2021 FSHD Research Update Meeting

Posted by Friends of FSH Research on Mar 2, 2021

Friends of FSH Research hosted our annual FSHD Research Update Meeting on Saturday February 27, 2021. See video of event below the list of Q & A that were not answered during the meeting.

4:15​ Actual start of meeting

6:36​ Rick & Terry Colella

9:57​ First research presentation

Logo t-shirt still available at https://www.bonfire.com/friends-of-fsh-research/

Unanswered Q & A

I. Peter & Takako Jones, PhD

Q1: Would it be logical to use CRISPR to cut out the D4Z4 repeats in FSHD?

Ans: Conceptually, cutting out the contracted/pathogenic D4Z4 would eliminate DUX4 expression. However, in practice this is not feasible for a couple of reasons. First, there are technical issues whereby the CRISPR cutting sites are present on both the 4q and both of the 10q arrays so it would be very hard to remove just one. In addition, these regions are present in other places in the genome. Again, conceptually, one could remove all 4 and why would it matter since you would be removing one bad one and three that are not expressed. However, CRISPR cutting is very inefficient and worse, repair after cutting is extremely inefficient in non-dividing cells such as muscle. The problem is that if the CRISPR cuts and it is not repaired, thus leaving a chromosome without a telomere end, that cell will undergo programmed cell death. This is a cellular protection mechanism against cancer and chromosomal breaks that, in this case, would be triggered and cause a problem. So, while in theory using CRISPR to remove the DUX4 expressing array could solve the problem, in practice it will not work.

II. Angela Lek, PhD

Q1: How long do you think before you go to clinical trial?

Ans: I cannot provide a time line at this stage as science is very unpredictable and we do not know if we will get the results to make this compound attractive enough for clinical trials. Funding is also another factor to consider when planning clinical trials.

III. Jeffrey Statland, PhD

Q1: Do you think 18 months is sufficient time to see changes in patients in RESOLVE?

Ans: Since ReSolve is a large study, with over 200 people participating; we expect to see changes in a number of clinical measures at 18 months. The size of the clinical change, however, may be modest, in the 3-5% range. But because we collect a broad array of different kinds of outcome measures, including questions about FSHD-reported impact on physical health or quality of life, we can put the changes we do see into the perspective of group experience over the same timeframe.

Q2: Many people in the Facebook group Living with FSHD complain of "frozen" diaphragm halves, but last I knew you didn't credit these diagnoses. Is that still true? If it's helpful, I could recruit testimony from group members.

Ans: I credit whatever people tell me or we see in clinical practice – this is how we learn about FSHD. I think the diaphragm can be involved but it is not common – out of the ~150 people I see in clinic think I have ~2 who have paralyzed diaphragms. That said, it is intriguing that it is often asymmetric (one half a diaphragm) like we see with other muscles. More work needs to be done to better understand this.

IV. Leo Wang, MD, PhD

Q1: Are there plans to target performance indices as suggested by MRI? For example, winging, biceps and hamstrings as opposed to walking, which involves several muscles?

Ans: There may be plans to see how the measure called Reachable Workspace correlates with arm MRI measures.

Q2: Why does FSHD affect muscles asymmetrically? (i.e. one leg affected more than the other)

Ans: It seems as thought DUX4 is turned on randomly in different muscles and when there is too much of it activated it starts the process of the muscle having problems.

V. Charles Marusak, PhD

Q1: How to prevent degradation of the synthetic RNA before it reaches DUX4 in the cells?

Ans: The RNA molecules we employ in our therapeutic contain unnatural chemical modifications that are synthesized in the lab. There are a variety of different chemical modification patterns we use but in general these modifications increase stability and efficacy of the RNA to be far greater than natural unmodified RNA. We have done stability tests that demonstrate some of our RNA can survive for weeks in human serum. The downside of these chemical modifications is that they can sometimes be immunogenic so we have to do additional testing to verify they are safe.

Q2: Is this an antagomir approach or shRNA?

Ans: We are interested in using whichever works best and have tested antagomir approaches as well as shRNA and other ASO strategies.

Q3: Can a muscle cell that has turned to fat be regenerated?

Ans: This is a difficult question to answer and I think it's really still up in the air. It will take halting FSHD first for us to know for sure but it very well may take an additional therapy to restore lost muscle mass once FSHD is halted.

Q4: This question is for miRecule, Dyne and Avidity. Fulcrum can also comment. For those severely afflicted is there any reason not to expect access to INDs during a clinical trial phase 2 via expanded access (nothing precludes this per FDA parallel track clarification).

Ans: I am no expert on this type of question but I think most patients will have a shot at gaining access to our clinical trials if they are interested since getting as diverse a group as possible is ideal. We will be sure to reach out to the Friends of FSH Research and other groups to get the word out when enrollment starts.

VI. John Davis, PhD

Q1: This question is for miRecule, Dyne and Avidity. Fulcrum can also comment. For those severely afflicted is the any reason not to expect access to INDs during a clinical trial phase 2 via expanded access (nothing precludes this per FDA parallel track clarification).

Ans: At Dyne we aren’t in clinical trials yet – but are moving as rapidly as we can. When we have finalized our clinical trial plans, we’ll be sharing the key elements of our trial design with the community via our advocacy partners, our social media channels and website, and via the federal studies site, clinicaltrials.gov.

Q2: How long does it take to see results of shutting down Dux4 and how it then translates to muscle growth or rebirth?

