Impact case study database

Functional impairments of arm and hand movement comprise the commonest stroke related disabilities, affecting 75% of the 100,000 new stroke cases each year in the UK. Guidance from the Royal College of Physicians in 2016 and National Institute for Health and Care Excellence (NICE) in 2013 recommended that arm weakness after stroke should be treated with repetitive task training, outcomes of which are dependent on frequency and repetition. However, the amount of upper limb therapy provided on the NHS is markedly less than what is known to be effective because of inadequate provision of therapists delivering services [ A]. Although UK NICE guidelines recommend at least 45 minutes of therapy per day for meaningful improvements after a stroke, the 2019-20 UK national stroke audit showed that actual inpatient therapy is an average 25 minutes per day, which decreases still further when patients were discharged [ B].

Conventional physical rehabilitation requires 1:1 interactions between a physical therapist and patient and therefore is expensive to deliver and limited by staff time. Service provision could be improved for better patient outcomes using technologies enabling patient-directed rehabilitation. This is not a new idea, but previous rehabilitation technologies were not widely adopted because of unit costs, complexity, and special site requirements. To address these challenges, researchers at Imperial College developed ‘GripAble^TM’, a low-cost, accessible, mobile patient-directed upper limb rehabilitation device. GripAble^TM was designed to enable a broad range of patients with arm disability to engage in self-directed arm training without the need for professional supervision, including those with severe weakness and cognitive impairment. It can be used by patients in their homes, as well as in hospitals, with the option that home performance can be monitored by physical therapists or doctors logging in remotely.

GripAble^TM [ C] prototypes were used by therapists at Imperial College NHS Healthcare Trust and Imperial Private Healthcare to supplement standard upper rehabitation exercises for stroke and other neurological causes of arm weakness from early 2019. By 2020, the system was being offered to all patients with arm weakness as part of standard of care therapy; 10-20 new patients per month have been using the protocol system for part or the entirety of their hospital stay and, in selected cases, for up to several months post-discharge.

In the same year, Imperial College researchers founded Gripable Ltd to manufacture, distribute and further develop the system. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

Gripable Ltd. launched its first Gripable^TM product line in Summer 2020. By the end of 2020, Gripable^TM was deployed to neurological and rehabilitation centres across 17 countries; xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx including the Royal Hospital for Neurodisability, North-West London, and Aldebourne Rehabilitation Centres, King’s College Hospital, St Georges NHS Trusts, Cereneo (Switzerland) [ D], Hobbs [ E], BMI, HCA, and 12 Centres in the USA, India, Canada, Singapore, S Korea, Japan, UAE, and Qatar. Measured in terms of units in use, Gripable^TM became the most adopted technology in the UK for upper limb rehabilitation by the end of 2020. It also is the only rehabilitation system shown to allow patients continued use in the transition from hospital-based rehabilitation to home and fully self-directed rehabitation [ C].

xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx This demonstrates that as barriers to conventional physiotherapy increased and the number of supervised rehabilitation sessions dramatically decreased, GripAble^TM enabled patients to continue their essential rehabilitation exercises at home supervised remotely by their therapists using the patient’s online performance records.

While thus far GripAble^TM has predominantly benefited stroke patients, it is now increasingly used in the treatment of a wider range of conditions. GripAble^TM’s digital register currently includes xxxx patients with a diagnosis of multiple sclerosis, traumatic brain or spinal cord injury, peripheral neuropathy, Parkinson’s disease, arthritis, sporting injuries or complex hand surgery [ C]. Furthermore, at Great Ormond Street and the PACE Centre children with cerebral palsy and neurodevelopmental disorders are now using GripAble as part of their treatment.

The availability of GripAble^TM has added to options for upper limb physical rehabilitation endorsed by the Association of Chartered Physiotherapists in Neurology [ F]. The President of the Association, Prof. Jane Burridge wrote:

“[GripAble] fulfils a need for higher intensity, home-based, self-administered rehabilitation that cannot be practically met by increasing therapist numbers given NHS resource constraints… ACPIN fully support the translation of GripAble into routine clinical use and have actively supported dissemination of the evidence and information about the device.”

GripAble^TM also has had an impact on therapies recommended by other national rehabilitation information sites such as the UK’s leading online disability lifestyle magazine (AbleMagazine) [G]. Use by Key Opinion Leaders and Rehabilitation Centres was highlighted by a Parliamentary Under Secretary of State at the Department of Health and Social Care [ H].

In the UK each year, approximately 113,000 individuals suffer a stroke, 87% of which are of an ischaemic aetiology. There are around 1,000,000 stroke survivors who live with chronic stroke-related disability, the repercussions of which can be severe and widespread for both patients and carers. The current UK annual societal cost of stroke is £25.6 billion. Owing to the UK’s ageing population, these figures, based on retrospective data, are likely underestimates, as both the incidence of stroke and its economic burden from the needs for extensive hospitalisation and long-term care are rising each year. Currently, between 10,140 and 11,530 stroke patients per year in the UK could be eligible for MT, which approximates to 10% of all stroke admissions.

Despite the substantial evidence for the clinical effectiveness of MT for AIS, its use in routine practice in the UK had been limited by the lack of cost effectiveness data, especially given the significant costs of the procedure and its implementation. The latter challenges are related to high-level upfront investment required for an acute therapy like MT as well as the need for workforce training and service reconfiguration/integration in stroke and neuroscience centres nationwide.

Key to addressing this practical economic barrier to adoption in routine clinical practice was the demonstration that the associated long-term health benefits significantly outweighed the additional costs of the procedure. Research from Lobotesis at Imperial provided the first evidence of the substantial long-term cost savings that offset the higher treatment costs. These analyses, which are still the only UK-based cost-utility analyses of MT for AIS, singularly underpinned NICE policy recommendations in 2016, 2018 and 2019 that MT is a cost-effective treatment for patients with AIS in the UK [ A, B, C].

