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美国制药巨头默沙东（Merck & Co）近日宣布，美国食品和药物管理局（FDA）已受理新型HIV药物doravirine（MK-1439，DOR）的2份新药申请（NDA）。DOR是一种实验性非核苷类逆转录酶抑制剂（NNRTI），目前正在多个临床研究中进行开发，用于HIV-1成人感染者的治疗。这2份NDA中，其中一份申请将DOR作为一种每日一次的单一片剂，联合其他抗逆转录病毒药物，为患者提供一种量身定制的完整治疗方案；另一份申请将DOR与拉米夫定（3TC）和替诺福韦酯（TDF）组成的固定剂量组合单一片剂（DOR/3TC/TDF），作为一种每日一次的完整治疗方案。FDA已指定这2份NDA的处方药用户收费法（PDUFA）目标日期为2018年10月23日。

默沙东研究实验室全球临床开发副总裁George Hanna博士表示，自从HIV流行以来，默沙东一直致力于研究和满足HIV群体的需求。DOR是该公司开发出的一种新的HIV药物，将为患者提供一种有意义的新治疗选择，解决该领域存在的未满足医疗需求。

DOR两份NDA的提交，是基于2项正在开展的III期临床研究（DRIVE-FORWARD，DRIVE-AHEAD）的数据。这2个研究分别评估了DOR分别联合2种背景NRTI组合的完整治疗方案以及DOR/3TC/TDF固定剂量组合单一片剂完整治疗方案的疗效和安全性。除了这些研究之外，默沙东正在开展另一项III期临床研究DRIVE-SHIFT，在接受其他抗逆转录病毒方案实现病毒学抑制的HIV-1成人感染者中，评估转向DOR/3TC/TDF方案的疗效和安全性。

DRIVE-FORWARD：DOR单片联合背景NRTI疗效强劲，血脂参数更优

DRIVE-FORWARD（NCT02275780）是一项多中心、双盲、随机、非劣效性研究，在769例既往未接受抗逆转录病毒药物治疗（初治）HIV-1成人感染者中开展。入组该研究的患者在治疗前的HIV-1 RNA≥1000拷贝/毫升，研究中，这些患者以1：1的比例随机接受DOR（100mg剂量，每日一次），或利托那韦（ritonavir）增效的达芦那韦（darunavir）（DRV+r，800mg+100mg，每日一次），各组同时接受研究者所选择的2种常用NRTI背景方案（TDF/FTC或ABC/3TC，每日一次），治疗直至96周。该研究的主要终点是治疗第48周时实现HIV RNA＜50拷贝/毫升的患者比例，预先定义的非劣效性边界值为10%。次要终点包括DOR和DRV+r对空腹血脂的影响、CD4+T细胞计数从基线的变化，耐受性。

研究结果显示：（1）769例受试者中有766例接受了研究药物（每个治疗组383例）并纳入了疗效和安全性分析（平均年龄35.2岁，84%男性，73%白人，87%接受TDF/FTC）。在治疗第48周，DOR治疗组实现HIV-1 RNA＜50拷贝/毫升的患者比例为83.8%（n=321/383），DRV+r治疗组为79.9%（n=306/383，差异=3.9%，95%CI[-1.6，9.4]），数据达到了非劣效性标准。（2）在基线HIV-1 RNA＞100000拷贝/毫升的亚组中，治疗第48周时，DOR治疗组和DRV+r治疗组实现HIV-1 RNA＜50拷贝/毫升的患者比例分别为81.0%（n=64/79）和76.4%（n=55/72）。（3）主要安全性终点方面，不良事件发生率（总体、严重、药物相关、治疗停药）在DOR治疗组和DRV+r治疗组相似，最常见的药物相关不良事件（＞5%）为腹泻（5.5% vs 12.8%）、恶心（6.5% vs 7.6%）和头痛（6.0% vs 2.6%）。（4）次要终点方面，DOR治疗组空腹LDL-C和non-HDL-C水平相对基线降低（分别为：-4.5mg/dL和-5.3mg/dL），DRV+r治疗组空腹LDL-C和非-HDL-C水平相对基线均表现升高（分别为：+9.9mg/dL，+13.8mg/dL），数据具有统计学显着差异（空腹LDL-C：差异=-14.6mg/dL，95%CI[-18.2，-11.1]，p＜0.0001；空腹non-HDL-C：差异=-19.3，95%CI[-23.3，-15.4]，p＜0.0001）。