Ans: Published mouse model data in the field suggests that DUX4 knockdown results in fairly rapid (weeks to one month) changes in the biomarker expression and preservation of muscle function, but that model only partially reflects the disease seen in humans. There may be aspects of DUX4 induced bioactivity that could take longer to terminate or reduce than other features, which may change rapidly in response to treatment of patients. Additionally, there is insufficient data in animals to indicate if disease can be reversed although that is the desired goal in humans. 

Q3: After IND filing for clinical trials what are potential locations?

Ans: At Dyne we recognize that there is an urgent need for new therapies for FSHD worldwide, and we are very committed to advancing our potential therapy as quickly as possible. We are reviewing a broad array of possible sites and look forward to updating the community when we have a confirmed network of future trial sites ready to launch our study.

Q4: Is Dyne therapeutics currently doing FSHD clinical trials? If so, when will they announce their results?

Ans: Dyne has not launched our FSHD clinical trial. We plan to submit investigational new drug applications, or INDs, for our three disease programs between Q4’21 and Q4’22. Our IND submissions for our DMD and DM1 programs are expected in the early part of that window, with FSHD about 1-2 quarters behind.

VII. Michelle Mellion, MD

Q1: Earlier news indicated losmapimod is preferentially effective in severe DUX4 expression compared to mild expression. Does Fulcrum understand why, and what the implications might be?

Ans:

a. FSHD is a severe and complex disease with variable patient presentation across different muscles.

i. DUX4-driven gene expression is expressed stochastically in the muscles of FSHD patients and can show a wide range within individual skeletal muscles.

ii. FSHD patients continue to express the DUX4-driven genes over time, which has led to the understanding that this is the common basis of the disease.

iii. We don’t believe there are high and low expressing patients, but high and low expressing muscles.

iv. Any reduction in DUX4, based on Peter Jones, may be beneficial

b. In a small number of patients, we were very encouraged to see that muscles with highest DUX4-driven gene expression in pretreatment biopsies show greater reduction on losmapimod (38-fold) compared to placebo (5.4-fold).

i. These data are consistent with what we expected to see in a pre-specified sensitivity analysis.

ii. In the full analysis set, losmapimod did not separate from placebo.

iii. Interim analysis data is from biopsy only. We did not look at any secondary or exploratory endpoints and did not include a futility analysis.

iv. Analysis of the first part of ReDUX4 is ongoing. We are looking forward to sharing the totality of the data with the community in Q2.

Q2: My question to Fulcrum is why did your expanded access program not allow access during phase 2?

Ans: We understand the urgent need of patients with few treatment options to gain access to therapies in development, we are working to make the facioscapulohumeral muscular dystrophy (FSHD) Expanded Access Program available as soon as possible. We encourage patients and families to discuss if losmapimod is an appropriate treatment for you. Please refer to our EAP policy located here.

Q3: I hope this is not too controversial but the media framed the Fulcrum interim results released last year as disappointing. Would you disagree?

Ans: In a small number of patients, we were very encouraged to see that muscles with highest DUX4-driven gene expression in pretreatment biopsies show greater reduction on losmapimod (38-fold) compared to placebo (5.4-fold).

i. These data are consistent with what we expected to see in a pre-specified sensitivity analysis.

ii. In the full analysis set, losmapimod did not separate from placebo.

iii. Interim analysis data is from biopsy only. We did not look at any secondary or exploratory endpoints and did not include a futility analysis.

iv. Analysis of the first part of ReDUX4 is ongoing. We are looking forward to sharing the totality of the data with the community in Q2.

Q4: If one is interested in participating in clinical trials how do you go about it?

Ans: Your participation in clinical trials is critical to success in finding effective treatments for FSHD. The best way to find clinical trials is to go to clinicaltrials.gov. Contact information for the clinical trial you may be interested in participating in will be provided. You should always discuss with your doctor if participation in a clinical trial is right for you.

Q5: Could fulcrum phase 3 trial reach countries outside of the US?

Ans: Planning for Phase 3 is currently ongoing. All design options are being considered.

VIII. Asifa Lalji

Q1: Once you were diagnosed, did you feel the doctors had enough awareness to recommend treatments for symptoms of FSHD, or did you need to go to the FSHD community for guidance?

Ans: Both. I had been misdiagnosed/ignored by my family doctor growing up. When I switched doctors, my condition was still a mystery. But, he knew enough to send me to a rehabilitation specialist who recognized it right away and sent me to a neurologist who tested and diagnosed it right away.

The neurologist knew enough to tell me there was no treatment, but did tell me about the scapular fusion. The orthopedic surgeon who performed my scapular fusion had done it before and connected me with another FSHD patient he had performed the same procedure on.

But, all research and support was definitely through the FSHD community. I still print information on the condition, research, clinical trials etc. for my doctors. It's unfortunate our amazing medical and research community in Vancouver is not as keen on FSHD as other cities. Which is why we are so connected to the FSHD research community in Washington.

Q2: Have you ever received ignorant remarks from people who are unaware of FSHD and how do you deal with those?

Ans: I am constantly amazed by how few people, even in the medical community, know what FSHD is! So I definitely have to do a lot of educating.

Like many FSHers, I kept my condition hidden from many people. I would get comments on being lazy for taking the elevator instead of the stairs or driving instead of walking. Entitled for not being able to do heavy lifting and getting others to do those tasks. And, of course not being fun because I opted out of activities even though the real reason was the fatigue or inability to do something.

In retrospect, keeping it hidden inadvertently caused me to feel shame and low self-esteem unnecessarily.

Once people knew I had FSHD, everyone understood the best they could. As I started using a walker and wheelchair, people became more aware of accessibility issues in society and the feeling of discrimination people with disabilities (especially invisible disabilities) face. But, I had to be very open about my condition, the realities and what my needs were. It's hard to do, but very liberating.