The analyses also led to MT being commissioned at Imperial College Healthcare NHS Trust (ICHT) in 2017 as a new flagship clinical service, and nationally by NHS England (NHSE) in 2019 [ D]. This national Clinical Commissioning Policy [ D] was based on the NICE Medtech innovation briefing, ‘Mechanical thrombectomy devices for acute ischaemic stroke’ [ B], which looked into the cost of MT devices and the subsequent resource impact in England, Wales and Northern Ireland, of the cost of the procedure. Overall, 12 cost-effectiveness studies were analysed, including 2 from a UK payer perspective, both of which were led by Dr Lobotesis and his team at Imperial.

Prior to 2017 and the policy recommendations underpinned by Lobotesis’ research, only 424 patients were treated with MT in England, Wales and Northern Ireland in the period 2015-2016 (2016 Acute Organisational Audit data). Between April 2019 and March 2020 (Sentinel Stroke National Audit Programme [SSNAP] data), 1,607 patients were treated with MT by 26 teams across England, Wales and Northern Ireland [ E]. Nationally, 70.3% of treated patients who had a National Institutes of Health Stroke Scale score fully recorded on arrival and again 24 hours after thrombectomy, showed neurologic improvements. The research findings and clinical experience underpinned the development of guidelines for implementation of MT for AIS in the UK including business case development sponsored by the UK Stroke Association, NIHR and the Oxford Academic Health Sciences Network [ F].

Subsequent to establishing one of the first 24/7 comprehensive MT services, ICHT currently continues to be the largest MT service in the UK, receiving patients from across South West England. In 2020, a total of 201 stroke patients were treated with MT at ICHT. In the same period, an average of 56 MT procedures were performed in other neuroscience centres nationally. This adoption has also had a significant impact on outcomes for patients with severe deficits at ICHT. Of the 201 MT patients, 43% had Rankin scores 0-2 (“alive and independent”) and 81.6% achieved TICI2B/3 (“complete cerebral reperfusion”) angiographic outcomes [ E]. Subsequently the Stroke/Thrombectomy service at ICHT was awarded, in 2020, the Imperial Chair’s Award for its outstanding performance and excellent clinical outcomes.

The peer-reviewed published recommendations (detailed above) arising from these findings have been successfully endorsed and incorporated into local (ICHT), national (NICE, NHSE) and international (Stroke Alliance for Europe [SAFE], ESMINT) policy documents [ G].

Choroideremia is a rare degenerative retinal disease which presents as night blindness and progressive visual field constriction from late childhood, leading to blindness in men typically in the fourth decade. Choroideremia presents in a milder form in women. It affects approximately 1 in 50,000 people. Neither specific diagnostics nor any treatment for the disease were available before the Imperial College research.

The preclinical work from Prof Miguel Seabra in defining the underlying biochemical mechanisms of choroideremia has had a major impact on its diagnosis and subsequent treatment. Diagnosis of the disease, which can be strikingly variable even within the same family, was based previously only on characteristic fundus findings and family history. Diagnoses in suspected cases can now be confirmed by direct genetic testing or through immunoblot analysis with anti-REP-1 antibody to differentiate it from related disorders, which could have both therapeutic and prognostic relevance [ A].

Seabra developed the first mouse models for the disease and discovered the cells in the retina responsible for initiating the disease. With MacLaren, he developed a therapeutic adeno-associated virus serotype 2 (AAV2) treatment vector, AAV-REP1, and showed its potential efficacy and safety with sub-retinal injection in the mouse. This led to a first-in-man clinical trial that provided first evidence for clinical benefits. Based on this, a successful patent (US20140107185A1) for invention of gene therapy of choroideremia based on retinal gene therapy using the human CHM transgene and methods of preventing or treating this disease using the vector was filed with MacLaren and During [ B].

With completion of the first trial and follow up of patients, Seabra, MacLaren and their colleagues were able to show the gene therapy had a profound impact on treatment for vision in some of those who received it. Sustained visual acuity gains were seen over a period of several years in end-stage eyes, in which rapid visual acuity loss would ordinarily be expected, with several patients experiencing gains of three lines or more, an improvement widely accepted to be clinically significant [ C]. Professor Robert MacLaren, the ophthalmologist who led the trial, said:

“The early results of vision improvement we saw have been sustained for as long as we have been following up these patients and in several the gene therapy injection was over 5 years ago. The trial has made a big difference to their lives.” [ D].

The trial also led to surgical innovations in the development of an automated injection system directed by intraoperative retinal scanning using optical coherence tomography, that informed subsequent trials and whose impact has been to minimise surgical adverse events with the sub-retinal delivery of genetic therapies [ C].

The research has had substantial economic impact, in addition to that clinically. In 2014. the investigators formed a spinout company in conjunction with Isis Innovations in Oxford, NightstaRX Limited, (subsequently renamed Nightstar Therapeutics) in which Imperial College held an equity share. Treatment of choroideremia was the lead programme for Nightstar, which received series A, B, and C funding from Syncona Limited and other investors [ E].

The leading gene therapy programme, known as NSR-REP1, has been prosecuted in phase 1 and 2 trials, and the company started an international phase 3 study, the ‘STAR’ trial in 2018. Nightstar Therapeutics raised $75,000,000 through a NASDAQ IPO in 2017 [ F] to fund the phase 3 trial and its other programmes. Investment subsequently grew to $500,000,000 [ G]. In July 2019, Biogen acquired Nightstar for over $800,000,000 to boost its clinical ophthalmology assets, where gene therapy for choroideremia (NSR-REP1) was noted as the lead asset being purchased [ H].