Lay summary by Sophie Voase, reviewed by Dr Laura Evans
Background
Multiple sclerosis (MS) is a chronic disease which affects the central nervous system (made up of the brain and spinal cord). In MS, the immune system attacks the myelin sheath, the protective layer which surrounds neurons (the nerve cells that carry messages from different parts of the central nervous system and to the muscles that enable voluntary movement). This process is called demyelination and these repeated bouts of inflammation injure the neurons over time. This compromises the ability of these neurons to carry messages and leads to MS symptoms. These symptoms are different depending on which part of the central nervous system is affected. There are different types of MS and the type of MS a person has depends on the course of MS. The type of MS that this paper focuses on is relapsing MS which is the most common form. In this form, the person with MS develops new symptoms, called a relapse, followed by a recovery period. Not all these symptoms get better, and this can lead to disability getting worse after each relapse.
Why is the study important?
One of the focuses of treatment is on finding ‘disease-modifying treatments’ (DMT). This means finding a medication which aims to reduce the number of relapses a person with MS will have, protect the neurons and slow down the rate of progression of disability, not just treat the symptoms. When a new DMT is being developed, it is important to measure a) whether it works and b) assess whether it is safe. In a clinical trial participants are assigned to different medications or to a placebo at random (called a randomised placebo-controlled trial). The aim is to compare how effective and safe these medications are. After the clinical trial is finished, there can be a period called an ‘open label extension’ in which the medication is trialled for a longer period with all participants on the active medication in order to look at how safe and effective it is when it is taken for longer.
Ofatumumab is a medication which is given via an injection under the skin every four weeks (subcutaneous injection). It works on reducing the amount of one of the immune system cells called a B cell. The idea is that if you reduce how active the immune system is, you can reduce how much the immune system attacks the neurons. Four different clinical trials were carried out looking at how effective Ofatumumab is and how best to give the medication. Ofatumumab showed promising results in these clinical trials and was approved by the FDA for multiple sclerosis in 2020, and in Europe and the UK in 2021. Ofatumumab was shown to reduce annual relapse rates and had a lower number of people with worsening disability when compared to an oral DMT and compared with the placebo. As ofatumumab is given via an injection under the skin, reactions both throughout the body and at the injection site must be considered. After the initial clinical trial period had finished, the person with MS could choose to enter the open label extension period. This study is important as it reports the findings of the open-label extension from the four different clinical trials looking at the safety of ofatumumab up to a maximum of four years. This means that there are many people involved which means that people have more confidence in the safety of the medication.
What did the authors do and how did they do it?
The authors followed up with 1703 people continuing ofatumumab from four different clinical trials in an open label extension study called ALITHIOS, summarised in the diagram below.
There were eight main types of side effects, or adverse reactions that emerged from the clinical trials. The authors collected information on reactions which were thought to be related to the injection of ofatumumab (called injection-related reactions). These reactions then further analysed:
1. What type of reaction was it?
- Reaction involving the whole body (systemic injection-related reaction)
- Reaction at the site of the injection (local-site injection-related reactions)
2. How severe was the reaction?
- Mild
- Moderate
- Severe
- Life-threatening
3. How long after the person had the injection did they develop the reaction?
4. What number ofatumumab injection did the reaction happen with?
5. Was there anything else that was more likely to have caused the reported reaction?
- If yes, that case was removed from the analysis.
What are the results?
Almost a quarter of people had at least one systemic reaction to an injection over the whole period; these happened more commonly the first time they received ofatumumab. Almost all the reactions were classed as mild/moderate and non-serious. The three most common symptoms reported were fever, headache and chills. Only five people needed to stop receiving ofatumumab due to a reaction. There were no life-threatening reactions to ofatumumab during the four years. Some people received steroids, or non-steroidal anti-inflammatory medications before their injections but this had no effect on how many had a reaction or the severity of the reaction.
1 in 10 people had a local site reaction following an injection; almost all were mild/moderate and non-serious. None were life threatening and only one person stopped ofatumumab due to a local site reaction. The most common local site reactions were redness and pain.
What do the findings mean going forward for people with the disease?
This study has demonstrated that ofatumumab is generally well-tolerated over time. When reactions occurred, they were mainly mild and happened after the first injection. As medication side effects are one of the main reasons for switching disease-modifying treatments, this means that ofatumumab might be a good option for people with MS. Ofatumumab can be injected monthly and does not need to be given into a vein like other medications which require a cannula to be inserted. Therefore, people could self-inject at home which would reduce the amount of hospital visits needed.
This study can be found at
https://journals.sagepub.com/doi/10.1177/20552173231203816
Paper title
Tolerability of subcutaneous ofatumumab with long-term exposure in relapsing multiple sclerosis
Lead Authors
John Kramer and Patrick Vermersch
Publication details including date of publication
Published in Multiple Sclerosis Journal – Experimental, Translational and Clinical on the 10th October 2023.