PolyBio Spring 2025 Symposium

[Jonathan Edwards]

Lots of T-cell work that seems to indicate T cells responding to various viral antigens (quite neat methods) and becoming more activated in Long Covid compared to controls.

I suspect that is because that is what everyone is looking for. I can't make much of the figures shown. Persistent clonal expansions of T cells might Mae sense but I doubt these sorts of techniques will ever tell us anything definitive about what is driving the problem and how to deal with it.

 

[Stuart79]

Are there any relevant publications on Pemgarda?

No studies, which is shocking to me. It’s approved under EUA for a very limited set of immune deficiencies. EUA doesn’t allow it to be prescribed off label. It’s also around 10k per infusion. So, it’s very difficult to go for long covid. With that said, I’ve collected a dozen or so patient reports from Reddit and X. Some long covid clinics are using to successfully as well. Based on what’s out there, the response rate looks to be close to 50%.

I have LC, which is relatively severe. I’ve also had two post-viral illness from which previously recovered over a period of years. Interestingly, LC symptoms are quite different from the first two illnesses (which were similar to one another). My symptoms are generally similar to ME/CFS, but I do not get PEM. All of this leads me to wonder why LC is different and if it really could be driven by the spike fragments and/or ACE2 downregulation. If mAbs work, it almost has to be some form of viral or viral fragment persistence.

I’m getting a Pemgarda infusion in a few weeks and will report back on my experience. I know N1s can be misleading, but I’m cautiously optimistic. I’ve never experienced a placebo effect from anything I’ve tried. I find it difficult to believe that all of the N1s are placebo given how disabling these symptoms can be. Likewise, I’ve seen nothing else that has produced these types of anecdotes, which is why I am reminded of the failed Rituximab trial and the recent hopeful data on Dara.

The maker of Pemgarda stated that the FDA required a huge dose of antibodies because it couldn’t work out the minimum threshold. There isn’t much information available about AER-002 as it never got close to approval before the company that makes it folded. I’m curious how the antibodies dosages compare, and whether the issue maybe that AER-002 was under dosed.

Finally, there were 24 patients who received AER-002. I’ve found 4 of them on social media. 3/4 improved greatly and then relapsed around 1-2 months. Perhaps it’s wishful thinking on m part, but it sure feels like there is more to the story.

 

[Stuart79]

After doing a bit of digging into the AER-002 trial documents, there are reasons to believe the trial design, as opposed to mAbs generally, may be the problem. Here is what I found:

1. ⁠The AER-002 trial used a 1,200 mg dosage, which is about 1/4 of the Pemgarda dose, and then looked at changes from baseline at 90 days after infusion.

2. ⁠I found 4 trial participants on social media who received the AER-002. 3 responded, but all relapsed at 1-2 months. One was desperately searching for another dose due to the level of improvement. Obviously this sample size is too small to meaningfully extrapolate from, but it generally aligns with the response rates reported by Klimas in the Florida case studies (about 75%) and Pemgarda anecdotes on social media (>50%).

3. ⁠The Pemgarda dosage is almost 4x the AER-002 dosage (1,200 mg v. 4,500 mg).

So, it appears there were short term responders, but they relapsed before the 90 days. So, early favorable responses are likely not picked up since the endpoints occurred to after relapses.

Second, the dose was likely too low. Pemgarda relapses have been reported as well, but typically at 3 months or more instead of 1-2 months. This might align with the lower dose AER-002 falling below the threshold for effectiveness sooner than the larger Pemgarda dose. The dose might also explain the higher rate of relapse (i.e. incomplete clearance before the half life kicked in).

 

[rapidboson]

Dose means nothing without pk/pd data. If one or the other has a higher affinity, is more potent, bioavailable (would not expect this to be different with sc and iv) or what not, the doses will be different.

 

[Stuart79]

Dose means nothing without pk/pd data. If one or the other has a higher affinity, is more potent, bioavailable (would not expect this to be different with sc and iv) or what not, the doses will be different.

Thanks. Here is what I found on PK data. Does this tell us anything?

 

[rapidboson]

We'd also need pd data - and from pk affinity to spike, maybe something like potency for ADCC if they retain effector functions (and if ADCC would be deemed necessary for post COVID treatment).

 

[Jonathan Edwards]

We'd also need pd data

And if you want pharmacodynamics you need an effect read out, which without being able to measure any antigen doesn't look to be on the cards.

I sense whistling in the wind here.

 

[rapidboson]

And if you want pharmacodynamics you need an effect read out, which without being able to measure any antigen doesn't look to be on the cards.

I sense whistling in the wind here.

For sure.

I guess to compare dosing purely (and we assume the main moa is binding to spike) pk would suffice actually. We wouldn't know if that reflects any situation in vivo though - so doubtful how helpful this is.

