Gamechangers
I predict that cheap generic oral cladribine, fenebrutinib, prophylactic EBV vaccines and antiviral treatments for acute EBV-associated infectious mononucleosis will transform the MS landscape.
I attended a multiple sclerosis meeting with delegates from Central and South America last week, and I was asked what I would consider game-changers in how MS will be managed globally. I came up with three.
Oral cladribine is coming off patent with the emergence of very cheap generic drugs.
If fenebrutinib is shown to be superior to teriflunomide and ocrelizumab in the treatment of relapsing and primary progressive MS, respectively.
EBV vaccines or treatments to reduce the incidence and/or severity of infectious mononucleosis (IM).
Generic oral cladribine
Cladribine is a highly effective, easy-to-use oral disease-modifying therapy for active MS, which works as an immune reconstitution therapy (IRT). Cladribine kills cells gradually by a process called apoptosis. Cells dying from apoptosis are phagocytosed, or engulfed, by macrophages. As a result, there is no cell lysis or bursting open of the cells, and the release of their contents does not occur, which prevents the release of cytokines that can cause a cytokine release syndrome. This means there is no need to pre-treat patients with steroids.
Cladribine does not deplete monocytes and neutrophils and has a moderate impact on so-called NK cells. As the innate immune system is left intact, there is a low risk of bacterial and other infections during the depletion phase. Additionally, innate cells can help fight viral infections, such as SARS-CoV-2, JC virus, and the flu.
T lymphocytes are generally depleted by about 40%-50%, and most patients don’t drop their counts below 500/mm³. In the Phase 3 trial programme, approximately a quarter of patients experienced grade 3 or 4 lymphopenia; however, this tended to occur after the second course in year 2, particularly in subjects who were redosed when their lymphocyte counts had not recovered to above 800/mm³. We have used the trial data to model grade 3 and 4 lymphopaenia. I.e. less than 500/mm3, and estimate that about 5% of cladribine-treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the redosing guidelines. Even then, the lymphopaenia is transient and recovers quickly. Please note that the proportion of patients developing lymphopenia will be higher in patients exposed to other DMTs that affect lymphocytes, particularly those who have received prior treatment with dimethyl fumarate, S1P modulators (e.g., fingolimod), and anti-CD20 therapies. This is very important, as lymphopaenia is probably the most significant risk factor for viral and severe viral infections.
In the T-cell compartment, the CD8+ T-cells are less affected than the CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections. This probably explains, apart from a small risk of herpes zoster reactivation, why we didn’t see an increase in viral infections compared to placebo in cladribine-treated subjects in the phase 3 trial programme. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. The infection profile with cladribine, including the zoster signal, was much more similar to that seen with ocrelizumab compared to alemtuzumab. The incidence of shingles is expected to decrease further now that we are recommending vaccination with Shingrix before initiating cladribine.
Cladribine is a remarkably good depleter of B-cells. B-cell numbers drop more quickly than T-cell numbers, typically within a few days to a few weeks. In addition, B-cells are depleted by approximately 90%, and notably, memory B-cells are depleted to a similar level as seen with alemtuzumab. Importantly, when the B-cell numbers return, these are so-called naive B-cells, which come from the bone marrow and are not memory B-cells. Interestingly, when you stop an anti-CD20 therapy, such as ocrelizumab or rituximab, and allow B-cell reconstitution, the resulting B cells are also naive and do not return as memory B cells in the short term. In other words, cladribine, alemtuzumab, and anti-CD20 therapies (such as ocrelizumab) have similar effects on B-cells. As EBV resides in the memory B-cell compartment, cladribine is likely acting as an anti-EBV agent. As a small molecule, it penetrates the deep tissue compartment to kill memory B-cells. This explains why it appears to be more effective at targeting CNS resident B-cells than anti-CD20 therapies.
