New Nukes, Old Nukes

[Treatment Horizons]

Nuclear Waste
How to get overwhelmed by the data on new nukes, old nukes & lots of
different classes of ART at AIDS 2014
by Mariel Selbovitz, MPH, and David Miller

Photo by IAS/Steve Forrest
Photo by IAS/Steve Forrest

The summer of AIDS 2014 this July in Melbourne saw the community move beyond the wave of incidental, failed attempts at a cure and back to the discovery of optimal antiretroviral therapy, but are treatment-experienced patients invited to the party?

While combination antiretroviral therapy (cART) has significantly contributed to virologic suppression, improved immune function, and quality of life in people living with HIV, issues at AIDS 2014, including drug-drug interactions and cross-resistance, still pose significant barriers to long-term successful treatment and began to take center stage again. Presenters including Paul Sax and Joe Eron presented the need for newer anti-HIV drugs with increased potency and improved pharmacokinetic profiles either in existing classes or new classes of drugs with different targets.

A New Season for Nukes: ATC and the Legacy of Accelerating ARVs
NRTIs have always been the backbone of the drug combinations used in cART. Currently available NRTIs are hampered by problems of drug resistance and in some cases, particularly with the early ones, long-term toxicity, so regimens depend on a handful of well-tolerated NRTIs. Rising levels of drug resistance, including cross-resistance, are leaving an increasing number of patients with little to no treatment options. Apricitabine (ATC) is a Phase III deoxycytidine analogue NRTI with significant antiviral activity and good tolerability in treatment-experienced patients failing regimens containing 3TC and in those with the M184V mutation, thymidine analogue mutations (TAMs), nucleoside-associated mutations such as the L74V and certain mutations at codon 69.

Resistance to ATC has been shown to be slow to develop and there’s little evidence of resistance in clinical use, including in patients on ATC up to forty-eight weeks. The profile of ATC suggests there is little potential for cross-resistance with currently available NRTIs; in combination with its antiviral activity in the presence of the M184V mutation, ATC confers high level resistance to 3TC and FTC, making it a highly viable treatment option for patients who have failed regimens containing these NRTIs. The drug is eliminated by the kidneys, meaning there is a low potential for drug interactions with those eliminated by the liver.

Reviewing the Data on Old Nukes
In “Modifying Therapy in Treatment-Experienced Patients: When Should It Be Done?”, Joe Eron, MD, presented on switching from a three-drug regimen to a two-drug regimen, including to ritonavir-boosted protease inhibitors (PI/r) plus 3TC. However, many HIV patients are resistant to 3TC. During the session “Antiretroviral Therapy: Not All Strategies are Created Equal,” Eric Le Fevre reported on forty-eight-week data from the MODERN study, which compared maraviroc + darunavir/ritonavir to TDF/FTC + darunavir in treatment-naive HIV patients. The study found that the regimen containing two NRTIs was more effective than the PI-based regimen, with 86.8 percent of patients achieving viral suppression versus 77.3 percent. Jim Dearmast reported that in the dolutegravir SAILING study less people experienced virologic faulure on NRTI-based regimens than those on PI and other background regimens. No patients receiving NNRTIs with dolutegravir, regardless of how many were active, experienced virologic failure, including patients with the M184V mutation on 3TC/FTC with another NRTI.

It was reported at AIDS 2014 that the prevalence of ARV drug resistance in treatment-naive patients in Western Kenya was highest for NNRTIs at 8.3 percent and second highest for NRTIs at 2.1 percent. The same pattern has been found globally, indicating the need for new NNRTIs and NRTIs for drug resistant patients, both treatment-experienced and treatment-naive. This has important implications for the clinical management of HIV patients, as the risk of first-line treatment failure is increased. Additional data from Kenya found that, in HIV-infected children on cART, 78.8 percent had drug resistance mutations to NRTIs, 86.1 percent to NNRTIs and 77.4 percent had resistance mutations to both. Another study from AIDS 2014 found that drug resistant mutations persist in HIV proviruses for more than twelve years despite durable viral suppression, indicating that new treatments targeting the drug-resistant provirus may be necessary to achieve viral eradication.

