This week, Fulcrum Therapeutics announced results from an interim analysis of data collected from its Phase 2 ReDUX4 trial, which is testing the effect of a drug called losmapimod in individuals with facioscapulohumeral muscular dystrophy (FSHD). The drug, which is taken as a pill twice a day, is intended to reduce the expression of a gene called DUX4. This gene is seen as the prime “villain” causing FSHD by unleashing a mob of other genes that damage muscles. DUX4 is like a mob boss who gives the orders, while the other genes are the henchmen who carry out the crime spree. And like a mob boss, DUX4 is hard to detect, but the “DUX4-driven gene expression”—the henchmen—are easier to spot, and that’s what Fulcrum researchers measure in order to see if losmapimod is hitting its target, DUX4.
The ReDUX4 trial involves 80 patients, half of whom were randomly assigned to receive losmapimod, with the other half receiving a placebo. Neither the volunteers nor investigators know who is getting placebo or the drug, to avoid biasing the results. At the start of the trial (“time zero”), all of the patients had a biopsy in which a tiny sliver of muscle was collected using a hollow needle. Sixteen weeks into the trial, the volunteers had a second biopsy, but because of the coronavirus shutdown, only 29 were able to complete this step on time. Both the “time zero” and 16-week biopsied muscles were analyzed for DUX4-driven gene expression (the henchmen!).
The data are consistent with Fulcrum's hypothesis
In designing the ReDUX4 clinical trial, Fulcrum scientists drew on findings from previous studies which found variability among muscle biopsies from volunteers, with a subset of muscle biopsies having much higher levels of DUX4-driven gene expression. They hypothesized that those muscles with high DUX4-driven gene expression would show a larger change in response to losmapimod. The Fulcrum team therefore planned ahead of time to analyze the 16-week biopsy data to see if their hypothesis was valid. And that was exactly what they found.
Overall, there was no difference between the drug and placebo groups in DUX4-driven gene expression levels at 16 weeks. But when they looked at those muscle biopsies with high levels before the start of the trial, they found a 38-fold drop in DUX4-driven gene expression in those who were on losmapimod. In comparison, those who were on placebo had only a 5.4-fold reduction. Even though the large decrease in gene expression was detected only in those muscles with high levels, Fulcrum believes that all FSHD patients can potentially benefit from treatment with losmapimod because it is presumed that most or all FSHD patients have some muscles somewhere in their bodies that have high levels of DUX4.
“Preliminary evidence from our interim analysis suggests that muscles with higher DUX4-driven gene expression in pre-treatment biopsies show greater reduction of DUX4-driven gene expression following treatment with losmapimod compared to placebo. These results, which provide evidence of the ability of losmapimod to reduce DUX4-driven gene expression, are very encouraging,” said Robert J. Gould, PhD, president and chief executive officer. “This initial data represents the first time a treatment is being evaluated to impact the root cause of FSHD in a placebo-controlled trial and are helping to inform our longer-term clinical strategy for losmapimod. We look forward to further leveraging the open label study to evaluate the long-term effects of losmapimod in additional FSHD subjects. We remain on track to share topline results on the primary endpoint in the first quarter of 2021 and full data, including all secondary and exploratory endpoints, in the second quarter of 2021.”
Losmapimod was generally well tolerated with no serious drug-related adverse events (SAEs) reported. The interim analysis was not powered for statistical significance and did not include individual patient level data. ReDUX4 remains blinded.
“One of the critical factors in patients with FSHD is that there can be significant variability in the magnitude of DUX4-driven gene expression at the site of each pre-treatment needle biopsy,” said Diego Cadavid, MD, Fulcrum’s senior vice president, clinical development. “The initial observation of greater reduction by losmapimod over placebo in DUX4-driven gene expression in the biopsied muscles with the highest baseline expression may represent the potential losmapimod has to treat the root cause of the disease. We’re excited about the study progress and look forward to the final analysis.”
