PNS CONFERENCE- July 2024

Written By Sabrina Grays

The PNS conference was very useful. We found it to be even more relevant than the CMTRF and CMTA conferences we have attended previously, and we are already considering going to the May 2025 conference in Edinburgh. We could spend hours going through everything from the event, but here are our top takeaways.

More Clarity on the Foresee/Gene Therapy Plan

We had a few discussions with Sue Bruhn, Jeana, Dr Kleopa, and Dr Herrmann about aspects of this plan and we feel like we have a good understanding of what comes next. Unfortunately Dr. Gray was not present. The FDA pre-IND meeting will occur in <60 days and then the FDA will provide feedback and input. The CMTA STAR advisory board provided input as well last Friday.

New Research toward Potential Therapies in 4C

We spoke to Dr. Roos and Dr. Lia at length. We'd like to have them each come speak to this steering committee. We think we can help support their research, especially by getting them connected to other 4C patients as they are both in great need of human samples, but also potentially by reviewing their planned next steps and helping with fundraising or directing CMTA funds. It is very exciting to see more researchers choosing to work on 4C and we would like to continue to encourage that by being a well-organized and supportive patient community! We weren't able to connect with the Nationwide Childrens' researchers but we are going to reach out via email.

Lots of Discussion Around Clinical Trial Design, Safety, and Biomarkers

This was a huge topic with many presentations and so much information to think about. Some main takeaways that I think are going to be relevant to our efforts:

  • Measuring disease progression over a short period of time using exam scores and functional outcome measure is still extremely difficult

    • Katy Eichinger from Rochester presented the update validating the CMT-FOM (Functional Outcome Measure) in CMT1A. We are 24 months into a 36 month trial. There is no significant difference in scores from the beginning of the trial until now.

    • Kayla Cornett from Sydney presented the update on the CMT-Peds pediatric score. Longitudinal data shows that 4C patients have very slightly faster progression than 1A patients but there is still not enough difference in scores over 1-2 years.

    • More mildly affected patients seem to have more measurable declines over a short timeframe

    • The FDA will still require a functional outcome score/exam score to be the primary outcome measure for drug approval. The EMA in Europe is even more strict about this.

  • A lot of work going on in the biomarker realm to find outcome measures that actually do change significantly over 1-2 years

    • Again, this will still have to be a secondary outcome even if it is validated

    • No biomarkers are validated in 4C

    • Only MRI is (mostly) validated in 1A

    • Amanda Dragon from Iowa presented the first non-MRI longitudinal biomarker data in CMT1A, for plasma microRNA biomarkers. Sensitivity and progression over 1-2 years is decent.

    • Tyler Rehbain from Rochester has been working on ultrasound measurements with the hope that they are a less expensive biomarker that can eventually replace MRI. He is looking at this in 1A for now, no longitudinal data

      • Will also mention Tyler is working with Dr. Herrmann on the 4C natural history study and seemed very excited to be working on 4C and would like to work with us more - he would be a great person to join our meeting and he is very knowledgeable about these biomarker concerns

    • Another researcher from Rochester is working on microscope imaging of Meissner corpuscles in the finger

      • This is very low cost and shows good correlation with exam scores but unfortunately does not progress quickly

    • Neurofilament light chain remains controversial - Dr. Saporda strongly believes it is not useful because it varies a lot over time and between patients, others think it could be useful to show a treatment effect.

  • A very important point: the biomarkers that are sensitive to progression over a short timeline are not necessarily the ones that would respond to treatment over a short timeline

    • For instance, MRI shows significant progression in 1A over just one year. However, a treatment may not stop or reverse that progression quickly enough to be seen in a 1-2 year trial

    • Conversely, the size of the Meissner corpuscles does not change much over time. But there is reason to believe that the corpuscles are enlarged in CMT patients compared to healthy patients because of ongoing axon death, and if a treatment were to stop the axon death, these could revert to the size seen in healthy patients fairly quickly.

