Doravirin (1) – Pifeltro®

• Clinical trials
  • In the double-blind, randomised, parallel-group studies (007, 018 and 021) conducted in treatment-naïve adults infected with HIV-1 to support marketing authorisation, the appropriate comparator therapy was not implemented in any of the studies.
  • Study 007 is a dose-finding study in which DOR was compared with EFV, in each case with the fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF).
  • In study 018, DOR was compared with DRV/r, in each case against the fixed-dose combination of FTC/TDF or abacavir/lamivudine (ABC/3TC), whilst in Study 021, the fixed-dose combinations DOR/3TC/TDF and EFV/FTC/TDF were compared.
  • The FLAMINGO, SINGLE and SPRING-1 studies were randomised, parallel-group trials.
  • In the FLAMINGO trial, DTG was compared with DRV/r, each in combination with the fixed-dose combination of FTC/TDF or ABC/3TC, and in the SINGLE trial, DTG + ABC/3TC was compared with EFV/FTC/TDF.
  • The SPRING-1 study is a dose-finding study of DTG.

a) Treatment-naïve adult HIV-1 patients whose HIV viruses do not harbour mutations known to be associated with resistance to the NNRTI class of drugs

• The additional benefit is not proven.
• mortality
  • For the endpoint of overall survival, the meta-analysis of the two adjusted indirect comparisons showed no statistically significant difference between DOR + 2 NRTIs and DTG + 2 NRTIs.
  • Consequently, additional benefit from DOR compared with DTG for the endpoint of mortality is not proven.
• Morbidity – AIDS-defining events (CDC Class C)
  • For the endpoint of AIDS-defining events (CDC Class C), the adjusted indirect comparison using EFV as the bridge comparator showed no statistically significant difference between DOR + 2 NRTIs and DTG + 2 NRTIs.
• Morbidity – Virological response
  • For the endpoint of virological response, the meta-analysis of the two adjusted indirect comparisons found no statistically significant difference between DOR + 2 NRTIs and DTG + 2 NRTIs.
• Morbidity – CD4 cell counts
  • For CD4 cell counts, the adjusted indirect comparison using EFV as the bridge comparator showed no statistically significant difference between DOR + 2 NRTIs and DTG + 2 NRTIs.
• morbidity
  • Based on the overall analysis of the results regarding AIDS-defining illnesses, virological response and CD4 cell counts, additional benefit of DOR compared with DTG is not proven for the endpoint of morbidity.
• Health-related quality of life
  • In studies 007, 018, 021, SINGLE, SPRING-1 and FLAMINGO, endpoints in the health-related quality of life category were not investigated.
  • Consequently, the additional benefit of DOR compared with DTG for the quality of life endpoint is not proven.
• Side effects
  • For the endpoints serious adverse events (SAE) and severe adverse events (AEs; Division of AIDS (DAIDS) Grade 3–4), the meta-analysis of the two adjusted indirect comparisons revealed no statistically significant difference between DOR + 2 NRTIs and DTG + 2 NRTIs.
  • For the endpoint of discontinuation due to AEs, the meta-analysis of the two adjusted indirect comparisons found no statistically significant difference between DOR + 2 NRTIs and DTG + 2 NRTIs.
  • For the endpoint of specific adverse events, the pharmaceutical manufacturer submitted incomplete analyses both in the dossier and during the commenting procedure; these were not taken into account for the benefit assessment.
  • In the category of side effects, there are no statistically significant differences between DOR + 2 NRTIs and DTG + 2 NRTIs when viewed as a whole.
• Overall assessment / Conclusion
  • For the endpoint of overall survival, the meta-analysis of the two adjusted indirect comparisons showed no statistically significant difference between DOR + 2 NRTI and DTG + 2 NRTI.
  • In the overall review of the results in the morbidity category regarding AIDS-defining illnesses, virological response and CD4 cell count, the additional benefit of DOR compared with DTG is not proven.
  • In the ‘Side effects’ category, the meta-analysis of the two adjusted indirect comparisons found no statistically significant difference between the treatment arms.
  • In summary, for treatment-naive adult patients infected with HIV-1, an overall assessment of the results on mortality, morbidity and side effects shows no additional benefit for DOR compared with DTG.

b) Treatment-experienced adult HIV-1 patients whose HIV viruses do not harbour mutations known to be associated with resistance to the NNRTI class of drugs

• The additional benefit is not proven.
• For this patient population, the pharmaceutical manufacturer did not submit any study that would have been suitable for assessing the additional benefit of DOR compared with the appropriate comparator therapy.
• Overall, therefore, an additional benefit of DOR is not proven for treatment-experienced adult patients infected with HIV-1.

Courtesy translation only, please refer to the German original.