Read Fulcrum’s press release here.
Comments from earnings conference call on August 11, 2020
Reported by Yahoo
From Robert Gould, PhD, CEO of Fulcrum:
"Our own evidence as well as independent evidence suggest we do not have to turn DUX4 off completely to provide benefit. There's a spectrum of DUX4 expression in FSHD presentation that suggests that even an incremental reduction may be beneficial to patients. Thus, we believe, as do independent researchers, that any reduction in DUX4-driven gene expression has a potential for benefit to patients.
DUX4 is expressed stochastically in the muscles of FSHD in patients, and expression levels can vary widely. From both independent researchers as well as our own proprietary studies, we know that FSHD patients continue to express DUX4 over time as the disease progresses throughout the body. What this means is that while we cannot define people with FSHD as high and low expressing patients, expression levels vary by region and muscle within each patient. We're encouraged with the data reported today that showed a promising reduction in the DUX4-driven genes in the muscles expressing the highest DUX4-driven genes at baseline."
From Diego Cadavid, MD, SVP of clinical development:
"Due to the stochastic nature of DUX4 expression and wide range of DUX4 expression between muscles within an individual patient, we utilized MRI-guided biopsy to identify those muscle areas most likely to express DUX4. MRI can accurately identify affected muscles, but it cannot determine the level of DUX4-driven gene expression within an individual patient's muscle. To address this challenge in identifying muscle biopsies with high baseline DUX4-driven gene expression, in order to quantify a reduction, we prespecified a sensitivity analysis of the different ranges of expression.
Results from the interim analysis highlighted a greater than 1,000-fold difference between pretreatment muscle biopsies with higher and lower DUX4-driven gene expression. This confirms what we say in preclinical research, where all the FSHD subjects' derived cell lines used preclinically had high baseline DUX4-driven gene expression, and we observed a reduction in all of them.
As a result of the 1,000-fold difference in DUX4-driven gene expression observed between biopsies, we believe that observing a reduction may require capturing muscle biopsies with higher baseline expression. As shown on Slide 13, muscle biopsies with higher baseline provide greater dynamic range to observe a reduction compared to muscle biopsies with lower baseline. Using a prespecified sensitivity analysis based on learnings from our open-label study, the interim analysis evaluated the treatment effect on DUX4-driven gene expression in muscle biopsies with the highest baseline expression. The higher ranges were comparable to the ranges in the cell lines used preclinical.
The interim analysis of the first 29 randomized subjects assessed changes in baseline DUX4-driven gene expression in subjects who had the 16-week biopsy. The study remains blinded, and we have not looked at individual subject data this time. This interim analysis was also not powerful statistical significance. A prespecified sensitivity analysis was included to evaluate treatment effects on muscle biopsies with a range of baseline DUX4-driven gene expression.
Here on Slide 15, you can see from the demographics in the interim analysis that subjects were well balanced between losmapimod and placebo. In losmapimod-treated subjects, mean, median drug concentration was greater than 100 nanomolar in muscle, and no drug-related SAEs were reported.
On Slide 16, we are now showing the log 2 data on a linear scale, which is how PCL data is traditionally displayed. Here, you can see the 2 data plots in all muscle biopsies on the left and highest expressing biopsies on the right. Here, we see the results on a log 10 scale given the greater than 1,000-fold difference in DUX4-driven gene expression between biopsies. We saw no separation from placebo in the total randomized population assessed, as seen on the left, and a reduction observed with losmapimod treatment in the highest expressing muscle biopsies, a 38-fold reduction in expression in the losmapimod-treated arm versus a 5.4-fold reduction in placebo. The highest expressing muscle biopsies represent a top quartile of biopsies assessed for baseline DUX4-driven gene expression.
