Therapeutic Focus - Hopes on the horizon for respiratory syncytial virus

Respiratory syncytial virus, considered the single largest cause of hospitalisation in infants in developed countries, has no vaccine to prevent it and only two options to treat it, both of which have substantial drawbacks. Causing considerable burden on health care systems, the illness represents a significant unmet need.

The challenges the virus presents means work in this area is thin on the ground. Hope is on the horizon, however, with vaccine candidates from AstraZeneca’s MedImmune and Novavax. In addition, some promising work is being done with antivirals, albeit in early stages (see table). “There are lots of promising developments. I wouldn’t be surprised if we didn’t have a vaccine within three or four years at the current rate of progress,” says Professor Peter Openshaw, Director of the Centre for Respiratory Infection at the National Heart and Lung Institute, Imperial College London.

Burden

Respiratory syncytial virus (RSV) is a contagious viral infection that the World Health Organisation describes as the single most important cause of severe respiratory illness in infants and young children. The virus primarily manifests as bronchiolitis, inflammation of the small air passages in the lungs, or viral pneumonia.

Almost all children will have had an RSV infection by their second birthday, and infection can be severe in premature infants, young children and the elderly.  Symptoms include sneezing, coughing, fever and wheezing. In young infants it can cause pneumonia and severe breathing problems, and in rare cases it can be fatal.

“It’s really an amazing economic burden, it doesn’t really cause that much morbidity or mortality [in children] but it really does cause a lot of disruption. Having any impact on that at all will really have a great vital benefit,” says Dr Steven Projan, head of R&D at MedImmune’s Infectious Disease & Vaccines unit, AstraZeneca’s biologics operation.

Citing a study Dr Projan says that 5% of children under the age of three months end up in hospital from RSV. According to WHO there are 64 million cases globally of RSV and 160,000 deaths per year. In the US it is estimated there are 85,000-144,000 hospitalisations annually in infants less than a year old due to the virus, which causes 20-25% of pneumonia cases and up to 70% of bronchiolitis cases seen in hospital.

Limited options

There are currently only two drugs on the market for RSV and neither address the broad burden that this disease presents, albeit for different reasons.

Developed by MedImmune and approved by the FDA in 1998, Synagis was the first monoclonal antibody launched in the US targeting an infectious disease. However, it is only used to prevent the development of serious lower respiratory tract disease in high risk paediatric patients. It cannot treat children already suffering from the disease and it cannot completely prevent infection by the virus.

The antibody is directed against a neutralising epitope on the F protein found on the virus envelope. An RNA virus, RSV’s envelope consists of the F and G glycoproteins which are involved in fusion and attachment, respectively.

Due to its 20 day half-life Synagis is administered via monthly injections, the first dose prior to the November start of the RSV season. A typical treatment course is five doses.

MedImmune’s attempts to develop a higher potency follow-on product have so far been fruitless, the failure of motavizumab being the highest profile set back. Not only did the company fail to establish that the product was any better than Synagis at reducing hospitalisations, it was found to induce severe allergic reactions; the project was abandoned 18 months ago (AstraZeneca scales back motavizumab, December 21, 2010).

“The data we saw with motavizumab demonstrated to us that we could do better than Synagis” says Dr Projan.

Efforts are still ongoing at MedImmune. The company has an extended half-life antibody, MEDI-557, in phase I development, which it hopes will cover an infant for the entire RSV season in one injection.

Doing little

The second available therapy is an inhaled version of ribavirin, sold by Valeant as Virazole. The antiviral, a nucleoside analogue, interferes with RNA metabolism required for viral replication.

It is used to treat severe lower respiratory tract infections in infants and young children, and given via a nebuliser. Treatment runs for 12 to 18 hours per day for three to seven day; however its use is very limited.

“Essentially almost everyone is of the view that it [ribavirin] really does very little for babies, it’s used more in hope than expectation of benefit. It’s not easy to deliver, so it clogs up ventilators, actually it causes very significant problems in paediatric intensive care wards,” Imperial’s Professor Openshaw says.

Antivirals

As such there is much need for new treatments that can check the progress of RSV once it has taken hold. The challenges that the influenza virus presented in this regard suggests the path forward will be tricky.

Research into antibodies has largely ruled these compounds out, as they do not work quickly enough. More effective antivirals are considered a viable option although the narrow treatment window for RSV presents problems.

“What we are beginning with our small molecule colleagues at AstraZeneca is trying to come up with small molecule RSV polymerase inhibitors. If we intervene at the level of viral replication we might demonstrate therapeutic activity,” says Dr Projan.

Candidates are in very early stages of development he says.

Other attempts

No molecule has been shown to work therapeutically for RSV to date, Dr Projan adds. This no doubt explains the thin pipeline of products being worked on in this area, although a couple of companies are active.

MicroDose Therapeutx is working with fusion inhibitors, which prevent viral entry into cells through direct interaction with the F protein.

Its phase I candidate MDT-637 is an inhaled drug that has so far been well tolerated, achieving levels in the respiratory tract where it could inhibit clinical isolates of the virus in vitro. It is expected to move into phase II this year.

