August 5, 2020

expert reaction to phase 3 trial of ofatumumab for multiple sclerosis

A study, published in the New England Journal of Medicine, looked at the drug ofatumumab for multiple sclerosis in a phase 3 trial. 

Dr Su Metcalfe, Senior Research Associate in the Department of Clinical Neurosciences, University of Cambridge, and Founder of LIFNanoRx, said:

“Reduction of relapse rate in people with multiple sclerosis is a key goal for therapy.  This impressive Phase III clinical trial led by Stephen Hauser has succeeded, showing Ofatumumab is superior to Teriflunomide.

“The underlying logic of the therapy is to remove B lymphocytes – a new target to treat in MS.

“Here my one concern is that focus on B cells may detract from the actual root cause of MS, namely an error of normal immune self-tolerance.  Here powerful neuro-protective T lymphocytes turn rogue, switching into auto-immune T cells that attack myelin.  These rogue T cells orchestrate inflammation including B cells that contribute to drive relapses.

“Now the question is – can targeting B cells, to reduce inflammatory relapses, be combined with targeting T cells, to reset self-tolerance ? Can the driving trigger of inflammation be switched off?”

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“This paper describes two trials comparing active treatments to prevent relapses in multiple sclerosis.

“It is an unusual trial to be funded by the pharmaceutical industry – they do not usually have ‘head-to-head’ comparisons of active treatments but usually have a placebo group having the usual standard of care as the comparator.

“Ofatumumab was introduced to treat chronic lymphocytic leukaemia and is used in the US for this purpose – it was withdrawn in the EU.  It is not licensed for use in multiple sclerosis MS) as yet.  It is given by injection (as with some other treatments for MS), every four weeks after the first few weeks.

“Teriflunomide is licensed to treat MS.  It is a daily oral treatment.

“This paper shows that ofatumumab does better than teriflunomide in reducing the likelihood of a relapse though the difference in absolute terms is small from just over 0.2 per year to just over 0.1 per year.  Prior to treatment, the rates of relapse were about 1 per year.

“There were suggestions that severe infections were more likely with ofatumumab than with teriflunomide.  In the US ofatumumab has a ‘black box’ warning of the possibility of progressive multifocal leukoencephalopathy, a very rare but serious and sometimes fatal disease in the brain.  This has been seen in other similar treatments for MS, but not shown to definitely occur with teriflunomide.

“Neither drug is a cure for MS but both seem effective in reducing relapses.  The question of whether the extra benefit, if confirmed by trials independent of the manufacturer and if ofatumumab becomes licensed in the UK for MS, is worth the extra possible side effects and inconvenience of injections will be a question for individual decision making.”

‘Ofatumumab versus Teriflunomide in Multiple Sclerosis’ by S.L. Hauser et al. was published in the NEJM at 22:00 UK time on Wednesday 5 August 2020.

DOI: 10.1056/NEJMoa1917246

Declared interests

Prof Stephen Evans: “No conflicts of interest in relation to this.  I am funded (1 day/week) by LSHTM.  They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator or any grants obtained from them.  I am the statistician to the “meta-Data Safety and Monitoring Board” for CEPI.  I will probably be paid for my attendance at meetings and expenses for travel.”

None others received.