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Animal drug could be repurposed to help osteoarthritis sufferers

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Millions of osteoarthritis sufferers across the world could soon benefit from a pain relief drug currently used to treat joint issues in horses, cats, dogs and even racing camels.

Australian late-stage clinical development company Paradigm Biopharma is investigating injectable pentosan polysulfate sodium (iPPS) as a potential disease-modifying treatment for knee osteoarthritis (KOA).

The plant-derived, semi-synthetic drug has been used in the veterinary space for over 80 years to improve joint health and preserve cartilage integrity. It is registered for use by vets in more than 20 countries.

Until now, pentosan polysulfate sodium has only been used in humans over the age of 16 to treat blood clots and the discomfort or bladder pain associated with interstitial cystitis.

However, a number of current and former Australian Football League (AFL) players have been using Paradigm’s iPPS under a Special Access Scheme (SAS). This is a programme set up by the Therapeutic Goods Administration (TGA) for doctors to prescribe medications that are not listed on the Australian Register of Therapeutic Goods (ARTG).

After being repurposed and provided via subcutaneous injections in various trials, Paradigm has said the drug’s capabilities are proving to be more applicable in treating osteoarthritis, caused by the breakdown of cartilage in joints.

Now the company aims to bring hope to the estimated half a billion osteoarthritis sufferers around the world – 70% of whom are affected by the degenerative joint disease in the hip or knee.

There are currently no disease-modifying osteoarthritis drugs approved for the treatment of KOA. Instead non-steroidal anti-inflammatory drugs, analgesics and glucocorticoid injections are commonly prescribed for treatment.

But each of these drugs only deal with the symptoms, leaving the underlying degenerative problems untreated.

With osteoarthritis expected to become the single greatest cause of disability globally by 2030, there is a considerable unmet medical need for a disease-modifying drug.

Paradigm, which has its head office in Melbourne, Victoria, is focused on improving patients’ health and quality of life through the development of known therapeutics to address unmet medical needs in conditions where sustained inflammation is present.

People with osteoarthritis need alternative therapeutic solutions, as the current treatments often don’t provide sufficient relief, leaving them in pain and with a reduced quality of life.

Former Geelong, Sydney Swans’ and Carlton AFL player, Greg ‘Diesel’ Williams, 59, understands only too well how knee OA can have a devastating impact on your life.

Greg, who played AFL for 14 years during the 1980s and 1990s and is a dual Brownlow Medal winner who at his peak was the then-highest-paid player in the history of the sport, suffers with severe knee OA. A one-time world class athlete, he now can’t run, and has difficulty walking.

He explained: “If you’ve got OA people really don’t understand what we’re going through. It’s so painful. It’s so sore. It’s so, so hard to put up with. And it’s about time we did something about it.”

He has tried all kinds of medication, and spoken with the best surgeons, but is still in severe pain with KOA. He added: “If I could find a solution that’s medical, not surgical, yeah, I’d be going for that 100mph.”

As yet he doesn’t want to go down the path of having a knee replacement. “I may have stopped playing, but I don’t want to stop living,” he said.

Dr Philip Bloom, a specialist sports physician with over 20 years’ experience and specialist training in treating and managing musculoskeletal injuries and diseases to maximise function, explained: “Osteoarthritis of the knee is not just an isolated pain in the knee. It has a trickle-down effect on the rest of your life, particularly in regards to losing the ability to be active, which causes obesity, more aches and pains in other joints, and also psychological problems such as depression and anxiety.”

Whilst anyone can get osteoarthritis, most cases affect adults over the age of 45 and it is a major cause of disability in people aged 65 and over. Women are more likely than men to suffer from the condition – often referred to as ‘wear and tear’ arthritis – especially after the age of 50.

Results from a six-month long phase 2 trial run by Paradigm Biopharma have already shown that iPPS may slow the progression of KOA.

The exploratory 61-patient phase 2 randomised, double blind, placebo-controlled trial for synovial biomarkers in knee osteoarthritis showed changes consistent with disease modifying efficacy in subjects with moderate to severe osteoarthritis. Seventy eight per cent of subjects had moderate to severe osteoarthritis of the knee.

The six-month data indicated disease modifying potential for the drug in KOA based on less cartilage loss, as measured by MRI, in the iPPS group compared to those on placebo. MRIs of the placebo group cartilage showed an increase in its loss.

Levels of synovial biomarkers of cartilage and aggrecan disintegration were down at six months in the iPPS group. The same biomarkers increased in the placebo group.

Statistically significant reductions in bone marrow lesions, measured by MRI, were seen compared to placebo, with a trend towards reduced marginal osteophytes (bone spurs) compared to an increase in the placebo group.

