Public Release: 

First patients dosed with 'gene silencing' drug for Huntington's disease

Trial of innovative drug aims to reduce production of the toxic protein that causes devastating brain disease

University College London

The first few patients have received doses of an experimental RNA-targeting drug for Huntington's disease, it was announced today.

The trial aims to test the safety of an experimental drug known as ISIS-HTTRx, discovered and developed by Isis Pharmaceuticals. Administered by injection into spinal fluid to improve its delivery to the brain, the drug is the first tested in patients that targets the known cause of the disease: a toxic protein called mutant huntingtin which slowly damages and kills neurons, leading to the progressive and ultimately fatal decline in mental and physical abilities that is the devastating hallmark of Huntington's disease.

The huntingtin gene and its lethal protein product have been the focus of intense research across the world since their discovery in 1993. 'Gene silencing' drugs, also known as 'antisense' drugs, are designed to reduce production of a chosen protein by attaching to the mRNA 'message molecule' that's made whenever a gene is activated. ISIS-HTTRx targets the huntingtin message molecule, telling the cell to dispose of it, thereby reducing production of the mutant huntingtin protein.

There are no treatments to prevent, slow or cure Huntington's. RNA-targeting antisense drugs, like ISIS-HTTRx, that lower huntingtin production are widely considered the most promising therapeutic strategy currently under investigation. Isis's Huntington's disease therapeutics underwent over a decade of refinement and preclinical testing before human trials could begin. The first Phase 1/2a trial is focused principally on safety, using slowly increasing doses of ISIS-HTTRx with careful monitoring of patient wellbeing, scans and laboratory parameters. In addition, the researchers will be looking for chemical signs that the drug is having the desired effect - by measuring the level of mutant huntingtin protein in the cerebrospinal fluid using a newly developed assay.

The trial is set to recruit patients with very early symptoms of Huntington's from six centres in Europe and Canada. Prof Sarah Tabrizi, director of the Huntington's Disease Centre at University College London's Institute of Neurology, is the global chief clinical investigator of the trial. "I'm thrilled that this antisense drug has now been safely administered to the first patients. Families ravaged by Huntington's disease have been waiting for this milestone for decades. I look forward to ensuring the smooth running of this first trial and hopefully seeing ISIS-HTTRx through to efficacy testing and licensing," said Prof Tabrizi.

Isis Pharmaceuticals has partnered with Roche to develop ISIS-HTTRx to treat Huntington's disease. C. Frank Bennett, Ph.D., senior vice president of research at Isis Pharmaceuticals, said,

"Antisense drugs have great potential for many neurodegenerative diseases because they can be tailored to modify the production of any target protein. Huntington's is ideally suited to this innovative therapeutic technology because it comes with genetic certainty: everyone with the mutant gene will get the disease at some point. We designed ISIS-HTTRx to target the huntingtin gene and reduce the production of huntingtin protein, which is the known cause of the disease. This approach has the potential to prevent or slow the progression of this disease. If this first-in-human trial proves the drug is safe, we look forward to continuing our successful partnership with Roche to bring the drug to market."

At UCL, the trial is hosted in the new Leonard Wolfson Experimental Neurology Centre, a custom-built centre designed to accelerate innovative treatments for neurodegenerative diseases, headed by Prof Vincenzo Libri. The administration of the first doses of ISIS-HTT-Rx marks the Centre's first use as a phase 1 'first into human' trial facility, as well as the first time that an experimental drug has been given by spinal injection in the 156-year history of the National Hospital for Neurology and Neurosurgery, part of University College London Hospitals (UCLH) NHS Foundation Trust. Crucial support for this important achievement came from a groundbreaking partnership with the Clinical Trials Pharmacy at nearby Great Ormond Street Hospital (GOSH) where the ISIS-HTT-Rx is prepared for administration. The trial also demonstrates the value of successful collaboration between NHS and academic infrastructures in the form of the National Institute for Health Research (NIHR) UCL/UCLH Biomedical Research Centre.

Cath Stanley, Chief Executive of the Huntington's Disease Association of England and Wales, welcomed the news that the first doses of ISIS-HTTRx had been given to Huntington's patients. "As well as being desperate for good news, the Huntington's community is uniquely well-informed and engaged with progress in research across the world," she said. "RNA-targeting approaches are especially exciting because they tackle the problem at its source - the production of the mutant huntingtin protein. The ISIS-HTTRx trial has been eagerly awaited for many years and we hope that the news from the trial continues to be positive."



About Isis and Roche

Roche and Isis are collaborating to develop antisense drugs to treat HD. The alliance combines Isis' antisense expertise with Roche's scientific knowledge in developing neurodegenerative therapeutics. With the initiation of the Phase 1/2a study for ISIS-HTTRx, Isis earned a $22 million milestone payment from Roche. Roche has the option to license ISIS- HTTRx from Isis through the completion of the Phase 1/2a study. Prior to option exercise, Isis is responsible for the discovery and development of ISIS-HTTRx. If Roche exercises its option, it will assume responsibility for global development, regulatory and commercialization activities for the drug.

CHDI Foundation, Inc. provided financial and scientific support to Isis' HD drug discovery program through a development collaboration with Isis. Over time, CHDI will be reimbursed for its support of Isis' program out of milestone payments received by Isis.

About Huntington's Disease

Huntington's disease is a fatal genetic neurological disease. It usually develops in adulthood and causes abnormal involuntary movements, psychiatric symptoms and dementia. Approximately 10,000 people in the UK have HD with around 25,000 at risk. It is incurable, and no effective treatments exist to slow it down. Patients usually die within 20 years of the start of symptoms. HD is caused by a single known genetic mutation, and each child of a carrier of the mutation has a 50% chance of inheriting the disease.


