Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Doravirine · 6 trials · 4 indications
The percentage of participants in each arm achieving HIV-1 RNA levels \<50 copies/mL was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) "snapshot" approach and all missing data were considered treatment failures, regardless of the reason.
Per protocol, intensive pharmacokinetic (PK) sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine AUC0-24hr.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine Cmax.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine C24.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine Tmax.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine AUC0-12hr.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine Cmax.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine C12.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine Tmax.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study interventions.
Grade 3 or 4 AEs are "severe symptoms that cause inability to perform usual social and functional activities with intervention or hospitalization indicated" (Grade 3), or "potentially life-threatening events" (Grade 4).
The percentage of participants with events of death at Week 24 will be reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study interventions.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, that is considered to be related to the study interventions.
Assessment of the percentage of participants receiving doravirine at all doses (25 mg, 50 mg, 100 mg, or 200 mg), compared with participants receiving efavirenz 600 mg, who had at least 1 AE over 24 weeks of treatment. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.The percentage of participants in any treatment group with at least 1 AE was primarily assessed for Weeks 0-24.
Assessment of the percentage of participants receiving doravirine at all doses (25 mg, 50 mg, 100 mg, or 200 mg), compared with participants receiving efavirenz 600 mg, who discontinued therapy due to an AE over 24 weeks of treatment. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.The percentage of participants in any treatment group who discontinued therapy due to an AE was primarily assessed for Weeks 0-24.
Assessment of the percentage of participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg, who had at least 1 AE over 24 weeks of treatment. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.The percentage of participants in any treatment group with at least 1 AE was assessed for Weeks 0-24.
Assessment of the percentage of participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg, who had CNS events over 8 weeks of treatment. CNS events were pooled and evaluated as pre-specified by the protocol (depression, nightmare, confusional state, suicidal ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, delirium, depressed level of consciousness, hallucination, hallucination auditory, hallucination visual, completed suicide, suicidal behavior, major depression, depressed mood, depressive symptom, insomnia, disturbance in attention, somnolence, dizziness, or concentration impaired). The percentage of participants in either treatment group with CNS events was assessed over Weeks 0-8.
Assessment of the percentage of participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg, who had CNS events over 24 weeks of treatment. CNS events were pooled and evaluated as pre-specified by the protocol (depression, nightmare, confusional state, suicidal ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, delirium, depressed level of consciousness, hallucination, hallucination auditory, hallucination visual, completed suicide, suicidal behavior, major depression, depressed mood, depressive symptom, insomnia, disturbance in attention, somnolence, dizziness, or concentration impaired). The percentage of participants in either treatment group with CNS events was assessed over Weeks 0-24.
Assessment of the virologic response to doravirine at all studied doses (25 mg, 50 mg, 100 mg, and 200 mg), compared to efavirenz, each in combination with TRUVADA, as measured by the percentage of participants with plasma HIV-1 RNA \<40 copies/mL at Week 24. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay, which has a limit of reliable quantification of 40 copies/mL. The percentage of participants in any treatment group with a virologic response was assessed at Week 24. The Non-Completer = Failure (NC=F) approach, in which participants who prematurely discontinued assigned treatment for any reason and were considered as failures thereafter, was used as the primary approach to handle missing data this analysis of efficacy.This primary outcome was analyzed for HIV-1 RNA \<40 copies/mL in Part I.
Assessment of the virologic response to doravirine at 100 mg, compared to efavirenz, each in combination with TRUVADA, as measured by the percentage of participants with HIV-1 RNA \<40 copies/mL at Week 24. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay, which has a limit of reliable quantification of 40 copies/mL. The percentage of participants in any treatment group with a virologic response was assessed at Week 24. The NC=F approach was used as the primary approach to handle missing data this analysis of efficacy. This primary outcome was analyzed for HIV-1 RNA \<40 copies/mL in Part I \& Part II combined.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method
The change from baseline to Day 7 in plasma HIV RNA viral load was determined for each arm. Results are expressed as change in HIV RNA log10 copies/mL after 7 daily doses of doravirine or placebo. It was hypothesized that at least 1 dose of doravirine would be superior to placebo as documented by the upper bound of the 90% confidence interval \<-1. Plasma HIV RNA levels were determined using the Abbott RealTime HIV assay which has a linear range from 40 to 10 million copies/mL.
