Six drugs that could TRANSFORM Parkinson’s treatment

For people with Parkinson’s disease and their families, there is rarely much good news.

The neurological condition slowly robs sufferers of their ability to move freely and live independently, causing worsening tremors and muscle stiffness – and, for some, problems with memory and thinking.

And despite 166,000 people in the UK now diagnosed, there is still no cure or approved drug capable of slowing its progression. But that, doctors cautiously suggest, may finally be about to change.

Experts speaking to The Mail on Sunday have revealed we are on the cusp of a revolution in Parkinson’s treatment, with a new generation of drugs designed not simply to manage symptoms but to tackle the disease itself.

It means that, for the first time, these disease-modifying drugs – which could slow the progression of Parkinson’s and potentially even halt it – are on the near horizon and may be available within three years.

Other drugs which can better control symptoms with fewer debilitating side effects could also be available on the NHS as early as next year.

The advances are thanks to cutting-edge science which has unpicked the ways in which Parkinson’s develops – and the cascade of damaging processes these trigger in the brain. Crucially, diagnosis is also set to get faster, with pinprick blood tests already shown to pick up tell-tale signs up to seven years before symptoms emerge. This could allow treatment before too much damage has been done to brain cells – and when new drugs may be most effective.

And the need could hardly be greater. Parkinson’s is the world’s fastest-growing neurological disorder, with cases in the UK rising 38 per cent in 15 years.

Globally, the number affected could double to more than 12 million by 2040.

Professor David Dexter, head of research at Parkinson’s UK and professor of neuropharmacology at Imperial College London, says there is now a real prospect of everyone in the UK who has Parkinson’s getting access to treatments which will improve their lives. And more astonishingly still, he argues that some people who have early signs of the disease in their blood – but who are not yet experiencing symptoms – may never go on to develop full-blown Parkinson’s because intervening early could hold it off for good.

‘The stars are really aligning when it comes to treating and potentially stopping Parkinson’s in its tracks,’ Prof Dexter says.

‘There’s a lot of positivity in the field. The promising thing is that these developments are likely to benefit people who are living with Parkinson’s now – even those in the later stages of the disease. And in the not-too-distant future we could be identifying people with Parkinson’s years before they’d ordinarily be diagnosed, giving them one of the new medications and preventing them from developing symptoms of the disease at all. We’re now at a stage where it’s feasible to think that way. It’s very exciting.’

One of the UK’s leading experts on the disease is Professor Miratul Muqit, who heads the UK Dementia Research Unit’s dedicated Parkinson’s Research Centre at the University of Edinburgh.

He cautiously shares Prof Dexter’s excitement while acknowledging challenges remain. He says: ‘We know so much more about the mechanisms of how this disease develops, and while the development of drugs to target these mechanisms remains challenging, what’s exciting is we have this new framework of knowledge about how cells in Parkinson’s are deteriorating.’

The new drugs that could slow it down

While Parkinson’s disease does not generally shorten lifespan, it can have a huge impact on the lives of sufferers.

Largely a disease of ageing, it is thought to be triggered by the accumulation of a normal brain protein called alpha synuclein, which forms abnormal clusters known as Lewy bodies. Precisely what causes the protein to form clumps remains unclear.

But scientists now understand that they gradually spread throughout the brain and damage the mitochondria – the ‘battery packs’ which power cells.

In turn, that damage stops brain cells producing enough dopamine, a chemical which plays a crucial role in controlling movement.

As levels fall, messages from the brain that control the muscles are disrupted, leading to the tremors, stiffness and slowed movement characteristic of Parkinson’s. Other symptoms include problems sleeping, depression, memory loss and balance issues.

These worsen over time – although each individual’s experience will be different – and can leave people needing a wheelchair, with speech and swallowing difficulties, incontinence and suffering hallucinations. About 80 per cent will eventually develop Parkinson’s-related dementia.

Treatment involves managing symptoms with physiotherapy, drugs such as levodopa which turn into dopamine in the brain, and dopamine agonists which mimic the effects of the chemical. Drugs known as MAO-B inhibitors also work to help increase dopamine in the brain.

These can be very effective in easing symptoms, but they do not stop the disease from progressing and some patients go on to require deep brain stimulation, a surgical procedure which places electrodes in the brain.

But now six drugs which could slow disease progression are in phase III trials – the crucial final stage of testing, in which treatments are typically given to hundreds or thousands of patients to confirm they work and are safe before regulators decide whether to approve them.

The most exciting is prasinezumab, an antibody treatment which binds to toxic clumps of alpha synuclein and stops it spreading from one cell to another. If it works, it would prove alpha synuclein’s role in Parkinson’s development, and that stopping it spreading slows the disease.

