Leading experts in the fields of pharmacology and advanced materials, Professor Andrew Owen and Professor Steve Rannard talk about their pioneering work into long-acting therapeutics (LATs) for the treatment of HIV, and how their collaboration across scientific disciplines has brought about amazing results.
Can you tell us about your pioneering HIV research?
Andrew Owen (AO): Our work focusing on long-acting drug delivery for HIV is funded by the Engineering and Physical Sciences Research Council (EPSRC) in the UK, as well as by the National Institutes of Health and USAID in the US.
We’ve focused on taking drugs already used for the treatment of HIV, which require daily taking of pills by patients, and transforming them through various technologies into drugs, which can be administered for much longer periods of time - typically once every month or even longer than that. We also have several collaborative programs with major pharmaceutical companies working to develop long-acting formulations for the proprietary drugs.
Steve Rannard (SR): Long-acting injectables are one of the formats we are looking at. The idea there is that you use drugs, that might normally be taken orally and reformulate them so they can be injected either into the muscle or into the subcutaneous tissue, so that the drug is released over a long period of time.
Rather than asking a patient to take an oral tablet every day for several months, an injection will give them the same benefit. We're also developing implants, which deliver drugs without an injection. But we do not know how effective these will be yet.
Microneedle patches present a really interesting opportunity for HIV treatment, especially for children as they are much less invasive than injections or tablets. Our hope is that we could put a patch on the skin which would deliver enough drug for a significant period of time before simply removing it and applying another.
Can you tell us about your work with industrial collaborators?
AO: Where drugs have already been approved for oral administration in HIV, we try to apply advanced material science through the technologies that we have to transform those already approved drugs into long-acting drug delivery.
The work that we are doing with major pharmaceutical companies is working with new drugs that have been specifically developed for long-acting drug delivery. The hope is that by understanding the medicinal chemistry of the drug, and the materials chemistry of the formulation, then the next generation of long-acting medicines will provide even longer durations of exposure in HIV. HIV has been the disease which has been the focus of this development work with the approval this year of the first long-acting medicine.
SR: Although long-acting therapeutics, and the benefits of them have been known for a while it has been slow to gain interest from companies. Over the last 10 years, more and more companies have become aware of the potential for long-acting therapeutics. As a result, there's a greater interest from industry in the research that we are doing at Liverpool.
Professor Andrew Owen
Andrew is co-director of the Centre of Excellence in Long-acting Therapeutics (CELT). He is principal investigator for LONGEVITY, an international project funded by Unitaid that aims to translate long-acting medicines for malaria, tuberculosis, and Hepatitis C Virus. He sits on the executive group for the NIH-funded Long-acting/Extended-release Antiretroviral resource Program (LEAP).
Since March 2020, he has been intensively engaged in evaluation of SARS-CoV-2 antiviral candidates. He is a member of the Trial Management Group for the AGILE National phase I/IIa COVID-19 trial platform, and sits on the UK COVID-19 Therapeutics Advisory Panel (CTAP) antiviral and prophylaxis subgroups.
Professor Steve Rannard
Steve is also a co-Director of CELT and Director of the Radiomaterials Laboratory in the Department of Chemistry. He leads a materials chemistry and Nanomedicine research group with very strong multidisciplinary and industrial interactions, focusing on new therapies for infectious and chronic disease treatment.
He leads the materials programmes within LONGEVITY, NIH-funded programmes developing new implants for HIV therapies and CRUK/UKRI funded projects targeting new cancer nanomedicines. Through funding from UKRI, his team developed, translated and conducted the first human evaluation of orally-dosed nanomedicine candidates for HIV therapy in collaboration with Andrew Owen’s group.
He has co-founded four spin-out companies, Hydra Polymers Limited, IOTA NanoSolutions Limited, Polymer Mimetics Ltd and Tandem Nano Ltd. He also co-founded the British Society for Nanomedicine.
HIV is a lifelong commitment to therapy. Patients are required to take tablets every day for the rest of their life and this is not an easy request to make. Anything that can be done to minimize this burden could be life changing.Professor Steve Rannard
How could your work benefit people with HIV in the UK and globally?
AO: HIV is a chronic disease, we have very effective medicines now since the advent of highly active antiretroviral therapy in the mid 90s. Effectively those developments in potent antiviral drugs for HIV transformed it into a disease which can be managed. Patients can now live relatively normal life expectancies, but it requires the daily intake of tablets.
However, when patients skip a dose of the drug, the drug concentrations within the body dip below those concentrations required to inhibit viral replication. That gives an opportunity to the virus to adapt to the drug. If this happens too frequently, the virus will become resistant to the drug.