| Arm | Type | Description |
|---|---|---|
| Immediate Switch to Doravirine, Tenofovir, Lamivudine | EXPERIMENTAL | Participants receiving continuous antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) or cobicistat-boosted elvitegravir or a non nucleoside reverse transcriptase inhibitor (NNRTI) (specifically, efavirenz, nevirapine, or rilpivirine) in combination with 2 NRTIs for \>=6 months with undetectable HIV-1 RNA will switch on Day 1 to doravirine, tenofovir, lamivudine single tablet by mouth once daily for 48 weeks in the Base Study and, optionally, for up to an additional 6 years in the Study Extensions |
| Delayed Switch to Doravirine, Tenofovir, Lamivudine | ACTIVE_COMPARATOR | Participants receiving continuous antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) or cobicistat-boosted elvitegravir or a NNRTI (specifically, efavirenz, nevirapine, or rilpivirine) in combination with 2 NRTIs for \>=6 months with undetectable HIV-1 RNA will continue on this therapy until Week 24, at which time they will switch to doravirine, tenofovir, lamivudine single tablet by mouth once daily for 24 weeks in the Base Study and, optionally, for up to an additional 6 years in the Study Extensions |
| Doravirine as a single entity plus 2 NRTIs or Doravirine as a FDC with 3TC and TDF | EXPERIMENTAL | Participants receive doravirine (DOR) at 7.2 mg to 100 mg, based on weight, PLUS 2 nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs), based on local label, for 96 weeks, OR a fixed-dose combination (FDC) of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF), based on weight, for 96 weeks. |
| Doravirine 25 mg | EXPERIMENTAL | Doravirine 25 mg + TRUVADA® Participants in this arm will receive doravirine 25 mg in Part I and the selected doravirine dose (either 25 mg, 50 mg, 100 mg, or 200 mg) in Part II. These participants also receive placebo that matches efavirenz. |
| Doravirine 50 mg | EXPERIMENTAL | Doravirine 50 mg + TRUVADA® Participants in this arm will receive doravirine 50 mg in Part I and the selected doravirine dose (either 25 mg, 50 mg, 100 mg, or 200 mg) in Part II. These participants also receive placebo that matches efavirenz. |
| Doravirine 100 mg | EXPERIMENTAL | Doravirine 100 mg + TRUVADA® Participants in this arm will receive doravirine 100 mg in Part I and the selected doravirine dose (either 25 mg, 50 mg, 100 mg, or 200 mg) in Part II. These participants also receive placebo that matches efavirenz. |
| Doravirine 200 mg | EXPERIMENTAL | Doravirine 200 mg + TRUVADA® Participants in this arm will receive doravirine 200 mg in Part I and the selected doravirine dose (either 25 mg, 50 mg, 100 mg, or 200 mg) in Part II. These participants also receive placebo that matches efavirenz. |
| Efavirenz | ACTIVE_COMPARATOR | Efavirenz + TRUVADA® Participants in this arm will receive efavirenz in Part I and in Part II. These participants also receive placebo that matches doravirine. |
| Severe Renal Impairment | EXPERIMENTAL | Participants with severe renal impairment receive a single oral dose of 100 mg doravirine |
| Healthy Matched Control | EXPERIMENTAL | Healthy participants matched for age and weight receive a single oral dose of 100 mg doravirine |
| Part 1: Moderate Hepatic Insufficiency | EXPERIMENTAL | Participants with moderate hepatic insufficiency receive a single oral dose of 100 mg doravirine on Day 1 of Part 1. All participants in this arm were to have moderate hepatic insufficiency based on the Child-Pugh scale. |
| Part 1: Healthy Matched Control | EXPERIMENTAL | Healthy participants matched for age and weight receive a single oral dose of 100 mg doravirine on Day 1 of Part 1. |
| Part 2: Mild Hepatic Insufficiency | EXPERIMENTAL | Participants with mild hepatic insufficiency receive a single oral dose of 100 mg doravirine on Day 1 of Part 1. All participants in this arm were to have mild hepatic insufficiency based on the Child-Pugh scale. This arm was to be enrolled and investigated only if a clinically meaningful increase in exposure of doravirine was observed in participants with moderate hepatic insufficiency in Part 1. |