    • For this reason, a well-designed trial needs to look at as many outcome measures as possible (talk from Vera Fridman)

  • Clinical trial design - super important - in order to see a statistically significant effect you would need enough patients

    • Vera Fridman would recommend 45 patients receiving therapy and 45 receiving placebo, for 1A

    • Even with 100% attenuation (a therapy that stops the disease perfectly) you would not see a statistical effect with fewer than 10 patients

    • A lot of discussion about placebo control. CMTA/patient orgs are not for it, and it is anyway not ideal for a gene therapy. But Dr. Fridman and Dr. Finkel are both strongly in favor because you can see if the therapy is working much faster and help more patients.

  • Safety concerns - a lot of discussion here re gene therapy

    • Gene therapy is not without significant risks

      • Mutagenic insertion/germline mutation - this is not supposed to happen with AAV vector but it has been shown to occur (Dr. Finkel, St Jude's)

      • Heart and liver toxicity

      • Immune suppression - has led to death in recent DMD trial

        • 4C patients with premature stop codon need even stronger immune suppression because there is auto-immunity to vector and to SH3TC2 protein

      • Risk/benefit is more favorable for younger/milder patients because there is more likelihood of improvement from therapy

    • Greater risk with CRISPR therapies, ASO, non-AAV vector gene therapies. Less risk with RNAi and AAV gene therapies. AAV gene therapies have been given to 4000 patients globally with no serious adverse effects from the vector itself (still risk from the immuno-suppression)

Lessons from Other Diseases

  • There was a lot of discussion about SMA, DMD, and Giant Axonal Neuropathy (GAN)

  • Dr. Finkel's talk was mostly about the lessons from SMA therapy development

    • Main takeaways - patient advocacy groups funded and supported all the early research

    • Natural history and biomarker development was teed up before trials commenced

    • Controversy about including a placebo arm but it was the right decision because it allowed them to quickly see that the drug was working and cross-over the placebo group to receive treatment

    • Gene therapy is not sufficient for most patients, especially if dosed after disease progression begins. Most are also receiving the other two SMA drugs for life, even after receiving gene therapy.

  • DMD is an interesting case, Sarepta's AAV gene therapy went to market with accelerated approval and then when they did their Phase 3 trial it failed to meet their endpoint on the primary functional score

    • Even though the trial failed, the FDA kept the drug on the market and even expanded its approval indication because they saw that the drug was effective via their biomarker (dystrophin)

  • GAN gene therapy was developed as an investigator-led drug trial for a small number of patients

    • The therapy was picked up by a biotech, Taysha Gene Therapies

    • Trial data was rejected by the FDA in 2022 because there was no placebo control and insufficient natural history data

    • Revised, retrospective natural history data was then submitted but was subsequently rejected as well due to heterogeneity of the disease

    • Taysha dropped the program in late 2023

Other Interesting Info

  • Unlike other forms of CMT, 4C has been linked to cerebellar dysfunction and ataxia. This came up a couple of times. Thankfully it does not seem to be linked to cardiovascular effects of ataxias that can cause early death, but we should look more into this and try to understand what it means.

  • A presentation from Kayla Cornett confirmed that exercise is helpful for CMT patients and associated with improvements

  • There seems to be a big move toward human cell-based models and away from mouse and rat models. I expect this will keep growing - good in that it is easier to scale. More relevant in some ways, less relevant in others.


My summary and editorializing:

Some exciting interest from other researchers in 4C that I think we should support.

AAV9 gene therapy is not without risks, especially around immune suppression, but it seems fairly well tolerated.

The most likely risk I see with Dr. Gray's approach is that the gene therapy will show no effect. This is likely to occur even if the therapy works well because we have no validated biomarkers in 4C, so we would rely on exam scores that don't change in most patients over 1-2 years. The STAR board and the FDA recognize this and will likely require us to have validated biomarkers that show progression over a short timeline, before dosing patients. We have no idea which biomarkers might show a treatment effect - even in 1A this still requires a lot of development. With a very small trial and no placebo control, it is likely that the therapy will still fail to show an effect, even with validated biomarkers, so we should be prepared for that as well. Dr Bruhn made the point that an initial trial is focused more on safety than on treatment effect, but a trial that shows no measurable impact will surely not help this therapy develop any further and solicit investment.


Sabrina Grays