Repurposing Medicines Toolkit - Guidance for navigating the process

Deborah O’Neil, Chief Executive Officer at NovaBiotics, shares the progress towards repurposing cysteamine (or NM001) as a treatment for cystic fibrosis and non-CF bronchiectasis. She emphasises the importance of seeking input from patients every step of the way.

What is cystic fibrosis?

Cystic fibrosis (CF) is an inherited condition that causes sticky mucus to build up in the lungs, digestive system, and other organs, causing lung infections and other symptoms. People with CF have a faulty gene called CFTR, which encodes a protein that helps to control the movement of salt and water in and out of cells.

Most people with CF will require several tablets and/or treatments every day - including different medicines to treat and prevent lung problems. These include antibiotics to treat chest infections, inhaled medications to promote mucus clearance, and anti-inflammatory drugs to widen the airways and make breathing easier.

More recently, CTFR modulator therapies have been approved that are designed to correct the faulty protein made by the CTFR gene. But these medications are only effective in a subset of CF patients with specific mutations.

What is non-cystic fibrosis bronchiectasis?

Non-cystic fibrosis bronchiectasis (NCFBE) is a long-term condition where the airways of the lung become widened, leading to a build-up of excess mucus that can make the lung more vulnerable to infection.

What problem are you trying to address?

When a person with CF or NCFBE has a chest infection that becomes severe, it is called an exacerbation or flare-up. Repeated exacerbations can lead to progressive lung damage that can seriously impact a person’s quality of life and even shorten their life expectancy. There is an urgent need for new treatments that can prevent or reduce lung exacerbations from occurring - and clear them more effectively. In particular, there is currently a lack of treatments that can be used during exacerbations to lessen the impact and reduce the length of these episodes - as CTFR modulators and most other existing treatments for CF are instead designed to reduce their frequency.

How did this repurposing project come about?

We initially set out to look for 'biofilm busting' compounds with activity against problematic bacteria associated with CF which exist in structures called biofilms that make them harder to treat. Through this work, we identified cysteamine, which is the active compound in candidate treatments we called NM001. This compound is also present in an existing medicine used to treat an unrelated rare genetic condition called cystinosis, which particularly affects the eyes and kidneys.

Through further laboratory experiments, we then realised that NM001 had several promising properties as a potential candidate for treating CF and NCFBE-associated lung disease. These included anti-inflammatory effects, potent mucolytic activity (the ability to break down mucus), antimicrobial, anti-virulence, and antibiotic-potentiating effects.

Importantly, NM001 is not a mutation-specific CTFR-targeting intervention - so it has the potential to benefit all CF patients.

What happened next?

The existing forms of cysteamine that were approved for treating cystinosis were oral capsules, which have a very distinct smell and aftertaste - so they can be unpleasant to take. When planning more palatable formulations of cysteamine for patients experiencing acute exacerbations and those with more stable disease, we engaged with CF patients. They surprised us by saying they’d much prefer to take the drug as an oral formulation when they were unwell - and would be ok with an inhaled (dry powder) version for maintenance when they were well.

That led us to develop two forms of NM001 - an oral (tablet) form for patients with CF experiencing lung exacerbations, and an inhaled (dry powder) formulation with no odour and a pleasant taste as a maintenance treatment for patients with stable disease.

What stage has it reached?

We recently completed an exploratory phase 2b global clinical study of NM001 in oral form in CF patients, following the encouraging results from an earlier phase 2a trial which was part-funded by the Cystic Fibrosis Trust. These studies have provided data confirming that the drug is safe, as well as determining the best dose and how we should measure its effectiveness in patients in a larger trial. We now plan to progress the tablet form of NM001 in registrational studies that will include both CF and NCFBE patients - and we’ve also sought patient input when developing the protocols for these studies.

Our inhaled formulation of NM001 has shown very encouraging data in laboratory studies, and we’re working towards initiating phase 1 clinical studies in CF and NCFBE patients as soon as possible.