Its history is chequered because it failed to meet its main outcome – essentially, an improvement in a score which broadly measures Parkinson’s symptoms and function compared to a placebo – in an earlier trial. But when researchers looked specifically at an arm of that study which measured motor symptoms, the evidence suggested people taking the drug were deteriorating around 20 per cent more slowly.

A further analysis over the next two years confirmed those results, and found those also taking levodopa experienced less progression in their symptoms.

‘In the extended study, disease progression was 55 per cent slower in some patients receiving it after 2.5 years of treatment compared to placebo,’ says Prof Dexter. ‘It’s been shown to be very safe and doesn’t have the complicated side effects of some of the Alzheimer’s drugs which stopped NICE from approving them. We could get to a stage where you could give someone without symptoms this drug and it could be a game-changer – they may never develop the disease at all.’

The latest trial will report its results in 2029.

Several other drugs in the latest stages of trials are already licensed for other conditions which, if found to be effective, would make it even easier for patients to get access.

One is the cough medication ambroxol, a once-a-day pill which helps patients with respiratory disease to cough up mucus. It also boosts levels of an enzyme called GCase, which helps clear away waste products – such as alpha synuclein – from brain cells.

Trials involving a higher concentration of the drug are being run by researchers at University College London. ‘It would be quite easy for a manufacturer to gain a licence for Parkinson’s and gain regulatory approval quite quickly,’ says Prof Dexter. ‘It would be a lot cheaper for the NHS than a brand-new pharmaceutical.’

Existing medicines that may hold the key

One of the world’s biggest trials to evaluate new Parkinson’s treatments is also set to investigate three other drugs already licensed for use in other conditions.

The trial, EJS ACT-PD, will look at telmisartan, a blood pressure drug, terazosin, used to treat an enlarged prostate, and UDSA, a liver and gallstone drug.

Epidemiological studies have already found ‘very strong data’ that people taking telmisartan and terazosin for their original purpose have a lower rate of Parkinson’s disease, Prof Muqit says.

The trial is groundbreaking because it will allow many drugs to be tested together. And if one shows no effect after 18 months, it can be replaced with another.

‘It’s exciting, and we have to be optimistic, but we don’t yet really know how effective they are in Parkinson’s,’ says Prof Muqit. ‘It’s still uncertain.’

The final drug in late-stage trials is buntanetap, which reduces the production of toxic brain proteins, including alpha synuclein.

Even if these drugs all fail there are promising candidates further back in the development pipeline. They include one targeting the LRRK2 gene mutation, which is linked with Parkinson’s disease and may account for about 3 per cent of cases in the UK.

And there remains interest in the ability of GLP-1 drugs, used for type 2 diabetes and weight loss, to slow Parkinson’s by reducing brain inflammation.

Blood test that can spot it years early

Alongside improvements in treatment, the ability to pick up cases of Parkinson’s much earlier would make a huge difference to patient outcomes.

At present there is no definitive blood test or scan that can diagnose Parkinson’s.

Instead, doctors largely rely on symptoms and a clinical examination by a specialist, looking for signs such as tremor, stiffness and slowed movement.

Around 21,000 people in the UK are currently waiting for a diagnosis. Some have been waiting for years – and without one they cannot begin therapies that could help control their symptoms.

A blood test in development by UCL researchers has already identified a pattern of proteins in the blood that can predict, up to seven years before symptoms emerge, whether someone will go on to develop Parkinson’s.

Tests are now under way to see whether the same protein signature can be detected using a simple dried blood spot – potentially requiring only a finger-prick sample – which could then be analysed in a hospital pathology lab using existing equipment.

The results so far are looking ‘quite promising’, Prof Dexter says.

He adds: ‘Currently they’re hoping this will improve the diagnostic journey and reduce waiting times. But if we can use the test in large studies, we could end up with something that identifies people early and allows them to take a disease-modifying drug before they develop symptoms.’

Better treatments and fewer side effects

The good news in the shorter term is that treatments to manage symptoms are improving.

Once-a-day pill tavapadon is being assessed by US regulator the Food and Drug Administration and may have fewer side effects than those currently available. It could be available in the UK next year, Prof Dexter says.

Tavapadon stimulates only two out of five dopamine receptors in the brain – unlike other similar drugs – and may reduce serious side effects which can cause compulsive behaviour such as excessive spending or over-eating.

Patients on trials reported significantly longer periods when their symptoms were under control.

Adaptive DBS, brain stimulators which control tremors automatically, are already being rolled out on the NHS and lead to much better symptom control.

And ondansetron – already used to manage sickness in people undergoing chemotherapy – is being tested to see if it can reduce the distressing hallucinations which affect up to 75 per cent of people with Parkinson’s.

‘When I speak to patient groups today, they get really excited because they can see things on the horizon which will benefit them,’ Prof Dexter says. ‘Finally, we have reached a point where real success could be very close.’

• To get involved in Parkinson’s research, visit parkinsons.org.uk