Update on Clinical Trails

October 14, 2019  Update on the Phase III GENERATION HD1 Study 
Dear global HD patient community,
Today we are pleased to announce that we are increasing the total enrolment in the GENERATION HD1 study (NCT03761849) from 660 to 801 participants worldwide. We believe that increasing enrolment now – before study recruitment closes – keeps the study on track to complete within expected timelines. This study change does not impact participants already enrolled in the study, but it allows for additional patients to enrol in each of the three study groups.
The GENERATION HD1 study is evaluating the efficacy and safety of the investigational molecule RG6042 in people with manifest HD. The 25-month study is testing two dosing regimens compared to placebo – RG6042 once every two months (eight weeks) or RG6042 every four months (16 weeks). The open-label extension of the Phase I/IIa study is ongoing and supports the exploration of the two dosing groups in the GENERATION HD1 study.
Why are we making this change?
• More data: The additional number of participants will provide more data to equally evaluate both dosing groups, as well as increase the statistical power of the study. This is a technical study design term that refers to the study’s ability to detect a treatment effect. In interactions with the HD community, we have learned the importance of testing both doses – while acknowledging that less-frequent dosing would be less demanding for patients, families and the overall healthcare system in the real-world setting.
• More confidence: Prior to GENERATION HD1, a study of this size involving an intrathecally administered investigational medicine has never been conducted in HD. Since the study started recruiting this summer, enrolment has been remarkably rapid worldwide. Based on the interest from the HD community, we are confident that a larger study can fully recruit.
• More diversity: Expanding recruitment allows for enrolment of more patients in different parts of the world. US recruitment in particular has exceeded expectations and is now complete. Therefore the additional participants will be enrolled from our network of existing trial sites in nearly 20 countries outside of the US to diversify the study population. Achieving broader global representation in clinical trials is important to our company, as well as health authorities around the world.
We are also pleased to announce that the GENERATION HD1 study is being extended to China. This will be the first time a study testing a Huntingtin-lowering therapy will be brought to the country. Information about Chinese study sites will soon be posted on ClinicalTrials.gov.
The community has been a critical partner throughout the development and progress of the GENERATION HD1 study. The speed of recruitment is thanks to the clinical-trial readiness and commitment of the HD medical and patient community to researching treatment options. We appreciate the partnership with the community and we look forward to providing future study updates.
Sincerely, Mai-Lise Nguyen, on behalf of the Roche & Genentech HD team Global Patient Partnership, Rare Diseases
Wave Life Sciences Provides Timing Update on PRECISION-HD Clinical Programs 
April 10, 2019 at 7:00 AM EDT

Topline data readout from Huntington’s disease clinical trials now expected by year end 2019

CAMBRIDGE, Mass., April 10, 2019 (GLOBE NEWSWIRE) — Wave Life Sciences Ltd. (NASDAQ: WVE), a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases, today provided an update on the timing of the topline data readout from its ongoing PRECISION-HD program, which consists of two global Phase 1b/2a clinical trials evaluating investigational therapies WVE-120101 and WVE-120102 for patients with Huntington’s disease (HD). The company now expects to report topline clinical data from the PRECISION-HD program by the end of the year. The reason for the revised timeline is operational, resulting from slower than anticipated patient enrollment because of the logistics of screening and scheduling across global sites. This update is not due to a preclinical or clinical safety finding and the PRECISION-HD clinical program remains blinded. The company expects the topline clinical data will include a summary of clinical safety results, the degree of mutant huntingtin protein lowering in cerebrospinal fluid (CSF) and the ratio of total huntingtin versus mutant huntingtin protein in CSF to assess wild-type huntingtin protein.