What advice do you have for others?

Our project is an example of repurposing a compound rather than a drug, so it’s more complex than using an existing drug to treat a new condition, but it gives you the scope to make changes - such as improving the formulation and changing the route of administration.

But in any repurposing project, you will need to consider whether it’s going to be feasible to repurpose a compound or existing drug from a clinical and patient perspective - and not just because of even the most encouraging activity data you might have seen in the laboratory. First and foremost, it has got to be safe for patients - and you will also need to think carefully about the dose required for benefit in the new patient population and how you’re going to administer it. You should also consider the specifics of their health condition and other medications they take, which will be very different from the patients and condition the drug or compound was initially used to treat. There will already be a lot of safety data available, which is a big advantage of a drug repurposing project compared to developing a new molecule from scratch. However, you should be aware that this may not necessarily be for the dose you need to use it at in the new group of patients, your new formulation and the route of administration you are intending to develop it for.

It is also absolutely critical to engage with patients at every stage of the project. You can think something is a great direction - and then they can just blow that out of the water. They will provide you with absolute gold dust.

Nick Sireau is the Chair and CEO of the Alkaptonuria (AKU) Society. His two sons were both diagnosed with this very rare inherited condition shortly after birth. A drug called nitisinone has recently received approval as a treatment for the disease in Europe.

AKU, or black urine disease, is caused by a faulty enzyme required to break down certain protein building blocks, such as tyrosine, into a substance called homogentisic acid (HGA). Over many years, this chemical slowly builds up in tissues throughout the body, which can lead to a range of health problems over time.

“Apart from dark urine, there aren’t many other symptoms in childhood,” he says. “But the real issues typically start in their late 20s to early 30s. They will develop severe joint damage which can be extremely painful - and also problems with their eyes, tendons, ears, heart, and other parts of the body.”

AKU is a lifelong condition - and before nitisinone, there was no effective treatment to slow down or stop the progression of the disease.

“Both of my boys are now receiving nitisinone - so I can see the difference it’s making every day,” says Nick. “I also get to speak to patients from all over Europe - for some of them, this drug has changed their lives.”

Repurposing nitisinone for AKU

In 2009, nitisinone was approved for treating another rare disease - called hereditary tyrosinemia type 1 (HT-1) - which is also due to problems with the breakdown of tyrosine and can lead to severe liver problems. In combination with dietary restrictions, this medicine has dramatically changed the lives of patients with the condition - greatly extending their life expectancy, with few side effects.

“Nitisinone was initially developed as a weedkiller in the 1980s, but it was never commercialised because it was too powerful,” says Nick. “But scientists discovered that it works by blocking the activity of an enzyme involved in the final breakdown of tyrosine, which led to the clinical trials in HT-1 patients.”

As nitisinone stops the production of HGA, in theory, it should also have a beneficial effect on patients with AKU. But in 2009, the results of an initial clinical trial were not positive.

“Looking back, this study was too small and wasn’t carried out for long enough to see an effect,” explains Nick. “It also only had a single evaluation criterion - hip rotation - which probably wasn’t sensitive enough.”

The AKU Society worked with Prof Jim Gallagher, a researcher at the University of Liverpool, who developed a mouse model of AKU - and subsequent experiments showed nitisinone could completely halt the disease in these mice. They also funded a three-year natural history study, which enabled Prof Lakshminarayan Ranganath, a clinician at the Royal Liverpool University Hospital to develop the AKU Severity Score Index (AKUSSI). By scoring all parts of the body affected by AKU, this new measure could be used to reliably track the progress of the disease over time.

Clinical evaluation

The team then joined forces with Swedish Orphan Biovitrum (SOBI), the company that owned nitisinone, and an expert in rare disease clinical trials called Dr Tony Hall. They created a consortium of 13 partner organisations from across Europe to carry out major clinical trials to test whether the drug could be an effective treatment for AKU.

