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Promising HIV Treatments in Late-Stage Clinical Development

Lyn K. Chesna MA, ELS
Chris Fellner

Human immunodeficiency virus (HIV) infection involves one of two similar retroviruses (HIV-1 and HIV-2) that destroy CD4-positive lymphocytes and impair cell-mediated immunity, thereby increasing the risk of certain opportunistic infections and cancers.1

Treatments for HIV infection are generally aimed at inhibiting HIV enzymes, which in turn suppresses viral replication. 1 More than 25 HIV medications have been approved by the Food and Drug Administration (FDA).2 Usually, a patient’s first HIV regimen includes two nucleotide reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (INSTI), a non-nucleotide reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) boosted with cobicistat (Tybost, Gilead Sciences) or ritanovir (Norvir, Abbott Laboratories). Cobicistat or ritonavir increases (boosts) the effectiveness of the PI.2

Despite the abundance of HIV medications, analysts have identified several unmet needs in the marketplace, including:3

  • Long-acting regimens that require less frequent administration to improve patient adherence
  • Safe and effective treatments for patients with drug-resistant HIV strains
  • Therapies with improved safety and tolerability profiles
  • Progress toward a functional cure

With these needs in mind, pharmaceutical companies are working to develop novel treatments for patients with HIV infection (Table 1). The following monotherapies and combination regimens are in late-stage clinical development or FDA review.

The fixed-dose regimen of bictegravir 50 mg, a novel investigational INSTI, and emtricitabine/tenofovir alafenamide 200 mg/25 mg (Descovy, Gilead Sciences), a dual-NRTI backbone, is an unboosted anti-HIV regimen that combines these drugs into a single, once-daily tablet.4,5 In July 2017, Gilead announced detailed 48-week results from two phase 3 studies evaluating the efficacy and safety of this three-drug combination for the treatment of HIV-1 infection in treatment-naïve adults. Bictegravir/emtricitabine/tenofovir alafenamide was found to be statistically noninferior to regimens containing dolutegravir 50 mg (Tivicay, ViiV Healthcare) in combination with a dual-NRTI backbone. The most commonly reported adverse events in the trials were nausea, diarrhea, and headache. The results, along with data from two ongoing phase 3 studies in treatment-experienced patients, formed the basis of Gilead’s regulatory applications in the United States and the European Union.6 If approved, bictegravir/emtricitabine/tenofovir alafenamide is likely to be positioned for treatment-naïve adults (18 years of age and older) with HIV-1 infection.3

Janssen is developing a four-drug combination consisting of darunavir (Prezista, Janssen), cobicistat, and emtricitabine/tenofovir alafenamide as a single once-daily tablet for use in both treatment-naïve and treatment-experienced adults with HIV infection. Darunavir is a PI; emtricitabine and tenofovir alafenamide are NRTIs; and cobicistat is a pharmacokinetic booster with no effect on HIV.3 The efficacy of this PI-based combination is being evaluated in two phase 3 studies—one in treatment-naïve adults and the other in treatment-experienced adults.7,8 The first study is scheduled to be completed in March 2018,7 and the second in November 2020.8

ViiV Healthcare is developing a once-daily, fixed-dose combination tablet consisting of dolutegravir and lamivudine (Epivir) for adults with HIV-1 infection. Dolutegravir is an INI, and lamivudine is an NRTI for which the FDA requires a boxed warning.3 The treatment is being compared with dolutegravir plus tenofovir disoproxil fumarate/emtricitabine (Truvada, Gilead) in two identical phase 3, randomized, double-blind trials (Gemini 1 and Gemini 2). Approximately 700 HIV-infected patients will be evaluated at week 48 and week 148 in each study. The scheduled completion date for both trials is in 2024.9,10

Janssen and ViiV Healthcare are collaborating on the single-tablet, two-drug regimen of dolutegravir plus rilpivirine (Edurant, Janssen). Janssen announced in June that regulatory submissions to both the FDA and the European Medicines Agency have been completed. The submissions were based on phase 3 studies that included more than 1,000 patients who previously achieved viral suppression on a three- or four-drug anti retroviral regimen. The most commonly reported adverse events in the trials were nasopharyngitis, headache, diarrhea, and upper respiratory tract infection. If approved, this will be the first two-drug regimen for the maintenance treatment of HIV-1 infection.11,12