“When we initiated these exciting clinical trials to explore the potential of an allele-selective approach to treating Huntington’s disease, we set aggressive timelines for ourselves in recognition of the enormous need in the global Huntington’s disease community. While we are disappointed that enrollment is not as fast as we anticipated, we are pleased that patient and physician interest in the trials remains high,” said Michael Panzara, MD, MPH, Chief Medical Officer at Wave Life Sciences. “Like others in the community, we are focused on advancing these trials quickly and are eagerly looking forward to the first clinical results from the program.”

About WVE-120101 and WVE-120102

WVE-120101 and WVE-120102 are investigational stereopure antisense oligonucleotides designed to selectively target the mutant huntingtin (HTT) mRNA transcript of SNP rs362307 (SNP1) and SNP rs362331 (SNP2), respectively. SNPs, or single nucleotide polymorphisms, are naturally occurring variations within a given genetic sequence and in certain instances can be used to distinguish between two related copies of a gene where only one is associated with the expression of a disease-causing protein. In vitro studies in patient-derived cell lines have shown that WVE-120101 and WVE-120102 selectively reduce levels of mutant HTT mRNA transcript and protein, while leaving wild-type, or healthy, HTT mRNA transcript and protein relatively intact. The healthy transcript is required to produce healthy HTT protein, which is critical for neuronal function, as evidenced by multiple preclinical studies indicating that long-term suppression of healthy HTT protein may have detrimental consequences. Wave’s allele-specific approach may also enable the company to address the pre-manifest, or asymptomatic, HD patient population in the future.

About Huntington’s Disease

Huntington’s disease (HD) is a debilitating and ultimately fatal autosomal dominant neurological disorder, characterized by cognitive decline, psychiatric illness and chorea. HD causes nerve cells in the brain to deteriorate over time, affecting thinking ability, emotions and movement. HD is caused by an expanded cytosine-adenine-guanine (CAG) triplet repeat in the huntingtin (HTT) gene that results in production of mutant HTT protein. Accumulation of mutant HTT causes progressive loss of neurons in the brain. Wild-type, or healthy, HTT protein is critical for neuronal function, and suppression may have detrimental long-term consequences. Approximately 30,000 people in the United States have symptomatic HD and more than 200,000 others are at risk for inheriting the disease. There are currently no approved disease-modifying therapies available.

About Wave Life Sciences

Wave Life Sciences (NASDAQ: WVE) is a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases. Wave aspires to develop best-in-class medicines across multiple therapeutic modalities using PRISM, the company’s proprietary discovery and drug development platform that enables the precise design, optimization and production of stereopure oligonucleotides. Driven by a resolute sense of urgency, the Wave team is targeting a broad range of genetically defined diseases so that patients and families may realize a brighter future. To find out more, please visit www.wavelifesciences.com and follow Wave on Twitter @WaveLifeSci.


Wednesday, June 26, 2019

Roche restarts redesigned Phase 3 Huntington’s disease trial

Three months after announcing it would reduce dosing in its historic Phase 3 Huntington’s disease clinical trial – and pausing for a reset – pharma giant Roche announced on June 20 that it has reopened recruitment for the study, known as GENERATION HD1.

GENERATION HD1 aims to measure whether Roche’s gene-silencing drug, RG6042, will slow, halt, or perhaps even reverse HD symptoms. In late January, Roche announced that it had enrolled the first participant in the trial, which will include a total of 660 volunteers at more than 90 sites in at least 18 countries around the world.

In the original trial design, participants would undergo monthly spinal tap (lumbar puncture) procedures over 25 months. One third of participants would receive RG6042 each month and one third every other month. A third would get a placebo.

However, with new, promising data in hand from an open-label extension (OLE) of the Phase 1/2a trial, on March 21 Roche announced that it would decrease lumbar punctures to once every other month over the same period of time (click here to read more). In this revised design, one third of participants will receive RG6042 every other month and one third every four months. One third will receive a placebo every other month.

The change in dosing required Roche to stop the trial to obtain updated approval from regulatory agencies in the respective countries where the program is operating. Recruitment had to start from scratch, with all new volunteers. Roche completed the necessary details for resuming the trial in just a few months, as it had hoped.