Licensed to Gilead Sciences in 2011, the HIV and hepatitis C giant will take over development of the drug after phase IIa.

Belgium based Ablynx currently has a nanobody, ALX-0171, in phase I with results due towards the end of the year. The compound is a trimeric molecule made up of three identical nanobodies, which bind to the F protein in the virus, preventing it from entering lung cells.

Meanwhile what now looks like to be a dud, Alnylam’s RNAi-based ALN-RSV01 is an aerolised drug that works by silencing the nucleocapsid ‘N’ gene required for viral replication. However a phase IIb study in lung transplant patients failed earlier this year and the company could well decide to abandon the project.

Professor Openshaw holds out some hope for the fusion inhibitor approach, but remains sceptical that RNAi will yield answers.

“I think RNA interference was an interesting proof of concept but to me it never seemed really likely that was going to be something that could be used in the clinic,” he says.

Vaccine development

While treating the infection once it has taken hold represents one path being followed, efforts to develop a vaccine have been gathering pace over the last few years. This could then be offered to all infants, and address the burden on healthcare systems that RSV presents.

This has also presented challenges over the years, with researchers struggling to come up with safe candidates. The catastrophic failure of a project in the 1960’s stymied research for some time – a formalin-inactivated RSV vaccine not only failed to protect against infection but also caused an increased risk of severe disease, resulting in the death of two infants while 80% of the vaccinated children had to be hospitalised.

However, the RSV pipeline is now heavily skewed towards vaccine approaches, the table below shows. These are either based on RSV subunit proteins or live attenuated vaccines that can induce both local and systemic immunity.

One of the most advanced is Novavax, which plans to start two dose-ranging phase II trials this year in elderly and paediatric RSV. 

The company discovered that subjects exposed to RSV produce anti-F protein antibodies but almost none of these bind to a specific antigenic site, called site II, on the virus. The company’s F protein nanoparticle RSV vaccine contains copies of this antigenic site region, inducing antibodies that bind and compete with this site.

Phase I studies in 150 healthy adults were successful; the intramuscular vaccine was well tolerated, immunogenic and produced functional antibodies that neutralised the virus.

MedImmune’s lead vaccine is MEDI-559, a live attenuated candidate being developed in conjunction with National Institute of Allergy and Infectious Disease. 

Results from a phase I/II trial in healthy children are due later this year, and the company hopes to move into phase IIa/IIb towards the end of this year or with the RSV season next year.

AstraZeneca is looking for collaborators in this area, however, because of the huge studies that will be required to demonstrate safety and efficacy.

“That’s the issue we are going to be confronting. That is why it was critical we worked with the NIH, and why we are actively looking for commercial partners to develop our paediatric RSV vaccines,” says Dr Projan.

Infection in the older population

One area that has yet to be fully explored by drug developers is infection in the elderly, which is also a huge burden but really only recently understood. While diagnosing primary infection in childhood can be done using simple antigen detection tests, in adults the viral load is often much lower, resulting in the need for more sensitive diagnostics.

“The elderly do tend to have very high morbidity and mortality from RSV, which was really unappreciated until we started using modern PCR based diagnostics to detect the virus” says Professor Openshaw.

“It’s been estimated that for every child that dies from RSV probably about 100 adults die. It’s an area that really needs to be appreciated and developed.”

Epidemiology studies in the elderly have shown that RSV is comparable to influenza, with perhaps even higher rates of hospitalisation.

“From a medical point of view, it’s a significant unmet medical need,” says Dr Projan.

“We have a vaccine in early, preclinical development for vaccinating the high risk elderly as well as the healthy elderly for RSV. In that particular instance, we are attempting to increase not only the antibody response but T cell response using an adjuvant. We think annual vaccinations for RSV appropriately adjuvanted can give significant protection from disease.”

Future outlook

With few current options for those suffering from RSV and huge sections of the population vulnerable to its symptoms, there is an obvious need for therapeutics. While universal vaccination programmes would seem to provide an answer, effective antivirals would still come in useful, as has been seen in influenza.

Promising vaccine candidates in the pipeline could come to fruition within the next couple of years, however significant investment is still required to get these to market. Acceptance in vaccine programmes would present a further challenge.

So despite the promising advances seen, historically slow progress in this disease needs to accelerate signficantly to make an impact any time soon.

Mid stage RSV pipeline
Product Company Pharmacological Class Trial ID
Phase II ALN-RSV01 Alnylam Pharmaceuticals/Cubist Pharmaceuticals RSV RNAi therapeutic NCT01065935
Phase I ALX-0171 Ablynx Anti-RSV MAb NCT01483911
MDT-637 Gilead Sciences/MicroDose Therapeutx RSV fusion inhibitor NCT01355016
NCT01489306
NCT01556607
MEDI-557 AstraZeneca Anti-RSV MAb NCT00578682
NCT01562938
NCT01475305
MEDI-559 AstraZeneca RSV vaccine NCT00767416
MEDI-534 AstraZeneca Parainfluenza virus (PIV) & RSV vaccine NCT00686075
RSV Vaccine Novavax RSV vaccine NCT01290419

To contact the writer of this story email Joanne Fagg in London at joannef@epvantage.com

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