fara Patient Information Forum, Nov 2020, note 1 of 3

In previous years, I’ve picked out just a few highlights I’d learned at these info forums but that was mostly because I couldn’t make detailed notes while paying attention. This latest info forum was recorded so I’ve been able to watch it over again, and don’t have that excuse. This is the first of three notes to cover all the presentations. They’re still intended to be explanations, translations into normal FAer language, but this time I plan to try to cover what was covered in all the presentations, and even in some cases, expand on something referred to only in passing. So they’ll be more comprehensive than previously. I still recommend very strongly that you make time to see and hear the full presentations from the researchers themselves.

To view the presentations, click here. The passcode is Bbv2Nl=P (that’s a small letter L after the N).

The session opened with a summary from Sherelle Fyfe, CEO of fara Australia, of how and what fara does and what they’ve been up to in the past year. Rather than repeat that here, I’ll take this opportunity to recommend you visit fara‘s website (fara.org.au) where you can find that and much more. If you do nothing else, scroll to the bottom of the homepage where you can and download a copy of fara‘s annual report.

Separately Sherelle made the point that while every physician learns about FA in their training, there are probably fewer than 400 FAers in Australia so it’s very possible we’re the only live case any medical professional or allied health therapist will encounter. Often it’s as important for us to educate them on what works as vice versa. fara‘s keen to develop a directory of medical professionals and therapists who are familiar with FA so they can share knowledge with one another as appropriate. Please send a note to Sherelle (sherelle@fara.org.au) with contact details of any medical professionals or allied health therapists you work with who you believe understand FA.

Next up was Jen Farmer, CEO of FARA US. Jen made three key points, two of which she’s made before but are worth repeating:

  1. The success of FA research is directly related to how many FAers are in the Global Patient Registry. It helps with trial design, participant recruitment, everything. It was relaunched last year and you may need to sign up again. You can find it by clicking here.
  2. There’s a huge amount of FA research happening and different projects are at different stages towards getting approval for a treatment to be given to FAers. FARA keeps a Research Pipeline updated on its website which can be viewed by clicking here.

Her third point was to run through various research projects in a way I hadn’t seen before. I found it enthralling because it shows there are active research projects related to every step of where and how FA affects us.

As you can see from the image below, there are multiple target areas for researchers and companies who are looking to develop new drugs & potential treatments for FA. This image provides an overview of different types of treatment approaches. The orange boxes show the natural history of the disease, from the mutation in the gene through to FA symptoms.

How FA affects us:

Within every cell in your body (most recent count – about 30,000,000,000,000 of them!) there’s a copy of your whole genome, your complete set of DNA, the instruction book for you. Different genes on that genome are switched on or off depending on that cell’s type or its job, but the whole genome’s there. In an FAer, there is an error in FXN gene that causes a repeat (like if someone pressed a key on the keyboard too hard when typing up an instruction manual) and whereas the letters GAA (an example of a DNA sequence) might be repeated in that gene about 30 times in a non-FAer, they might be repeated 1,000 times in us FAers. Same error in every single cell.

Continuing the analogy a bit, if you came to that passage in an instruction book you’d be hard pressed to make sense of it. In the same way, in FAers the engine in your cells that reads its instructions from the sequence of DNA gets confused and does a very poor job of what that gene should be causing to happen – production of a protein called Frataxin.

Frataxin’s job should be to help with processing iron in the mitochondria (the powerpack) in cells. When there’s not enough Frataxin, there’ll be too much iron in one part of the cell, too little in another which causes oxidative stress (the simplest explanation I give of my FA is that I’m rusting on the inside); mitochondria can’t do their job effectively, cells are damaged and die.

Cells that are damaged and die are a problem because they should be making up our organs like our hearts, livers etc. When those cells are damaged and die, those organs don’t do their jobs efficiently or effectively and that’s what causes the FA symptoms we all live with.

Now, I’ll repeat all that and pop in a note about the research that’s being undertaken at each stage:

Within every cell in your body there’s a copy of your whole genome, your DNA, the instruction book for you. Different genes on that genome are switched on or off depending on that cell’s type or its job, but the whole genome’s there. In an FAer, the FXN gene has a repeat and whereas the letters GAA might be repeated in that gene about 30 times in a non-FAer, they might be repeated 1,000 times in us FAers. Same error in every single cell.

Gene editing would be the full stop, the cure. There’s exploratory work being done on gene editing (via CRISPR CAS-9 – there’s a TED talk that explains it here). Gene editing will be fantastic when it comes but progress towards it needs to be really careful so it’s still a while off yet. The correction needs to happen in many many cells so a process needs to be figured out that’ll start and won’t stop (there are about 30 trillion of them, remember?!) It’ll be irreversible so probably the most obvious thing they want to be sure of before any human trials start is that the only thing that’ll change is correction of the FXN gene.

Continuing the analogy a bit, if you came to that passage in an instruction book you’d be hard pressed to make sense of it. In the same way, in FAers the engine in your cells that reads its instructions from the sequence of DNA gets confused and does a very poor job of what that gene should be causing to happen – production of a protein called Frataxin.

