On Feb 29th, 2024 fara gathered the leading FA researchers in the country, brought them to Brisbane and held a forum at UQCCR for them to tell us about their work. I was lucky enough to attend those presentations, but having rewatched them, I realise that I missed much that was presented at the time. Fortunately fara organised for them all to be recorded and you can view them in your own time at https://www.fara.org.au/news/watch-all-presentations-from-our-recent-patient-and-families-information-forum. Alternatively, you can read my summaries of what was presented (two previously, another below and a few more in coming weeks); or check out both video and write-up and let me know if you think I’ve done a good job!

I’ve previously written a note summarising presentations from Ian Harding, Mirella Dottori, John O’Sullivan, Monique Bueno-Alves and Lucas Tocchini. you can find them HERE and HERE.

The next presenters were Liz Soragni, Director of Research at FARA in the USA and Martin Delatycki from MCRI in Melbourne. Now it’s obvious that we should be thankful that FA is such a rare condition because few people are afflicted with it. But another reason is that it’s not only possible but essential for the global research community to be well networked. We simply wouldn’t have sufficient budget for the same thing to be researched in parallel by different groups. Instead, research grants and the research pipeline is managed through a single network. And that network is coordinated through FARA in the USA. Trials with an Australian link are usually coordinated via the MCRI.

There’s a regularly updated chart online that shows the most important drug development projects and their development stage available here.

Liz explained the structure of that chart against what we know of how FA works and how its effects impact on an FAer. And the chart shows the drugs in development according to a timeline from first ideation through to “available to patients”, with colour coding on that chart as follows:

• FA symptoms

o   Drugs and treatments to aid management of symptoms like scoliosis, diabetes, heart disease

o   (those symptoms are caused by…)

• Dysfunction at the broad cellular level

o   Drugs to address cellular degeneration caused by low energy

o   (that dysfunction is caused by…)

• Impaired mitochondrial function (mitochondria are the powerpack inside each cell)

o   Drugs to boost mitochondrial defences, for example against oxidative stress

o   (that functional impairment is a result of…)

• Frataxin deficiency (Frataxin  helps the assembly of the machinery that produces energy)

o   Drugs to enhance the body’s production of Frataxin

o   (that deficiency is a result of…)

• The genetic issue that defines FA

o   Therapy to edit an FAer’s genes, reducing “GAA” repeats.

And Liz gave specific updates on some of those drug or treatment developments as follows:

Skyclarys (previously Omaveloxolone and RTA408):

• Approved by the FDA for sale to US patients on 29th Feb 2023. As noted elsewhere Biogen is currently working on getting equivalent approval for Australia.

Nomlabofusp (previously CTI-1601) (here’s hoping that’s just a working name and it’ll be given a catchier one after it’s qualified through research!), a drug to replace Frataxin in cells and even in mitochondria of cells:

• Positive results recently published and shared in a company update (and important findings noted) after phase 1 and phase 2 clinical trials – with daily and every other day dosing:

o   Frataxin levels in skin cells were up to 45% of the frataxin level in healthy individuals (remember that FA carriers are asymptomatic and have a little over 50% of the frataxin levels of healthy individuals)

o   Increase in Frataxin levels wasn’t so pronounced when dosage reduced from daily.

o   Increase in Frataxin levels wasn’t so pronounced in buccal cells (from inside the cheek) – postulated that’s because those cells divide more rapidly, unlike cells in organs most affected by FA (brain, heart etc.)

o   No major safety concerns

• Further trials planned (open label extension, paediatric study, global trial) aiming for special FDA submission (called BLA, based on demonstration of effect on biomarker levels (Frataxin) rather than mFARS measures) 2nd half of 2025.

Vatiquinone (previously PTC743), a drug that helps remove harmful oxygen molecules from the mitochondria even when Frataxin levels are low:

• Disappointing results published in May 2023. Benefit was demonstrated but key benchmarks weren’t met to a statistically significant level.

• PTC (the drug development company) will have further discussions with the FDA (US regulator) to understand if a path to approval can be found giving consideration to a range of factors (no safe alternative exists for young FAers, some portions of the mFARS do show a stastistical significant improvement, COVID restrictions hampered original trial etc.)

DT-216, a drug that helps cells overcome problems caused by GAA repeats to produce Frataxin normally:

• Promising results published in August 2023 after Phase 1 clinical trial. Frataxin level increased in muscle, although it seems to require at least weekly doses to be sustained.

• But it couldn’t proceed further as there were important adverse effects in the trial. (That’s what a phase 1 clinical trial is for). It was identified that these were due to the “carrier” (excipient) rather than the drug itself, so a new phase 1 clinical trial with a new excipient (but the same drug) will be conducted this year (2024).

Gene therapy to deliver the frataxin gene to the heart, so heart cells can produce Frataxin and combat cardiomyopathy:

• Reminder – gene therapy can’t be reversed, and the dosage needs to be right first time since once a dose is administered, the patient’s immune system will recognise the (AAV) delivery mechanism and neutralise it if it’s administered a second time.

o   So this trial is specific: it’s an “open label” trial - everyone’s fully aware what’s being administered, very limited number of trial participants, and very close follow-up (parameters measured every fortnight for first year, and follow-up will continue for five years after administration of the therapy).

• Positive results in first reported result: increased Frataxin production 3 months after dosage in one participant, reduced heart hypertrophy (cardiomyopathy)  and reduced Troponin levels (an indicator of heart damage) at 6 months after dosage in two other participants.

• Lexeo are developing plans to extend this trial outside USA.

Since Professor Martin Delatycki serves a role as liaison between FA research projects in Australia and elsewhere, much of what he’d have updated was covered already by Liz Soragni. He did though give updates from a few other trials that he and his team have been involved with here in Australia.

Resveratrol, a compound intended to boost Frataxin levels and have an antioxidative effect and consequently enhance mitochondrial function:

• Final results from this trial will be documented shortly. Suffice to say that while I’ll continue to enjoy red wine, I won’t expect any change in my FA symptoms.

Intensive physiotherapy/rehab (tested on patients with a range of ataxias, not just FA):

• The results from this trial have been formalised to be published shortly and a link will be shared when that’s achieved.

• In the meantime, it’s been said before that “if exercise was a pill, everyone would take it”. Well get (stay) active FAers!

MIB-626, a version of nicotinamide intended to have a protective effect on mitochondria especially in heart cells:

• Melbourne team involved in safety trial, no results yet.

Gene therapy to correct GAA repeats on an FAer’s DNA:

• MCRI team involved in development of protocols for this testing when it will be done in Australia.

 This is the third of a number of these write-ups. Please comment on Facebook or via Contact Us if you find them useful and have comments about any of the research underway. Look out for the next one in another few weeks.