Betting on the little guy: Could small molecule drugs be a solution to dengue fever?

Dengue fever now threatens half of the world’s population, but small molecule treatments could be an answer to treating the virus.

Small molecule treatments have shown great promise in diseases like Covid, Hepatitis C and HIV. Pic: Getty Images

• About 4 billion people are now at risk of contracting dengue fever

• Small molecule treatments targeting virus replication mechanisms could be an effective answer

• Treatment options currently only include symptom management, with no approved methods to fight the virus directly

Dengue fever poses a growing global threat, putting 4 billion people at risk with no targeted treatments available.

As infections surge and mosquito ranges expand, the search for effective therapies is urgent.

One promising pathway lies in small molecule drugs, which can target virus replication directly, circumventing many of the challenges vaccines face in tackling the disease.

Island Pharmaceuticals (ASX:ILA) is developing a small molecule treatment for exactly that purpose with its lead asset ISLA-101, which is targeted at mosquito-borne (or vector) diseases like dengue fever.

“We became particularly interested in mosquito-borne viruses several years ago, following the Zika outbreak in 2016,” ILA managing director Dr David Foster said.

“I’m sure you recall the 2016 Olympics in Brazil – many women chose not to attend because they were concerned about Zika's effects on pregnancies, given the serious complications associated with the virus.

“That experience really highlighted for us the broader problem of mosquito-borne viruses.”

Island quickly turned its attention to dengue fever, which infects about 400 million people per year, with about 100 million of those patients requiring some form of medical intervention.

At present, there is no approved antiviral intervention.

Treatment is limited to symptom management, typically involving IV fluids, pain killers and fever management with severe cases requiring hospitalisation or even blood transfusion.

Dengue cases on the rise

Somewhere between 20,000 and 50,000 people die from the disease every year, and the threat is only growing.

The World Health Organisation has cautioned that half the world’s population is now living within dengue risk zones, with 4 billion people at risk of contracting the disease.

Climate change is a major factor, expanding the native ranges of many dengue-carrying mosquitoes, but a new carrier in the form of the tiger mosquito is compounding the issue.

Unlike its tropical cousins, the tiger mosquito is well suited to multiple types of environments and has already begun to move into Europe, Australia and the South Pacific, including places such as Fiji where dengue wasn’t much of a problem until now.

Queensland Health reports there were 124 confirmed cases of dengue fever in Queensland by April this year – that’s four times more cases than we’ve had in the previous five years for that three-month period.

The need for an effective anti-viral treatment is dire, and it is urgent.

Treating dengue without a vaccine

The US government has been trying to develop a vaccine for dengue fever for more than 100 years, without success.

The problem is that dengue comes in four different serotypes, imaginatively numbered from 1-4.

If you contract one type of dengue, you will develop antibodies for that serotype, but that immune response won’t protect you from any of the other three virus types.

In fact, exposure to a second serotype can lead the immune system to mount an ineffective response, causing the virus to spread further and faster and increasing the severity of the illness.

Typically, it’s the second infection that’s most dangerous, leading to the worst complications like haemorrhagic fever or even death.

Vaccines essentially mimic minor infections, meaning a vaccine targeting just one serotype of dengue could actually make people sicker if they were to be infected with a secondary type.

To date, we’ve been unable to create a vaccine that accounts for all four serotypes, so the medical community has looked to other potential solutions.

“From the beginning, our strategy was to look for small molecules. We deliberately chose not to pursue vaccines,” Foster explained.

“Instead, we looked to a different model: Hepatitis C, where small molecule drugs have effectively provided a cure without the need for a vaccine.

“We believed a similar approach could work for dengue.”

Picking the right molecule for the job

Island Pharmaceutical’s attention was drawn to the EL-101 molecule, originally developed by Johnson & Johnson as a cancer therapy.

After J&J released the Investigative New Drug (IND) application to the US National Cancer Institute (NCI), it was tested in thousands of people in more than 40 clinical trials globally, although it’s yet to be approved for any indication.

More recently, Monash University’s David Jans Laboratory found EL-101 had strong activity against all four dengue serotypes, as well as other mosquito-borne viruses like Zika, West Nile, and yellow fever.

An animal study revealed startling results – a single daily dose saved about 20% of infected mice, while two daily doses increased that number to an astounding 70%.

