This has been a lively year for HIV research says an i-base report. Even though only one new drug was approved (a once-daily version of raltegravir) several key generic approvals (dolutegravir and tenofovir/FTC) are perhaps just as important.
The report says: “Three new fixed-dose combinations (FDCs) have been submitted to the US Food and Drug Administration (FDA)/European Medicines Agency (EMA) with expected decisions soon, including one with a new integrase inhibitor (bictegravir).
“Early data presented for several new compounds, including from new drug classes that are in early stages of research, are an optimistic sign that HIV is still a potential market for new drugs.
“While current ART is safe and effective there are ways it could become better still: formulations with smaller pills, less frequent dosing, long-acting compounds (weekly, monthly, yearly), with lower doses, fewer side effects and drug interactions, stronger resistance profiles – and it could be cheaper and more accessible. Some of these factors feature in compounds already filed for regulatory approval.”
The report says this year the pipeline includes compounds in current classes (NRTIs, NNRTIs, PIs and integrase inhibitors) and compounds with new targets and mechanisms of action (including a capsid inhibitor and several monoclonal antibodies), see Figure 1. It also includes a two-drug combination submitted with an indication as maintenance therapy (dolutegravir/rilpivirine).
Importantly, compounds from new classes – monoclonal antibodies (mAbs), entry inhibitors, maturation inhibitors and capsid inhibitors – are all expected to work for people with multiple drug resistant (MDR) HIV who are dependent on new drugs. And, the report says, some of these drugs have potential to be used in very different ways – as treatment, as part of a cure strategy and for prevention as PrEP.
The report says only new HIV drug approval since the pipeline report in July 2016 was for a once-daily formulation of raltegravir. The new version still requires a two-pill dose (2 x 600 mg) but has improved pharmacokinetic (PK) properties that allow once-daily dosing without regard to food. Approval was based on 48-week results from the phase 3 treatment-naive ONCEMRK study. The improved PK profile also results in lower peak drug concentrations and higher trough levels, and less interpatient variability.
The report says the regulatory approval of several generic formulations over the last year is also important – in September 2016, tentative approval by the FDA of a generic formulation of dolutegravir has the potential to significantly improve treatment in countries who have access to in-patent generics. This will be especially true once the FDC (with TAF/FTC) also becomes available.
EMA approval of three generic formulations of TDF/FTC that use a different base salt for tenofovir, but that has been referred to European courts to decide on patent issues. The FDA also approved a generic version of TDF/FTC. The patent implications and timeline for US generic access and pricing is unclear and might take years: generic drugs are sometimes priced very highly in the US.
The report says several compounds have already been submitted for regulatory evaluation based on primary endpoint results from phase 3 studies. In September 2016, the first single pill protease-inhibitor based fixed dose combination (FDC) of darunavir/cobicistat/FTC/TAF (D/C/F/TAF) was submitted in both the US and Europe, with a decision expected later in 2017.
The applications are based on studies with darunavir/cobicistat plus tenofovirDF/FTC as control and at least one study at IAS will report on this FDC. The reduced milligram dose for TAF compared to TDF makes this formulation possible as a single tablet.
On 12 June 2017, a new drug application was issued to the US FDA for a single tablet FDC of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). A similar submission to the EMA in Europe is expected during 3Q 2017.
Bictegravir (formerly GS-9883) is a once-daily integrase inhibitor, that (unlike elvitegravir) does not need to be boosted or to be taken with food. This is also a potent compound, used at low milligram dose (50 mg) leading to a small pill when combined with TAF, few drug-drug interactions and a similar resistance profile to dolutegravir.
Four phase 3 studies include a treatment naive study comparing it to dolutegravir and several switch studies in people with viral suppression on current treatment.
The most recent publicly presented data were results from a small phase 2 non-inferiority study in 98 treatment-naive study that showed very similar results compared to dolutegravir.
The report says results from two phase 3 studies in treatment naive adults will be presented as late breaker abstracts at the IAS 2017 in Paris.
Although both dolutegravir and rilpivirine are long-approved as oral drugs (in 2013 and 2011 respectively, in the US), in June 2017 a new oral coformulation with both drugs in a single pill was submitted for regulatory approval as an FDC for maintenance therapy.
The application is for use as a switch option in people with suppressed viral load on earlier treatment and is notable for being the first FDC that doesn’t include NRTIs. The application is based on results from the SWORD 1 and 2 studies presented at CROI 2017 that showed dual arm was non-inferior to continuing ART.
Dolutegravir-based dual therapy with 3TC is also discussed below.
The report says the unpredictability of drug development is always important to remember and this year included gains and losses of some compounds and the re-emergence of others.
Doravirine is a once-daily NNRTI that can be taken with or without food that has few drug-drug interactions and that retains activity against common first generation NNRTI mutations (K103N, Y181C, G190A and E138K). It is being developed in an FDC with generic TDF/3TC and has the compound name MK-1439A. Results from a two-part, dose-finding, phase 2 study in treatment-naive participants presented at CROI 2016 last year, reported doravirine to be non-inferior compared to efavirenz with 78% in each group having undetectable viral load at week 48.
This year another randomised phase 3 study reported doravirine to be non-inferior compared to boosted darunavir with similar safety and efficacy results. New nano-formulations of this compound are also in development and IAS 2017 will include phase 3 results comparing the MK-1439A FDC to efavirenz/TDF/FTC in people on first ART.
Cabotegravir (CAB) is a second-generation integrase inhibitor being developed by ViiV Healthcare as both an oral tablet and long-acting (CAB-LA) injectable formulation. It has potential use as both treatment and, the injectable formulation, as PrEP.
CAB-LA has an extremely long half-life: a single injection results in drug levels that are still detectable in some people more than a year later. This requires that a lead-in phase using the oral formulation is essential before using the injection to screen for likely risk of hypersensitivity reaction. The long half-life means that anyone stopping CAB-LA when used as treatment needs to switch to alternative ART. When used as PrEP, current studies recommend switching to daily oral PrEP for a year.
The oral formulation has a similar drug resistance profile to dolutegravir, and is also being studied as part of dual oral therapy with rilpivirine (see dolutegravir/rilpivirine above). Results from a phase 2b included 144-week results from 243 treatment-naive participants who started triple therapy ART (dose-ranging cabotegravir or efavirenz, plus background TDF/FTC NRTIs), and who switched to oral cabotegravir plus rilpivirine maintenance therapy at week 24 if viral load was undetectable.
The report says the phase 2 LATTE-2 study, using dual injection maintenance therapy (CAB-LA co-formulated with rilpivirine LA) reported good efficacy and tolerability at week-48 with >90% of participants having undetectable viral load and high patient satisfaction with injections (even though these caused usually minor side effects). See study details.
Several international phase 3 studies of cabotegravir LA for PrEP are already underway, with oral TDF/FTC as the comparison. New nano-formulations of cabotegravir LA are also in development.
The phase 3 programme includes two large international studies in treatment-naive and -experienced participants: FLAIR (First Long-Acting Injectable Regimen) and ATLAS (Antiretroviral Therapy as Long-Acting Suppression). IAS 2017 will include updated 96-week results from LATTE-2.
Dolutegravir showed a higher barrier against drug resistance in treatment-naive studies than any other antiretroviral to date and this led to several independent research groups looking at whether dolutegravir could be used in combinations with less than three active drugs.
In addition to using dolutegravir with rilpivirine (see above), several studies are using dolutegravir with lamivudine (3TC) including with the two drugs co-formulated in an FDC. This includes use both as first-line ART and as a switch option in people who are stable on current ART (usually defined as having undetectable viral load for year). Of these, the single-arm treatment naive PADDLE study reported rapid reductions in viral load, including in four people with baseline viral load >100,000 copies/mL with 18/20 maintaining undetectable viral load at week-48. Results from week-96 of this study will be presented at IAS 2017.
The report says several larger phase 2 and 3 studies are ongoing including the single arm LAMIDOL and ACTG A5353 studies and the randomised ASPIRE and TRULIGHT studies. Of these, only the French ANRS 167 LAMIDOL single arm switch study has reported results. At CROI 2017, after 40 weeks of dual therapy, 101/104 participants remaining undetectable, with a single person with viral rebound (>50 – 200 copies mL) who switched back to triple ART. ACTG A5353 in 122 treatment-naive participants is due to report results at IAS 2017.
Finally, in August 2016, ViiV announced two large international randomised phase 3 studies (GEMINI 1 and 2) that will compare dolutegravir/3TC FDC to dolutegravir plus separate TDF/FTC. Together these will enrol 1,400 treatment-naive participants and will quantify whether dual-NRTIs are still needed for some integrase-based regimens, with data collection for the primary endpoint (viral suppression at week-48) expected in 2018.
If these studies produce positive results, a modelling study published last year reported potential savings of $550m in the US alone over five years if dolutegravir/3TC was used as maintenance therapy by 50% of people who suppressed viral load on triple ART and $800m if used as initial ART. This increased to $3bn if 25% of people currently on stable ART switch to dolutegravir/3TC dual therapy.
The report says it is also important that although several studies using dolutegravir as monotherapy maintained viral suppression in most participants, the unpredictable risk of viral rebound in some people with the development of integrase resistance means that monotherapy with dolutegravir is now clearly not recommended. All dolutegravir monotherapy studies should have now changed all participants back to dual or triple therapy.
Ibalizumab is a monoclonal antibody that has been in development for over a decade. Previous development names included TMB-355 and TNX-355 and phase 1 efficacy results were first reported in 2008. Ibalizumab blocks initial HIV entry by attaching to CD4 receptors and stopping conformational changes that are needed for the virus to enter a CD4 cell. It is active against CCR5 and CXCR4-tropic virus. The half-life of >3 days enables the intravenous (IV) infusion to be given every two weeks.
For much of the development programme, access was limited to an open-label expanded-access study but results from a small phase 3 study (TMB-301) were presented at CROI 2017. This study in 40 people with multidrug resistant HIV, reported a mean viral load decrease from baseline was –1.6 log copies/mL, with 55% and 48% having reductions >1 log and >2 log respectively.
Results from an intramuscular formulation were also presented at CROI 2017 but although initial viral load reductions were similar to the IV version, rebound after one week suggests greater vulnerability to drug resistance.
Ibalizumab is being developed by the Taiwanese company TaiMed but marketing and distribution rights for the US and Canada have been sold to Theratechnologies (who market tesamorelin for visceral hypertrophy). A press release from the developing companies reported that FDA had granted a priority review with an expected deadline for submission in January 2018.
The report says a further phase 3 study is also ongoing and updated results in treatment-experienced patients are due to be presented at IAS 2017. PRO 140 is a humanised IgG4 antibody that blocks HIV entry by binding to CCR5 but is active against maraviroc-resistant virus. PRO 140 has been in development for more than ten years, but that paradoxically has been designated “fast-track” status, for having potential activity against MDR HIV.
The most recent phase 3 data were presented at CROI 2017 where a small number of people (n=41 originally and 16 in a follow up phase) switched to PRO140 monotherapy after stopping ART. PRO 140 uses weekly dosing of 350 mg self-administered sub-cutaneous injections of PRO 140 and 10/16 people continued to have undetectable viral load without ART for up to two years.
Ongoing phase 3 studies include a monotherapy switch study in 300 participants with viral suppression >48 weeks on ART and in addition to ART as part of salvage combination in 30 participants with multidrug resistance to other classes. No new results are expected at IAS 2017.
Fostemsavir (GSK3684934) is an attachment inhibitor that binds to gp120 that is active against nearly all HIV-1 subtypes, though not sub-type AE or group O and has no in vitro cross resistance to drugs from other classes. This compound is being developed by ViiV but was previously a BMS compound (BMS-663068).
Results from a phase 2b randomised dose-ranging study in 251 treatment-experienced participants that used atazanavir/r in the control arm were presented at the Glasgow conference in 2016. Rather than using 2 NRTIs as background drugs, all participants used raltegravir (400 mg twice-daily) plus TDF (once-daily) as the background drugs. At 96-weeks, 61% vs 53% had undetectable viral load <50 copies/mL (GSK934 vs atazanavir) with no difference by baseline subgroups.
Ongoing research is in a large international phase 3 study (enrolled, no longer recruiting) in treatment-experienced patients with drug resistance and who are sensitive to only two or fewer drug classes. This study was launched in 2015 with an estimated end date in 2020. Although no new clinical data are due to be presented at IAS 2017, two drug interactions studies are due to be presented as posters.
UB-421 is a broadly neutralising mAb that targets CD4 binding with in vitro data suggest comparable or greater potency compared to other compounds, including VRC01 and 3BNC117.
A phase 2 study in 29 virally suppressed participants on ART who used UB-421 monotherapy during an 8-week ART interruption had no cases of viral rebound during the monotherapy phase. UB-421 was given by infusion either 10 mg/kg weekly or 25 mg/kg every two-weeks. Two current phase 3 studies in people with MDR HIV are listed but not yet enrolling. No new data are expected at IAS 2017.
VRC01 is another broadly neutralising mAb that targets the CD4 binding site that can be given by infusion or sub-cutaneous injection and that is in phase 1/2 development with multiple indications: for treatment, as part of cure research and for prevention.
One study at CROI reported no additional impact on reducing the latently infected viral reservoir from adding VRC01 to ART. Other studies in cure research are ongoing. This includes using a single injection in infants after birth to limit risk of vertical transmission and a potential role of additional injections for breastfed infants.
Two large international phase 2 PrEP studies PrEP are already ongoing.
Although new clinical data are expected at IAS 2017, a study on lack of effect on reservoirs will be presented, similar to published results from last year.
ABX464 is a molecule thought to work by blocking the end stages of viral assembly. A phase 2a dose-ranging study presented at CROI 2016 in 80 treatment-naive participants in Thailand reported modest antiviral activity (~0.5 log copies/mL) but only in 4/6 people using the highest 150 mg dose (with no responses in 2/6).
The compound is also being studied for impact on viral reservoir and whether it can limit viral rebound in absence of ART, included a related study due to be presented at IAS 2017 in Paris.
As many companies do not widely publicise pre-clinical work, this section is restricted to a few studies.
MK-8591 is a very interesting NRTI now in phase 1 development by Merck that is notable for high potency (currently using a 10mg oral daily dose), a long plasma half-life that allows once-weekly oral dosing, a slow-release removable implant that might only require annual dosing and ongoing studies looking at use for both treatment and PrEP. MK-8591 is active against both HIV-1 subtypes and HIV-2, including against NRTI mutations K65R and Q151M (although the M184V variant conferred 10-fold resistance).
EFdA reaches good drug levels in vaginal and rectal tissue – supporting further PrEP studies.
IAS 2017 is expected to include important new results for both use as treatment and prevention.
GS-9131 was reported ten years ago at CROI 2006. Other published studies highlight the potential for low risk of toxicity in animal studies and retains in vitro phenotypic sensitivity to broad NRTI resistance including mutations at K65R, L74V and M184V and multiple TAMS. The poster at CROI 2017 confirmed results from previously published studies into the activity against common NRTI mutations. No new data are expected at IAS 2017.
The maturation inhibitor GSK3640254 (previously BMS-986197) is in pre-clinical stages of development with GSK with a molecule acquired from BMS. An earlier maturation inhibitor, BMS-955176, also acquired from BMS was discontinued in October 2016 due to GI toxicity and drug resistance. New data on tolerability and side effects will be presented at IAS 2017.
Combinectin (GSK3732394) is a combined adnectin/fusion inhibitor that stops viral entry by targeting multiple sites of action on gp41 and CD4. This compound has the potential for self-administered once-weekly injections. This compound was in pre-clinical development with BMS and was acquired by ViiV in late 2015. Latest data presented at Glasgow 2016 summarised, in vitro activity and resistance data and virologic data from mouse studies.
GS-PI1 is a once-daily un-boosted protease inhibitor with high potency and a long half-life, and in vitro sensitivity against some second-generation PI resistance, in pre-clinical development by Gilead. An oral presentation at CROI 2017 reported a high barrier to resistance both after in vitro passaging and against multiple resistance complexes from multiple PI-resistant clinical isolates, and pharmacokinetic data from rat and dog studies.
GS-CA1 – capsid inhibitor First data was presented on GS-CA1, the first compound in a new class of HIV capsid inhibitors, with a formulation that can be used for slow-release injections, with monthly or longer dosing.
Capsid is the cone-shaped structural core within the virion that protects HIV RNA and related enzymes. As part of a dynamic process, the capsid protein (p24) first breaks down to release viral contents into the CD4 cell to enable reverse transcription and also needs to reassemble inside new virions as part of the maturation process at the end of the lifecycle.
GS-CA1 acts in both the early and late stages by binding at a site that blocks both disassembly and assembly leading to defective new virions that are non-infectious.
Although the following compounds are not being developed for use in high-income counties, they are progressing though clinical research.
Albuvirtide is a second-generation fusion inhibitor similar to T-20 (enfuvirtide) that is being developed by Frontier Biotechnologies as an alternative second-line combination in China. The long half-life enables once-weekly intravenous infusion (rather than twice-daily sub-cutaneous injections with T-20) and a side effect profile that does not include injection site reactions (ISRs). Partial interim phase 3 results from 175/389 participants were presented in Glasgow in October 2016 included approximately 80% viral suppression at 24 weeks and generally good tolerability.
Based on these results, albuvirtide has already been submitted for conditional approval in China and there are plans to run additional international studies in other countries next year, especially with other long-acting drugs. A sub-cutaneous formulation of albuvirtide is also in development that would allow self-injections at home, rather than weekly clinic visits needed in the current version.
Elsulfavirine (a pro-drug of VM-1500A) is an NNRTI being developed by Viriom for registration in some middle-income countries. 48-week results from a phase 2b study at CROI 2017 reported similar viral suppression compared to efavirenz (81% vs 73% <50 copies/mL) using TDF/FTC background NRTIs. A long-acting injectable formulation is being used in ongoing studies for treatment and PrEP with new results due at IAS 2017.
The report says several other compounds that featured in earlier pipeline reports have not lead to new data being presented over the last year.
GS-9695 and GS-9822 were promising integrase inhibitor compounds that were discontinued due to unpredictable kidney/urothelial toxicity in monkeys. The decision to end the development programme for BMS-955176 due to gastrointestinal intolerability was mentioned earlier in this report. The follow-on compound GSK3640254 is still in development.
The report reiterates that this is still an exciting time for HIV drug development. It says this year the HIV pipeline is remarkable for a potential range of drugs that could improve many aspects of the traditional approach to treating HIV using three-drug oral therapy.
It includes responses to the changing situation in which all countries now have access to some generic anitretrovirals – and drug pricing will continue to drive access in all countries. It also includes some compounds that are only developed for low- and middle-income countries, and coformulations that will not be available in high income-countries.