Doravirine (MK-1439) is an experimental NNRTI under development by Merck.3 It has been combined with lamivudine and tenofovir disoproxil fumarate in a once-daily, fixed-dose single tablet. The new regimen was compared with a fixed-dose combination of efavirenz, emtricitabine, and tenofovir disoproxil fumarate and met efficacy and safety endpoints in a phase 3 trial in treatment-naïve adults infected with HIV-1. The most commonly reported adverse events in the trial were headache, diarrhea, nasopharyngitis, dizziness, nausea, abnormal dreams, and rash. Merck plans to submit new drug applications to the FDA by the end of 2017.13

A long-acting injectable formulation of the dolutegravir analogue cabotegravir, an investigational INSTI developed by ViiV Healthcare, plus Janssen Science’s rilpivirine, an NNRTI, is being codeveloped by the two companies as an HIV-1 treatment.14 If approved, the combination has the potential to replace NRTI-based therapies.3 In July, ViiV Healthcare announced positive results from a phase 2b, open-label study that evaluated injectable cabotegravir and rilpivirine dosed once every four or eight weeks compared with daily oral dosing with cabotegravir plus two NRTIs. The most commonly reported adverse events not related to injection-site reactions for the injectable treatment groups were nasopharyngitis, headache, and diarrhea.15 ViiV Healthcare and Janssen Sciences are conducting a phase 3 study of this injection. 3 Experts expect the combination treatment to be launched in the U.S. in 2020 as the first integrase inhibitor (INI)-based, NRTI-free, long-acting injectable formulation to reach the market.3

Fostemsavir, a prodrug of temsavir, was developed by Bristol-Myers Squibb and acquired by ViiV Healthcare in February 2016. The drug, which received a breakthrough therapy designation from the FDA, is being evaluated in heavily treatment-experienced adults with multidrug-resistant (MDR) HIV-1 in a phase 3 clinical trial. Phase 2a and 2b studies showed a positive safety profile for fostemsavir. The most common adverse events were headache and rash, but no severe adverse events or deaths occurred.3

Ibalizumab, an investigational human monoclonal antibody (mAb), is being developed by TaiMed Biologics and Thera technologies. It is the first humanized mAb for the treatment of HIV-1 to reach phase 3 development. The ongoing trial is being conducted in patients with MDR HIV-1. The treatment received breakthrough therapy and orphan drug designations from the FDA and is under priority review with the agency.16 The drug is being administered as a twice-monthly intravenous injection in trials, but it is also being evaluated as a monthly or twice-monthly intramuscular injection.3 In phase 2 studies, the most commonly reported adverse events, most of which were considered mild to moderate, were rash, diarrhea, headache, and nausea.17

PRO-140 (CytoDyn, Inc.), another investigational fully humanized mAb in development, is being studied in treatment-experienced adults with HIV-1 in a phase 2b/3 trial. This mAb has received fast-track and breakthrough therapy status from the FDA. Patients enrolled in the phase 2a trial most commonly experienced diarrhea, headache, lymphadenopathy, and hypertension.3