And Then There Were Two: Another New NNRTI on the Horizon
NNRTIs are part of almost every durable HIV regimen; however the options are extremely limited with efavirenz being the dominant drug in this category and the serious adverse events (SAEs) make it intolerable for many patients. There is a need for new NNRTIs that are more efficacious and have better toxicity profiles.

VM-1500 is an NNRTI currently in Phase I/II development by a small biotechnology company, Viriom, that fits this unmet need in HIV treatment. VM-1500 is a bioavailable potent inhibitor of wild-type HIV and broadly active against strains carrying mutations associated with resistance to other NNRTIs, including the K103N, Y181C, L100I, K103N, G190A and V106A. In preclinical testing, VM-1500 inhibited ninety-two percent of HIV viruses in a panel of fifty viruses derived from NNRTI-treated patients, compared to zero percent with efavirenz and sixty-two percent with TMC-125. VM-1500 was not associated with any significant pathological or clinical findings.

At AIDS 2014 data on VM1500 from an open label Phase I clinical trial studying doses of 10 mg, 20 mg, 40 mg and 80 mg of VM-1500 in twenty-four healthy volunteers, the drug was found to be well tolerated and safe, with no SAEs reported. Significant plasma concentrations remained at the last sampling point of forty-eight hours, indicating the drug can be developed as a long-acting ARV. VM-1500 was rapidly and efficiently converted to the active substance and reached steady-state levels in plasma after six days.

In a Phase Ib/IIa, placebo-controlled randomized study of the safety and pharmacokinetics in healthy volunteers and safety, tolerability and antiviral activity of VM-1500 in HIV infected patients, 12 healthy volunteers were randomized to receive a single oral dose of 20 mg or 40 mg of VM-1500 or placebo with a 3:1 drug/placebo ratio. VM-1500 was well-tolerated and again no SAEs were reported. In part two of the study, a total of sixteen HIV-infected, treatment-naive subjects were randomized to receive 20 mg or 40 mg of VM-1500 or placebo QD for seven days. The 20 mg dose was safe and well-tolerated with no SAEs reported. The pharmacokinetics analyses confirmed rapid and efficient conversion of the prodrug to the active substance. All seven HIV-infected subjects from the 20 mg cohort achieved strong virologic response with median HIV RNA reduction of 1.73 log10 IU/ml after seven days of treatment. To date, the clinical studies have demonstrated that VM-1500 is a well-tolerated, safe and efficacious NNRTI that can be developed as a long-acting ARV. Thus far, the data indicates VM-1500 is superior to efavirenz, the dominant NNRTI in today’s ART regimens.

While the ACTG is focused on evaluating a number of HIV drugs, there is a plethora of HIV therapies intended to treat the virus still waiting to move forward into mature stages of clinical research. Future studies could be developed to measure the response of treatment-experienced, drug-resistant patients with regimens based on ATC, cenicriviroc, and VM-1500, with emerging therapies such as Sangamo, PRO140, and therapeutic vaccines from Inovio, Theravectys, Biosantech and Profectus.

The clinical data on new drugs at AIDS 2014 was encouraging for improving the long-term success of HIV treatment in drug-resistant treatment-experienced patients. ATC has antiviral activity and potent viral suppression comparable to 3TC against strains resistant to other NRTIs, good tolerability, a low proneness for the development of drug resistance, a favorable toxicity profile, including a low chance for mitochondrial toxicity, and a low potential for drug interactions. VM-1500 is active against NNRTI-resistant strains, has superior antiviral activity and superior tolerability and toxicity profiles and available data indicates it can be developed as a long-acting ARV. BIT225, a VPU inhibitor from Biotron, and other therapies in development give us some hesitant reason for hope for new treatments to construct viable regimens in drug resistant treatment-experienced patients. Clinical trials of ATC and VM-1500 may meet the urgent need of an increasing number of HIV patients and should be high on the priority list of the ACTG leadership and community advocates.

Mariel Selbovitz, MPH, serves as the Chair of the Cornell ACTG Community Advisory Board and has authored over thirty abstracts and articles.

A former member of ACT UP NY, David Miller is an AIDS treatment activist and current member of the Cornell ACTG CAB.