When scientist Susan Scott was diagnosed with relapsing-remitting multiple sclerosis (RRMS) in 2001, she had just started a senior management role in drug development for a French pharma company, travelling back and forth between Paris and her then-hometown, Slough.

“Within a year of starting with that company, I started to get weird balance and visual signs. Later my walking was affected, I would get very weak and couldn’t walk far,” Scott told Clinical Trials Arena.

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“For the next nine to 12 months I had a miserable time. I would relapse and then get better and be able to function reasonably normally again. Then I would catch the flu or something and it would trigger another relapse. It meant that I had to step back from my job, going down to three days a week working predominantly from home, so it really affected my career.”

Around a year after being diagnosed, Scott was lucky enough to get referred to the clinical trials unit at Addenbrooke’s Hospital, where she joined a Phase II trial of a drug called Lemtrada (alemtuzumab) for RRMS. The drug worked, and Scott hasn’t had a relapse since.

“It was a godsend! The fatigue gradually disappeared after two to three years and I went back to work full time. It gave me the chance to return to a normal life. I was able to get back to the things I love doing – walking, skiing – I was able to dance again at the next Christmas party. Things improved greatly.”

Scott is one of the lucky ones, and since she was diagnosed more and more treatments for RRMS have been discovered.

“In neurological circles, RRMS treatment is a huge success story,” says MS Society assistant director of research Dr Emma Gray. “We’ve now got over a dozen treatments that can target this earlier, relapsing form of MS.”


The Spectrum of MS

MS is an unpredictable and devastating neurodegenerative disease affecting more than 130,000 people in the UK alone. The condition causes the immune system to attack a fatty substance called myelin that coats nerve fibres in the brain and spinal cord, which are essential for neurological communication.

This means electrical signals travel too slowly along the nerves or fail to get through at all, resulting in numbness, tingling, loss of balance and vision issues in the early stages. Around 85% of patients are initially diagnosed with RRMS and endure a cycle of symptoms that come and go as nerves are damaged and repaired, only to become damaged again.

Around 15% of MS patients suffer with a more debilitating form of MS called primary progressive MS (PPMS). Far less progress has been made in finding treatments to stop or slow the decline into disability in this form of MS.

With PPMS there aren’t any periods of remission. Instead, the nerve damage steadily advances, causing increasing degeneration. These patients often suffer from tremors, speech and cognitive problems, muscle stiffness and spasms and may end up unable to walk and completely relying on a wheelchair.

“This is where the unmet need is and where the MS Society Octopus trial comes in,” says Gray.

“Right now, there hasn’t really been anything found to slow progression. This means there are tens of thousands of people in the UK today that have nothing to stop their condition from getting worse. As you can imagine, they are very fearful for the future.”

A large proportion of patients with RRMS go on to develop secondary progressive MS (SPMS), which usually occurs within ten to 15 years. Similarly to PPMS, symptoms become progressive and do not improve over time.

“Fortunately for me, even 20 years on this [progression to SPMS] hasn’t happened, but I think that is because I got treated aggressively and early,” says Scott.

“But that is not the case for a large majority of people who have the worry of moving into SPMS or already have PPMS. That’s why I was interested in getting involved with Octopus.”


Octopus: an innovative trial design inspired by oncology

Octopus, the aptly-named multi-armed ‘mega-trial’, aims to find existing drugs to repurpose to slow disability progression in progressive MS. The initiative will be led by professor of neurology Jeremy Chataway and professor of medical statistics and epidemiology and director of the Medical Research Council’s clinical trials unit Mahesh ‘Max’ Parmar, both from University College London.

To design the MS Octopus trial platform, Gray and her team pulled together an expert consortium made up of neurologists, clinical trial experts, statisticians, scientists, healthcare professionals, physiotherapists and a diverse range of people with MS.

It comes after three years of planning by MS Society, which is funding the trial through its Stop MS Appeal and has raised around £50m so far.

Gray, who has been involved with the trial from its conceptual beginning, says that Octopus’ design has been heavily influenced by cancer trials – particularly the STAMPEDE trial for prostate cancer, which was also led by Parmar and harnessed the same multi-arm, multi-stage (MAMS) design.

“The society is hugely inspired by the oncology field and the breakthroughs they have made using this methodology,” says Gray.

“Max and Jeremy will be working in collaboration, so we’ve got the best partnership on this. I think it’s fantastic that we’ve bought the cancer field into MS to help us do this – that partnership is absolutely vital.”

