A clinical trial to look at how safe RO7204239 plus risdiplam is and how well this drug combination works to improve muscle function in people with spinal muscular atrophy

1. Why is the MANATEE clinical trial needed?

Risdiplam works by helping the body produce more survival motor neuron protein throughout the body. This means fewer motor neurons (which pass impulses from the nerves to muscles, causing movement) are lost, which may improve how well muscles work in people with spinal muscular atrophy (also known as SMA). RO7204239 works by lowering the amount of myostatin protein in the body; a protein which can reduce muscle growth and development. RO7204239 with risdiplam may have a combined effect to improve muscle function in people with SMA. This clinical trial aims to compare the effects, good or bad, of RO7204239 plus risdiplam versus placebo (medicine with no active ingredients) plus risdiplam in people with SMA.

2. How does the MANATEE clinical trial work?

This clinical trial is recruiting people aged 2–25 years old with SMA. This clinical trial is split into two parts.

Part 1 will look at the safety of RO7204239 plus risdiplam and find a dose of RO7204239 that could benefit people with SMA. Part 2 will use the RO7204239 dose found during Part 1 and will study how well it works when combined with risdiplam, as well as how safe the combination is in a larger number of people with SMA. You, or your child, will only be enrolled into one part of this clinical trial.

People who take part in this clinical trial (participants) will be given a daily dose of risdiplam at the approved dose throughout the clinical trial. Participants in Part 1 who have not previously been treated with risdiplam for at least 8 continuous weeks before joining this clinical trial, and all participants in Part 2, will receive risdiplam alone for at least 8 weeks. Then, the combination treatment will be given as follows:

Part 1: RO7204239 or placebo every 4 weeks for 6 months. Then, participants who received placebo and risdiplam will switch treatments - everyone will be given RO7204239 and risdiplam for a further 18 months.

Part 2: RO7204239 or placebo every 4 weeks for 18 months.

Participants may continue RO7204239 and risdiplam treatment in an open-label extension phase of the clinical trial for up to 2 more years. Participants will be monitored at the clinic for at least 6 hours after the first two injections of RO7204239, and for 2 hours after the remaining injections. The clinical trial doctor will see participants regularly throughout the trial. These hospital visits will include checks to see how they respond to the treatment and any side effects they may have. Total time of participation in the clinical trial will be about 4 years, including the extension phase. Participants can stop trial treatment and leave the clinical trial at any time. After stopping treatment, participants will have follow-up appointments with the clinical trial doctor 3 months and 6 months after their last dose.

3. What are the main endpoints of the MANATEE clinical trial?

The main clinical trial endpoints (the main results measured in the trial to see if the drug has worked) are:

Part 1

●        The number and seriousness of any side effects

●        How the body processes RO7204239 and risdiplam

●        How RO7204239 affects the immune system and any chemical effects of RO7204239 on the body

●        Any change in the size of the participants’ muscles

Part 2

●        How effective RO7204239 is, based on the participant’s change in physical ability and strength

The other clinical trial endpoints for Part 2 are:

●        The number and seriousness of any side effects

●        How the body processes RO7204239 and risdiplam

●        How RO7204239 affects the immune system

●        Any change in the size of the participants’ muscles

4. Who can take part in this clinical trial?

People can take part in this trial if they:

●        Have SMA which has been confirmed by genetic diagnosis

●        Are aged 2–10 years old (Part 1) or 2–25 years old (Part 2)

●        Can walk/run (Parts 1 and 2) OR sit up without help, and lift a drinking cup to their mouth (Part 1 only)

People may not be able to take part in this trial if they are unable to have the required scans during the trial, or if they have taken certain other medications.

5. What experimental treatment will participants be given in this clinical trial?

Each part of the trial has two phases. The first phase is double-blinded, which means that neither the participant nor the clinical trial doctor can choose or know the group the participant is in, until the phase is over. This helps to prevent bias and expectations about what will happen. However, the participant’s clinical trial doctor can find out which group the participant is in, if their safety is at risk. The double-blind phase is ‘placebo-controlled’, which means that one of the groups will be given a substance with no active ingredients (also known as a ‘placebo’); it looks like the drug being tested but does not contain any real medicine. Comparing results from the different groups helps the researchers know whether any changes seen result from the drug or occur by chance.

In the double-blind phase of each part, everyone will be split into 2 groups randomly (like flipping a coin) and given either RO7204239 OR a placebo, as an injection under the skin every 4 weeks, as well as risdiplam, given as a liquid to swallow at home once a day. Participants will have a 2 in 3 chance (Part 1) or a 1 in 2 chance (Part 2) of being given RO7204239, and a 1 in 3 chance (Part 1) or a 1 in 2 chance (Part 2) of being given placebo. The double-blind phase will last 6 months for participants in Part 1 and 18 months for those in Part 2.

The second phase of each part is open-label - which means everyone involved, including the participant and the clinical trial doctor, will know the clinical trial treatment the participant has been given – everyone will be given RO7204239 plus risdiplam in the open-label phase.

6. Are there any risks or benefits in taking part in this clinical trial?

The safety or effectiveness of the experimental treatment or use may not be fully known at the time of the trial. Most trials involve some risks to the participant. However, it may not be greater than the risks related to routine medical care or the natural progression of the health condition. People who would like to participate will be told about any risks and benefits of taking part in the clinical trial, as well as any additional procedures, tests, or assessments they will be asked to undergo. All of these will be described in an informed consent document (a document that provides people with the information they need to decide to volunteer for the clinical trial).

Risks associated with the clinical trial drugs

Participants may have side effects (an unwanted effect of a drug or medical treatment) from the drugs used in this clinical trial. Side effects can be mild to severe, even life-threatening, and vary from person to person. Participants will be closely monitored during the clinical trial; safety assessments will be performed regularly.

RO7204239 has not yet been tested in people with SMA. For this reason, all this drug’s possible side effects may not be known now. Participants will be told about the possible side effects based on laboratory studies or knowledge of similar drugs. Participants will be told about the known side effects of risdiplam (given as a liquid to swallow), and possible side effects based on human and laboratory studies or knowledge of similar drugs. RO7204239 and placebo will be given as an injection under the skin; participants will be told about any known side effects of injections under the skin.

Potential benefits associated with the clinical trial

Participants' health may or may not improve from participation in the clinical trial. Still, the information collected may help other people with similar medical conditions in the future.