 

[forestglip]

Now on Youtube:

00:00 Amy Proal–An overview of PolyBio’s complex chronic illness research & clinical trials program
10:35 Resia Pretorius–Heterogenous fibrinaloid complexes (microclots): characterizing different phenotypes
19:46 Mark Painter–T cells as biosensors of viral persistence in Long COVID
32:05 David Price–Infectious, immune, and microbiome signals in the long COVID lung
44:39 Johan Van Wyenburgh–A real-world prospective study of antiviral and anticoagulant use in Long COVID

56:24 Q&A (Painter--What are the current pathways to get the Wherry Lab's T cell biosensor technology into the clinic?)
59:16 Michael Peluso–SARS-CoV-2 monoclonal antibodies in long COVID: Key findings and future directions
1:14:52 Nadia Roan—Phenotypic features of CD8+ T cells specific for SARS-CoV-2 and herpesviruses in people with and without Long COVID
1:26:47 Lael Yonker–Long COVID gut barrier permeability and neutrophil/clotting/spike interactions
1:40:58 Chris Dupont–An update on the Tissue Analysis Pipeline: a focus on craniocervical ligament

1:46:50 Gene Tan–Deep Characterization of antiviral immune responses and long COVID pathogenesis
1:58:01 Marcelo Freire–Analysis of small fiber neuropathy punch biopsy and other tissue samples via spatial transcriptomics
2:10:17 Michael VanElzakker–A study of the neuroimmune basis of brainfog symptoms
2:21:54 Francis Eun Lee–Use of MENSA to identify an immune snapshot for SARS-CoV-2 persistence and herpesvirus reactivation in Long COVID
2:35:08 Timothy Henrich–Molecular imaging in long COVID, plus tissue biopsy project updates

2:46:15 Huaitao Cheng–Uncovering mucosal immune dysregulation in long COVID patients with gastrointestinal symptoms
2:55:32 Akiko Iwasaki–Uncovering mucosal immune dysregulation in long COVID patients with gastrointestinal symptom
3:05:19 Victoria Cortes Bastos–Cerebrospinal fluid and plasma phenotyping reveals distinct subgroups of ME/CFS
3:15:49 Mario Murakami–Ultrahigh resolution neuroimaging shows neuroimmune sensitization across infection-associated chronic conditions
3:25:32 Sara Cherry–Long COVID: Defining viral RNA reservoirs in the gastrointestinal tract

3:35:08 Saurabh Mehandru–Investigating the role of SARS-CoV-2 gastrointestinal tract persistence in Long COVID pathogenesis
3:48:40 Q&A (VanElzkker–What are your thoughts on treatment for vagus nerve neuroimmune signalling? And which medications have vagus nerve innervation activity?)
3:51:26 Esen Sefik–A humanized mouse model of SARS-COV-2 RNA persistence
4:01:34 Melanie Walker–Characterization of the vagus nerve microbiome/virome
4:12:41 Steven Deeks–The Reservoir Assay Validation and Evaluation Network (RAVEN) as a model to inform SARS-CoV-2 reservoir diagnostics

4:22:15 Shannon Delaney–The Reservoir Assay Validation and Evaluation Network (RAVEN) as a model to inform SARS-CoV-2 reservoir diagnostics
4:33:04 Shannon Stott–Microfluidics capture of SARS-CoV-2 particles in long COVID blood
4:44:06 Q & A (Proal–What efforts are being done to address Post-Vaccine symptoms for COVID-19?; Differentiating Spike protein from COVID infection versus vaccine; Delaney–Medical Diagnostics lab for Bartonella testing; Walker–Can bacteria infect the vagus nerve?)
4:50:01 Daniel Izquierdo Garcia–Evaluation of tissue fibrin accumulation in long COVID via PET imaging & blood analysis
5:01:33 David Putrino–Update overview of Long COVID, Lyme+ and other CoRE clinical trials

5:17:13 Silvia Lage–Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection
5:27:15 Zian Tseng–The COVID POST SCD (POstmortem Systematic invesTigation of Sudden Cardiac Death) Study
5:39:52 Benjamin Readhead–Validation of a Cytomegalovirus-based biomarker for Alzheimer's disease
5:52:53 Max Qian –Long COVID endotype identification
6:06:18 Daniel Chertow–Overview of new NIH long COVID tissue biopsy trial
6:16:50 Amy Proal discusses NIH trial participation, thank-you to IACI community

 

[Stuart79]

Dose means nothing without pk/pd data. If one or the other has a higher affinity, is more potent, bioavailable (would not expect this to be different with sc and iv) or what not, the doses will be different.

Thanks for taking a look. All of this is well beyond my understanding. For what it’s worth, I put the PK tables into AI. After adjusting to 1,200mg v. 4,500mg doses, AI says Pemgarda is roughly double the dose, but has a shorter half life. So, Pemgarda starts off at double, but they are roughly equally at 90 days after infusion.

Both mAbs are primarily aimed at neutralizing, but maintain some degree of ADCC. Unfortunately, there doesn’t seem to be any ADCC data available.

I have LC w/o PEM and am getting a Pemgarda infusion in a few weeks. I’ll report back on how it goes.

 

[SNT Gatchaman]

59:16 Michael Peluso–SARS-CoV-2 monoclonal antibodies in long COVID: Key findings and future directions

Study of a monoclonal antibody to ancestral and early variant SARS-CoV-2, with inclusion criteria being LC 2 years out from Covid contracted prior to Aug 2022. 24 patients got AER002 and 12 patients got placebo.

No significant difference in primary endpoint (PROMIS-29) and all secondary outcome measures. The graphs overlap: both subjective questionnaires and objective measures including 6MWT and active stand test.

Compare and contrast with the usual "promising" BPS tripe. 1) Appears demonstrably and convincingly ineffective compared with placebo. 2) There does not appear to have been any biasing effect on patient reported outcomes in this study (ie no-one was trying to convince the patients to report on questionnaires being better than they were). The patients were of course blinded.