Trial of Long Covid treatment - AXA1125 from Axcella Therapeutics, 2021

To state the obvious - my knowledge is very limited. Would you expect to see changes in mitochondria i.e. visible on an electron microscope? Also, Ron seems to be interested in proteins which transport manganese into the cell & into the mitochondria - would you expect changes in mitochondria if these enzymes weren't working properly?

 

Thanks -my question is why they didn't chase up/replicate what seems to be an important finding?

Yea very severe patients are so ill it would appear that they won't survive long - Maureen Hanson showed a slide of Whitney and said this is how severe patients live for years - patients with AIDS are only this ill near the end of their lives.

Way back in the day (2015?), in a webinar, Chris Armstrong suggested that the changes in metabolism changed the production of stomach acid (increased?) and this created a non-virtuous loop - stable but -ve.

 

@Midnattsol

What if the enzymes involved in making the conversion to energy are gone or disabled somehow? Is that possible?

Isn't it important for a cell to carefully match the activity of its fuel breakdown (pathways to its energy needs) at a given moment?

I have no clue what I'm taking about, but I seem to recall someone in the biochemical field telling me many years ago that sometimes some enzymes are just . . . not there anymore.

 

Axcella previews long Covid registrational trial plans for AXA1125

"Earlier this morning, Axcella announced results for a 41-patient Phase IIa trial of AXA1125 in long Covid (NCT05152849). The trial did not meet its primary endpoint of phosphocreatine (PCr) recovery rate following moderate exercise, but it achieved secondary endpoints measuring mental and physical fatigue. The company’s trading volume increased by a little more than 13 times compared to yesterday, before market close.

(...)

In the previous Phase IIa study, Axcella chose PCr recovery rate as a primary endpoint to assess mitochondrial function as a possible biomarker for fatigue, CMO Margaret Koziel explains. However, the upcoming trial will focus on clinically meaningful outcomes of fatigue based on positive results along these measures in the Phase IIa study, she notes.

As a primary endpoint, the forthcoming AXA1125 trial will likely use a patient-reported outcome (PRO) measure assessing fatigue, Koziel says. The Phase IIa trial reported statistically significant improvements on the Chalder Fatigue Questionnaire (CFQ-11), a patient-reported assessment of fatigue commonly used in chronic fatigue syndrome.

In addition, the upcoming study will likely include an endpoint measuring physical function, Koziel adds. The Phase IIa trial assessed physical function using a secondary endpoint of the 6 Minute Walk Test (6MWT), which measures the distance a person can walk in six minutes.


However, the registrational trial will not necessarily use the 6MWT, instead potentially using an outcome that holistically assesses a patient’s daily fatigue, Koziel explains. For instance, Axcella could consider monitoring activity digitally, using an endpoint such as change in average activity over seven-day periods, she notes.

Because there are no standardised long Covid outcome measures, Axcella will rely on ongoing regulatory conversations to finalize its exact endpoint choices, Hinshaw says. “We believe we can start up the trial quickly once we have regulatory feedback, implement [the feedback], and recruit rapidly given the high unmet need and interest in long Covid,” he says."

 

Eric Topol is not impressed:

 

Charles Shepherd's comments from their linked article

“Myself and Dr Karl Morten, who receives funding from the MEA Ramsay Research Fund to carry out research into mitochondrial dysfunction in ME/CFS, have been following this Oxford-based clinical trial very closely.

“As the trial is taking place in Oxford, where Karl is also based, we have been in contact with Dr Betty Raman (see below) to discuss the possibility of extending the trial to people with ME/CFS – where debilitating physical and mental fatigue is a key concern and the role of mitochondrial dysfunction and defects in cellular energy production are well documented.

“The results from this small clinical trial obviously have to be regarded with caution at this stage. Only 14% of patients were shown to have fatigue return to normal levels and it failed to demonstrate restoration of mitochondrial function. Further work involving larger numbers of people with Long Covid needs to be carried out in order to establish whether this intervention can really improve functional ability.

“If this can be determined by additional research, the MEA Ramsay Research Fund would welcome a grant application to repeat the trial in people who have ME/CFS.”

 

A reminder of the forum's submission on issues with the Chalder Fatigue Questionnaire, S4ME: Submission to the public review on common data elements for ME/CFS: Problems with the Chalder Fatigue Questionnaire

 

This implies that the companies shares were more popular as a result of the news, and stock prices therefore increased, but doesn't say it.

It could equally mean that people were desperate to offload their shares in the company and as a consequence the share price fell through the floor.

Why else would they use the term 'trading volume' rather than 'share price' ?

 

The AXA1125 group achieved a reduction of about four points on the Chalder fatigue scale relatively to the control group; in comparison, three points was considered to be the minimal clinically important difference in GETSET.

Given the small number of participants in both groups, the broad inclusion criterion per the trial registration (“fatigue-predominant PASC”) that does not discriminate severities adequately, and the natural fluctuations of the illness, I am very uncertain this result could be replicated.

 

Presentation slides are here. https://ir.axcellatx.com/events-and-presentations Also since the treatment is 70g! this is one study where the composition of the placebo is important—that’s 3/4 of a Quarter Pounder.

 

No, I think the 60g figure is likely correct—each stick pack was 6g so they probably had 10 packs per day. (One dose is 2-4 sticks and probably repeated throughout the day).

“The study products were packaged in dry powder stick packs. Each AXA1125 stick pack was composed of leucine 1.00 g, isoleucine 0.50 g, valine 0.50 g, arginine HCl 1.81 g, glutamine 2.00 g, and NAC 0.15 g (5.65-g free AA/stick pack), and each AXA1957 stick pack was composed of leucine 1.00 g, isoleucine 0.50 g, arginine HCl 1.61 g, glutamine 0.67 g, serine 2.50 g, carnitine 0.33 g, and NAC 0.43 g (6.76-g free AA/stick pack). Each dose (2–4 stick packs) was to be reconstituted as an orange-flavored suspension in 8 oz (∼240 mL) of water and administered 30 minutes before a meal. The initial dose was administered at the day 1 (baseline) visit.”

 

It was 60g - I did the trial and it was alot of powder!
It's really rubbish they are justifying carrying on from "statistically significant' results from the CFQ. Another crap fatigue trial based on the CFQ

 

It was interesting they were so surprised that the pCR rates were so high. I'm not sure what they thought the fatigue associated with Long Covid is like? But that's the problem of calling it fatigue - it downplays the whole body shutdown awfulness of it. I wish they would focas on that - it's a really interesting finding and needs looking at as it's potentially something tangible that patients can be assessed for. It might well link to severity too. Mine was 131 but my PESE/fatigue is full on. Instead we get the CFQ

 

https://g.co/finance/AXLA:NASDAQ

Up 18% today!