDF) in a complete single tablet regimen. Phase 3 trials include DRIVE-FORWARD, a trial comparing DOR to once-daily ritonavir-boosted darunavir (DRV+r), each administered in combination with FTC/TDF or abacavir (ABC)/3TC, in treatment-naïve adults; DRIVE-AHEAD, a trial comparing DOR/3TC/TDF to EFV/FTC/TDF in treatment-naïve adults; and DRIVE-SHIFT, a trial evaluating a switch to DOR/3TC/TDF in HIV-1 infected adults who are currently virologically suppressed on another antiretroviral regimen. Other ongoing Phase 2 clinical trials include an evaluation of DOR/3TC/TDF in treatment-naïve adults with transmitted resistance to NNRTIs and in individuals switching from EFV due to intolerability.
  • Lamivudine and tenofovir disoproxil are substrates and competitive inhibitors of HIV reverse transcriptase.

Company: Merck&Co (USA - NJ)

Disease: HIV-1 infection in adults

Latest news:

  • • On September 20, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Delstrigo™, intended for the treatment of HIV-1 infection. This fixed dose combination of three active substances, doravirine, lamivudine and tenofovir disoproxil will be available as 100 mg / 300 mg / 245 mg film-coated tablets . The benefits with Delstrigo are its ability to achieve a potent antiretroviral response in a once daily, single pill regimen. The most common side effects are nausea and headache. The full indication is: “Delstrigo is indicated for the treatment of adults infected with HIV-1 without past or present evidence of resistance to the NNRTI class, lamivudine, or tenofovir." It is proposed that Delstrigo be prescribed by physicians experienced in the management of HIV infection. Marketing authorization applications for Delstrigo™ and Pifeltro™ are also under review in other countries, including Canada, Australia, and Switzerland.
  • The CHMP positive opinion was based on findings from two 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 prior antiretroviral treatment history.
  • In DRIVE-AHEAD, Delstrigo™ demonstrated sustained viral suppression through 48 weeks, meeting its primary endpoint of non-inferior efficacy compared to efavirenz (EFV)/emtricitabine (FTC)/TDF.
  • In DRIVE-FORWARD, Pifeltro™ demonstrated sustained viral suppression through 48 weeks, meeting its primary endpoint of non-inferior efficacy compared to darunavir + ritonavir, each in combination with FTC/TDF or abacavir (ABC)/3TC.
  • • On August 30, 2018, the  FDA has approved two new HIV-1 medicines: Delstrigo™ (doravirine / lamivudine / tenofovir disoproxil fumarate), a once-daily fixed-dose combination tablet as a complete regimen and Pifeltro™ (doravirine), an NNRTI to be administered in combination with other antiretroviral medicines. Both Delstrigo™ and Pifeltro™ are indicated for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience, and are administered orally once daily with or without food. Delstrigo™ contains a boxed warning regarding post-treatment acute exacerbation of hepatitis B (HBV) infection. Delstrigo™and Pifeltro™ do not cure HIV-1 infection or AIDS. Delstrigo™ and Pifeltro™ are 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 Delstrigo™and Pifeltro™. Delstrigo™ is contraindicated in patients with a previous hypersensitivity reaction to 3TC.
  • The FDA approvals of Delstrigo™, the once-daily fixed-dose combination tablet as a complete regimen, and Pifeltro™, a new NNRTI, 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-AHEAD Clinical Trial: In DRIVE-AHEAD, 728 participants with no antiretroviral treatment history were randomized and received at least one dose of either Delstrigo™ or efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV 600 mg/FTC 200 mg/TDF 300 mg) once daily. Delstrigo™ demonstrated sustained viral suppression through 48 weeks, meeting its primary endpoint of non-inferior efficacy compared to EFV/FTC/TDF (84% in the Delstrigo™ group achieved viral suppression of HIV-1 RNA <50 copies/mL vs. 81% in the EFV/FTC/TDF group; treatment difference: 3.5%, [95% CI:] -2.0%, 9.0%). Of the 21 percent of study participants with a high viral load at baseline (HIV-1 RNA >100,000 copies/mL), 77 percent in the Delstrigo™ group and 72 percent in the EFV/FTC/TDF group achieved HIV-1 RNA <50 copies/mL at Week 48.
  • At Week 48, Delstrigo™-treated participants showed statistically significant superior lipid profiles as measured by changes from baseline in LDL-cholesterol and non-HDL-cholesterol (LDL-C: -2.1 mg/dL in the Delstrigo™ 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 Delstrigo™ 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, the clinical benefit of these findings has not been demonstrated. In addition, a statistically significant lower proportion of Delstrigo™-treated participants compared to EFV/FTC/TDF-treated participants reported neuropsychiatric adverse events in the three 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).
  • The rate of discontinuation of treatment due to adverse events was lower in the Delstrigo™ treatment group than in the EFV/FTC/TDF treatment group (3% and 6%, respectively). Clinical adverse reactions of all grades occurring in ?5 percent of participants in the Delstrigo™ treatment group included dizziness (7%), nausea (5%) and abnormal dreams (5%). No adverse reactions of Grade 2 or higher (moderate or severe) occurred in ?2 percent of participants treated with Delstrigo™.
  • 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™.
  • Delstrigo™ and Pifeltro™ can be co-administered with a wide range of non-antiretroviral agents, and Pifeltro™ can be co-administered with a wide range of antiretroviral agents. Delstrigo™ and Pifeltro™cannot be co-administered with enzalutamide, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, mitotane or St. John’s wort. If Delstrigo™ is co-administered with rifabutin, patients should 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, 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.
  • 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.
  • The approvals of Delstrigo™ and Pifeltro™ come ahead of the original FDA target action date of Oct. 23, 2018. Merck anticipates that Delstrigo™ and 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, Delstrigo™ and Pifeltro™ will be covered products under the Merck Patient Assistance Program and will be available to eligible patients when the medicines are available. Doravirine is also under regulatory review by the European Medicines Agency (EMA).     • On January 8, 2018,  Merck&Co announced that the FDA has accepted for review two New Drug Applications (NDAs) for doravirine, the company’s investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of HIV-1 infection in adults. The NDAs include data for doravirine (DOR) as a once-daily tablet for use in combination with other antiretroviral agents, and for use of doravirine with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) in a once-daily fixed-dose combination single tablet as a complete regimen (DOR/3TC/TDF). The FDA has set a target action date of Oct. 23, 2018, for both applications under the Prescription Drug User Fee Act (PDUFA).
  • The NDAs are based upon the findings at Week 48 of two ongoing Phase 3 trials, DRIVE-FORWARD and DRIVE-AHEAD, evaluating the efficacy and safety of doravirine and the fixed-dose combination regimen of DOR/3TC/TDF, respectively. These data were previously presented at CROI-2017 and IAS 2017, respectively.
   

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2018-08-30

UE authorization:

Favourable opinion UE: 2018-09-20

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes