Switching from one interferon to another may be beneficial

S

I was at a meeting, albeit stuck in my bedroon for a virtual meeting. The talk was about therapeutics for progressive MS. I was making the point for treating early and effectively to save the nervous reserve and that standard immunomodulators should be on the base of a pyramid below protective and repair agents…..I believe this is based on biology, but recognise this has not been an approach and suspect that economics are at play, as using two expensive agents may be problematic.

One question was whether one should avoid this approach because of safety issues as exposing people with progression to a potent drugs could have have consequences.

I accept this concern but countered it by saying people with progessive MS are willing to try HSCT and surely it has to be the choice of an informed person with disease to make the choices as they must live with the consequences of their choice, whether it is control of their disease, partial control of their disease or maybe side-effects.

As you know I am not a fan of the CRAB drugs but I am not a neuro and dont have to live with such actions. However, to move from one ineffective CRAB to another in this day and age……em. To go for three ineffective/potentially treatments, when time is brain…em em

But by 2015 there were quite a few alternatives. So 50% fail the first treatment and 50% fail the switch and as a consquence they progress……so I wonder how safe is this
Baumhefner RW, Leng M
Standard Dose Weekly Intramuscular Beta Interferon-1a May Be Inadequate for Some Patients with Multiple Sclerosis: A 19-Year Clinical Experience Using Twice a Week Dosage..Neurol Ther. 2022 Jul 7. doi: 10.1007/s40120-022-00377-1.

Introduction: Results from several clinical trials suggest there is a dose-response effect for beta interferon-1a (INFβ1a) in multiple sclerosis (MS).

Methods: Our objective was to confirm these results through a retrospective analysis of patients with MS who had breakthrough disease (BD) on intramuscular (IM) INFβ1a (Avonex®) once per week (QW), who were switched to twice per week (BIW) IM INFβ1a between 1995 and 2015. The primary outcome measure was no further BD for at least 24 months. A secondary outcome measure was decrease in mean percentage of disease activity over time. BD was defined as continued relapses, new T2 or enhanced lesions on magnetic resonance imaging (MRI) of the brain, or worsening of the Expanded Disability Status Scale (EDSS) or the neurological examination.

Results: Among 92 patients on QW IM INFβ1a, 53 patients with BD were switched to BIW IM INFβ1a. Of these 53 patients, 44 had adequate follow-up for at least 2 years. Twenty-three of these had no further BD for 24 months or more (range 24-192 months). Beta interferon neutralizing antibody testing was negative in 19 patients. An intent-to-treat analysis of the uncensored data from 52 switched patients also supported a treatment benefit.

Conclusion: For patients with MS having breakthrough disease on QW INFβ1a, switching to more frequently administered INFβ may be an option. Advantages to using IM INFβ1a for this include no skin reactions and a lower incidence of neutralizing antibodies. Further pragmatic, observational, larger-group studies comparing treatment with Avonex® and higher dosed IM INFβ1a, such as the recently FDA-approved IM peginterferon beta-1a, may be indicated.

Krämer J, Wiendl H. What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us? Neurotherapeutics. 2022 Jul 6. doi: 10.1007/s13311-022-01246-3.

In the past two decades, monoclonal antibodies (mAbs) have revolutionized the treatment of multiple sclerosis (MS). However, a remarkable number of mAbs failed due to negative study results were withdrawn because of unexpected serious adverse events (SAEs) or due to studies being halted for other reasons. While trials with positive outcomes are usually published in prestigious journals, negative trials are merely published as abstracts or not at all. This review summarizes MS mAbs that have either failed in phase II-III trials, have been interrupted for various reasons, or withdrawn from the market since 2015. The main conclusions that can be drawn from these ‘negative’ experiences are as follows. mAbs that have been proven to be safe in other autoimmune conditions, will not have the same safety profile in MS due to immunopathogenetic differences in these diseases (e.g., daclizumab). Identification of SAEs in clinical trials is difficult highlighting the importance of phase IV studies. Memory B cells are central players in MS immunopathogenesis (e.g., tabalumab). The pathophysiological mechanisms of disease progression are independent of leukocyte ‘outside-in’ traffic which drives relapses in MS. Therefore, therapies for progressive MS must be able to sufficiently cross the blood-brain barrier. Sufficiently long trial duration and multicomponent outcome measures are important for clinical studies in progressive MS. The success of trials on remyelination-promoting therapies mainly depends on the sufficient high dose of mAb, the optimal readout for ‘proof of concept’, time of treatment initiation, and appropriate selection of patients. Failed strategies are highly important to better understand assumed immunopathophysiological mechanisms and optimizing future trial designs.

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