The Efgartigimod (Vygart) Phase 2 RCT, first discussed here on this forum, for Post-COVID-19 POTS, which also has an open label extension arm, has finished enrolment and will have results in the next few months (possibly by June). Efgartigimod is a novel therapeutic and acts as an FcRn inhibitor (IgG1–derived antibody Fc fragment). It was recently approved for the treatment of Generalised Myasthenia Gravis as well as for the treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). It effectively reduces IgG levels 1,2,3. As such it’s one of the few drugs where both negative and positive trial results can tell you something about the pathogenesis of a disease based on the trial (and seemingly this was already the case in CIDP). As such I thought it would be interesting to discuss what this trial data could possibly tell us about Post-Covid POTS and possibly even ME. Of course the majority of this discussion would heavily depend on the trial data itself, is further complicated by the size of the trial (53 participants) as well as the rather very vague criteria of “Post-Covid POTS” and the unknown relationship between this and ME and until then everything remains highly speculative. However, it might still be valuable do discuss possible implications of this drug such as: What could negative trial results tell us about an autoimmune hypothesis of POTS? Are there plausible mechanisms by which Efgartigimod could work in ME, even if RTX doesn’t work? How should short term data vs long-term data be interpreted? Are there antibodies that an RTX treatment addresses that Efgartigimod doesn’t address and vice versa? Alongside the above Efgartigimod trials, Phase 2 Proof-of-concept studies for the following conditions will have their readouts in 2024: Lupus Nephritis Sjogren’s Myositis (IMNM, ASyS, DM) (this is actually a Phase 2/3 trial with 240 participants) Furthermore the following Efgartigimod trials have also been launched/will be launched in 2024: Phase 3 trial for Graves Ophthalmology Phase 2 Proof of concept study for Guillain-Barré Syndrome Efgartigimod is currently in review as a treatment for Primary Immune Thrombocytopenia (ITP) in Japan after a phase 3 study was conducted 2 years ago (4,5,6). Efgartigimod is well placed in a competitive market (and could even be seen as a competitior to BC007) and extremely similar biologics exist that are currently undergoing different clinical trials. The direct competitors are Batoclimab (by IVMT-Roivant) and Nipocalimab (Johnson & Johnson). Batoclimab is currently undergoing Phase 2 studies for Graves Disease and CIDP, as well as Phase 3 studies for Graves Ophthalmology (see also 7) and Generalized Myasthenia Gravis, whilst Nipoclimab has undergone a Phase 3 trial for Generalized Myasthenia Gravis and a Phase 2 trial for Sjörgens, supposedly there have also been positive results in Rheumatic Arthritis and haemolytic disease of the foetus and newborn https://www.clinicaltrialsarena.com/news/jj-touts-success-of-nipocalimab-in-two-rare-disease-trials/. When looking at all the trials that have been conducted and are planned with Efgartigimod (and other anti-FcRn drugs that degrade IgG) the Post-Covid POTS trial sticks out like a sore thumb. It is the only trial for a condition that hasn’t been shown to be an autoimmune disease or an autoimmune-like diseases and it is also the only trial for a condition where Rituximab and/or steroids haven’t shown to have efficacy. Argenx has stated that the rational for the trial is the possible role of Anti-adrenergic receptor AutoAbs in POTS. In fact none other than Artur Fedorowski is involved in this trial after he was approach by Argenx to contribute his POTS knowledge to the trial (more details are mentioned here). Some of his work on POTS includes some work on Anti-adrenergic receptor AutoAbs but also includes the study showing that the very questionable with Celltrend is not be able to differentiate between POTS and healthy controls. The second rational for their trial is efficacy of IVIG/PLEX in POTS, that as well is questionable and a recent IVIG trial found no effects for POTS. Compared to many of the other Post-Covid trials this trial appears to be somewhat half-decently run (POTS assessment via measuring supine and standing heart rate, evaluation of compass score during treatment, evaluation of Malmö POTS symptom score, PROMIS fatigue scale and also the PROMIS cognitive function scale and of course pharmacodynamics and pharmacokinetics and immunogenicity of efgartigimod), or at least has stricter recruitment criteria than some other trials (POTS assessment, PCR confirmed infection, Compass score of at least 35 points, i.e. moderate to severe dysautonomia, BMI below 35 and a few more detailed criteria). Perhaps the trial should be more accurately viewed as a complete shot in the dark by Argenx, than anything concrete, with the hopes of being able to expand their product to a massive market of patients. A market that surpasses anything that their other current trials could deliver, as they estimate the US prevalence numbers of Post-Covid POTS to be far higher (at 500 000) than for all of their above trials combined (it’s still interesting though that they have prioritised Post-Covid POTS rather than something like Multiple Sclerosis which has a similar patient population in the US or even Rheumatic Arthritis which affects a larger population and for which trials are far easier to conduct). It’s probably also important to mention some conditions in which Efgartigimod underwent large studies, but failed to show efficacy. As far as I could find out this currently only applies to: Pemphigus (Vulgaris or Foliaceus) (see also 8).
Yes, Argenx believes it's a multibillion dollar drug, which currently also still has to managed by a single injection (they have a pre-filled syringe that is undergoing clinical trials and are also working on an autoinjector pen), so that will also be more complicated than some other treatments. They already said they had a revenue of $1.2B for gMG in 2023 which "only" affects 65 000 Americans. Seems like they initially only targeted conditions where essentially no treatment was available, but at least Graves would be a condition where they would have to show they are superior to cheaper products (admittedly Graves Ophtomology is what Argenx is targeting and there the market is far less saturated). Might be interesting to see whether some pwME can get it prescribed in the future by their insurance company for a comorbid autoimmune condition that isn't responsive to the usual treatment.
Not sure where to post this: list of clinical trials for LC and ME: https://crunchme.notion.site/4d00e39f9f874a4c85cb9046149aeba7?v=2c3284eb773a403e817db9598480a768
IIRC fc receptors are also on other immune cells such as macropahges and dendritic cells, i am expecting this to go to phase 3 but it will be unlikely it will prove the aab theory
Sad news: PC-POTS Update Results from the Phase 2 ALPHA study of efgartigimod in post-COVID-19-mediated postural orthostatic tachycardia syndrome (PC-POTS) show that treated patients had no clinically meaningful improvement compared to placebo on the total Malmö POTS symptom (MaPS) score and COMPASS31. The observed safety and tolerability profile of efgartigimod in the ALPHA study was consistent with previous clinical trials. argenx will not move forward with development in PC-POTS and plans to prioritize resources to the nearly 50 active clinical trials in its expanding pipeline. argenx to unveil its ‘Vision 2030: Taking Breakthrough (globenewswire.com)
damn shame, another one bites the dust. heard the normal "life changing" stories from a few on the trial, they dont know if placebo and they are contacting them. if im allowed to report on that i will let everyone know
Two high profile trials for long covid failed in the space of one week. I think it's weird companies are launching these expensive clinical trials without doing any preclinical work to figure out what mechanism needs to be targeted. We have no idea what's wrong with these patients or what POTS even is and you have some companies doing expensive N=150 trials with some random drug without a plausible pathophysiological mechanism. It's the equivalent of throwing shit at the wall and hoping something sticks. So far, nothing is sticking.
Yes, but if no shit is thrown at the wall, there is zero chance that anything will stick. Yes, I do advocate for throwing shit at the wall, especially when trial costs are borne by pharma companies.