该研究证实：在初治HIV-1成人群体中，与2种常用背景NRTI方案联合用药时，在治疗第48周，DOR表现出了强劲的疗效，与DRV+r相比具有非劣效性，并与基线HIV-1 RNA水平无关。安全性方面，DOR的安全性和耐受性良好，与DRV+r相比具有更优越的血脂参数属性。

DRIVE-AHEAD：DOR/3TC/TDF复方单片疗效强劲，神经精神安全性更好，血脂参数更优

DRIVE-AHEAD（NCT02403674）是一项多中心、随机、双盲、非劣效性研究，在734例既往未接受抗逆转录病毒药物治疗（初治）HIV-1成人感染者中开展，评估了每日一次固定剂量组合单一片剂DOR/3TC/TDF（100mg/300mg/300mg）相对于每日一次固定剂量组合单一片剂EFV/FTC/TDF（600mg/200mg/300mg）的疗效和安全性。入组该研究的患者在治疗前的HIV-1 RNA≥1000拷贝/毫升，研究中，这些患者以1：1的比例随机接受DOR/3TC/TDF或EFV/FTC/TDF治疗直至96周，随机化分组通过HIV-1 RNA水平（≤/＞100000拷贝/毫升）和乙肝/丙肝共感染（是/否）进行分级。研究的主要疗效终点是治疗第48周时HIV RNA＜50拷贝/毫升的患者比例，预先定义的非劣效性边界值为10%。主要安全终点是治疗48周期间发生下述神经精神不良事件的患者比例：头晕、睡眠障碍和紊乱、感觉改变。次要终点包括：DOR/3TC/TDF和EFV/FTC/TDF对空腹血脂的影响、CD4+T细胞计数从基线的变化，耐受性。

研究结果如下所示：（1）734例受试者中有728例接受了研究药物（每个治疗组364例）并纳入了分析（平均年龄33岁，85%男性，48%白人）。在治疗第48周，DOR/3TC/TDF治疗组实现HIV-1 RNA＜50拷贝/毫升的患者比例为84.3%，FEV/FTC/TDF治疗组为80.8%（差异=3.5%，95%CI[-2.0，9.0]）。（2）主要安全性终点方面，DOR/3TC/TDF治疗组头晕、睡眠障碍和紊乱、感觉改变发生率比EFV/FTC/TDF治疗组低（分别为：8.8% vs 37.1%[p＜0.001]，12.1% vs 25.5%[p＜0.001]，4.4% vs 8.2%[p=0.033]）。（3）次要终点方面，DOR/3TC/TDF治疗组空腹LDL-C和non-HDL-C水平相对基线降低（分别为：-1.6mg/dL和-3.0mg/dL），EFV/FTC/TDF治疗组空腹LDL-C和非-HDL-C水平相对基线均表现升高（分别为：+0.7mg/dL，+13.3mg/dL），数据具有统计学显着差异（空腹LDL-C：差异=-10.0mg/dL，95%CI[-13.5，-6.5]，p＜0.0001；空腹non-HDL-C：差异=-17.0，95%CI[-20.9，-13.2]，p＜0.0001）。

该研究证实：在初治HIV-1成人群体中，在治疗第48周，DOR/3TC/TDF单一片剂方案与EFV/FTC/TDF单一片剂方案在疗效方面具有非劣效性和相似性，并与基线HIV-1 RNA水平无关。DOR/3TC/TDF方案的安全性和耐受性良好，神经精神事件明显少于EFV/FTC/TDF方案，同时具有更好的血脂参数

