The phase 2 data of frexalimab in relapsing multiple sclerosis has just been published in the New England Journal of Medicine. This is very big news and has rejuvenated my enthusiasm for the future of MS treatments.
CD40 is a critical costimulatory signal that drives T-cell activation and is involved in B-cell and innate immune activation. The phase 2 Frexalimab study results are strikingly positive and are the most exciting to emerge in MS in the last 12-24 months. Firstly, the impact on MRI activity in MS put the therapy in the very high efficacy bracket, but against the odds, considering the duration and size of the study, we saw an effect on blood neurofilament and CXCL13 levels and quality of life outcomes. These results are extraordinary.
These results also tell us a lot about the pathogenesis of MS by confirming a critical role for T-cells in the pathogenesis of MS and strongly support MS as being an autoimmune disease. As you are aware, I have taken a very strong position on EBV, and I have been convinced that EBV causes MS and is the driver of MS disease activity. Hence, I push for developing EBV antivirals as a treatment for MS. Therefore, the obvious question is, how are the frexalimab results compatible with EBV being the driver of MS disease activity?
From an evolutionary perspective, It should not be surprising that EBV has hijacked CD40 and the CD40-ligand signalling pathways to promote its survival. EBV's latent membrane protein 1 (LMP1) is a CD40 mimic that augments the normal CD40 signalling pathway. This gives EBV-infected B cells a survival advantage. Blocking the normal CD40 pathway with Frexalimab may be enough to remove the pro-survival signal that results in the selective loss of EBV-infected B-cells over time, i.e. they die off because of reduced CD40 signalling. Alternatively, anti-CD40L may be inhibiting the function of EBV-infected B-cells.
In a little-known and rarely quoted study, it has been shown that EBV-infected B-cells aberrantly express CD40L (Imadome et al. Proc Natl Acad Sci USA. 2003 Jun 24;100(13):7836-40). Non-infected B-cells don’t express CD40L. This aberrant CD40L expression may augment EBV-infected B-cell's ability to present antigens, even autoantigens, to T-cells. Blocking this aberrantly-expressed CD40L on EBV-infected B-cells will reduce EBV-infected B-cells presenting antigens to T-cells.
Even if I am wrong about EBV and Frexalimab, there is no doubt the results of this study are sending a buzz through the MS community, particularly the immunologists and genomics experts who predicted these results two decades ago.
Because Frexalimab blocks the co-stimulation of autoreactive T-cells, it may convert a stimulating autoreactive signal into a tolerogenic or anergic signal. So, will Frexalimab put pwMS into long-term remission and mimic the stunning results we see with alemtuzumab or AHSCT? Blocking CD40-CD40L interactions should stop autoimmunity. You can now understand why I am so excited about Frexalimab as a potential treatment for MS.
I was asked by a colleague yesterday where I see the MS market in 10 years. Considering the stunning results of anti-CD20 and the potential emergence of BTK inhibitors, he wanted to know whether there is space for Frexalimab in the treatment landscape. I suggested to this colleague that he should read my extensive commentaries on anti-CD20 therapies in MS. It is clear that despite anti-CD20 therapies being very effective at suppressing relapses and focal MRI activity, they don’t stop smouldering MS, i.e. they are not getting to the core pathology that is driving MS worsening. In addition, it is highly unlikely that people with MS (pwMS) will be able to stay on an anti-CD20 therapy life-long. Over time, some people develop hypogammaglobulinaemia, and with ageing, the risk of infection increases. This is why we need an exit strategy from anti-CD20 therapies or an alternative treatment approach.
So if the phase 3 Frexalimab study shows it to have a more pronounced effect on the end-organ, i.e. reduced brain volume loss, fewer paramagnetic rims lesions, fewer slow expanding lesions getting larger, a reduction in spinal fluid biomarkers of B and plasma cell activity and less microglial activation, Frexalimab will win hands down. Then there is this tantalising possibility that Frexalimab may re-establish immune tolerance and not need to be given continuously. So, there is a lot to play for when it comes to the future MS market.
I also suspect the BTK inhibitors may not be as effective as anti-CD20 therapies and, as a class, will be handcuffed with a major pharmacovigilance burden given the liver toxicity signal with these therapies. So I don’t necessarily see the BTKi’s threatening the anti-CD20’s dominance in the short to medium term.
Even if Frexalimab and other anti-CD40L and anti-CD40 therapies fail, we will have induction-maintenance strategies, i.e., using immunodepleting therapies as an induction followed by a safer maintenance therapy. This would also threaten the hegemony of the anti-CD20s in that they will only be used for a short period and replaced by a safer, non-immunosuppressive therapy. The latter could be a fumarate (dimethyl fumarate, diroximel fumarate, …), a dihydroorotate dehydrogenase inhibitor (teriflunomide, vidofludimus, … ), or an EBV antiviral. This is the iTeri study that I proposed several years ago. I have just completed a review article on potential EBV antivirals, and there are a lot of drugs that need to be tested in MS. What we now need are brave Pharmaceutical companies that have little experience in MS to join the party.
It is clear to me, and it should be clear to my colleagues, that anti-CD20 therapies have a limited shelf-life as a treatment for MS and will not be the mainstay of MS treatment in 10 years. I am not sure if you are aware that all of the big pharma companies that have a licensed anti-CD20 therapy for MS are not sitting on their hands; they all have deep and very interesting MS development pipelines. This tells us they know that their anti-CD20 products are not good enough and that we must go beyond preventing relapses and suppressing focal MRI activity. The most exciting of these products are CNS penetrant therapies targeting smouldering MS. The latter includes CD19-targeted CAR T-cells and proteasome inhibitors (ixazomib).
I know some of the information in this newsletter may be difficult to understand, so please ask questions if you don’t understand anything.
Paper 1
Background: The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis.
Methods: In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab.
Results: Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches.
Conclusions: In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).
Paper 2
Epstein-Barr virus (EBV), implicated in numerous human diseases, including lymphoid malignancies, persistently infects peripheral B cells and transforms them into lymphoblastoid cell lines. Here we found that EBV equally infected B cells from patients with X-linked hyper IgM syndrome and those from healthy donors; however, it hardly transformed X-linked hyper IgM syndrome B cells, because of the dysfunctional gene of CD40 ligand (CD40L) of the patients. Unlike CD40, CD40L is not usually expressed on B cells. However, we found that EBV infection of normal B cells induced CD40L expression as a critical effector in host cell transformation and survival. Moreover, chronic active EBV infection of peripheral T cells, implicated in T cell malignancies, was associated with ectopic expression of CD40, and, in Jurkat T cells, EBV infection induced CD40 expression. These results suggest that EBV infection induces CD40L/CD40 signaling in host cells, which appears to play an essential role in its persistent infection and malignancies of lymphocytes.
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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
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