ISIS-HTTRx is a Gen. 2.0+ antisense drug in development for the treatment of Huntington's disease. ISIS-HTTRx is designed to reduce the production of all forms of the huntingtin (HTT) protein, which is the protein responsible for HD. As such, ISIS-HTTRx offers a unique approach to treat all patients with HD.

About the Leonard Wolfson Experimental Neurology Centre

The Leonard Wolfson Experimental Neurology Centre (LWENC, is the first Clinical Research Facility (CRF) in the UK fully dedicated to accelerating progress towards finding effective treatments for neurodegenerative disorders. It was established in 2013 through a £20 million award from the Wolfson Foundation* to the University College London's Institute of Neurology to support translational research and early phase (including 'first into human') clinical trials in neurodegenerative diseases. The LWENC-CRF is the clinical hub of translational research at UCL Institute of Neurology, bringing together the expertise of leading clinicians and scientists across a broad range of neurological and neurodegenerative diseases. It acts as the crucial bridge between laboratory-based research and clinical expertise and is a major asset in fostering high quality clinical research studies.

Strong working relationships exist between the LWENC-CRF and multiple UCL and UCLH endeavours and a strong partnership is in place with the UCLH Biomedical Research Centre - Neuroscience Programme which has been instrumental to the setting up and running of the facility by providing additional financial support for the appointment of key members of clinical and operational staff. Since opening to patients in March 2014, the LWENC has adopted 50 studies (including investigator-led trials, industry collaborative studies, and major cohort studies) serving the unmet need for a bespoke CRF that specialises in neurological disorders. The LWENC has been providing crucial support for planning, setup and execution for the clinical trials and patient-facing work of the first ever Huntington's disease 'gene silencing trial' with Isis Pharmaceuticals, following a complex protocol involving patient preparation, intrathecal administration, subject monitoring and day-to-day support for the trial in a safe and well-equipped clinical research setting and in compliance with Good Clinical Practice and the highest regulatory standards.

*The Wolfson Foundation is a charity that promotes excellence in the fields of science and medicine, health and disability, education, and the arts and humanities. Since 1955 it has awarded over £800 million (£1.7 billion in real terms) to some 10,000 projects across the UK. The Wolfson Foundation celebrates its 60th anniversary in 2015.

About UCL Institute of Neurology

The Institute of Neurology (ION) is a specialist postgraduate institute of UCL. It is closely associated in its work with the National Hospital for Neurology & Neurosurgery, University College London Hospitals' NHS Foundation Trust, and in combination they form a national and international centre at Queen Square for teaching, training and research in neurology and allied clinical and basic neurosciences.

About the UCL Huntington's Disease Centre

Let by Prof Sarah Tabrizi (Director) and Prof Gillian Bates (Co-Director) and opened in 2015 in a dedicated, purpose-built space, the UCL Huntington's Disease Centre is uniquely placed world-wide to translate mechanistic insights into 'first in human' studies. It combines sophisticated cell-based systems with rigorously standardised preclinical target validation to prime mechanistically-driven drug development initiatives. The Centre integrates clinical and laboratory work with small proof-of-concept studies in patients in the Leonard Wolfson Experimental Neurology Centre (LWENC) prior to initiating larger phase 2 and 3 clinical trials including novel huntingtin-lowering trials.

About the National Hospital for Neurology & Neurosurgery

The National Hospital for Neurology and Neurosurgery, Queen Square, is the UK's largest dedicated neurological and neurosurgical hospital. Founded in 1859, it provides comprehensive services for the diagnosis, treatment and care of all conditions that affect the brain, spinal cord, peripheral nervous system and muscles. Together with its neighbour, the Institute of Neurology, it is a major international centre for research and training.

About UCLH NHS Foundation Trust

University College London Hospitals NHS Foundation Trust (UCLH) is one of the largest, most complex and high-performing NHS trusts in the UK, providing academically-led acute and specialist services to a diverse population in London, from across the UK, and internationally. One of the first NHS trusts to achieve Foundation Trust status, UCLH's mission is to deliver top-quality patient care, excellent education and world-class research. With annual revenues of over £800m, the Trust provides first-class acute and specialist services to more than 700,000 out-patients and 120,000 in-patients annually, in six hospitals. UCLH will continue to invest in its colleagues, facilities and services to ensure it remains at the forefront of outstanding healthcare, research, education and innovation

About the NIHR University College London Hospitals Biomedical Research Centre

The National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre is a partnership between University College London Hospitals NHS Foundation Trust and UCL, and is funded by the NIHR. The centre, set up in 2007, is at the forefront of research into major causes of illness and disease-related death and has already invested over £100m in research projects and infrastructure. Awarded a further £100m in government funding from the NIHR in 2011, the centre helps take innovations in basic science and turn them into therapies that directly benefit patients. In particular the centre supports experimental medicine research which tends to be 'first in man' studies such as research into new therapies and devices or the mechanisms of disease.

About Great Ormond Street Hospital

With the UCL Institute of Child Health, we are the largest centre for paediatric research outside North America. The Biomedical Research Centre (BRC) is funded by the National Institute for Health Research (NIHR) and supports paediatric experimental medicine research at Great Ormond Street Hospital and UCL Institute of Child Health. The research aims to accelerate discoveries into the basis of rare diseases and to develop novel diagnostics, imaging techniques and new treatments, including cellular and gene therapies.

Additional information

UCL Institute of Neurology acknowledges the support of the National Institute for Health Research Clinical Research Network.

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