Doravirin (1) – Pifeltro®
HIV infection
Characteristics
| Start date | 15.01.2019 – Marketing authorisation: 22.11.2018 |
|---|---|
| Resolution | 04.07.2019 |
| INN | Doravirin |
| Brand name | Pifeltro® |
| Pharm. company | MSD SHARP & DOHME GMBH |
| G-BA Procedure ID | D-421 |
| ATC code | J05AG06 Non-nucleoside reverse transcriptase inhibitors (J05AG) |
| ICD-10 codes (AIS) | B24, Z21Asymptomatic human immunodeficiency virus [HIV] infection status |
| Alpha-ID codes (AIS) | I24822HIV infection, I29605HIV disease |
| DDD | 0.1 g O |
| Therapeutic area | Infectious diseases HIV |
| Reason for procedure | Initial assessment |
| Specialty | Combination therapy |
| Therapeutic indication of the resolution |
|---|
|
Pifeltro is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults infected with HIV-1 without past or present evidence of resistance to the NNRTI class. |
| Subpopulation | Indication | Comparator |
|---|---|---|
| a) | Therapy-naïve adult HIV-1 patients in whom the HI viruses do not have mutations that are known to be associated with resistance to the NNRTI substance class | Rilpivirine in combination with tenofovirdisoproxil/-alafenamide plus emtricitabine or in combination with abacavir plus lamivudine or dolutegravir in combination with tenofovirdisoproxil/-alafenamide plus emtricitabine or in combination with abacavir plus lamivudine |
| b) | Therapy-experienced adult HIV-1 patients in whom the HI viruses do not have mutations that are known to be associated with resistance to the substance class of NNRTIs | Individual antiretroviral therapy depending on the previous therapy(ies) and taking into account the reason for the change in therapy, in particular therapy failure due to virological failure and any associated development of resistance or due to side-effects |
Studies and Results
|
No. of studies
(best subpopulation) |
6 (Studie 007, Studie 018, Studie 021 vs. SINGLE, SPRING-1, FLAMINGO) |
|---|---|
|
Study design
(best subpopulation) |
H2H vs. non-ACT + ITC (MTC) |
|
Meta analysis
(best subpopulation) |
yes |
| Reason for dividing into subpopulations (G-BA) | Previous treatment |
- 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.
Associated procedures
| Doravirin (2) | Pifeltro® | MSD Sharp & Dohme GmbH | HIV infection, 12 to < 18 years | 130–140 | 100% additional benefit not proven | |
| Doravirin (1) | Pifeltro® | MSD SHARP & DOHME GMBH | HIV infection | 57,800–73,700 | 100% additional benefit not proven |
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