A first-in-human-study to compare different doses of RG6496 with a placebo in Huntington's disease gene expansion carriers with an open-label-extension part

1. Why is this study needed?

Huntington's Disease (HD) is a genetic disease caused by a mutated version of the huntingtin gene that leads to progressive damage of nerve cells in the brain. This affects a person's ability to think, talk, and move. There is a high unmet medical need for therapy to slow or stop the clinical progression of the disease.

This study is testing a medicine called RG6496. It is being developed to treat HD.

RG6496 is an experimental medicine. This means health authorities (like the U.S. Food and Drug Administration and European Medicines Agency) have not approved RG6496 for the treatment of HD.

This study aims to test how safe RG6496 is (at different doses) and to understand what happens to RG6496 once it is in the body.

2. Who can take part in the study?

People (males or females) of 25 65 years old (inclusive) can take part in the study if they carry the selected genetic variation in the huntingtin gene with an expanded cytosine-adenine-and guanine (CAG) mutation and are Huntington's Disease-Integrated Staging System (HD-ISS) Stages 2-3.

People may not be able to take part in this study if they have certain conditions related to brain and spinal cord or other medical conditions, or if they are receiving certain medications.

People who are pregnant, breastfeeding, or planning to become pregnant cannot take part in the study.

3. How does this study work?

This study has two parts: Part 1 and Part 2. Participants should complete Part 1 before they can enter Part 2 of the study. Participants will be screened to check if they are able to participate in the study. The screening period will take place from up to 12 weeks to the start of treatment.

Everyone who joins Part 1 of this study will be split into groups randomly (like flipping a coin) and given either RG6496 OR placebo. This will be given as a single injection into the fluid around the spinal cord through a procedure called a lumbar puncture (also known as an intrathecal [IT] injection). Participants will have a 3 in 4 chance of being placed in the RG6496 group and a 1 in 4 chance of being placed in the placebo group.

Part 1 of this study is 'placebo-controlled'. This means that participants are put in a group that will receive a medicine or a group that will receive 'placebo' (a medicine that contains no active ingredients but looks the same and is taken in the same way as the study medicine). Comparing results from the different groups helps researchers know if any changes seen result from the study medicine or occur by chance.

Part 1 is also a double-blinded study. This means that neither the participants in the study nor the team running it will know which treatment is being given until the study is over. This is done to make sure that the results of the treatment are not affected by what people expected from the received treatment. However, the study doctor can find out which group the participant is in, if the participants' safety is at risk.

In Part 1, participants will stay overnight at the study site on Day 1 after receiving RG6496 or placebo. They will be dismissed on Day 2 and will return on Day 3 for some safety tests. The study doctor will call the participants a few days after the treatment injection. Afterwards, the study doctor will see participants at the study site once a month for 7 months and will call them in between these visits. They will see how well the treatment is working and any unwanted effects participants may have. The total time of participation in Part 1 will be about 40 weeks.

Participants who complete Part 1 and are eligible based on the assessment results from Part 1 can proceed to Part 2 of this study. In Part 2, all participants will be given RG6496 as a single IT injection.

Part 2 is an open-label study. This means everyone involved, including the participant and the study doctor, will know the study treatment (i.e., RG6496) the participant has been given. No placebo will be given in Part 2.

During Part 2, the study doctor will see participants every 4 to 8 weeks for 5 times (about 34 weeks) and will call them in between the visits. They will see how well the treatment is working and any unwanted effects participants may have. Participants will receive a final follow-up telephone call from the study doctor to check on their well-being approximately 58 weeks after the study treatment administration. The total time of participation in Part 2 will be about 58 weeks.

Overall, the total time of participation in the study, including both Part 1 and Part 2, will be about 23 months. Participants have the right to stop study treatment and leave the study at any time, if they wish to do so.

4. What are the main results measured in this study?

The main results measured in the study to assess if the medicine has worked are how often and serious unwanted effects happen during the study and changes from start of the study in safety assessments and brain functions. Other key results measured in the study include the parameters showing how RG6496 is distributed and eliminated from the body, if antibodies against RG6496 are produced by the body, and the level of mutant huntingtin protein in cerebrospinal fluid (CSF) collected through lumbar punctures.

5. Are there any risks or benefits in taking part in this study?

Taking part in the study may or may not make participants feel better. But the information collected in the study can help other people with similar health conditions in the future.

It may not be fully known at the time of the study how safe and how well the study treatment works. The study involves some risks to the participant. But these risks are generally not greater than those related to routine medical care or the natural progression of the health condition. People interested in taking part will be informed about the risks and benefits, as well as any additional procedures or tests they may need to undergo. All details of the study will be described in an informed consent document. This includes information about possible effects and other options of treatment.

Risks associated with the study drug and procedure
Participants may have unwanted effects of the drugs and procedures used in this study. These unwanted effects can be mild to severe, even life-threatening, and vary from person to person. During this study, participants will have regular check-ups to see if there are any unwanted effects.

RG6496
RG6496 has not yet been tested in humans. Therefore, the unwanted effects of this medicine are not known now. Participants will be told about the possible unwanted effects based on laboratory studies or knowledge of similar medicines. Possible unwanted effects include temporary problems with movement and walking, changes in protein and white blood cell counts in the protective layers around the brain and spinal cord, and changes in immune cells.

RG6496 and placebo will be given by IT injection performed via a lumbar puncture. Known unwanted effects related to the IT injection include allergic reaction to the local anaesthetic medication and an injection reaction, such as rash and pain at the injection site.

RG6496 may be harmful to an unborn baby. Women and men must take precautions to avoid exposing an unborn baby to the study treatment.

Lumbar Puncture
Lumbar punctures are routine medical procedures. Known unwanted effects related to the lumbar puncture include pain, nausea, headache, discomfort, bruising, stiffness, and rarely, infection.