“In March we announced our plan to amend the dosing frequency and study design, which will make study participation less demanding for patients, their families and HD centers,” Mai-Lise Nguyen, Roche’s HD patient partnership director, wrote to the HD community in a June 20 e-mail update on the trial. “Since then, our team has been working to implement study changes and obtain approvals from clinical trial review boards and authorities around the world. Today I am pleased to share that we have reopened the study for recruitment of new patients.”

To read the full article, visit:  https://curehd.blogspot.com/2019/06/roche-restarts-redesigned-phase-3.html?m=1&fbclid=IwAR1Uu48X1FGn8ftEPcS_wI9zmsmPq2RX0dIDsRiqky5w4KpgAoJoOlQhEvQ



July 2019

At the recent Huntington’s Disease Society of America annual convention in Boston, UniQure announced crucial details of its planned clinical trial for its experimental therapy, AMT-130. We previously wrote about AMT-130 here, so this article covers the basics and what’s just been announced.

Huntingtin-lowering gene therapy in an nutshell

AMT-130 is a huntingtin-lowering treatment, because it seeks to reduce production of the harmful mutant huntingtin protein, which is harmful to neurons and is the cause of Huntington’s disease.

A virus is used to deliver AMT-130 to the brain. Once there, the virus programs neurons with new instructions to make a huntingtin-lowering molecule.
A virus is used to deliver AMT-130 to the brain. Once there, the virus programs neurons with new instructions to make a huntingtin-lowering molecule.

However, AMT-130 differs in several important ways from the anti-senseoligonucleotide (ASO) trials that are currently underway, run by Roche and Wave Life Sciences.

AMT-130 is a gene therapy, which means that it seeks to permanently change the genetic makeup of the treated patient. AMT130 doesn’t try to delete the HD mutation – that is much harder to achieve than you might think. Instead, AMT130 utilizes a harmless virus known as an adeno-associated virus (AAV) to add a small extra piece of genetic code to neurons. That code is a set of instructions for making a huntingtin-lowering drug.

Once a neuron is treated with AMT-130, it will continuously manufacture additional copies of the new Huntingtin-lowering molecule. So while the neuronstill contains the harmful HD gene, and still sends messages to make the mutant huntingtin proteinat the same time it will be producing a new set instructions to delete the huntingtin message. The result should be reduced production of the harmful protein, with a very long duration of effect – possibly lifelong.

What about the trial?

UniQure announced some preliminary but important details about its planned trial in a statement to the HD community. Here’s what we know so far.

The focus of the first trial will be safety and tolerability – finding out whether there any harmful or unpleasant effects of receiving AMT-130 treatment.

UniQure also includes efficacy in the stated aims of the study: that means getting an idea of whether the treatment is doing what it’s supposed to do. In the broader sense, that means slowing the progression of Huntington’s disease. It’s theoretically possible, but very unlikely, that this small first trial will show evidence of slowed progression. A more achievable aim is to test whether treatment reduces huntingtin production, which we can now measure using techniques we’ve described on HDBuzz here.

The AMT-130 trial will be based at HD clinical sites in the Unites States. We don’t know what sites or how many, yet. These will be publicly announced when they come online. UniQure hopes to begin enrolling patients before the end of 2019.

The trial will enrol just 26 patients with early symptoms of Huntington’s disease. That means people with abnormal movements, within the first few years after diagnosis was ‘officially’ confirmed by a neurologist. The age range is 25 to 65 years of age.

Unusually, uniQure has set a cutoff of 44 CAG repeats or more in the HD gene. About 50% of people with a positive genetic test for HD have between 40 and 45 repeats, so this cutoff may well exclude quite a few people. It’s likely that uniQure set this cutoff to skew the trial towards people likely to progress more quickly, so that they can get a better chance of showing that AMT-130 slows progression.