If we can remove the necessity for the patient to take drugs daily, they don’t need to be reminded all the time of their disease, they don't need to take tablets every morning, and there's less opportunity for the virus to escape and form resistance to the drug. This is a huge benefit.
SR: When medicines are taken orally, only a fraction of the drug enters the bloodstream and ends up at the point of need; much is simply not absorbed and is wasted with no benefit. If the amount of drug that enters the bloodstream can be optimised by using long-acting therapies, it is possible that more patients can benefit from the available supply.
Long-acting administration of drugs may mean that we could decrease the amount of drug needed per patient, reducing the cost and offering more therapy to more people globally. This would have real impact in low and middle income countries and would help to increase access to drugs for those who desperately need them.
Changing the way HIV are drugs are administered will also benefit infected children, especially the very young that can't eaily be given tablets. Part of our work is focusing on ways to administer poorly soluble but highly efficacious drugs to children.
What other research have you been involved with relating to HIV?
AO: Liverpool has an enormously strong HIV pharmacology group with Professor David Back, and Professor Saye Khoo, collectively we have been working on many challenges with antiretroviral pharmacology over the last 20 years, including drug interactions and how to manage the administration of treatments for other diseases, alongside management of HIV.
In HIV management, we've also done a lot of work on trying to understand variability in drug exposure and variability in drug response for oral medicines. So we’re trying to understand on a molecular basis, what underpins the difference in drug exposure between one individual and another individual, or between one population and another population. We’re also trying to understand the genetic basis for it with the hope that you could identify genetic polymorphisms which would be able to predict drug response in different individuals or sub populations.
Another area of research we are involved in is drug optimisation. We have completed studies to try and optimize the doses required for effective therapy, with a view to reducing the dose and measuring efficacy. We worked on a large clinical trial called Encore One, which demonstrated that a particular antiretroviral drug was able to be just as efficacious at a lower dose than it was at the full approved dose. This paves the way again to a reduction in the manufacturing supply in order to maintain effective therapy in low and middle income countries.
SR: One of the first projects that Andrew and I worked on together was focused on applying nanomedicine approaches to HIV. We generated new orally dosed candidate HIV therapies, which aimed to optimise the amount of drug that was needed. We had two grants from EPSRC that allowed us not just to show the principle, pre-clinically in animals, but to conduct an evaluation in healthy volunteers.
This was the first orally dosed nanomedicine trial in humans. In 2014 we translated two candidates from my laboratories through to clinical manufacture and worked with colleagues at the St Stephen’s AIDS Trust to study how the drug was absorbed. This was a truly exciting moment for the team.
We've seen COVID drugs and vaccines rolled out in quite a short space of time, do you think some of the learnings from this can benefit HIV treatment research?
AO: As a pharmacologist, I actually wish that the COVID-19 community would learn a little bit more from the HIV drug development community about pharmacological interventions. In the late 80s and early 90s, there were single drugs nucleosides, very similar to the class of drug that got a recent conditional approval in the UK. They were there in the late 80s and in early 90s for HIV, and they were deployed as single agents, and they rapidly generated resistance within HIV. It wasn't until we realised that we had to give multiple drugs together, that we could really effectively treat the disease and durably control viral replication without the virus rapidly generating resistance. Resistance emerged extremely quickly to monotherapies deployed for influenza also.
SARS-CoV-2 is different from HIV and influenza, but I struggle to think of any infectious disease that humankind has ever encountered, that doesn't develop resistance to single agents when deployed in a community. In the coming months, we'll learn a lot about the speed at which resistance emerges to, to anti SARS-CoV-2 drugs. I'm certainly a huge advocate of not rolling out mono therapies, but rather deploying drug combinations to increase the ultimate lifespan of the antivirals that we have.
Are long-acting therapeutics the future of HIV treatment?
SR: We are highly convinced that long-acting therapeutics have a considerable role to play. We also believe that long-acting therapeutics are probably the future for a lot of different diseases, but the benefits are already being made available in HIV treatment.
HIV is still a huge problem globally. Managing an HIV infection and maintaining good health is a lifelong burden, and there is no known cure.
AO: The first long-acting injectable was approved last year by the European Medicines Agency and this year by the Food and Drug Administration. There's a lot of community engagement activities which have been conducted, with patients and providers in order to understand what their preferences are. These have overwhelmingly suggested that this is what patients want, because it simplifies therapy and they no longer have to worry about taking tablets on a daily basis.
Also in some areas of the world, the taking of tablets, particularly for HIV, is very stigmatising. So a long-acting injectable is very effective method of drug delivery which is compatible with health care privacy, which is extremely important. I'm confident we'll see a lot more LATs being developed in the coming years.