| Panel A: Doravirine 25 mg or Placebo | EXPERIMENTAL | Participants will receive oral doses of doravirine 25 mg or placebo once daily for 7 days. |
| Panel B: Doravirine 200 mg or Placebo | EXPERIMENTAL | Panel B (doravirine 200 mg or placebo once daily for 7 days) will initiate upon satisfactory review of safety and tolerability from Panel A, and all safety, tolerability and pharmacokinetic data from the study MK-1439-001. |
| Panel C: Doravirine or Placebo | EXPERIMENTAL | Panel C is optional. If conducted, the dose will be confirmed after review of data from prior panels. |
| Name | Type | Description |
|---|---|---|
| Doravirine, Tenofovir, Lamivudine | DRUG | Single tablet containing MK-1439 (doravirine) 100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg |
| Baseline regimen of ritonavir- or cobicistat-boosted protease inhibitor | DRUG | Baseline regimen of antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) administered according to the product circular |
| Baseline regimen of cobicistat-boosted elvitegravir | DRUG | Baseline regimen of antiretroviral therapy with cobicistat-boosted elvitegravir administered according to the product circular |
| Baseline regimen of a non-nucleoside reverse transcriptase inhibitor | DRUG | Baseline regimen of antiretroviral therapy with a NNRTI (efavirenz, nevirapine, or rilpivirine) administered according to the product circular |
| Baseline regimen of two nucleoside reverse transcriptase inhibitors | DRUG | Baseline regimen of antiretroviral therapy with two NRTIs administered according to the product circular |
| Doravirine | DRUG | Administered orally |
| 2 NRTIs | DRUG | Administered orally |
| DOR/3TC/TDF | DRUG | Administered orally |
| Efavirenz | DRUG | Efavirenz 600 mg tablet orally at bedtime taken without food on an empty stomach for 96 weeks |
| TRUVADA® | DRUG | Open-label TRUVADA® (fixed combination 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate) tablet taken orally with food in the morning for 96 weeks |
| Placebo for Doravirine | DRUG | Placebo tablets matching doravirine |
| Placebo for Efavirenz | DRUG | Placebo tablets matching efavirenz |
| Placebo | DRUG | Placebo tablets once daily for 7 days. |
Inclusion Criteria: Inclusion Criteria include, but are not limited to: * Have plasma Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) levels below the limit of quantification (BLoQ) (\<40 copies/mL by the Abbott RealTime HIV-1 Assay as determined by the central laboratory) at the scree...
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Doravirine is an investigational small molecule being studied for the treatment of HIV-1 infection, including in patients with renal impairment. It is being developed as a single agent and in combination with tenofovir DF and lamivudine for virologically suppressed HIV-1-infected adults.
Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that targets the reverse transcriptase enzyme of HIV-1. By inhibiting this enzyme, it interferes with viral replication. The drug is being studied in combination with other antiretrovirals to maintain viral suppression in HIV-1-infected patients.
Doravirine is being developed by Merck & Company, Inc. (NYSE: MRK). The company is conducting clinical trials to evaluate the drug's safety and efficacy in HIV-1-infected participants, including those switching from other antiretroviral regimens.
Doravirine is in Phase 2 clinical development. While some completed trials were Phase 1 and Phase 3, the most recent completed trial was a Phase 2 study evaluating a switch to doravirine, tenofovir, and lamivudine in virologically suppressed participants.
Doravirine has been studied in several clinical trials, including NCT01466985, a Phase 1 study in HIV-1-infected participants; NCT02089659, a Phase 1 hepatic impairment study; NCT02397096, a Phase 3 switch study; and NCT02652260, a Phase 2 switch study from efavirenz-based therapy.
Doravirine is the single-agent form, while doravirine plus tenofovir DF and lamivudine is a fixed-dose combination being studied under the code MK-1439A. Clinical trials have evaluated both the single agent and the combination in HIV-1-infected patients.