Last week, Parent Project Muscular Dystrophy and Action Duchenne hosted a webinar update on the recent report that Summit has announced positive 24-week interim results from the open-label Phase 2 proof of concept clinical trial, PhaseOut DMD. The webinar recording as well as Summit's responses to community questions are now available below.
Summit Webinar Question Responses:
1. Would patients be able to reduce or eliminate steroid use with long-term use of ezutromid?
In PhaseOut DMD, patients are taking steroids in addition to ezutromid. To answer whether ezutromid could be of benefit without steroids, or with a reduced dose of steroids, we would need to test that in a clinical trial setting.
2. Would there be any negative reactions with other potential treatments, such as anti-myostatin, exon-skipping, gene therapy, etc, or would there be a positive add-on effect?
We believe that ezutromid has the potential to provide significant benefit for patients with DMD on its own, but also believe that it could be complementary to other DMD treatment approaches. Our current focus is understanding what benefit ezutromid used in combination with steroids could provide to patients with DMD and on conducting clinical trials that could support regulatory submissions for single-agent use. We think that combination trials could be interesting in the future.
3. Could this be useful for BMD?
We believe ezutromid could potentially benefit patients with BMD. While our current clinical focus is on DMD, we are considering the possibility of future clinical trials in BMD.
4. Can you explain what the clinical significance is of a reduction of myosin in the muscle that you have seen in these results?
The muscle damage that happens in DMD involves a relentless cycle of muscle fiber degeneration and repair. Developmental myosin increases during repair and is therefore an indicator of this muscle damage. Prior to looking at biopsy samples from patients in PhaseOut DMD, we looked at a series of Duchenne, Becker and control samples from a biobank. In these biobank samples, we found that on average, there was a correlation between the amount of developmental myosin and the disease phenotype, meaning that patients with DMD had more developmental myosin on average than patients with BMD and controls had the least amount of developmental myosin. We are therefore encouraged by the 23% decrease in developmental myosin found in the patient biopsies in PhaseOut DMD after 24 weeks of ezutromid treatment, and are optimistic that with longer term dosing this could translate into a beneficial impact on various clinical measures, which will be assessed at 48 weeks and beyond.
5. Why did only 14 of 22 patients show a decrease in developmental myosin, when all patients achieved plasma levels of Ezutromid sufficient to modulate utrophin?
In this study there is no control group which would tell us how untreated patients might have seen their developmental myosin change over 24 weeks. There is always some variability in results with clinical development, and we think it's still possible that all patients are benefitting from ezutromid treatment. We will continue to evaluate this over time.
6. Do you intend to validate myosin as a biomarker and can you explain your work in fast tracking other utrophin biomarkers to the clinic? Are you validating myosin in EU/EMA and US/FDA?
We have performed analytical validation of the assays that we have used to measure both developmental myosin and utrophin, and have had discussions with both the FDA and EMA on these validation methods. We believe that the techniques developed are robust and generate highly reliable and reproduceable biopsy data.
7. Is previously damaged muscle being repaired or is it only newer fibers showing less damage?
Ezutromid is thought to work by maintaining the production of utrophin to stabilize muscle fibers, and assume dystrophin's usual role in mature muscle fibers, in the absence of dystrophin. We do not have specific information as to where the reduction in damage is coming from, but are very encouraged by the data at hand. We believe that ezutromid could slow or stabilize DMD disease progression.
8. Are the validation samples of DMD and BMD all from the same age - does this affect the amount of repair as there are fewer fibers?
We used a range of ages and disease severities in our validation work to ensure the range of biomarker detection in our measurements. In this work, we observed a correlation between the amount of developmental myosin and disease phenotype i.e. in general, DMD diagnosis had a higher percentage of positive developmental myosin fibers than a Becker diagnosis.
9. How much utrophin is needed for clinical benefit and why do you think that everyone in this cohort achieved plasma levels of drug sufficient to modulate utrophin?
We believe the key to achieving benefit from utrophin modulation is to maintain utrophin protein expression. This is supported by data from Professor Kay Davies' original experiments in the mice. In these experiments, mice expressing utrophin at similar levels to what's found in a dystrophin-deficient mouse had significant rescue of the dystrophin deficient pathology and function.
As we stated in the Webinar, we believe that utrophin is functionally similar to dystrophin and like dystrophin, continual expression should help stabilize muscle damage.
All patients in PhaseOut DMD achieved plasma levels that we believe are sufficient to modulate utrophin. We base this belief on the observation that all patients in PhaseOut DMD had plasma levels that were shown to modulate utrophin in animal or cell-based studies.
10. Would the level of utrophin increase after 48 weeks of treatment? Do we need to increase the amount of utrophin?
As stated above, we think the key to achieving benefit from utrophin modulation is to maintain utrophin protein expression. The levels of utrophin in patients with DMD prior to treatment is very high, so we wouldn't expect to see large increases of utrophin with ezutromid treatment. The 24-week interim results provide evidence that ezutromid is able to significantly and meaningfully reduce the amount of muscle damage, and yet we observed a maintenance and even an increase in utrophin levels. We think these changes observed could be followed by clinical benefits with longer-term dosing and would be excited to see similar changes in the biopsies after 48 weeks of ezutromid treatment.
11. Can you explain the differences between the formulations in your wider pipeline and go through the timelines for each?
PhaseOut DMD is testing two different formulations of the same drug - both of these are ezutromid. The only difference is how the drug is formulated which impacts the average plasma concentrations. One is a powder that's mixed in liquid before it is taken - this formulation gives higher blood concentrations; the other comes as a pre-mixed liquid. Importantly, we do not see any differences between these formulations in regard to any of the measures tested after 24 weeks of treatment in PhaseOut DMD.
