July 2018
by Tim Horn
The past 12 months has been historic in terms of the number of new HIV treatment modalities reaching pharmacy shelves, at least in the United States. Four originator products – the first dual-drug regimen for maintenance therapy, the first biologic for HIV treatment, the first protease inhibitor-based single-tablet regimen (STR), and a new integrase strand transfer (INSTI)-based STR – have been approved since the last antiretroviral update to the Pipeline Report (Table 1, below). The U.S. also ushered in the commercialization of four generic ARVs over the past year – stand-alone versions of tenofovir disoproxil, efavirenz, atazanavir, and ritonavir – and the approval of three lower-cost branded products containing off-patent ARVs.
Expansion of the HIV treatment armamentarium with new drugs and biologics with efficacy advantages (particularly for treatment-experienced individuals), safety improvements, and the potential for significant cost savings to health care systems and consumers has always been a goal of HIV/AIDS activism. HIV treatment products launched over the past year in the U.S. speak to all three priorities, though with limited overlap between safety and efficacy advancements, and cost considerations. Monopoly products continue to debut at astonishing prices, including a biologic with a wholesale acquisition cost in the six digits that will likely set the tone for other biologics that may follow.
The ARV development pipeline continues to look bright, including late-stage development of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based coformulation containing doravirine and off-patent tenofovir disoproxil and lamivudine, as well as the dual-drug coformulation of dolutegravir and off-patent lamivudine (Table 2, below). Whether these will debut at favorable price points remains to be seen – it will serve the manufacturers well to consider reduced cost as a favorable sales point.
Among the several products continuing development in North America and Europe are two drugs primarily developed to meet affordable treatment needs in middle-income countries: Frontier Technologies’ albuvirtide, recently approved in China, and Viriom’s elsulfavirine, approved in Russia last July. The introduction of drugs and biologics developed exclusively for middle-income countries, particularly those with strict national patent laws that prevent the importation of low-cost generics, is essential to the UNAIDS 90-90-90 global treatment target to help end HIV as an epidemic.
There is a great deal of optimism driving efforts to end HIV as an epidemic, locally, nationally, and globally. However, HIV remains a significant health challenge in all countries. Innovative – and affordable – ARV treatment options are a cornerstone of every plan to dramatically reduce new HIV infections and minimize HIV-related mortality.
TABLE 1. US APPROVALS SINCE JULY 2017
|
Product
|
Class/Type
|
Company
|
FDA Approval Date
|
US Launch Price
(annual WAC)
|
Dolutegravir/
rilpivirine (Juluca) |
INSTI/NNRTI |
ViiV Healthcare |
Nov 21, 2017 |
$30,948 |
- Approval based on 48-week data from Phase III SWORD-1 and SWORD-2 switch studies, demonstrating non-inferiority of the dual-drug coformulation for maintenance therapy compared to remaining on three-drug regimen.
- US HHS Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV recommend dolutegravir/rilpivirine as reasonable dual-drug maintenance therapy option when use of NRTIs is not desirable and when resistance to either dolutegravir or rilpivirine is not expected.
|
| Ibalizumab-uiyk
(Trogarzo) |
Post-attachment inhibitor |
TaiMed/
Theratechnologies |
Mar 6, 2018 |
$118,000 |
- Approval based on 48-week data from Phase III TMB-301 study in heavily treatment-experienced volunteers, with median viral load reductions of 2.5 log10 copies/mL when combined with optimized background regimens at Week 24 and sustained through Week 48.
- Requires intravenous infusions every two weeks; evaluations of subcutaneous administration under way.
|
Bictegravir/
tenofovir alafenamide/emtricitabine (Biktarvy) |
INSTI/NtRTI/NRTI |
Gilead Sciences |
Feb 7, 2018 |
$35,839 |
- Approval based on two phase III trials establishing non-inferiority of bictegravir vs. dolutegravir, with both drugs combined with two NRTIs (Study 1498 and Study 1490).