Doravirine

 Audio iconAudio IconOther Names: DOR, MK-1439Drug Class: Non-nucleoside Reverse Transcriptase InhibitorsMolecular Formula: C17 H11 Cl F3 N5 O3Registry Number: 1338225-97-0 (CAS)Chemical Name: 3-chloro-5-[[1-[(4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-3-pyridyl]oxy]benzonitrileOrganization: Merck & Co., Inc.Phase of Development: Doravirine is in Phase III development as a single-drug tablet and as part of a fixed-dose combination tablet containing doravirine/lamivudine/tenofovir DF (DOR/3TC/TDF; MK-1439A).

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2  and ClinicalTrials.gov3,4)

 

 

What is an investigational drug?

An investigational drug is one that is under study and is not approved by the U.S. Food and Drug Administration (FDA) for sale in the United States. Medical research studies are conducted to evaluate the safety and effectiveness of an investigational drug. These research studies are also called clinical trials. Once an investigational drug has been proven safe and effective in clinical trials, FDA may approve the drug for sale in the United States.

To learn more about investigational drugs, read the AIDSinfo What is an Investigational HIV Drug?fact sheet.

What is doravirine?

What is doravirine?

Doravirine is an investigational drug that is being studied for the treatment of HIV infection. Doravirine is being studied as a single-drug tablet and also as part of a fixed-dose combination(FDC) tablet that includes doravirine plus 2 FDA-approved HIV medicines.3,4

Doravirine belongs to a class (group) of HIV drugs called non-nucleoside reverse transcriptaseinhibitors (NNRTIs).2 NNRTIs attach to and block an HIV enzyme called reverse transcriptase. (An enzyme is a protein that starts or increases the speed of a chemical reaction.) By blocking reverse transcriptase, NNRTIs prevent HIV from multiplying and can reduce the amount of HIV in the body.

In vitro, doravirine appears to work on certain HIV strains against which other FDA-approved NNRTIs, such as rilpivirine (brand name: Edurant) and efavirenz (brand name: Sustiva), may no longer work.5 (In vitro refers to studies done in test tubes or other laboratory equipment and not on animals or humans.)

How are clinical trials of investigational drugs conducted?

How are clinical trials of investigational drugs conducted?

Clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.6

· Phase I trials: Researchers test an investigational drug in a small group of people (20–80) for the first time. The purpose is to evaluate its safety and identify side effects.

· Phase II trials: The investigational drug is administered to a larger group of people (100–300) to determine its effectiveness and to further evaluate its safety.

· Phase III trials: The investigational drug is administered to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments, and collect information that will allow the investigational drug to be used safely.6

In most cases, an investigational drug must be proven effective and must show continued safety in a Phase III clinical trial to be considered for approval by FDA for sale in the United States. Some drugs go through FDA’s accelerated approval process and are approved before a Phase III clinical trial is complete. After a drug is approved by FDA and made available to the public, researchers track its safety in Phase IV trials to seek more information about the drug’s risks, benefits, and optimal use.6

Some clinical trials are categorized as “a” or “b,” such as “Phase Ia” or “Phase IIb.” These different subphases typically mean that a study is researching certain types of information or using a certain type of participant population.

In what phase of testing is doravirine?

In what phase of testing is doravirine?

Doravirine is currently being studied in Phase III clinical trials as both a single-drug tablet and as part of an FDC tablet.3,4

What are some studies on doravirine?

What are some studies on doravirine?

Doravirine single-drug tablet

Study Names: MK-1439-007; Protocol 007 (P007); NCT01632345
Sponsor: Merck Sharp & Dohme Corp.
Phase: IIb
Status: This study has been completed.
Location: Not available
Participants:

· Participants were adults with HIV who had never taken HIV medicines before entering the study.