Remember when I said that some genes are “switched on” or “switched off” in any given cell? Well because of the repeats, this gene might sometimes look like it’s switched off. There is research work happening to see how that could be corrected.

For people with FA, when the cell should be producing Frataxin, it does it poorly so there are research projects looking for ways to either overcome or compensate for that, up to and including whether an alternative to Frataxin could be induced that might do Frataxin’s job instead.

Frataxin’s job should be to help with processing iron in the mitochondria in cells. When there’s not enough Frataxin, there’ll be too much iron in one part of the cell, too little in another which causes oxidative stress; mitochondria can’t do their job effectively, cells are damaged and die.

A number of research projects are exploring ways to prevent this oxidative stress and help the iron processing so the mitochondria can function more efficiently.

Cells that are damaged and die are a problem because they should be making up our organs like our hearts, livers etc.

There are projects to explore protecting those organs at a more macro scale to keep them working as they should.

When those cells are damaged and die, those organs don’t do their jobs efficiently or effectively and that’s what causes the FA symptoms we all live with.

And finally there’s research happening to try to quantify the benefits that can accrue through directly addressing FA symptoms – what kind of exercise or speech therapy works best?, how much?, when? etc. These are important to allow researchers to better understand how a treatment may work.

The best news of all is that the different kinds of research are done by researchers with different specialities, so they can all happen in parallel and none impacts on the timing of any other.

Next up came a presentation from Kara Fick from Reata Pharmaceuticals.

Many will have seen excited postings on social media in October 2019 when the results of Reata’s trial of Omaveloxolone (knows as MOXIe or Omav) were first published. It was the first time a double-blind, placebo-controlled trial (the gold standard) of any drug had shown statistically-relevant improvement in mFARS. Kara’s presentation was to explain those results in detail and current status for the drug. (Was she bathed in blue as it’s a corporate colour? Your guess is as good as mine!)

The first thing to understand is that FDA approval hasn’t yet been obtained. Even though we are in Australia (where our local regulatory agency is the TGA), approval by the FDA is still important as their review and approval is the gold standard and would make obtaining subsequent approval by the TGA faster.  I know it feels slow, particularly in a COVID-19 world where several vaccines have been developed from scratch in less than a year and are already being administered to patients. But there are clear points of comparison and context.

Quick diversion: SARS-COV 2 (the virus) and COVID-19 (the disease caused by the virus) represent a global pandemic. At time of writing, more than 91 million people worldwide have been infected with that virus. More than 1.9 million people have died with the disease. For all the devastation it causes, there may be fewer than 25,000 people with FA in the world.

Also at time of writing, the COVID-19 vaccines being administered (including the ones developed in China and Russia) have obtained emergency use authorisations only; none has yet obtained full approval. Now, back to Omav.

With a total population of more than 350 million people and the biggest economy in the world, USA is by far the most important market for drug makers. Often in fact, if they can’t get FDA approval, a drug maker won’t even bother pursuing approval elsewhere as the total available market for their drug will be too small for them to ever recoup their development costs. Additionally, if a product is not approved by the FDA, other regulatory agencies such as the TGA, or agencies in the UK or Europe would likely also not approve its use. FDA approval would open up that huge USA market so it’s necessarily very difficult to obtain. (As a corollary of that, if a drug is FDA-approved, it’s relatively easy afterward, to get approval elsewhere). So Kara’s presentation focussed on the results that are being presented to the FDA.

The good news is that the participants in that trial (which included participants in Australia) showed improvement in mFARS score which represented on average, across the year of the trial, reversal of approximately a year’s worth of normal FA deterioration.

Not so good is that the FDA said that the results from this single trial weren’t enough evidence to obtain approval.

Fortunately another data point was able to be generated. After the Part 2 trial was complete, an open-label phase had continued, where participants from both the trials were given the opportunity to take Omav (no placebo this time) for a further 48 weeks. 98% of all trial participants chose to take part (so there’s a good qualitative indicator that most people who’d taken Omav already, jumped at the opportunity to keep taking it).

When the original trials were being done, some participants (and neither they nor their doctors knew who they were) were receiving a placebo so their progress could serve as a control to compare with those receiving Omav.

In this extra trial, patients who’d unknowingly received a placebo in the earlier trials also showed statistically significant improvement in mFARS score which represented on average, across the year of the trial, reversal of more than a year’s worth of normal FA deterioration.

Current status is that we and Reata await a determination from the FDA on whether they accept results from this additional phase of the trial, which wasn’t originally set up expecting to prove anything, represent sufficient evidence for them to approve Omav.

FARA US prepared a letter ostensibly addressed to Reata acknowledging these trial results and asking them to push forward with their FDA submission. It generated more than 74,000 signatures of support from around the world. Click here to follow the status of the letter and Reata’s submission.

As I said, this is the first of three notes I plan. I need three separate notes because there’s so much FA research happening. Yes this is an exciting time! Two more to follow.

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