The Progress on Genentech and RG6042

16 September 2018

Update on RG6042 (formerly known as IONIS-HTTRx) Huntington’s disease global development programme: Two clinical studies to begin by end of 2018

Dear Global Huntington’s Community, Thank you for your ongoing support and interest in the investigational medicine RG6042 for Huntington’s disease (HD).

Over the past months we and our partner Ionis Pharmaceuticals have been heavily engaged with communities around the world (patient groups, medical professionals, Health Authorities and payers) to collaborate and build the RG6042 global development programme and upcoming studies. We are eager for RG6042 to advance into further clinical development. In addition, as announced last month, the European Medicines Agency granted RG6042 PRIME (“PRIority MEdicine”) designation, which provides promising medicines enhanced interactions with the agency and the potential for accelerated evaluation.

Next steps for the global RG6042 development programme Following the completion of the Phase I/IIa first-in-human study of RG6042 in December, there are several important questions that still need to be answered before this investigational medicine can potentially be approved by Health Authorities in countries around the world:

● What are the effects on lowering mutant huntingtin (mHTT), the toxic protein believed to cause HD, over a period of time longer than the 13-week Phase I/IIa study?

● Does sustained treatment with RG6042 slow or stop the progression of HD?

● Do any safety concerns emerge when RG6042 is given to a larger group of people, and for a longer time, than the 46 individuals in the Phase I/IIa?

● Could a less frequent dose than the monthly dose used in the Phase I/IIa study be effective? Our upcoming studies have been designed to answer these questions as quickly and as robustly as possible, whilst considering the number of people exposed to an investigational medicine or placebo.

Update on ongoing and upcoming clinical studies All 46 participants who took part in the Phase I/IIa study are continuing to receive RG6042 as part of an ‘open-label extension’ study run by Ionis. This study assesses the safety and tolerability of longerterm dosing of RG6042 and is being conducted at the nine sites involved in the Phase I/IIa study in Canada, Germany and the United Kingdom.

Two additional clinical studies, run by Roche, are planned to start by the end of 2018. Information about these studies was presented today to the HD community during the European Huntington’s Disease Network Plenary Meeting in Vienna, Austria.

● The HD Natural History Study: This 15-month observational study aims to further understand the role of mHTT in disease progression. There is no drug treatment in this study, as the goal is to understand the natural progression of HD. This study will include up to 100 participants with early manifest (Stage I and II) HD at up to 17 sites in Canada, Germany, the United Kingdom and the United States. This study is expected to start towards the end of 2018.

● GENERATION HD1: This will be the world’s first Phase III study testing a molecule designed to lower huntingtin protein. The study design will be submitted to Health Authorities and Ethics Committees/Institutional Review Boards (IRBs) this year. The GENERATION HD1 study will 2/5 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).

o This global study will enroll up to 660 patients with manifest HD at 80-90 sites in approximately 15 countries around the world. The study is expected to begin at the end of 2018 with patients starting to enroll by early 2019.

o Participants will be randomised to one of three treatment study arms: RG6042 monthly, RG6042 bi-monthly or placebo monthly. This means for every two participants randomised to RG6042, one will receive placebo. The study is designed to test the potential effects of RG6042 compared to placebo, whilst limiting the number of people who will be given placebo. o 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.

● Future open-label extension study for all patients who complete the HD Natural History and GENERATION HD1 studies: If approved by Authorities and Ethics Committees/IRBs, and if data support the continued development of RG6042, we plan to offer an open-label extension study that would provide the option of receiving RG6042 (no placebo control) to all patients who complete these studies.

Our team is working with urgency to start the HD Natural History and GENERATION HD1 studies and we understand that you are eager for more detailed information, such as specific sites, countries and dates.

Study site/country information will be shared on a progressive basis. Once a site is nearly ready to enrol patients, we will update the information on and on North America’s On the next pages of this letter you’ll find additional study information and frequently asked questions and answers about these new studies.

The urgency in which families are seeking a medicine that can slow or stop the progression of HD is deeply felt and shared by our team. Because the need in HD is greater than the capacity of our development programme, we recognise that not every person, nor every capable HD clinic or centre, interested in participating in these clinical studies will be able to participate. Please understand the studies are designed to provide Authorities with the required data so that the benefit-risk of RG6042 can be determined as quickly as possible.

Our team is committed to addressing the scientific questions and promptly completing the RG6042 studies with appropriate rigour. The ultimate goal is that this investigational medicine can be approved by Health Authorities, and made accessible to the broader HD community – a goal that we share with you, the global HD community. We look forward to providing you updates later this year, and thank you for your continued partnership.


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