Treatment with AMT-130 requires major brain surgery, which comes with risks of its own. This is true of all currently planned 'gene therapy' treatments.
Treatment with AMT-130 requires major brain surgery, which comes with risks of its own. This is true of all currently planned ‘gene therapy’ treatments.

The 26 patients will be split at random into two groups. 16 patients will receive active treatment with AMT-130, at either a low dose or a high dose. 10 patients will undergo “imitation” treatment, which could also be referred to as “placebo” or “sham” treatment.

The potentially big benefit of treatment with AMT-130 is that it’s only performed once per participant, but it’s a big deal. It involves brain surgery, carried out under general anaesthesia. Between two and six small holes will be drilled in the skull, and thin tubes called catheters inserted into the brain. The AMT-130 cocktail is then injected down the tubes into the brain.

Patients assigned to the imitation treatment will undergo general anaesthesia, and shallow holes will be drilled into the outer layer of the skull but won’t pass right through it. No tubes or injections are involved.

The purpose of the imitation group is to help figure out whether any effects seen in the trial – be they helpful or harmful – are caused by the AMT-130 therapy itself, the placebo effect (the psychological boost that comes from being in a clinical trial), or the effects of undergoing anaesthesia and surgery.

Patients will be followed up intensively for 18 months, with investigations including MRI scans and lumbar punctures (spinal taps). Patients in the active group will then be asked to return for annual visits for 5 years.

The neurosurgical team will know which patients are in which group, but the patient and the HD trial team will not know. This means the study is double-blinded and helps minimize the placebo effect, enabling the trial to deliver on its scientific aim of figuring out whether the drug is safe and whether it works.

The upside for patients assigned to the imitation group is that 18 months after their mini-operation, if an independent review of the trial data is satisfactory, they will be invited to undergo full treatment with AMT-130 in a second, bigger operation.

Risk and reward

The main potential advantage of AMT-130 is also its biggest potential drawback. It’s a gene therapy, so a single treatment is expected to be permanent.

If everything works out as planned, it will be a treatment that could be given early after a positive genetic test result, that will have long-lasting, possibly lifelong benefits. It could slow progression or even delay the onset of HD without requiring repeated dosing.

AMT-130 will be injected into a deep part of the brain called the striatum, shown here in orange. The striatum is affected early in HD, but will the virus spread the huntingtin-lowering treatment far enough to produce benefits for patients?
AMT-130 will be injected into a deep part of the brain called the striatum, shown here in orange. The striatum is affected early in HD, but will the virus spread the huntingtin-lowering treatment far enough to produce benefits for patients?

However, if the treatment turns out to have harmful side-effects, these could be long-lasting too – and there is no way to switch off the treatment once it’s been given. As a purely fictional example, what if the treatment for some reason causes a worsening of movement control, an acceleration of the person’s Huntington’s disease, or a permanent feeling of nausea? Patients might be left with major symptoms or even disabilities. The medical team would do everything they could to improve things, but removing the treatment or switching it off won’t be an option.

Another important detail is that AMT-130 is designed to reduce production of both forms of the huntingtin protein – not just the harmful mutant form, but its innocent ‘normal’ sibling, which scientists call ‘wild-type’. One concern is that reducing wild-type huntingtin in the brain of adults with HD might come with risks of its own, which could eclipse any benefits from lowering the mutant protein. These concerns come largely from experiments carried out in mice, which all have major differences from human patients, and at the moment the actual effects of lowering wild-type huntingtin in patients are unknown. Important insights on this will hopefully come from the two ongoing huntingtin-lowering programs involving drug injections into the spine: Roche’s RG6042, which lowers both forms of the protein, and Wave’s Precision-HD program, which is attempting to lower the mutant form selectively.