Please note that because ofatumumab, ocrelizumab, ubletuximab, and rituximab are administered as maintenance or continuous therapy, there is an increase in the incidence of serious infections over time, as well as the development of hypogammaglobulinaemia in a proportion of patients. This is not seen with cladribine. Once the immune system reconstitutes after cladribine, it can fight infections, survey the body for cancer, and mount immune responses to new viral infections, such as SARS-CoV-2, as well as vaccines. Regarding vaccines, both live and inactivated component vaccines can be administered after cladribine.
Another important aspect of cladribine is that its monitoring requirements are minimal. Once you have had a course, you only need a complete blood count to be done 3 and 7 months after starting treatment. The rationale for this approach is that the 3-month time point corresponds to the nadir, and the 7-month time point is used to assess recovery of lymphocyte counts. You may be able to avoid blood monitoring. However, note that a drop in lymphocyte counts indicates the patient has responded to the treatment from a haematological perspective. It is essential to check lymphocyte counts before the second course to ensure they are above 800/mm³, as this helps prevent grade 3 and 4 lymphopenia with the second course.
When you look at how cladribine works, i.e. it needs to be activated by an enzyme call DCK (deoxycytidine kinase) and broken down by an enzyme called ADA (adenosine deaminase), the profile of cells expressing the correct ratio of these enzymes matches the B-cell population that expresses CD19 and CD20 and explains why B-cells are more susceptible to the effects of cladribine than T-cells.
Another advantage of cladribine is that, as a small molecule, it penetrates the CNS. Cerebrospinal fluid (CSF) levels are about 25% of what is found in the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. This explains why cladribine impacts smouldering MS and has been shown to reduce brain volume loss, retinal nerve fibre layer thinning, CSF NFL levels, CDF immunoglobulin and cytokine levels. In a small study, it has been shown to reduce both slowly expanding lesions on MRI and paramagnetic rim lesions. Therefore, it is the only licensed therapy we have to impact the smouldering component of MS. This will change with the emergence of new CNS-penetrant DMTs such as tolebrutinib and hopefully fenebrutinib.
Another factor that cannot be underestimated is that cladribine is the only oral tablet to have been included on the WHO’s Essential Medicines List (EML) for the treatment of MS. The other two agents are glatiramer acetate and rituximab. This means that when cheap generics become available, there should be rapid adoption of oral cladribine as the go-to first-line therapy to treat active MS. This will is of particular importance for people with MS living in low- and lower-middle-income countries, or those who have no healthcare insurance coverage in high-income countries.
I have also been making the case for some time that cladribine is the ideal agent for treating active RIS (radiologically isolated syndrome) or asymptomatic MS. How many patients with RIS would want to undergo continuous immunosuppressive or immunomodulatory therapy?
Cheap generic versions of oral cladribine will also allow investigators to do interesting induction-maintenance and other trials. It could also form the base of the pyramid for treating smouldering MS. There are also several unique populations of pwMS where oral cladribine addresses specific issues, such as derisking immunosuppressive DMTs in older patients, patients with prior cancers, those planning pregnancy, people with advanced MS to protect upper limb and hand function and pwMS who want to receive vaccinations. The elephant in the room is the potential for an MS cure. A significant proportion of patients treated early with cladribine go into long-term remission. I am convinced that a proportion of these people will be shown to have been cured of having MS. That, to me, is the most exciting aspect of the class of immune reconstitution therapies in general.
Please note that I am one of the most enthusiastic MSologists when it comes to the advantages of cladribine as a treatment for MS. You should keep in mind that I may be biased, as I was the principal investigator on the Phase 3 CLARITY and CLARITY-EXTENSION studies. So, you can take my opinion seriously or dismiss it as conflicted, but before making a decision either way, please consider cladribine as a cheap generic, and not as a high-cost DMT.
Please refer to my more detailed MS-Selfie Newsletter (September 20, 2023) for additional information on cladribine.
Fenebrutinib
One of the most significant unmet needs in treating MS is going beyond focal inflammation (relapses and MRI activity) as a treatment target in MS to target smouldering disease. This does not mean that focal inflammation, which causes relapses and focal MRI activity, is not important. Relapse-associated worsening (RAW) contributes about 10-20% of disability events in contemporary clinical trials. The remainder of the disability events are due to PIRA (progression independent of relapse activity). This is why we need CNS-penetrant DMTs to tackle the pathological processes driving smouldering MS.
