Rituximab works in relapsing MS…phase III trial results

This is a study from rituxiland and demonstartes that rituximab is more effective at inhibiting relapses than dimethyl fumarate. It also shows that a lower dose of antibody than used in other previous studies also works well. This was done as a randomised phase III study.

This indicates that rituximab, CD20-depleting antibody works in MS

Svenningsson A, Frisell T, Burman J, Salzer J, Fink K, Hallberg S, Hambraeus J, Axelsson M, Nimer FA, Sundström P, Gunnarsson M, Johansson R, Mellergård J, Rosenstein I, Ayad A, Sjöblom I, Risedal A, de Flon P, Gilland E, Lindeberg J, Shawket F, Piehl F, Lycke J. Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial. Lancet Neurol. 2022;21(8):693-703.

Background: B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines.

Methods: RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis….. This trial is registered at ClinicalTrials.gov, NCT02746744.

Findings: Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0·19 (95% CI 0·06-0·62; p=0·0060). Infusion reactions (105 events [40·9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47·4 per 100 patient-years]) and flush (65 events [47·4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns. Interpretation: RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed.

You say “So what we know this already”. However in the land of evidence-based medicine, you need evidence and anecdote is not accepted evidence. Change occurs after trials have been done…So here you have one.

Now remember as a non-neuro my opinion doesn’t really matter, and it is just an opinion, so keep your hair on;-).

This was a phase III study and demonstrates what I think we would predict.

So the big question is whether this is going to be enough to convince the World to use rituximab?

I suspect that in Sweden, little persuasion is needed….they are an educated group of people and can read the literature and this study demonstrates the predicted benefit as previously seen in phase II trials in MS. Swedish neuros have been using rituximab for years……..however, What about the rest of the World?

The authors of the paper suggetst “Because rituximab is available at a lower price than dimethyl fumarate in some countries, rituximab could be an attractive treatment option, especially in resource-limited settings. So from an economic perspective one may say it seems to be a no-brainer to use rituximab as suggested.

But it may not be so simple.

The cost card may not work, in the UK the NHS is paying the bills and the doctors have guidelines from NICE…….I suspect that rituximab is not on the horizon for MS as you have two other anti-CD20 approved for MS. In resoucre poor countries although cheaper than the licensed products they are still significantly expensive. You say UK is not resource limited, but it is, but they in part have created the Big Pharma machine and don’t want to break it. Therefore funders don’t want to be anti-pharma, because without them there will be no new drugs.

I have played the cost card previously and am sad to say the powers that be, may not really care. ProfK and I wanted to compare subcutaneous cladribine to alemtuzumab in a head to head study. They didn’t accept that the trial would save them money, as we said it would save about £30,000,000 if I remember properly. The trial would have been costed about £2,000,000 to the funder (NIHR) + drug costs (from the NHS). They didn’t accept the saving to the NHS…but as the trial planned to compare 600 people on cladribine (max 12 doses at £165/dose) verses 600 people on alemtuzumab, meaning that 600 people eligible for alemtuzumab would not need the drug. You just need to do the maths.

The list cost of the cladrine was about £2,000/person for 2 years so drug cost was £1,200,000. Cost of alemtuzumab was £56,320 (+ VAT) per person = £33,792,000 (+ 20% VAT)/600 people over two years, but remember a significant number of people in the alemtuzumab arm would have disease break-througth and need re-treating (£6,336,000 for 50%) and also remember people would need dosing with steroids etc for each infusion and about 30-50% would have the cost of treating secondary autoimmunity and people had to be monitored monthly also, etc. etc.

However back to the question

Will the MS World start to embrace this?

I guess it depends on how the regulators and insurers respond. If the insurers or Governments won’t re-imburse the costs then there wil,l I suspect be more limited uptake. Ocrelizumab and ofatumumab are already approved for MS and ublituximab may be on the way soon. So pharma may say what are the scientific advantages? If you are treating within the drug label, as a neuro you may be less exposed to litigation issues if something bad happens and you have support from pharma such as pharma funded medical science liaison (MSL) officers, which is scientific expert for specific drugs, acting as the key link between clinicians, research and the pharmaceutical industry. Also they may provide funding for MS nurses such as infusion nurses that deliver your treatments.

What will pharma do? They develop drugs to make money? If they can’t they may go elsewhere. They have made money and look at the array of approved drugs available….some other neurological conditions have none. After the positive phase I and Phase II trials with rituximab, the manufacturers decided to develop ocrelizumab for MS. This is humanized anti-CD20 and so should induce less anti-drug antibodies than rituximab. It was also more potent. I suspect that rituximab patents would probably have expired by the time the phase III trials and regulatory approval were obtained and it would have allowed generics to be used.

However, pharma could say that they have to do studies to a higher standard to get a drug approved. They have to do two phase III trials not one and they have to have large group sizes (n=500-1000) with 90% power to detect efficacy not 80% (n= less than 100) as used in the current study. To get drugs approved pharma has to spend millions. However, the authors of the current paper indicated that “regulatory approval” is unlikely to be sought regardless of any positive phase 3 data from independent trials. However, there are major unmet medical needs worldwide regarding access to affordable multiple sclerosis treatments as a consequence of the high prices of licensed MS drugs.

Rituximab is a fraction of the cost of ocrelizumab and there are now generics of rituximab so what variant should be used….the cheapest? If you are concerned about the resource-limited setting, you could wonder why generic subcutaneous cladribine has not been adopted more, as the cost is way lower than rituximab.

Maybe we need a head to head of rituximab verses ocrelizumab to see if there are any major differences

COI: Multiple

Disclaimer: These are the views of the author.