Table

Therapies in Late-Stage Development for Human Immunodeficiency Virus Infection3

Drug(s)
Developer(s)
Therapeutic Class Mode of Administration Anticipated U.S. Pricing Strategy Estimated U.S. Cost Per Year Anticipated U.S. Launch
Bictegravir + emtricitabine/TAF
Gilead Sciences
STR (INSTI + NNRTIs) Single tablet, once daily 5% premium over Triumeq (abacavir/dolutegravir/lamivudine, ViiV Healthcare) because of its novel chemical entity (bictegravir); its reduced toxicity profile (including risk of hypersensitivity); and its once-daily regimen $30,759 2018
Cabotegravir + rilpivirine
ViiV Healthcare/Janssen Sciences
LAI (INSTI + NNRTI) Long-acting injection 10% premium over Triumeq because of novelty of compound and formulation $32,224 2020
Darunavir/cobicistat/emtricitabine/TAF
Janssen Sciences
STR (boosted PI + NRTIs) Single tablet, once daily 10% discount from Descovy (emtricitabine/TAF, Gilead) and Prezcobix (darunavir/cobicistat, Janssen) because of competition from INI-based STRs and because of patent expiry of Descovy and Prezista (darunavir, Janssen) before 2025 $33,047 Undetermined
Dolutegravir/lamivudine
ViiV Healthcare
STR (INI + NRTI) Single tablet, once daily 5% premium over Tivicay (dolutegravir, ViiV Healthcare) and Epivir (lamivudine, ViiV Healthcare) because of improved convenience $23,404 2019
Dolutegravir/rilpivirine
ViiV Healthcare
STR (INI + NNRTI) Single tablet, once daily 5% premium over Triumeq because product does not contain an NRTI; therefore, fewer adverse effects may be expected $30,759 2018
Doravirine/lamivudine/TDF
Merck
FDC (NRTI + NNRTIs) Single tablet, once daily 15% discount from Atripla (efavirenz/emtricitabine/TAF, Bristol-Myers Squibb/Gilead) because of competition $24,732 2019
Fostemsavir
ViiV Healthcare
EFI Single tablet, twice daily 10% premium over Fuzeon (enfuvirtide, Genentech) because of novelty and high unmet medical need $17,352 2018
Ibalizumab
TaiMed Biologics/Theratechnologies
EFI (mAb) IV injection, twice monthly 110% premium over Selzentry (maraviroc, ViiV Healthcare) because of novelty and high unmet medical need $33,128 2018
PRO-140
CytoDyn, Inc.
EFI (mAb) SC injection, once weekly 100% premium over Selzentry because of novelty and high unmet medical need $31,550 2018

EFI = entry/fusion inhibitor; FDC = fixed-dose combination; INI = integrase inhibitor; INSTI = integrase strand transfer inhibitor; IV = intravenous; LAI = long-acting injection; mAb = monoclonal antibody; NNRTI = non-nucleotide reverse transcriptase inhibitor; NRTI = nucleotide reverse transcriptase inhibitor; PI = protease inhibitor; SC = subcutaneous; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate.