Paradigm is now undertaking a comprehensive global phase 3 clinical trial designed to maximise the potential of iPPS, which it will market under the name Zilosul.

To this end the company has launched a clinical trial website to facilitate current and potential trial participants and support its development programme for KOA therapy called Hope4OA.com.

Here people living in either Australia or the US, can put their name forward as a potential trial participant, and find the answers to commonly asked KOA questions alongside patient support.

Mobility

Videoconferencing gets older adults moving

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An Osaka Metropolitan University-led research team has been exploring how videoconferencing can improve the health of older adults living in the countryside.

The COVID-19 pandemic made videoconferencing software commonplace in businesses and even schools, but this communication tool has the potential to offer benefits beyond the office or classroom.

OMU Associate Professor Kazuki Uemura of the Graduate School of Rehabilitation Science and colleagues devised a 12-week health education programme conducted using the videoconferencing software Zoom, with the aim of having participants engage in active learning. A control group was provided a similar 12-week programme by email, with attached pdf files giving health instructions in a passive learning format.

The researchers assessed the participants before and after the 12 weeks, then performed a follow-up at 36 weeks. Their results showed that compared to the control group the videoconferencing group tended to follow the health advice and showed some improvement in the amount of time spent doing physical activities as opposed to sedentary behaviour.

“This study proposes a new health education programme that is not dependent on location or distance and takes sustainable behavioural changes into consideration,” Professor Uemura suggested. “In the future, by expanding the implementation scale and conducting further verification, we aim to popularize such health programmes that everyone, everywhere can participate in.”

The findings were published in the Journal of Aging and Physical Activity.

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Independence

NHS health records help predict risk of falling

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Patients’ risk of falling in the next 12 months could be predicted from their NHS data using a newly developed calculator.

eFalls is a falls prediction model which uses routinely available primary care electronic health record data, the first of its kind in the world.

Developed and tested by researchers from the University of Leeds, the University of Birmingham, and a team of collaborators*, with funding from the National Institute for Health and Care Research (NIHR), it can be used to help identify people at risk of hospitalisation or emergency department attendance after a fall over the next 12 months. This means these people can be provided with interventions to prevent falls taking place.

A research paper outlining the findings is published in Age and Ageing

Falls are common among people aged over 65 and can be devastating for people’s personal independence. The risks are multifactorial and include conditions that affect mobility or balance; medications, and home hazards. A history of falls is the strongest risk factor. The incidence of falls is also projected to rise in line with the global ageing demographic.

The findings help proactive identification of people who are at risk of experiencing a fall in the next 12 months. eFalls uses existing primary care data, reducing the need for intensive clinical falls assessment, saving doctors and nurses valuable time. Once identified as at risk of falling, people can be referred on to a specialist falls prevention service for assessment and treatment to prevent future falls.

The National Institute for Health and Care Excellence (NICE) estimates that 40% to 60% of falls result in major lacerations, traumatic brain injuries, or fractures. Other complications of falls include distress, pain, loss of self-confidence, reduced quality of life, loss of independence, and mortality.

Principal Investigator Andrew Clegg, Professor of Geriatric Medicine in the University of Leeds School of Medicine, said: “Falls are a global health problem of major importance to health and social care systems. Currently, people’s fall risk is usually only assessed when they have already experienced a fall, which means that they might have already experienced a major injury such as a hip fracture.

“Our eFalls calculator means that, for the first time, it is possible to proactively identify a person’s risk of future falls which means that they can be referred to specialist falls prevention services, reducing the risk of a fall from happening. The ability to put plans in place to protect those at risk is invaluable to the patient and their loved ones.

“The benefit to the health service is that it reduces the need for treatment and care in hospital and in the community, and the associated costs to the NHS of that treatment. We hope that eFalls will be widely adopted across the NHS to prevent falls from taking place.”

Lead author Lucinda Archer, Assistant Professor in Biostatistics at the University of Birmingham, said: “The eFalls calculator can be used to predict a person’s risk of a fall, based on information that is already included in their GP records. The accuracy of the tool has been thoroughly tested in two large datasets, containing routinely recorded information on patients from Wales and England, which has shown promising results.

“If this accuracy is consistent across the wider population, the use of eFalls to target those who would benefit from specialist assessment could vastly improve the way that falls prevention services are provided in the UK.”

Health Minister Andrew Stephenson said: “Suffering from a fall can be traumatic for both the individual and their family but innovations such as eFalls could provide a fantastic solution to prevent such incidents, saving people from a lot of pain, as well as time and resource for the NHS.