All of the drug compounds that are in development in collaboration with the University of Oxford are brand new drug compounds, not different formulations of ezutromid. These are very early in the discovery stage so as yet we have no planned clinical trials for any of these compounds.
12. Have Summit done any preliminary analysis on the differences between F3 and F6. This is an open label trial. Were the 5 boys who had an over 40% decrease in developmental myosin on F3 or F6?
We did not see any differences in the measures between the two formulations in the 24-week data. We remain blinded to data beyond the 24-week timepoint.
13. Functional data showed small declines in both six-minute walk distance and North Star Ambulatory Assessment. While this data is from an early time point, how do you reconcile these trends with the positive myosin and utrophin results mentioned? Do you expect these trends to reverse?
The 24-week interim look at the data was intended to show just what we showed: target engagement, meaning modulation of utrophin, and an effect on muscle health as shown by a significant reduction in developmental myosin. We believe it is too early in the trial to draw any conclusions from the functional data. We expect that utrophin modulation could slow or stabilize disease progression. Therefore, we would not expect to see an improvement in functional measures, but could have the potential to see a slowing or a stabilization in functional decline with longer-term dosing. This is similar to the impact one might expect from dystrophin-restoration therapeutic approaches. From the data we do have at 24 weeks, however, we are encouraged that that no boy has lost ambulation.
14. Would it be possible to see the details of the functional data for all 22 patients in a table that showed their ages as well? Is it possible that the older boys (age >8.5) declined more than compared to younger boys (age <8.5) who might have gained some functionality to bring the mean data close to where it is reported?
As stated above, there are many analyses ongoing from the 24-week data, so we do not yet have this breakdown available.
15. Any data on how ezutromid affects heart/lung/brain/diaphragm?
We are measuring cardiac and respiratory function in PhaseOut DMD, and we expect these data will be reported in the future. In our animal studies, we did observe increased utrophin in the heart and diaphragm after treatment with ezutromid.
16. Is muscle diameter decrease a positive result?
The decrease in muscle diameter from baseline to 24 weeks of treatment was unexpected; however, it was also relatively small and not statistically significant. We are charting new territory here, as no one has observed what happens to a muscle in humans when utrophin occupies the dystrophin sites in a mature or maturing muscle fiber. We do not yet know how to interpret this finding and will continue to monitor changes in muscle fiber diameter at the end of 48 weeks of treatment.
17. Are you performing Western blots on the biopsies?
We do not plan to perform Western blots on the biopsies from PhaseOut DMD as the utrophin levels are already very high in patients with DMD and Western blots are not likely to be able to detect small changes. Our automated techniques provide us with details on utrophin and developmental myosin levels and very importantly, localization that Western blots could never achieve.
18. Did you measure CK levels? What did they show?
We are measuring CK levels in PhaseOut DMD, and expect to report these with the 48-week data.
19. Will you allow older and younger ambulant patients in the next trial provided they meet the other criteria?
With the positive 24-week data, we are accelerating the planning of the next trial, which is expected to be designed to support regulatory submissions in the US and Europe. The details of that trial are still being worked out and we need to see 48-week data from PhaseOut DMD before we finalize our plans.
20. What are you thinking in terms of the design of your next trial? Will you continue with biopsies?
As stated above, the details of the next trial are in the works, and we will update the community after the 48-week results, once we've finalized the trial details.
21. Will you conduct a trial for non-ambulatory patients?
We are beginning to plan to study ezutromid in other populations, such as the non-ambulatory population, and believe that ezutromid is a universal approach that could benefit all patients with DMD. We will evaluate these plans more fully after the 48-week readout.
22. Is there a plan to initiate a trial for steroid-naïve patients? What about patients on steroid alternatives?
We are currently focused on designing the pivotal trial for ezutromid, which will evaluate the drug on top of steroids since these medicines are regarded as a standard of care for the patient group we will study. For any future trials, for example in younger boys, we will consider whether there is a different baseline standard of care and take that into account. The steroid alternatives look promising but as none is approved yet it is too early to start evaluating combinations with these agents in clinical trials.
23. How could my child take part in the next trial?
To take part in any clinical trial, a patient must meet several inclusion and exclusion criteria and be approved by a participating study doctor at a clinical trial site. We find that for small clinical trials, many physicians will choose patients who are already under their care. For larger clinical trials, they may consult a registry or consider families who contact their site. We do not yet have details for the next clinical trial available to share with the community, but plan to share them when we are able. We need to see the 48-week results from PhaseOut DMD before plans for the next trial are finalized. In the meantime, we recommend signing up for a registry if you have not already.
24. In which countries will you conduct the next trials?
We expect that the next trial would be conducted in several countries, but do not yet have details. We need to see the 48-week results from PhaseOut DMD before plans for the next trial are finalized. Once we are able to share the plans with the community, we will.
25. Are there any plans for combination trials?
We are focused on demonstrating single agent activity with ezutromid, but see the potential to combine with other approved treatment approaches or ones in development down the road.
26. When will ezutromid be approved by the FDA and EMA?
We are awaiting the 48-week data from PhaseOut DMD prior to finalizing our plans for our next clinical trial of ezutromid. Once we have these plans in place, we will be able to better predict when we could potentially file for regulatory approvals. These filings would need to be approved by the applicable regulatory authorities before ezutromid would be available on the market.
27. How long after approvals would it be until ezutromid is available for purchase?
If ezutromid were to receive regulatory approval, our goal would be to make ezutromid available as quickly as possible in the jurisdiction(s) where it was approved for sale.
28. Will ezutromid be difficult to access and afford?
Our goal is to ensure that patients have access to ezutromid in all countries where it is approved.