HIV: Competitive Highlights at CROI 2024

CROI 2024:  Key Conference Themes and Highlights

IAS-USA Guideline Update for CAB+RPV in Select Viremic Populations

On March 1, 2024 two days prior to CROI 2024, IAS-USA panel updated its guidelines to recommend CAB+RPV for select viremic PWH, based on the latest data from the Ward 86 SPLASH program as well as ViiV’s IDWeek 2023 OPERA cohort analysis. The guidelines now suggest, when supported by intensive follow-up and case management services, CAB+RPV IM may be considered for people with viremia who meet the below criteria when no other treatment options are effective due to a patient’s persistent inability to take oral ART:

• PWH unable to take oral ART consistently despite extensive efforts and clinical support.
• PWH at high risk of HIV disease progression (CD4 <200 cells/µL or a history of AIDS-defining complications).
• PWH with no resistance-associated mutations (RAMs) that could limit efficacy of CAB or RPV.

Assessment: This guideline update reflects the growing interest for long-acting CAB+RPV use in viremic populations and among patients who are unable to take oral ART. This may increase clinician appetite for off-label CAB+RPV use; however, this reflects a very specific population and must be carefully supported by intensive follow-up and case management. ViiV is likely to lean into this update as meeting unmet needs and bolster patient-centric messaging around providing options for PWH who are not well served by current oral therapies. ViiV may also try to encourage other guideline bodies to update in line with IAS-USA guidelines. While this will likely not enable a CAB+RPV label update, ViiV has expressed interest investigating CAB+RPV further in a viremic population and is “currently engaging with the FDA” to explore potential options.

HIV Treatment

• CAB+RPV (Cabenuva) superior efficacy vs daily oral SoC in PWH with adherence challenges (LATITUDE)
  • Planned interim analysis of the NIAID-sponsored Ph3 LATITUDE trial demonstrated superior efficacy of CAB+RPV (based on secondary endpoints) in maintaining viral load suppression compared to daily oral SoC in individuals with a history of ART adherence challenges. This represents a very specific population, who were heavily incentivized to achieve virologic suppression on oral ART before being randomized to CAB+RPV, challenging the real-world applicability of these findings.  Further, higher rates of treatment-emergent resistance with IM CAB+RPV continue to raise concern with this regimen, particularly in a population that struggles with adherence.
• CAB+RPV (Cabenuva) real world evidence regarding use in viremic populations, using data from Ward 86
  • Week 48 CAB+RPV data demonstrated durable suppression and persistence with VS in viremic populations from Ward 86, when supported by wrap around case management services; however, there was continued concern over cases of RAMs.
• DTG/3TC (Dovato) switch in PWH with a history of/suspected resistance, using data from VOLVER
  • VOLVER sub-analysis data concluded that detection of M184V/I at baseline did not predict virologic outcomes of DTG/3TC for VS maintenance.

HIV Prevention

• CAB for PrEP (Apretude) emerging real world evidence
  • Following limited CAB for PrEP RWE, injection adherence and HIV incidence data has been generated from OPERA and TRIO cohort studies, with both studies demonstrating high proportions of delayed or missed injections.
• CAB for PrEP (Apretude) implementation and market shaping, using data from PILLAR
  • The PILLAR telehealth implementation toolkit components and supporting data were presented by ViiV, with study staff participants (SSPs) reporting high levels of acceptability and feasibility of CAB for PrEP delivery and implementation support including telehealth services for CAB for PrEP delivery, such as online appointment scheduling, virtual visits, appointment reminders, at-home testing, and at-home

HIV Pipeline

• CAB-ULA safety and PK data
  • Ph1 CAB-ULA modelling study reported that the new CAB400 formulation (SC and IM) exhibits favorable safety and PK commensurate with dose intervals of ≥4 months. CAB-ULA IM Q4M (dose TBD) is progressing into upcoming late-stage HIV-1 PrEP and treatment studies.
• N6LS SC and IV efficacy data
  • Efficacy data for N6LS administered IV and SC from Ph2a BANNER trial along with safety and tolerability data from Ph1 SPAN trial were presented, noted to have informed the Ph2b EMBRACE study design, which will likely determine N6LS suitability as a CAB-ULA partner for Q4M treatment.
• MK-8527 discovery and Ph1 data across both healthy individuals and TN PWH
  • Data from the MK-8527 discovery stages as well as Ph1 efficacy, safety, and PK data have demonstrated LA capabilities, which can be applied to either an HIV treatment or PrEP setting.

CAB+RPV (Cabenuva) Superior to Oral ART in PWH with Adherence Challenges

Long-Acting Injectable CAB/RPV Is Superior to Oral ART in PWH With Adherence Challenges: ACTG A5359 (Rana, Oral Abstract 212)

• The study enrolled participants who had a history of sub-optimal adherence to daily oral therapy. Participants received cash incentives (up to $675 total) and adherence support while taking Standard of Care (SOC) daily oral ART consisting of a 3-drug boosted PI- or INSTI-based regimen to achieve viral suppression (including DTG- and BIC-based regimens). They were then randomized to QM IM CAB+RPV (n=146) or to continue taking a 3-drug daily oral regimen (n=148), while no longer receiving the cash incentives.
• 28/145 (24.1% cumulative probability) vs 47/148 (38.5% cumulative probability) participants met the primary endpoint of regimen failure in the CAB+RPV vs SoC arms respectively (14.5% difference), with 93% of injections being administered on time. This primary endpoint did not meet predefined stopping criteria for this interim analysis.
• Key secondary endpoints (virologic failure [6/145 (7.2%): CAB+RPV, 28/148 (25.4%): SoC] and treatment-related failure [9/145 (9.6%): CAB+RPV, 29/148 (26.2%): SoC] - virologic and treatment related failure and add %s) met the pre-defined stopping criterion, demonstrating superiority of the LAI arm vs. SOC. This resulted in the DSMB’s recommendation to stop trial randomization and provide all participants with the chance to switch to CAB+RPV.
• There were higher rates of treatment-emergent resistance with IM CAB+RPV, 33% (2/6) vs. 7% (2/28) in the SOC arm, with 2 cases of INSTI resistance on IM CAB+RPV and 0 on daily oral SOC ART.

Assessment:  Within this very specific population of participants who previously struggled to remain adherent on a daily oral regimen, as expected, they continued to do so once the incentives and support were removed.  As a result, the interim data favored the monthly CAB + RPV injectable arm and while the primary endpoint was not met, the DSMB stopped the study.  As seen in all pivotal Ph3 IM CAB+RPV trials, in those with confirmed virologic failure, there were higher rates of treatment-emergent resistance with IM CAB+RPV, 33% (2/6) vs. 7% (2/28) in the SOC arm, with 2 cases of INSTI resistance on IM CAB+RPV and 0 on daily oral SOC ART.  Results should not be extrapolated to broad populations with adherence challenges or viremic patients, and the real world applicability of this trial is questionable given the heavy adherence incentives and usage of QM CAB+RPV.

ViiV has released two press releases on the LATITUDE data and Kimberly Smith, MD, MPH, Head of Research & Development at ViiV Healthcare said that “it’s estimated that one-third of people living with HIV in the United States struggle with maintaining viral suppression. The findings of the LATITUDE study show that long-acting injectable cabotegravir + rilpivirine could be important for some people in this group, giving them another option to help keep their virus under control and improve their health.” ViiV is likely to continue to lean into this messaging around meeting unmet needs for patients who struggle with adherence, as well as a superiority claim for CAB+RPV over 3DRs in this population.  

CAB+RPV (Cabenuva) Real World Evidence in Viremic populations (Ward 86)

24-Week Viral Suppression in Patients Starting Long-Acting CAB/RPV Without HIV Viral Suppression: Findings from Ward 86 (Hickey, Poster 628)

• Data indicated the ability of CAB+RPV to suppress VL to <50 c/mL in viremic PWH from Ward 86, with 93% (n=55/59) achieving VS, and 81% (n=48/59) persisting on CAB+RPV at Week 48.
• Of the 6 cases of adverse virologic outcome, 3/59 patients (5%) had VF with emergent resistance and were able to suppress with a LEN combination (1 BIC/FTC/TAF + Q6M LEN, 2 LA CAB+RPV + Q6M LEN).
• The study concluded that loss to follow-up was low (3/59, 5%) and that LAI can be an important tool for improving VS in populations facing significant psychosocial and adherence challenges.

Assessment:  Despite seeing further Ward 86 data on successful RW CAB+RPV treatment in PWH with adherence challenges and viremia, it is important to note that Ward 86 targets a specific population and provides established implementation strategies to support provider referral, patient initiation and persistence, using heavily resourced wrap around services and ongoing monitoring to ensure treatment success. Therefore, it remains to be seen how replicable results are across multiple centers with more limited support options. However, this does represent a growing interest in studying LAIs in viremic patients who struggle with adherence to oral therapy, and critically influenced the recent IAS-USA guidelines. ViiV has expressed further interest in expanding CAB+RPV to viremic populations to meet unmet needs among this population.     

DTG/3TC (Dovato) Switch in PWH with Suspected Resistance

Impact of Archived Minority Populations With M184V/I on DTG/3TC for Maintenance of Viral Suppression (Buckley, Poster 693)

• PWH with a history of/suspected lamivudine (3TC) resistance switching to DTG/3TC was evaluated in a sub-analysis of the VOLVER trial, with results against the use of proviral DNA NGS to guide switches to DTG/3TC in this population.
• Week 48 efficacy results for participants with a VL ≥50 c/mL showed that 2.6% (n=2/76) participants had no mutations; 0% (n=0/21) participants had M184V/I mutations and 20% (n=2/10) had other mutations.
• 7 participants (2 with baseline M184V/I) had a blip on baseline visit (before switching to DTG/3TC).

Assessment:  Despite previous studies demonstrating elevated risk of DTG/3TC VF in the presence of M184V/I, this study concluded that its presence at baseline was not predictive of virologic outcomes. This VOLVER sub-analysis reports 48 Week data, which is a relatively short study period and so may be shortsighted and result in increased failure rates over the long term. Participants were also suppressed for a median of 9.1 years at baseline, which is an extended time period and may bias results, as it is unclear how long it will take M184V/I to reactivate. The recent BIC/FTC/TAF label update marked the regimen as the only FDA approved and DHHS recommended single tablet regimen for M184V/I resistant HIV; however, ViiV continues to present data and HCP messaging supporting the use of off-label DTG/3TC in the M184V/I setting to improve clinician confidence and encourage uptake.

CAB for PrEP (Apretude) Emerging Real World Evidence from the OPERA and TRIO Cohort Studies

Pre-Exposure Prophylaxis with Cabotegravir Long-Acting Injectable in the OPERA Cohort (Mills, Poster 1109)

• The US OPERA cohort study assessed 560 healthy individuals that received ≥1 CAB for PrEP injection between Dec 2021 and May 2023, with 89% (n=498/560) of those completing two initiation injections (complete initiators).
• Of the 498 ‘complete initiators’, 69% (n=344/498) received all injections on time, while 22% (n=107/498) had delayed and 11% (n=56/498) missed injections. 8% (n=34/498) discontinued CAB for PrEP. Only one person tested positive for HIV, but the timing of acquisition is uncertain.

Real-World Use of Cabotegravir Long-Acting for Pre-Exposure Prophylaxis: Trio Health Cohort (Mayer, Poster 1110)

• The US TRIO cohort study assessed RW effectiveness and adherence in 85 individuals that received ≥1 CAB for PrEP injection between 21 Dec 2021 and 31 March 2023 and were previously on oral PrEP (FTC/TAF, FTC/TDF, or both).
• 43 individuals had ≥3 CAB for PrEP injections, with 63% (n=27/43) of those having on-time injections vs 37% (n=16/43) that did not.
• 64 individuals had ≥2 CAB for PrEP injections, with 75% (n=48/64) of those having an on-time second injection vs 25% (n=16/64) that did not.
• No incident HIV diagnoses were identified, and no hypersensitivity reactions were observed.

Assessment:  Emerging CAB for PrEP RWE from both the OPERA and TRIO cohort studies shows that over 22% and 25% of participants with ≥2 CAB for PrEP injections having delayed/missed injections in each study respectively, suggesting there are challenges with LA PrEP adherence in the real-world setting. The long CAB PK tail adds an additional risk of resistance on top of HIV infection. Concerns around breakthrough infection rates with INSTI resistance on CAB for PrEP were raised in a recent WHO report, suggesting growing concern. However, ViiV could spin the data to highlight the adherence in “over two-thirds” of participants in OPERA, which also noted potential over-estimation of gaps in therapy, and the 0% HIV incidence in TRIO.

CAB for PrEP (Apretude) Implementation and Market Shaping

Healthcare staff acceptability and feasibility of telehealth delivery of cabotegravir for PrEP (Liu, Poster 1240)

• Staff study participants (SPPs) from 17 US study sites from PILLAR [randomized 2:1 to dynamic implementation (DI) which received standard and enhanced toolkits and supports, or routine implementation (RI) which received standard toolkits only], reported high levels of acceptability and feasibility of CAB for PrEP and implementation support at M1 and M4.
• At M4, 49% (n=39/80) of all SSPs reported that their clinic/practice uses some form of telehealth services for CAB for PrEP delivery, such as online appointment scheduling, virtual visits, appointment reminders, at-home testing and at-home injections [57% (29/51) of DI SSPs vs 35% (10/29) of RI SSPs], with a large proportion of SPPs (45%-87%) reporting that they were satisfied and found telehealth delivery to be both easy and helpful.

Assessment:  Following previous PILLAR data on SSP perspectives of CAB for PrEP implementation into SoC presented at IDWeek 2023, ViiV expanded on its designed implementation tools offered to clinics, showcasing its ability to provide optionality and efforts to increase PrEP administration in high-risk populations.  While ViiV’s implementation tools appear to be well-received, it remains unclear how access may be provided outside of the study setting, particularly for more resource intensive at-home services.  The challenges identified in the previous data, such as SSP adherence concerns for patients on Q2M CAB for PrEP and how to manage missed appointments were not reported in this data. This study also does not specify SPPs perceptions between high volume PrEP delivery sites or low volume sites and the differences in implementation support (DI vs RI) provided between these settings.

Pipeline CAB-ULA Safety and PK Data

Phase I Study of Cabotegravir Long-Acting Injectable Formulations Supports ≥4-Monthly Dose Interval (Han, Oral130)

• The ongoing Ph1 study evaluated safety and PK modelling of the approved CAB200 formulation administered SC with rHuPH20 and a new CAB-ULA (previously termed CAB400) formulation administered SC or IM without rHuPH20 to investigate less frequent dosing. Since this is interim data, CAB-ULA data is only for limited participants.
• The author concluded that the new CAB-ULA formulation (SC abdominal and IM gluteal) exhibits favorable safety and PK commensurate with dose intervals of ≥4 months. CAB-ULA half-life for SC and IM was predicted to be >6x and >2x the half-life of CAB200 IM, respectively.
• ViiV will be advancing a CAB-ULA IM Q4M formulation into future trials. The dosing is undisclosed and SC administration is still being evaluated.
• The overall tolerability/safety profile of CAB200 SC and rHuPH20 with ISRs reported in all 22/22 participants, along with PK considerations led to a decision not to progress this SC dosing strategy.

Assessment: ViiV has been developing higher concentration CAB formulations for some time, with the first CAB400 data presented at AIDS 2022 that showed to only support QM dosing.  However, the study presenter at CROI confirmed that CAB-ULA is a “completely new” formulation of CAB. The PK data appears promising for CAB-ULA to reach Q4M, with accompanying PR stating “ViiV Healthcare is conducting a registrational study of CAB-ULA in 2024 to further evaluate its use for the prevention of HIV in adults”.  As an H1 2024 date for the PrEP registrational study was indicated previously, this opens the potential for a slight delay, but broadly the PR statement suggests that ViiV remains on track to meet stated planned launch dates of 2026 (Q4M PrEP) and 2027 (Q4M treatment with either RPV or N6LS).  While it appeared that the half-life of CAB-ULA could enter Q6M territory, the presenter reported that research is ongoing to determine feasibility, with CAB-ULA potentially remaining on the table as a Q6M candidate.  Although the presenter noted that SC CAB200 + rHuPH20 was dropped due to ISRs, the SC dosing strategy was not ruled out for future CAB-ULA development.  Since N6LS is a lead combination asset for the Q4M treatment regimen, and ViiV has disclosed this will be administered SC, they may be motivated to continue investigating CAB-ULA SC to avoid mixed modality administration IM/SC for this combo.  From a lexicon perspective for its LAI therapies, ViiV seems to continue using its “ULA” terminology, likely in an attempt to bucket Q4M with Q6M aspirations and drive differentiation from Q2M dosing.

N6LS (bNAb) SC-administered Efficacy and Safety Data

VH3810109 (N6LS) in Antiretroviral Therapy-Naïve Adults With HIV-1: Phase IIa BANNER Efficacy Data (Losos, Oral 117)

• 62 TN PWH were split across 5 groups across part 1 and 2, undergoing either IV or SC-administration at varying doses (Part 1: (40mg/kg IV; n=8 OR 280mg IV; n=6), which set doses for Part 2: (700mg IV; n=16 OR 70mg IV; n=16 OR 700mg SC; n=16).
• N6LS was well tolerated whether administered IV or SC. The 700mg SC vs IV dose demonstrated a lower decline of –0.50 vs –1.54 log₁₀ c/mL, and a lower time to viral rebound post-treatment, of 17 vs 22 days.

High-Dose VH3810109 (N6LS) ±Recombinant Human Hyaluronidase PH20: Phase 1 SPAN Study Safety Results (Leone, Poster 639)

• Ph1 study assessing safety and participant perceptions of single-dose N6LS administered either IV or SC+ rHuPH20 in healthy adults (SC: 20 mg/kg [15 mL] OR 3000 mg [~40 mg/kg; 30 mL] + rHuPH20; IV: 60 mg/kg).
• No difference in overall AE incidence was observed between the SC dose groups, however, a higher frequency of AEs was reported in SC vs IV administration. SC administration was perceived as acceptable by participants at both doses.

Assessment:  Both Ph1 SPAN and Ph2a BANNER studies have informed N6LS dose selection and ongoing clinical development in the Ph2b EMBRACE trial (3000 mg SC infusion + rHuPH20 OR 60 mg/kg IV), which is moving to SC infusion (infusion understood through primary engagement) due to both studies demonstrating that SC injection could not support the volume required for efficacious dosing.  Since SC-administered N6LS is a potential CAB-ULA partner for Q4M treatment, EMBRACE study results (PCD: Oct 2024) will likely inform this decision about the viability of this regimen proceeding.  However, since this is quite high volume SC doses, it will be worth monitoring the safety and ISRs closely.  The need for baseline N6LS sensitivity tests to capture the ~15% of insensitive participants as confirmed in the BANNER Q&A adds an additional treatment hurdle, while also eliminating potential patients.

MK-8527 Discovery, Antiretroviral Activity, and Safety

Discovery of MK-8527: A Long-Acting HIV-1 Nucleoside Reverse Transcriptase Translocation Inhibitor (Diamond, Poster 638)

• Described preclinical MK-8527 research. Properties such as the mechanism blocking HIV RT translocation, and chain termination were similar to those seen for ISL-TP.

Safety and Pharmacokinetics of MK-8527, a Novel nRTTI, in Adults Without HIV (Gillespie, Oral 129)

• Ascending single doses (trial A) and ascending multiple doses (trial B) of MK-8527 were assessed in two Ph1 trials in healthy adults.
• Both single (0.5–200 mg) and multiple (3 x QW) doses (5-40 mg) of MK-8527 were generally well tolerated, with the study concluding that both the safety and PK data support continued clinical investigation.

Single Dose Administration of MK-8527, a Novel nRTTI, in Adults With HIV-1 (Carstens, Oral 115)

• Efficacy and safety of two Ph1 single-dose monotherapy MK-8527 trials in TN PWH was analyzed.
• Both trials showed a strong antiviral response with MK-8527 doses ranging from 0.5 to 10.0 mg, with a mean reduction of ≥1.0 log₁₀ c/mL observed by Day 7 post-dose (n=31). MK-8527 was generally well tolerated across all dosage levels.

Assessment:  Following discontinuation of QM oral ISL for PrEP due to lymphodepletion, development of the previously deprioritized NRTTI, MK-8527 was resumed in this indication.  Since Merck’s first announcement on MK-8527 for PrEP in its Q4 2022 earnings call, this is the first public launch of MK-8527 data, with studies collectively supporting its use as a long-acting oral, based on its PK properties demonstrated both at the discovery and Ph1 phases.  Despite having potential as an LAI, a Medicinal Chemistry Lead at Merck stated that development is limited by resource constraints, with a QM oral having a strong commercial opportunity.  While Merck could opportunistically develop MK-8527 for QM oral treatment, the limitation will be finding a partner agent that can match this dosing interval, therefore, Merck will likely prioritize the asset for QM PrEP.