After securing €6m funding from the European Commission in 2012, the consortium launched a study (SONIA1) to determine the best dose of the drug to test in a larger study. That dose (10mg) was then tested in a four-year trial (SONIA2) involving 138 patients from across Europe and the Middle East.

“The results showed that patients who had received nitisinone had a 99.7% reduction of HGA levels in their urine, compared to those who received no treatment,” says Nick.

The study also recorded a positive effect of the drug in reducing the severity of the disease according to the AKUSSI score. In 2020, the European Medical Agency (EMA) granted a label extension for SOBI to market the drug as a treatment for AKU.

“We’ve then spent the last couple of years getting it approved by healthcare providers in the different countries across Europe to ensure patients can access it, which has been an epic journey in itself,” describes Nick.

The power of collaboration

Nick’s advice to others involved in drug repurposing is to network with other organisations and patient groups who have been involved in successful projects - as well as to seek scientific advice from the regulators.

“Learn from others. Every barrier you face, someone else has likely faced it before and successfully overcome it,” he says. “So you need to find out what they did and how they solved the issue”

Jonathan Watkins is Head of IP Services at the University of Birmingham. He shares his experience of repurposing sodium valproate for Wolfram syndrome, a rare life-limiting disease that currently has no effective treatment.

What is Wolfram syndrome?

Wolfram syndrome is a rare genetic condition that affects about 100 people in the UK. It causes diabetes mellitus, hearing and vision loss and often diabetes insipidus where the kidneys can’t retain water, resulting in excessive amounts of urine. Affected individuals will also experience complications affecting the nervous system, such as problems with balance and coordination, breathing problems and seizures. It's a long-term debilitating condition that can be life-threatening due to complications such as respiratory failure.

How did this project come about?

Dr Zsuzsanna Nagy, a Senior Lecturer at the Institute of Inflammation and Ageing at the University of Birmingham, had developed a human cell model of Wolfram syndrome and used it to search for candidate drugs that could be developed into effective new treatments. These studies had initially identified sodium valproate, a well-known medicine approved for treating epilepsy, bipolar disorder and migraine. Further experiments showed this drug had the potential to help slow down or halt Wolfram Syndrome (WS)-related neurodegeneration by reducing nerve cell death.

These encouraging results suggested that sodium valproate could help slow or halt the disease process in Wolfram syndrome, helping to improve the quality of life and extend life expectancy for individuals affected with the condition.

How did you get involved?

Dr Nagy and Prof Tim Barrett, a clinician and Director of the Centre for Rare Disease Studies (CRDS) Birmingham, approached me to discuss how best to advance this drug repurposing project to maximise the chance of benefits for Wolfram syndrome patients.

I felt the project had a great team, and the right science - and importantly, there was a potential pathway to get this drug to the clinic for routine use in patients. So we had all the pieces of the jigsaw and could see a way to fit them together for a successful outcome.

What were the next steps?

Sodium valproate was discovered in 1881 and first came into medical use in the 1960s. It wasn’t authorised for treating Wolfram syndrome, which was unsurprising given the nature of the disease.

We obtained Orphan Drug Designation with the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the use of sodium valproate in the treatment of WS-related neurodegeneration. Orphan medicines are authorised for rare diseases or conditions and benefit from certain incentives - including several years of market exclusivity after approval.

What stage has the project reached?

Prof Barrett is currently leading a randomised controlled clinical trial recruiting 70 patients with Wolfram syndrome to test the safety and effectiveness of sodium valproate as a treatment for the disease.

If the results are positive, there are a few options we will consider to ensure the drug can benefit patients with Wolfram syndrome. These include licensing it out to a company for onward development - or publishing the data and relying on clinicians to prescribe the medicine off-label.

What advice do you have for others?

Seek advice from the appropriate people - and think about what pieces of the jigsaw you need and whether there is a potential commercial pathway to take it to market.