- US HHS Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV classifies BIC/TAF/FTC as one of the Recommended Initial Regimens for Most Adults with HIV.
|
Efavirenz/
tenofovir disoproxil/lamivudine (Symfi and Symfi Lo) |
NNRTI/NtRTI/NRTI |
Mylan |
Mar 2, 2018 (Symfi Lo); Mar 28, 2018 (Symfi) |
$19,600 |
- Symfi contains 600 mg efavirenz coformulated with tenofovir disoproxil and lamivudine; Symfi Lo contains 400 mg efavirenz coformulated with tenofovir disoproxil and lamivudine.
- Symfi approval based on bioequivalence of individual components with originator reference products, along with 144-week data from Study 903 evaluation of efavirenz combined with tenofovir disoproxil and lamivudine.
- Symfi Lo approval based on 48 week data from ENCORE1 study, comparing 400 mg and 600 mg efavirenz.
|
Tenofovir disoproxil/
lamivudine (Cimduo) |
NtRTI/NRTI |
Mylan |
Mar 2, 2018 |
$12,060 |
- Cimduo approval based on bioequivalence of individual components with originator reference products.
- US HHS Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV note safety, cost, and access are among the factors to consider when choosing between tenofovir disoproxil and tenofovir alafenamide; they also note lamivudine is a substitute for emtricitabine, and vice versa.
|
Darunavir/
cobicistat/tenofovir/alafenamide/emtricitabine (Symtuza) |
PI/PK booster/NtRTI/NRTI |
Janssen |
Jul 17, 2018 |
$41,784 |
- European Commission approval of Symtuza in September 2017.
- US approval based on 48-week data from Phase III AMBER and EMERALD clinical trials. AMBER demonstrated the non-inferiority of D/C/F/TAF, compared to D/C plus F/TDF, in 725 treatment-naïve participants; EMERALD demonstrated the non-inferiority of switching to D/C/F/TAF, compared to remaining on a multi-tablet boosted protease inhibitor regimen.
|
TABLE 2. ARV PRODUCTS IN DEVELOPMENT
|
Product
|
Class/Type
|
Company
|
Development Phase
|
| Doravirine and coformulated doravirine/tenofovir disoprovil/lamivudine |
NNRTI/NtRTI/NRTI |
Merck |
Phase III/NDA filed |
- 48-week data from Phase III DRIVE-FORWARD published, demonstrating non-inferiority of doravirine (DOR) versus ritonavir-boosted darunavir, each combined with either TDF/FTC or ABC/3TC in treatment-naïve patients.
- 48-week data from Phase III DRIVE-AHEAD reported at 2017 IAS, demonstrating non-inferiority of DOR/TDF/TDF versus EFV/TDF/FTC in treatment-naïve adults (subgroup analysis reported at 2018 CROI).
- Phase III DRIVE-SHIFT, evaluating a switch to DOR/3TC/TDF in HIV-1 infected adults who are currently virologically suppressed on another antiretroviral regimen, still under way (ClinicalTrials.gov).
|
Cabotegravir/
rilpivirine(long acting) |
INSTI/NNRTI |
ViiV/Janssen |
Phase III |
- International Phase III ATLAS-2M comparing long-acting formulations of cabotegravir plus rilpivirine administered every eight or four weeks open and enrolling (ClinicalTrials.gov).
- 96-week data from LATTE-2, demonstrating comparable efficacy between LA-CAB/RPV and combination oral treatment, published.
- Named patient/compassionate use program opened in March 2018; open only to individuals who can’t participate in the Phase III trial and can’t swallow pills (or do not adequately absorb oral medications), with some allowances for people who meet strict criteria for chronic non-compliance (ClinicalTrials.gov).
- 96-week data from Phase II LATTE-2 trial pub lished in July 2017.
|
| Fostemsavir |
CD4 Attachment inhibitor |
ViiV |
Phase III |
- Preliminary 24-week data from BRIGHTE, a two-cohort Phase III trial demonstrating superiority of fostemsavir versus placebo in heavily treatment-experienced adults, presented at 16th European AIDS Conference in 2017.
|
Dolutegravir/
lamivudine |
INSTI/NRTI |
ViiV |
Phase III |
- Phase III registrational trials (GEMINI 1 and GEMINI 2), comparing two-drug combination to standard three-drug regimens in treatment-naïve participants, have met primary endpoints with comparable results (ViiV press release; data to be presented at 2018 IAC).
