Developmental Clinical Studies - A Phase I study of a novel peptide fusion inhibitor for the treatment of chronic HIV infection

With the development of effective antiretroviral (anti-HIV) therapy over the last two decades, in resource rich countries, individuals with HIV infection can live for many years and as a consequence of this success, are now developing age related medical problems as seen in all ageing populations.

Dealing with an ageing HIV infected population is therefore a new medical phenomenon and poses new challenges including managing interactions between medication to treat HIV infection and medication to treat other medical conditions. This is problematic as the vast majority of current anti-HIV therapies are prone to interactions with other medications. Also, many current anti-HIV therapies have side effects which are more problematic in older individuals such as increasing risk of heart attacks or rises in cholesterol. Given these factors, new antiretroviral agents without the propensity to interact with other medication and with improved side effect profiles represent a crucial medical need.

We have developed a new antiretroviral drug, currently known as C34-PEG4-Chol, which prevents the HIV virus from entering cells. Although required to be given by injection, C34-PEG4-Chol only requires to be given twice or even once weekly and is likely to have minimal side effects with no interactions with other medicines. To date, C34-PEG4-Chol has been studied in the laboratory and in animal models. We propose to assess the safety and anti-HIV activity of this new agent in subjects with chronic HIV infection for the first time.

This proposal brings together scientific and clinical expertise in HIV medicine with the company who have developed C34-PEG4-Chol and the study will be conducted within a registered UK trials unit. This novel antiretroviral agent has the potential to offer a low toxicity, easily administered, antiretroviral agent as part of effective antiretroviral therapy for the future avoiding the treatment limiting toxicities of current licensed agents.

Current combination antiretroviral therapy (cART) utilises antiretroviral (ARV) agents from at least 2 different classes and has dramatically decreased HIV-related mortality and morbidity and increased survival. Many classes of ARV are associated with long term toxicities and are drug-drug interactions. With an ageing HIV infected population such factors are increasing challenging to manage making the development of new ARV a critical medical need. The majority of ARV in use and in development targets inhibition of the HIV viral enzymes reverse transcriptase and protease and recently the viral integrase. Only maraviroc and enfuvirtide target the mechanism of viral entry. Maraviroc is a CCR5 inhibitor and therefore is not active against HIV strains with other tropism, which represent a substantial proportion (>40%) of patients with advanced HIV infection and has significant drug-drug interactions. Enfuvirtide, a peptide administered by subcutaneous injection, does not have these limitations. It is safe and well tolerated with a favourable metabolic profile and without propensity for drug-drug interactions. However local injection-site reactions (ISR) are observed in the majority of patients. Its inconvenient administration profile and ISRs have progressively hampered its use. However, 2nd generation fusion inhibitors with improved profiles would fill an important gap in the existing therapeutic armamentarium. We have developed a novel peptide fusion inhibitor, C34-PEG4-Chol, which overcomes the key limitations of enfuvirtide: it has 100-fold more potent antiviral activity in vitro and prolonged duration of action in vivo. Available preclinical data suggest that this new agent should be efficacious in humans at a lower dose and reduced frequency of administration, possibly as a once-weekly subcutaneous injection. We aim to assess the safety, pharmacokinetics, and antiviral efficacy of this peptide in a Phase 1 study in HIV-infected adults.

Impact Summary

With the advent of effective combination antiretroviral therapy (cART) dramatic reductions in HIV-associated morbidity and mortality have been reported, to the extent that in resource-rich settings with ready access to cART, patients may live with chronic HIV infection for several decades with life expectancy, although reduced, approaching that of non HIV infected populations.
This new phenomena is leading to an ageing HIV infected population for the first time. Of those receiving HIV care in England in 2009, 18.4% were aged over 50 years, and increase from 11% in 20003. Projections from the UK CHIC Study (UK Collaborative HIV Cohort Study) suggest that by 2015, 27.4% of those seen for care will be aged >50 years. Whilst an age of 50 would not normally be considered as old, this cut-off reflects the fact that prior to cART few people were expected to survive to this age.

Many classes of antiretroviral drugs are associated with long term toxicities including dyslipidemia and impaired glucose tolerance and are prone to drug-drug interactions. With an ageing HIV infected population, such factors become increasing challenging to manage making the development of new antiretroviral agents free from such limitations a critical medical need.
A successful and safe antiretroviral drug would have considerable healthcare benefits for the future management of chronic HIV infection. Furthermore, this study will assess 'cholesterol-tagging' of antiviral agent. With ever changing viral pandemics, this principle of cholesterol-tagging may be crucial for future antiretroviral and antiviral drug development.

Who will benefit from this research?

The first group to benefit will be the academic community which has been working on antiretroviral drugs of the past 30 years. The research will also benefit the private sector and in particular PeptiPharma S.R.L.

The second group to benefit will be the wider academic community who are developing antiviral drugs in other fields.
The third group will be the HIV infected community.

How will they benefit from this research?

Academic Community: The principle of 'cholesterol tagging' an antiviral agent will be tested in this study. Knowledge gained will allow for new avenues of research to assess such principles for other viral illnesses and importantly may assist in rapid drug development for viral pandemics.
HIV infected community: Will benefit not only from this new potential antiretroviral drug, but also from the interest this creates in the wider community leading to the development of other highly tolerable antiretroviral agents and the potential for other 'cholesterol tagged' agents.

Timescales for the benefits to be realised

The results could lead to a Phase 2 Trial within 2 years of the completion of the study.

What research and professional skills will staff working on the project develop which they could apply in all employment sectors?
The collaborators have many years of successful internationally renowned experience in the field of HIV therapeutics, vaccine and prevention. This project will add to the continuation of their expertise as well as maintaining their training and development.