AMT-130 has been tested in animals, and would not have been permitted to proceed to a human trial if unacceptable risks had been discovered. But only humans can tell us what benefits and harms might be seen. On top of the risks of surgery, patients considering volunteering in this trial can expect to be thoroughly counselled about the possible risks, without any firm expectation that they will benefit personally from taking part. Such volunteers will be asked to undertake significant sacrifice on behalf of others – those that volunteer for first-in-human trials are among the HD community’s greatest individual heroes.

An important advance

Here at HDBuzz, our favourite cocktail is called Substantive Hope. It’s equal parts optimism and realism. After our previous reporting on huntingtin-lowering therapies, we’ve received some feedback that we’re being too positive, and some that we’re being too negative (the word “HDBuzzKill” has even been bandied about, and we’re OK with that). Perhaps this means we’re getting it about right – but it’s up to you to decide.

We encourage all readers to get their information from multiple sources. Our ‘Ten Golden Rules’ article, published in 2011, might help you cultivate a mind that’s open to cool new ideas but healthily skeptical towards hype. We are unashamedly in favour of HD family members volunteering for research projects including clinical trials: this is the only way we will ever make real progress in the fight against Huntington’s disease. We encourage anyone thinking of volunteering to weigh the risks and benefits and seek advice from smart people you trust, before signing up.

Our take on AMT-130: the first huntingtin-lowering gene therapy trial has the potential to pave the way for a new generation of truly revolutionary drugs. Those taking part are no less brave than the astronauts who stepped onto the surface of the moon almost exactly fifty years ago. At significant personal risk, they will volunteer to take a not-so-small step into the unknown, in the hope of producing a giant leap for HD families.


April 28, 2019

New data in Huntington’s disease support dose selection for Phase III trial and provide insight on mutant huntingtin protein (mHTT) reduction

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today that new data for its approved and investigational medicines for the treatment of neurological conditions will be presented at the 71st American Academy of Neurology (AAN) Annual Meeting from May 4-10 in Philadelphia, PA. Presentations include data from a pivotal study for risdiplam in spinal muscular atrophy (SMA), which has the potential to become the first oral treatment for this community. New research for OCREVUS® (ocrelizumab) in relapsing and primary progressive multiple sclerosis shows that its effect on reducing the risk of disability progression is associated with higher exposure and lower B-cell levels. Additional OCREVUS data demonstrate the importance of earlier treatment. New data for investigational medicines in neuromyelitis optica spectrum disorder (NMOSD), Huntington’s disease (HD), Alzheimer’s disease (AD) and Duchenne muscular dystrophy (DMD) will also be shared.

The HD platform session will include results from a translational modeling approach developed from preclinical data and includes clinical RG6042 data from the ongoing, open-label extension study in HD patients, including a safety update and mutant huntingtin (mHTT) protein reduction in the cerebrospinal fluid. These data also support the dose selection for the recently initiated Phase III GENERATION HD1 clinical trial investigating RG6042 in manifest HD.

RG6042 (formerly known as Ionis HTT-Rx) is an antisense oligonucleotide (ASO) designed to reduce the production of the toxic mHTT protein, the disease-causing protein in people with HD, by targeting human huntingtin RNA.

March 27, 2019

RG6042 on Horizon as a Potential Treatment for Huntington Disease

The associate group medical director and clinical science leader for the IONIS/Roche HTT Rx program at Roche/Genentech neuroscience spoke about the study design of GENERATION HD1 and the potential impact of RG6042 as a treatment for Huntington disease.


28 January 2019

Update on RG6042 Huntington’s disease (HD) programme: First patients enrolled in HD Natural History and Phase III GENERATION HD1 clinical studies

Dear Global Huntington’s Community,

Just over one year ago, we and our partner Ionis Pharmaceuticals announced the results of the first ever study that tested the huntingtin-lowering scientific hypothesis. Today, we are pleased to announce that the first patient has entered into the GENERATION HD1 clinical study – a pivotal, global Phase III study to investigate the efficacy and safety of RG6042 (formerly known as IONIS-HTTRx). If this clinical study is successful, it is our hope that RG6042 will be approved by health authorities and made available for the treatment of manifest Huntington’s disease.