· Participants had viral load levels of at least 1,000 copies/mL. (Viral load is the amount of HIV in a blood sample.)

· Participants had CD4 counts of at least 100 cells/mm3. (A CD4 count is a laboratory test that measures the number of CD4 cells in a sample of blood and is an important indicator of immune function.)

Purpose: The purpose of this study was to (1) find a safe and effective dose of doravirine, and then (2) compare the safety and effectiveness of the chosen doravirine dose to the safety and effectiveness of the HIV medicine efavirenz (brand name: Sustiva). Safety assessments included looking at side effects affecting the central nervous system. (The central nervous system includes the brain and spinal cord).7,8 


Study Names: DRIVE-FORWARD; MK-1439-018; NCT02275780
Sponsor: Merck Sharp & Dohme Corp. 
Phase: III
Status: This study is ongoing, but not recruiting participants.
Location: Not available
Participants: 

· Participants are adults with HIV who have never taken HIV medicines.

· Participants have viral loads of at least 1,000 copies/mL within 45 days of the start of the study.

· Participants have a type of HIV with no genetic mutations that would prevent the study drugs from working.

Purpose: The purpose of this study is to compare the safety and effectiveness of doravirine to the safety and effectiveness of darunavir (brand name: Prezista) plus ritonavir (brand name: Norvir).3,9


Fixed-dose combination tablet

The FDC tablet includes doravirine and the FDA-approved HIV medicines lamivudine and tenofovir disoproxil fumarate.

Study Names: DRIVE-AHEAD; MK-1439A-021; NCT02403674
Sponsor: Merck Sharp & Dohme Corp.
Phase: III
Status: This study is ongoing, but not recruiting participants.
Location: Not available
Participants:

· Participants are adults with HIV who have never taken HIV medicines.

· Participants have viral load levels of at least 1,000 copies/mL within 45 days of the treatment part of the study.

· Participants have a type of HIV with no genetic mutations that would prevent the study drugs from working.

Study Purpose: The purpose of this study is to evaluate the safety and effectiveness of the FDC tablet and to compare it to Atripla. (Atripla is an FDA-approved FDC tablet that includes the HIV medicines efavirenz, emtricitabine, and tenofovir disoproxil fumarate.)4,10

For more details on the studies listed above, see the Health Professional version. 

The FDC tablet is also being evaluated in 3 additional studies. A Phase IIa study (DRIVE BEYOND; NCT02629822) is evaluating the safety and effectiveness of the FDC tablet in adults who have never taken HIV medicines and who are infected with certain HIV strains that do not respond well to other NNRTIs. The other studies, a Phase IIb study (NCT02652260) and a Phase III study (DRIVE-SHIFT; NCT02397096), involve participants whose HIV is suppressed with antiretroviral therapy (ART). (ART is the recommended treatment for HIV infection and involves using a combination of different HIV medicines to prevent HIV from multiplying.) Both studies are investigating whether participants can safely switch from their current ART to the FDC tablet that contains doravirine.11-13

What side effects might doravirine cause?

What side effects might doravirine cause?

In the Phase IIb study (NCT01632345) discussed under the previous question, researchers evaluated brain-related side effects that occurred during the first 24 weeks of treatment. These side effects included dizziness, nightmares, and depression. The researchers found that, overall, these types of side effects were significantly less common in participants taking doravirine than in participants receiving efavirenz.7,14,15

An analysis at 48 weeks showed that the most common drug-related side effects that occurred in more than 5% of participants taking either 100 mg of doravirine or 600 mg of efavirenz were diarrhea, nausea, dizziness, headache, abnormal dreams, insomnia, nightmares, and sleep disorder. All of the above side effects, except nausea and insomnia, occurred in a greater number of participants in the efavirenz group than in the doravirine group. Three participants taking doravirine and 6 participants taking efavirenz stopped treatment because of a side effect.16,17