References

  1. Cachay ED. Human immunodeficiency virus (HIV) infection. Merck Manual: Professional Version 2017; Available at: www.merckmanuals.com/professional/infectious-diseases/human-immunodeficiency-virus-hiv/human-immunodeficiency-virus-hiv-infection#v1021367. Accessed May 23, 2017
  2. AIDSinfo, Department of Health and Human Services. What to start: choosing an HIV regimen May 23, 2017; Available at: https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/21/53/what-to-start--selecting-a-first-hiv-regimen. Accessed May 23, 2017
  3. Fratoni D, Pace CJ, Booth A, et al. Pharma Point: Human Immunodeficiency Virus (HIV): Global Drug Forecast and Market Analysis to 2025 New York, New York: GlobalData. April 2017;
  4. Gilead Sciences. Gilead presents new phase 2 data on bictegravir, an investigational integrase strand transfer inhibitor for the treatment of HIV February 13, 2017; Available at: www.gilead.com/news/press-releases/2017/2/gilead-presents-new-phase-2-data-on-bictegravir-an-investigational-integrase-strand-transfer-inhibitor-for-the-treatment-of-hiv. Accessed May 24, 2017
  5. Descovy (emtricitabine and tenofovir alafenamide tablets) prescribing information Foster City, California: Gilead Sciences. April 2017;
  6. Gilead Sciences. Gilead announces phase 3 results for investigational fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide for treatment of HIV July 24, 2017; Available at: www.gilead.com/news/press-releases/2017/7/gilead-announcesphase-3-results-for-investigational-fixed-dose-combination-of-bictegravir-emtricitabine-and-tenofovir-alafenamide-for-treatment-of-hiv. Accessed August 25, 2017
  7. ClinicalTrials.gov. Study to evaluate efficacy and safety of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) regimen versus boosted protease inhibitor (bPI) along with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) regimen in virologically suppressed, HIV-1 infected participants. NCT02269917 April 20, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02269917. Accessed May 31, 2017
  8. ClinicalTrials.gov. A study to evaluate efficacy and safety of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed dose combination (FDC) versus a regimen consisting of darunavir/cobicistat FDC with emtricitabine/tenofovir disoproxil fumarate FDC in treatment-naïve HIV type 1 infected subjects. NCT02431247 May 23, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02431247. Accessed May 31, 2017
  9. ClinicalTrials.gov. An efficacy, safety, and tolerability study comparing dolutegravir plus lamivudine with dolutegravir plus tenofovir/emtricitabine in treatment naïve HIV infected subjects (Gemini 1). NCT02831673 May 15, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02831673. Accessed June 1, 2017
  10. ClinicalTrials.gov. An efficacy, safety, and tolerability study comparing dolutegravir (DTG) plus lamivudine (3TC) with dolutegravir plus tenofovir/emtricitabine in treatment naïve HIV infected subjects (Gemini 2). NCT02831764 May 18, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02831764. Accessed June 2, 2017
  11. Janssen Sciences. Janssen announces submissions in Europe and U.S. for single-tablet regimen of dolutegravir plus rilpivirine— the first two-drug HIV maintenance treatment June 1, 2017; Available at: www.janssen.com/janssen-announces-submissions-europe-and-us-single-tablet-regimen-dolutegravir-plus-rilpivirine. Accessed August 28, 2017
  12. ViiV Healthcare. ViiV Healthcare announces detailed positive phase III results for investigational two-drug regimen of dolutegravir and rilpivirine for HIV treatment February 13, 2017; Available at: www.viivhealthcare.com/media/press-releases/2017/february/viiv-healthcare-announces-detailed-positive-phase-iii-results-for-investigational-two-drug-regimen-of-dolutegravir-and-rilpivirine-for-hiv-treatment.aspx. Accessed August 28, 2017
  13. Merck. Merck’s investigational NNRTI, doravirine, meets primary efficacy endpoint of non-inferiority to efavirenz, both in combination with other antiretroviral agents, in pivotal phase 3 trial for treatment of HIV-1 infection July 25, 2017; Available at: http://investors.merck.com/news/press-release-details/2017/Mercks-Investigational-NNRTI-Doravirine-Meets-Primary-Efficacy-Endpoint-of-Non-Inferiority-to-Efavirenz-Both-in-Combination-with-Other-Antiretroviral-Agents-in-Pivotal-Phase-3-Trial-for-Treatment-of-HIV-1-Infection/default.aspx. Accessed August 28, 2017
  14. ViiV Healthcare. ViiV Healthcare to progress collaboration with Janssen to develop the first long-acting, two drug injectable regimen for treatment of HIV January 7, 2016; Available at: www.viivhealthcare.com/media/press-releases/2016/january/viiv-healthcare-to-progress-collaboration-with-janssen-to-develop-the-first-long-acting-two-drug-injectable-regimenfor-treatment-of-hiv.aspx. Accessed May 26, 2017
  15. ViiV Healthcare. Phase II study results showed comparable viral suppression rates at 96 weeks for a two-drug regimen July 24, 2017; Available at: www.viivhealthcare.com/media/press-releases/2017/july/phase-ii-study-results-showedcomparable-viral-suppression-rates-at-96-weeks-for-a-two-drug-regimen.aspx. Accessed August 25, 2017
  16. Theratechnologies. Theratechnologies announces new findings with the investigational antiretroviral ibalizumab and with Egrifta (tesamorelin for injection) July 24, 2017; Available at: https://theratechnologies.s3.amazonaws.com/prod/media/nr-20170724-en.pdf. Accessed August 28, 2017
  17. AIDSinfo, Department of Health and Human Services. Ibalizumab March 8, 2017; Available at: https://aidsinfo.nih.gov/drugs/511/ibalizumab/0/patient. Accessed August 28, 2017