A team at Harvard independently discovered similar results through their own screening effort, identifying EL-101 as a potent antiviral agent and confirming its effectiveness against dengue and Zika in animal models.

“Having two world-class labs independently ask the same question and arrive at the same answer gave us a lot of confidence that we were onto something exciting,” Foster said.

Plugging into the anti-dengue ecosystem

Once they’d settled on EL-101, Island got in touch with the NCI and requested the IND application with the centre's full support.

“This access was critical,” Foster emphasised, “It gave us visibility into all the publicly available data, including J&J’s extensive development work and preclinical safety data.”

Satisfied EL-101 had a well-established safety profile, the company inked a licensing agreement with Monash for the use of EL-101 – officially called Fenretinide – for preventing and treating flavivirus infections.

Flaviviruses include dengue, Zika, Japanese encephalitis, West Nile, and Usutu among others.

Island Pharma now holds the patent for this method-of-use IP in Australia, Canada, Singapore, Brazil and the US, extending protection until 2034.

Foster estimates the huge amount of data available saved ILA years of clinical trials and tens of millions, if not more, in development costs.

If that wasn’t enough, Island has formed a relationship with the State University of New York in Syracuse and the US Department of Defense, which are running dengue human challenge studies with an attenuated (weakened) strain of dengue developed by the DoD.

The DoD has already run 20-25 people through control trials with this weakened strain of dengue, providing invaluable baseline data to compare ISLA-101 against.

With a Cooperative Research and Development Agreement in place, Island has been able to plug its ISLA-101 (renamed from EL-101) treatment directly into the ongoing clinical model assessing dengue fever in humans.

“We know what a normal dengue infection looks like and the associated symptoms, and now we can try to reduce and manipulate those outcomes with our drug,” Foster said.

“In exchange for providing the virus and data, the army wants to see the data from our study.

“They’re closely watching our progress.”

Addressing a desperately unmet need

With an extensive body of safety data, dual-sourced proof-of-concept, and a remarkably high-quality human dengue model for clinical trials available, Island Pharmaceuticals is exceptionally well placed to test – and ultimately prove – if ISLA-101 is an effective treatment.

At present, the company is running the second stage of a Phase 2 PROTECT trial with the goal of establishing evidence of ISLA-101’s prophylactic (preventative) and therapeutic (treatment after infection) effectiveness.

ILA began patient enrolment in January this year, and has already met key benchmarks for safety and anti-dengue activity.

“The most recent 2a clinical results show the potential for a preventative approach to dengue management that could aid millions of travellers who visit exposed countries, with malaria treatment a useful analogue to quantify this opportunity,” Island Pharmaceutical executive chair Phil Lynch said of the results.

If ISLA-101 continues to show promise as an effective dengue treatment, it could mark a step change in how the disease is treated globally.

“Giving ISLA-101 as a post-exposure prophylactic or early treatment could help suppress outbreaks or reduce their severity. That’s the vision,” Foster explained.

“We could work with organisations like the World Health Organization to bring ISLA-101 to lower-income countries where it’s really needed.”

A US$878m market

Treating dengue fever is already a huge market globally. Data Bridge Market Research estimates its value at US$878 million, with a compounding annual growth rate of 11.6% to reach about US$2.12 billion by 2031.

The value proposition for Island doesn’t end there, however – ILA also intends to apply for a Priority Review Voucher for ISLA-101, should it prove effective enough for the IND to be approved.

PRVs allow biopharmaceutical companies to get priority review for a second drug, streamlining FDA processes and reducing costly clinical trial timelines.

The vouchers can be sold on to other companies, and in recent months have garnered a sizeable price tag of anywhere between US$100m to US$150m.

An inject of cash that size would set up Island Pharmaceutical very well to pursue a second small molecule indication – the company has already issued a letter of intent to acquire the rights to a second molecule, which would also be eligible for a PRV.

For now, all of ILA’s attention is on its Phase2b PROTECT trial. The results will be available by the end of the month.

“Addressing the dengue problem will require vaccines, small molecules and continued work on vector control, like controlling mosquitoes,” Foster stressed.

“It’s going to take all three approaches to really make a dent in dengue.”

This article does not constitute financial product advice. You should consider obtaining independent advice before making any financial decisions.

Originally published as Betting on the little guy: Could small molecule drugs be a solution to dengue fever?