In the Phase III DRIVE-FORWARD trial (NCT02275780), which compared doravirine to a combination of darunavir and ritonavir, an analysis at 48 weeks showed that a similar number of participants in both treatment groups experienced side effects or dropped out of the study because of side effects. The most common drug-related side effects that occurred in 1 or both treatment groups were diarrhea, nausea, and headache. Two participants taking doravirine and 1 participant taking darunavir and ritonavir dropped out of the study because of rashes caused by the drugs. Participants in both groups experienced side effects related to the brain, including dizziness, depression, insomnia, and abnormal dreams, but no one dropped out of the study because of these side effects. Both drug regimens had an effect on participants’ cholesterol, with doravirine lowering cholesterol levels in the body and the darunavir/ritonavir combination increasing them.3,9,18

In the Phase III DRIVE-AHEAD trial (NCT02403674), only 8 participants in the group that received the doravirine FDC tablet dropped out of the study because of a drug side effect, whereas 21 participants in the group that received Atripla dropped out because of a drug side effect. Some of the most common side effects that occurred in both treatment groups were dizziness, headache, and diarrhea. Headache, diarrhea, and cold symptoms were the most frequently reported side effects in the group taking the FDC tablet that contained doravirine.4,10

Because doravirine is still being studied, information on possible side effects of the drug is not complete. As testing of doravirine continues, additional information on possible side effects will be gathered.

Where can I get more information about clinical trials studying doravirine?

Where can I get more information about clinical trials studying doravirine?

More information about doravirine-related research studies is available from the AIDSinfo database of ClinicalTrials.gov study summaries. Click on the title of any trial in the list to see the ClinicalTrials.gov trial summary and more information about the study.

How can I find more information about participating in a clinical trial?

How can I find more information about participating in a clinical trial?

Participating in a clinical trial can provide benefits. For example, a volunteer participant can benefit from new research treatments before they are widely available. Participants also receive regular and careful medical attention from a research team that includes doctors and other health professionals. However, clinical trials may also involve risks of varying degrees, such as unpleasant, serious, or even life-threatening side effects from the treatment being studied.6

Your health care provider can help you decide whether participating in a clinical trial is right for you. For more information, visit NIH Clinical Research Trials and You.

References

References

1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/1338225-97-0. Last accessed on September 8, 2017.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. NIAID ChemDB, HIV Drugs in Development. Available at: https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on September 8, 2017.

3. Merck Sharp & Dohme Corp. A Phase 3 Multicenter, Double-Blind, Randomized, Active Comparator-Controlled Clinical Trial to Evaluate the Safety and Efficacy of Doravirine (MK-1439) 100 mg Once Daily Versus Darunavir 800 mg Once Daily Plus Ritonavir 100 mg Once Daily, Each in Combination With TRUVADA™ or EPZICOM™/KIVEXA™, in Treatment-Naïve HIV-1 Infected Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 23, 2014. NLM Identifier: NCT02275780. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02275780. Last accessed on September 8, 2017.

4. Merck Sharp & Dohme Corp. A Phase III Multicenter, Double-Blind, Randomized, Active Comparator-Controlled Clinical Trial to Evaluate the Safety and Efficacy of MK-1439A Once-Daily Versus ATRIPLA™ Once-Daily in Treatment-Naïve HIV-1 Infected Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 26, 2015. NLM Identifier: NCT02403674. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02403674. Last accessed on September 8, 2017.

5. Feng M, Wang D, Grobler JA, Hazuda DJ, Miller MD, Lai MT. In Vitro Resistance Selection with Doravirine (MK-1439), a Novel Nonnucleoside Reverse Transcriptase Inhibitor with Distinct Mutation Development Pathways. Antimicrob Agents Chemother. 2015 Jan;59(1):590-8. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291404/. Last accessed on September 8, 2017.

6. National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at: https://www.nih.gov/health-information/nih-clinical-research-trials-you. Last accessed on September 8, 2017.