We are grateful to the patients and family members participating in clinical research, as well as everyone supporting them in the broader HD community. Scientific progress is only possible with your collaboration and participation.

Recent updates

• Two global clinical studies have started and first patients are enrolled – an important achievement for the research programme; study status is available on ClinicalTrials.gov

–HD Natural History study (NCT03664804)

This observational study for early manifest HD will run in the USA, Canada, Germany and the UK; planned study sites were announced in late 2018.

Initial sites have opened and the first patients have enrolled; our team continues to work to open recruitment at all study sites as quickly as possible.

–Phase III GENERATION HD1 study (NCT03761849)

We received health authority approvals in the USA and Canada to start this pivotal study for manifest HD. Planned study sites for those countries were announced at the end of 2018 and the first patient has now enrolled.

This study will run in approximately 15 countries; we are diligently working to set up study infrastructure and receive approvals in the remaining countries.

• Ongoing open-label extension of the Phase I/IIa study: sponsorship has been transferred from Ionis to Roche o Patients who completed the Phase I/IIa study have been participating in an openlabel extension study sponsored by Ionis (NCT03342053). Responsibility of this study has now transferred to Roche. Moving forward these patients will roll into a new Roche-sponsored, open-label extension study called GEN-EXTEND. GENEXTEND will allow us to continue to study longer-term effects of RG6042 in those participants who have previously completed a clinical trial for the investigational molecule.

Important to note

• At this time, access to RG6042 is only through clinical studies because the benefits and risks of RG6042 are not yet fully understood. • Additional countries/sites for the Phase III study: Information about additional countries/sites will be announced on a progressive basis, once sites are nearly ready to enrol participants; information will be posted on ClinicalTrials.gov

• Communications about study data: Roche is committed to transparent and timely communications, as well as ensuring the integrity of ongoing clinical trial operations and data collection. In line with our Global Policy on Sharing of Clinical Study Information, we will share overall programme updates and relevant data from completed and ongoing clinical studies with the scientific community via appropriate channels (e.g., scientific meetings, peer-reviewed journals, etc.).

Our team recognises that the need in HD is greater than the capacity of the RG6042 development programme, and that not every person nor every capable HD centre interested in these clinical studies will be able to participate. We can assure you that the studies are designed to provide health authorities with the required data so that the benefit-risk of RG6042 can be determined as quickly as possible. The ultimate goal is that this investigational medicine can be approved by health authorities and made accessible to the broader HD community. Our team continues to engage with health authorities and HD communities around the world on the RG6042 research programme. We look forward to providing you with further updates.

Sincerely, Mai-Lise Nguyen, on behalf of the Roche & Genentech HD team Patient Partnership Director, Rare Diseases Roche Pharma Research & Early Development / Roche Innovation Centre Basel, Switzerland

To read more:  Roche-global-HD-community-letter-Jan-2019.pdf


December 19, 2018:

RG6042 GENERATION HD1 Study: Expected Sites in USA & Canada Status

The observational HD Natural History study (Clinicaltrials.gov ID: NCT03664804) is open and currently recruiting. The planned sites in Canada, US, Germany and UK were announced in November. Information about the study, including individual site status, is posted on ClinicalTrials.gov.

We are pleased to inform you on progress on the Phase III GENERATION HD1 study (Clinicaltrials.gov ID: NCT03761849). The first countries to open recruitment will be the USA and Canada. Below is a list of planned sites – it is important to note that these sites are not fully activated nor recruiting yet. We hope to complete the final steps as quickly as possible. The GENERATION HD1 study will run in approximately 15 countries; additional countries/sites will be announced on a progressive basis – as we obtain country approvals and when sites are nearly ready to enroll patients. For any clinical study, it is possible that an expected study site does not proceed to enroll participants. This can be for various reasons and we do not want to raise hopes or expectations.