- Various trials evaluating switches to dolutegravir/lamivudine from three-drug regimens reported at 16th European AIDS Conference (iBase summary), including six-trial meta-analysis.
|
| Albuvirtide |
Fusion inhibitor |
Frontier |
Phase II/III |
- Approved in China in June 2018 based on 48-week data from Phase III TALENT study, demonstrating superiority of albuvirtide plus ritonavir-boosted lopinavir over lopinavir/ritonavir plus two NRTIs as second-line therapy.
- Long-acting intravenous infusion studies planned for U.S.
|
| PRO 140 |
CCR5 Antagonist |
CytoDyn |
Phase II/III |
- CD01 Phase IIb trial and extension study, demonstrating moderate efficacy of PRO 140 single-agent maintenance therapy, published online in April 2018.
- Preliminary results from CD02 Phase II/III trial of PRO 140 in treatment-experienced patients reported at ASM Microbe 2018.
- Phase II/III evaluation of PRO 140 as single-agent monotherapy in virologically suppressed patients currently under way; 350 mg weekly subcutaneous injections (ClinicalTrials.gov).
|
| MK-8591 |
NRTTI |
Merck |
Phase II |
- Additional Phase I dosing data (0.25–5 mg/daily well tolerated) presented at 2018 CROI.
- Evaluations of daily MK-8591 plus doravirine/lamivudine and long-acting therapy planned.
|
| GS-9131 |
NRTI |
Gilead |
Phase II |
- No new data reported since 2017 CROI (in vitro evaluations).
- Dose-ranging Phase II trial in treatment-experienced volunteers under way in Kampala (ClinicalTrials.gov).
- Additional Phase II trials planned.
|
| UB-421 |
CD4 Attachment Inhibitor |
United Biomedical |
Phase II |
|
|
| Elsulfavirine (VM1500; VM1500A) |
NNRTI |
Viriom |
Phase II |
- Approved in Russia (as Elpida) in July 2017 based on 48-week data from clinical trial establishing non-inferiority versus efavirenz.
- Long-acting subcutaneous and intramuscular formulation in development; pre-clinical data reported at 2017 IAS.
|
| ABX464 |
Rev inhibitor |
ABIVAX |
Phase I/II |
- Modest 0.5 log/copies10 viral load reduction in 14-day Phase I study among participants receiving highest dose (150 mg) reported at 2016 CROI.
- Phase I/II safety, pharmacokinetics, and pharmacodynamics study under way (ClinicalTrials.gov).
- Evaluations of effect on viral reservoir, as a component of HIV cure research, also under way.
|
| GS-6207 |
Capsid inhibitor |
Gilead |
Phase I |
- Preclinical evaluations of Gilead capsid inhibitors reported by company in 2017.
- Entering Phase I clinical trials in 2018.
|
| GSK3640254 |
Maturation inhibitor |
ViiV/GSK |
Phase I |
- Phase Ia trial involving HIV-negative participants under way (ClinicalTrials.gov).
- Phase Ib trial involving participants living with HIV in development; Phase IIa trial planned.
|
| Combinectin (GSK3732394) |
Adnectins and fusion inhibitor peptide |
ViiV/GSK |
Preclinical |
|
|
TABLE ABBREVIATIONS
CROI: Conference on Retroviruses and Opportunistic Infections
IAC: International AIDS Conference
IAS: IAS Conference on HIV Science
INSTI: Integrase Strand Transfer Inhibitor
NRTI: Nucleoside Reverse Transcriptase Inhibitor
NNRTI: Non-Nucleoside Reverse Transcriptase Inhibitor
NtRTI: Nucleotide Reverse Transcriptase Inhibitor