7. Merck Sharp & Dohme Corp. Multicenter, Double-Blind, Randomized, 2-Part, Dose Ranging Study to Compare the Safety, and Antiretroviral Activity of MK-1439 Plus TRUVADA Versus Efavirenz Plus TRUVADA in Antiretroviral Treatment-Naive, HIV-1 Infected Patients. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 28, 2012. NLM Identifier: NCT01632345. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01632345. Last accessed on September 8, 2017.

8. Gatell JM, Morales-Ramirez JO, Hagins DP, et al. 48-Week efficacy and safety and early CNS tolerability of doravirine, a novel NNRTI, with TDF/FTC in ART-naive HIV-infected patients. Poster presented at: International Congress on Drug Therapy in HIV Infection; November 2-6, 2014; Glasgow, Scotland. Poster O434. Available at: https://s3-eu-west-1.amazonaws.com/hivglasgow/wp-content/uploads/2014/12/ORAL-PAPERS.pdf. Last accessed on September 8, 2017.

9. Squires K. Doravirine is non-inferior to darunavir/r in Phase 3 treatment-naive trial at Week 48. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, Washington. Available at: http://www.croiwebcasts.org/console/player/33382?mediaType=slideVideo&. Last accessed on September 8, 2017.

10. Squires KE, Molina J-M, Sax PE, et al. Fixed-dose combination of doravirine/lamivudine/TDF is non-inferior to efavirenz/emtricitabine/TDF in treatment-naive adults with HIV-1 infection: Week 48 results of the Phase 3 DRIVE-AHEAD study. Slides presented at: International AIDS Society (IAS) Conference on HIV Science; July 23-26, 2017; Paris, France. Available at: http://programme.ias2017.org/PAGMaterial/PPT/2906_4292/IAS%20oral%20presentation__1439A-021%20Primary%20Results_Final_25July2017_Squires.pptx. Last accessed on September 8, 2017.

11. Merck Sharp & Dohme Corp. A Phase IIa Multicenter, Open-Label Clinical Trial to Evaluate the Safety and Efficacy of MK-1439A in Treatment-Naive HIV-1 Infected Subjects With Selected Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Transmitted Resistance Mutations. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 10, 2015. NLM Identifier: NCT02629822. Available at: https://clinicaltrials.gov/ct2/show/NCT02629822. Last accessed on September 8, 2017.

12. Merck Sharp & Dohme Corp. Phase IIb, Double-Blinded, Multicenter, Randomized Study to Assess the Effect on Central Nervous System (CNS) Toxicity of Switching From ATRIPLA™ (Efavirenz, Tenofovir, Emtricitabine) to MK-1439A (Doravirine, Tenofovir, Lamivudine) in Virologically-Suppressed Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 8, 2016. NLM Identifier: NCT02652260. Available at: https://clinicaltrials.gov/ct2/show/NCT02652260. Last accessed on September 8, 2017.

13. Merck Sharp & Dohme Corp. A Phase III Multicenter, Open-Label, Randomized Study to Evaluate a Switch to MK-1439A in HIV-1-Infected Subjects Virologically Suppressed on a Regimen of a Ritonavir-boosted Protease Inhibitor and Two Nucleoside Reverse Transcriptase Inhibitors (NRTIs). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 18, 2015. NLM Identifier: NCT02397096. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02397096. Last accessed on September 8, 2017.

14. Gatell JM, Raffi F, Plettenberg A, et al. Efficacy and Safety of Doravirine 100mg QD vs Efavirenz 600mg QD with TDF/FTC in ART-Naive HIV-Infected Patients: Week 24 Results. International AIDS Society Conference on HIV Pathogenesis, Treatment & Prevention; July 19-22, 2015; Vancouver, Canada. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2015. Available at: http://www.natap.org/2015/IAS/IAS_22.htm. Last accessed on September 8, 2017.

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Last Reviewed: September 8, 2017