“Our ongoing work to ensure people get the right care at the right time includes giving people access to local falls services and rehabilitations services, but I’m proud that the UK is at the forefront of developing further solutions to such a widespread issue, through co-funding the development of this technology.”

The team set out to produce and assess a robust and reliable method to proactively identify people for falls prevention interventions, due to the currently limited availability of such systems.

The team developed the eFalls tool using data from more than 750,000 healthcare records. Of these almost 35,000 people experienced a fall or a fracture resulting in A&E attendance or hospitalisation within 12 months.

The researchers now hope the eFalls prediction model to be successfully integrated into UK primary care electronic patient record systems and are keen to work with UK policymakers to explore how eFalls could be used to inform health policy.

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Mobility

New study helps shed light on why we move slower as we age

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Mary Kaupas participates in a experiment to study how humans of various ages reach for targets. Credit: Erik Summerside/Mary Kaupas

A new study led by University of Colorado Boulder engineers helps explain why the older we get, the slower we tend to move.

The research is one of the first studies to experimentally tease apart the competing reasons why people over age 65 might not be as quick on their feet as they used to be.

The research group reported that older adults may move slower, at least in part, because it costs them more energy than younger people—perhaps not too shocking for anyone who’s woken up tired the morning after an active day.

The findings could one day give doctors new tools for diagnosing a range of illnesses, including Parkinson’s disease, multiple sclerosis and even depression and schizophrenia, said study co-author Alaa Ahmed. She and her colleagues published their findings this month in the journal JNeurosci.

“Why we move the way we do, from eye movements to reaching, walking and talking, is a window into ageing and Parkinson’s,” said Ahmed, professor in the Paul M. Rady Department of Mechanical Engineering.

“We’re trying to understand the neural basis of that.”

For the study, the group asked subjects age 18 to 35 and 66 to 87 to complete a deceptively simple task: to reach for a target on a screen, a bit like playing a video game on a Nintendo Wii.

By analysing patterns of these reaches, the researchers discovered that older adults seemed to modify their motions under certain circumstances to conserve their limited supplies of energy.

“All of us, whether young or old, are inherently driven to get the most reward out of our environment while minimising the amount of effort to do so,” said Erik Summerside, a co-lead author of the new study who earned his doctorate in mechanical engineering from CU Boulder in 2018.

Using engineering to understand the brain

Ahmed added that researchers have long known that older adults tend to be slower because their movements are less stable and accurate. But other factors could also play a role in this fundamental part of growing up.

According to one hypothesis, the muscles in older adults may work less efficiently, meaning that they burn more calories while completing the same tasks as younger adults—like running a marathon or getting up to grab a soda from the refrigerator.

Alternatively, ageing might also alter the reward circuitry in the human brain.

Ahmed explained that as people age, their bodies produce less dopamine, a brain chemical responsible for giving you a sense of satisfaction after a job well done. If you don’t feel that reward as strongly, the thinking goes, you may be less likely to move to get it. People with Parkinson’s disease experience an even sharper decline in dopamine production.

In the study, the researchers asked more than 80 people to sit down and grab the handle of a robotic arm, which, in turn, operated the cursor on a computer screen. The subjects reached forward, moving the cursor toward a target. If they succeeded, they received a reward—not a big one, but still enough to make their brains happy.

Moving slower but smarter

Both the 18 to 35-year-olds and 66 to 87-year-olds arrived at their targets sooner when they knew they would hear that bing bing—roughly four to five per cent sooner over trials without the reward. But they also achieved that goal in different ways.

The younger adults, by and large, moved their arms faster toward the reward. The older adults, in contrast, mainly improved their reaction times, beginning their reaches about 17 milliseconds sooner on average.

When the team added an eight-pound weight to the robotic arm for the younger subjects, those differences vanished.

“The brain seems to be able to detect very small changes in how much energy the body is using and adjusts our movements accordingly,” said Robert Courter, a co-lead author of the study who earned his doctorate in mechanical engineering from CU Boulder in 2023.

“Even when moving with just a few extra pounds, reacting quicker became the energetically cheaper option to get to the reward, so the young adults imitated the older adults and did just that.”

The research seems to paint a clear picture, Ahmed said: Both the younger and older adults didn’t seem to have trouble perceiving rewards, even small ones. But their brains slowed down their movements under tiring circumstances.

“Putting it all together, our results suggest that the effort costs of reaching seem to be determining what’s slowing the movement of older adults,” she added.

The experiment can’t completely rule out the brain’s reward centres as a culprit behind why we slow down when we age. But, Ahmed noted, if scientists can tease out where and how these changes emerge from the body, they may be able to develop treatments to reduce the toll of aging and disease.

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