Octopus is the first MAMS trial for progressive MS in the world and will test multiple existing drugs at once compared to a standard-of-care control group, to see if they show any signs of slowing the progression of progressive MS. The trial will start with four arms, consisting of the control group and up to three carefully selected drugs, with 125 patients randomised into each arm.

MRI scans will be taken at six-month intervals and at 18 months used as an interim analysis to assess if a drug has the potential to slow disease progression. Those that look promising will stay in the trial and go on to be tested in a larger population of 600, including the original 125. The idea is that this trial design makes it possible to test treatments up to three times faster.

“It is a Phase III trial de-risked in a way by this interim analysis,” says Gray.

Drugs can be dropped if they don’t look promising and new candidates can be slotted in as they are identified.

Patients recruited into an arm that is dropped then have the option to be re-randomised into another arm.

“It’s just such a good idea,” says Scott, who in her long scientific career is no stranger to clinical trials. “This MAMS platform means that once we’ve found a drug that looks effective from MRI, then instead of having to stop the trial, analyse results and then re-prepare another protocol – which takes a year or two – Octopus is all set up for us to move seamlessly into what’s normally Phase III. Then we can recruit many more patients and make sure that the signs we see on MRI are borne out in clinical measurements at the end of Phase III.”

The primary endpoint is for the expanded disability status scale (EDSS), the most widely-used measure of neurological impairment in MS, to demonstrate the slowing or increase of disability before a drug is approved. The team will also use a composite measure with a wider range of assessments to capture more information, such as upper limb function and cognitive function.

The trial will utilise telehealth and home health whenever necessary or needed.

“With the pandemic, things have been more remote and we have been communicating more online and via video and teleconferencing,” says Scott. “Some people with MS will have limited mobility, so the more you can do from home the better.”


Drug discovery

Gray explains that to find promising drugs to include in the trial, they relied on a combination of systematic approach and expert opinion, involving independent experts and people with MS.

First, they consulted with their expert opinion group to decide the scientific areas and drugs to repurpose worth investigating. The society then commissioned the Medicines Discovery Catapult, which works with UK innovators to advance projects toward clinical impact, to do a data dive into potential drugs that could hit new targets

This helped them come up with a longlist of hundreds of prospective treatments. This was gradually cut down to around ten, which then went out to international peer review. Then, a final shortlist was considered by a treatment advisory committee made up of independent experts and recommended to the Octopus trial investigators.

The first drugs to be added to Octopus’ arms will hopefully be announced later this year, says Gray. She also says that the society is in talks with some pharma companies who might want to buy in to put a promising candidate into the Octopus trial platform.


Powered by patient involvement

Gray says that patient involvement has been hugely instrumental and fundamental to Octopus and that every aspect of the trial has been co-designed with patients from the start.

As a patient with a scientific background, Scott’s experiences have been integral to the planning and design of the trial.

“It’s very interesting from my perspective as I can look at it from the patient angle and from my background in clinical trials,” says Scott. “It’s a privilege to be able to do that and contribute from both to the trial.”

The MS Society gave the PPI forum a budget to manage their own activities’

The Octopus researchers have approached the forum with questions about numerous aspects of the trial. This has included maximum trial duration, drug choices and whether patients would want to be approached to be re-randomised into other arms if theirs did not meet the efficacy endpoints.

Scott has been particularly involved in making sure communication with participants is clear and understandable, as other MS patients may not have the depth of scientific knowledge that she has.

The MS Society also funds the UK MS Register, a longitudinal patient-reported outcome (PRO) cohort. Gray says that the Society is going to trial using it as a “one-stop-shop patient portal” and recruitment platform.

The hope is that participants will be able to use the register to get their information, interact with each other, spread the word and do their PRO work from there.


What’s next?

The Octopus trial is set to start recruiting later in the year and an announcement will be made when up to three drugs are finalised.

In the meantime, there are a few other trials currently, or soon to be, recruiting patients for MS research. The MS-STAT2 trial for progressive MS is testing whether anti-cholesterol drug simvastatin protects against nerve damage in patients with secondary progressive MS, and is currently recruiting participants. The Chariot MS trial, another MS Society-funded study, will investigate whether cladribine can slow the decline of arm and hand function in patients with advanced progressive MS.

“I’ve been at the MS Society for ten years and I’m so proud to see the development and progress in MS research. To pull together something like this you need a charity like MS Society and we’ve done that and raised the money,” says Gray.

“I’m genuinely really hopeful that it is going to speed up the development of treatments for people who don’t have any options at the moment.”