Just catching up with my reading. Whilst I was away on holiday the ASCLEPIOS I and II trials was published in the New England Journal of Medicine.
There is little doubt that ofatumumab is superior to teriflunomide when it comes to suppressing focal inflammation, i.e. relapses, MRI activity and peripheral blood neurofilament levels. However, ofatumumab’s effectiveness against teriflunomide on the real MS (delaying disability progression and reducing the relative loss of brain volume) is less impressive. Is this just another example of a dissociation between the anti-inflammatory effects of an anti-CD20 therapy and its impact on the end-organ as measured using brain volume loss or is it telling us something about teriflunomide and the cause of MS?
It is clear, at least to me, that MS the disease is not due to focal inflammation. Based on the Prentice criteria for disease surrogates, both relapse and focal MRI activity don’t predict disability outcomes in natural history studies and placebo arms of clinical trials. If focal inflammation was MS then relapses and focal MRI activity would predict outcome whether or not you are on a DMT. The point I making here may be a philosophical one, but it a critically important one. In comparison, sustained or confirmed disability progression has to be MS and is based on the pathological correlates that define MS (demyelination, neuroaxonal loss and gliosis).
So why does ofatumumab do so poorly on these metrics relative to teriflunomide, when you would expect it do better? I think teriflunomide is the outlier and this opinion is based on several observations.
Teriflunomide has effects on disability progression that are way and above what you expect from its impact on relapses and focal MRI activity; i.e. both teriflunomide phase 3 placebo-controlled trials were positive on disability progression, despite a moderate reduction in relapse rate (~33% vs. placebo).
Teriflunomide also has a significant and unexpected effect on brain volume loss compared to placebo, which again is out of proportion to its anti-inflammatory effects.
Teriflunomide is more effective when used 2nd and 3rd line. Teri is the only DMT to show the latter and this observation was seen in both phase 3 studies, which makes it likely to be a real, and a very important, finding.
Finally, teriflunomide is a broad-spectrum antiviral agent, which may be part of its mode of action in MS. Could teriflunomide be targeting the viral cause of MS independent of its effects on the immune system’s response to that virus? Could it be an anti-EBV agent? Although teriflunomide’s antiviral mode of action needs more study, I suspect this is the reason why teriflunomide is the outlier that disproves the dogma.
Despite these observations, I suspect the MS community is going to propel ofatumumab to blockbuster status within the first 12 months of its launch. However, I want to reiterate that I think anti-CD20 therapies are lulling us into a false sense of security, i.e. because anti-CD20 therapies are so good at suppressing relapses and focal MRI activity we think we have sorted out the treatment of MS. However, when you look carefully at the end-organ of pwMS on anti-CD20 it is clear that their brains are still being shredded by smouldering MS. It is clear to me that we need to go way and beyond ofatumumab and anti-CD20 therapies to target whatever is causing smouldering MS. This is why we need to think combination therapies and find an add-on therapy, possibly an antiviral, that normalises brain volume loss in people with MS who are rendered free of focal inflammatory activity.
Hauser et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med 2020; 383:546-557.
BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.
METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.
RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, −0.11; 95% confidence interval [CI], −0.16 to −0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, −0.15; 95% CI, −0.20 to −0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P=0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P=0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P=0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.
CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231).