Tolebrutinib, a second-generation BTK inhibitor (BTKi), will be the first licensed drug to target smouldering disease. Tolebrutinib is CNS-penetrant and has been shown to have additional effects beyond those achieved with a potent anti-inflammatory DMT, such as ocrelizumab. However, despite its potential to reduce PIRA, it is not that effective at suppressing relapses and focal MRI activity. In the Phase 3 relapsing trials, it was not superior to teriflunomide in terms of relapse suppression and had a modest impact on the development of new T2 lesions. In comparison, it is the first DMT to demonstrate a modest yet clear reduction in PIRA events in individuals with more advanced non-relapsing SPMS.
Fenebrutinib is another BTKi with CNS penetration. It is superior to tolebrutinib in suppressing focal inflammation (relapses and MRI activity) and has a more profound effect on peripheral B-cell counts. The phase 2 extension results have recently been presented at the CMSC meeting (see below). Therefore, there is a good chance that Fenebrutinib will be superior to teriflunomide in the Phase 3 trials currently testing these agents head-to-head. The one caveat is that the event rate with relapses is very low in contemporary trials, so let's hope there are enough events or relapses in the trials to answer this question.
More importantly, are the CNS effects of fenebrutinib sufficient? Suppose fenebrutinib is as effective as tolebrutinib in the CNS. In that case, it will be superior as it will be better at suppressing RAW (relapse-associated worsening) and equivalent at reducing SAW (smouldering-associated worsening). This is why the trial of fenebrutinib for PPMS is so essential, as it is being compared to ocrelizumab and not a placebo. So if fenebrutinib is shown to be superior to ocrelizumab in reducing disability worsening in PPMS, it will become the go-to drug to treat MS. If both the relapsing and primary progressive fenebrutinib trials are positive, fenebrutinib will get a broad license to treat MS.
What distinguishes fenebrutinib from tolebrutinib is its pharmacology. It is a non-convalent inhibitor that has a longer half-life and is more potent at inhibiting BTK. How this plays out in the CNS on smouldering MS is an unanswered question, but we will know the results within the next 12 months.
I am not sure the broader MS community has realised how important the results of the fenebrutinib versus ocrelizumab PPMS trial is for the MS community. Of interest to me is that the BTKi’s are also anti-EBV agents targeting latent EBV infection. This is why I am so confident that the class of BTKi’s will be the real game-changers for treating MS, and I suspect other EBV-related autoimmune diseases.
EBV vaccines and antivirals to treat IM
As you know, I have been proposing two MS preventive strategies. One is an EBV vaccine to prevent infectious mononucleosis, and the second is antivirals to treat IM. Based on epidemiological grounds, I believe both of these strategies will have a significant impact on the global incidence of MS. For more information on this topic, please watch my recent talk, which I gave at the Nobel Symposium in Stockholm, or you can download my slides.
Please feel free to disagree with me. I am sure a lot of you have a different perspective from me on what will move the dial in the next 10-20 years when it comes to the treatment of MS.
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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 experience any problems, please consult your healthcare professional, who will be able to assist you.
Email response:
As a 25+ MS patient mainly affected by spinal cord lesions, now considered Secondary MS patient, due to walking difficulties after a huge c3 lesion that affected both my legs and slowly affecting my arms, I urge you to start puting NVG 291 into the picture because for some of us it appears to be the only regeneration therapy with strong science behind and efficacy on the horizon. I have done Mavenclad 4th year now with no new lesions, and I started valacyclovir. For me and many others, NVG 291 would be a life-changing option that we believe should be offered to us.
all these things are very exciting. Anything that could stop smouldering MS would be fantastic I do worry about whether my children will end up with MS so EBV vaccines/treatment would be great. Hopefully in years to come MS will be a disease that is consigned to the past.