Expected sites for GENERATION HD1 study in the United States of America:

Alabama, Birmingham – University of Alabama Arizona, Phoenix – Barrow Neurological Clinic California, Davis – University of California, Davis California, Palo Alto – Stanford University California, Pasadena – Arcadia Neurology Center California, San Diego – University of California, San Diego Colorado, Englewood – Rocky Mountain Movement Disorders Center District of Columbia, Washington – Georgetown University Florida, Tampa – University of South Florida Illinois, Chicago – Northwestern University Maryland, Baltimore – John Hopkins University Massachusetts, Boston – Beth Israel Deaconess Medical Center Missouri, St Louis – Washington University New York, Amherst – Dent Institute New York, New York – Columbia University Pennsylvania, Pittsburgh – University of Pittsburgh Medical Center Tennessee, Nashville – Vanderbilt University Medical Center Texas, Houston – University of Texas Health Science Center Utah, Salt Lake City – University of Utah Washington, Kirkland – Evergreen Health

Expected sites for GENERATION HD1 study in Canada Alberta, Edmonton – University of Alberta British Columbia, Vancouver – University of British Columbia Ontario, Ottawa – Ottawa Hospital Ontario, Toronto – Centre for Movement Disorders Nova Scotia, Halifax – Queen Elizabeth II Health Sciences Centre Quebec, Montreal – Centre Hospitalier de l’Université de Montréal

Our Clinical Trial Information Support Line for the USA and Canada can be contacted at 1-888-662- 6728. Also, information about the GENERATION HD1 study and sites will soon be posted on ClinicalTrials.gov, including individual site status. Whether your HD clinic or centre is selected for participation or not, this is no reflection on the quality of the many outstanding HD clinics and dedicated care providers around the world. The need in HD is greater than the capacity of our development programme. We have designed the programme to provide the required data to Authorities so that the benefit-risk of RG6042 can be determined as quickly as possible. Our ultimate goal is that this investigational medicine can be approved by Health Authorities, and made accessible to the broader HD community. The decision to join a clinical trial is personal and involves many factors. We encourage anyone interested in participating in any clinical research to discuss with his/her HD specialist about what may be best for his/her situation.

About the Phase III GENERATION HD1 Study The GENERATION HD1 study will evaluate the efficacy and safety of RG6042 treatment given once per month or once every two months (bi-monthly) over a period of 25 months (approx. two years). This global study will enrol up to 660 patients with manifest HD at 80-90 sites in approximately 15 countries around the world. The study will begin at the end of 2018, with patients starting to enrol by early 2019. GENERATION HD1 is designed to determine the effectiveness and safety of RG6042, and therefore includes a comparison to placebo. Participants will be randomized to one of three treatment study arms: RG6042 monthly, RG6042 bi-monthly or placebo monthly. This means for every two participants randomized to RG6042, one will receive placebo. The study is “double-blinded,” meaning neither the participant nor his/her investigator or site staff will know which study arm the participant is assigned. For all patients who complete the GENERATION HD1 study, an open-label extension study with the option of receiving RG6042 (no placebo control) is planned, pending eligibility, approval by Authorities and Ethics Committees/Institutional Review Boards and if data support the continued development of RG6042.

How are the clinical study sites selected? A variety of factors influence site selection, including assessments on experience with HD studies, clinic infrastructure capacity to run the study as well as usual site activities, ability to operationalise the study as quickly and completely as possible, patient population, and geographic location. Whether your HD clinic or centre is selected for participation or not, this is no reflection on the quality of the many outstanding HD clinics and dedicated care providers around the world. The need in HD is greater than the capacity of our development programme. We have designed the programme to provide the required data to Authorities so that the benefit-risk of RG6042 can be determined as quickly as possible. Our ultimate goal is that this investigational medicine can be approved by Health Authorities, and made accessible to the broader HD community