Due to COVID-19, we amended we look forward from 24 to 48 weeks, which gave us the opportunity to introduce a 16-week interim analysis on the initial 29 randomized subjects. We are encouraged by these results that suggest losmapimod may be reducing DUX4-driven gene expression, the root cause of FSHD. While we did not see a separation from placebo in the total population and the 16-week cutoff, the data in the highest expressing muscle biopsies is consistent with initial data from the open-label study. We believe that all FSHD patients have muscles with high DUX4-driven gene expression and that losmapimod has the potential to offer a benefit to all FSHD patients.
This interim analysis has shown an important initial data on the change from baseline in affected muscle at 16 weeks of treatment in about 1/3 of the total 80 patients enrolled in the ReDUX4 trial. We are working now to advance several important next steps in this program. We will continue to collect additional data from the ReDUX4 trial, and we look forward to seeing top line results in Q1 2021 and the full results by Q2 2021. This will include not only the full data set on the DUX4-driven gene expression but also the whole body MRI evaluation of change from baseline in skeletal muscle volume, fatty infiltration and fat replacement and several clinical outcome assessments, including clinician reported, patient reported and assessments of muscle function and strength. We also look forward to the continued analysis of the single-center, open-label study, which also includes some analysis of change from baseline in skeletal muscle MRI biomarker and several clinical outcome assessments over longer-term treatment.
To help us better understand the potential benefit of losmapimod in FSHD, we will start to examine changes from baseline by qPCR in muscle biopsies in 24 other gene transcripts that measure important processes of muscle health, including muscle regeneration, fat deposition inflammation and cell death."
It would be useful to understand what kind of patient showed significant reduction in DUX4. Were people who show little signs of FSHD the patients who showed the most improvement, or were those who showed greater impact of FSHD the ones who had the largest benefit? One of the comments I found most interesting was that people on the placebo had a reduction of DUX4 as well. I would be wiling to take the placebo now if this was really true.
The effect was seen in the muscle biopsy of patients. At this stage, the study is blinded and they have not analyzed data on clinical symptoms, imaging, etc. in any of the patients. It is thought that all people with FSHD, whether they are barely symptomatic or quite affected, have some muscles that are expressing DUX4 at high levels, so being able to suppress DUX4 in any patient would be beneficial. The challenge with this (and any) clinical trial is to locate and retrieve high DUX4-expressing muscle samples from individual patients in a minimally invasive way.
What is the possibility of joining the trial, or a future trial? I am significantly affected by FSHD.
Also, how long before this medicine will be available to the public with fshd?
Does anyone know how the muscle to be biopsied was chosen? Was it the same muscle (e.g. left bicep) for all study participants, or a specific muscle per person based on relative muscle strength? Thanks!
Catherine, go here to learn more about the Phase 2 study:
https://clinicaltrials.gov/ct2/show/NCT04003974
When can we expect availability for the entire patient community? Isn’t “right to try” now a reality? I’m ready!
To those asking specifics about the losmapimod trial, at present the trial is active, but not recruiting.
https://clinicaltrials.gov/ct2/show/NCT04003974?cond=fshd&draw=2&rank=1
If Fulcrum (the drug company) finds the final analysis of the current phase2 trial encouraging, there will likely be either another phase2 trial or perhaps even a larger trial and a move to phase3.
The best way to keep informed of trial opportunities is to have your email address registered with the FSHD Society and to visit clinicaltrials.gov periodically searching on FSHD. I’d recommend searching clinicaltrials.gov at least once every six months. If you do the above you shouldn’t miss any trial opportunities. There are also, quite often, natural history study opportunities which are equally important, but don’t involve a study drug. Drug companies have far more interest in adding a disease to their drug pipeline when a disease has well run natural history study results to use in designing drug trials.
The ReSolve study is one such natural history study and it is actively recruiting:
https://clinicaltrials.gov/ct2/show/NCT03458832?cond=fshd&draw=2&rank=4
I believe there is another FSHD natural history study in the works that will likely be announced soon, so please watch for and consider that study. FSHD is a rare disease and recruiting adequate numbers of study and trial participants is often a challenge.
For those asking about public availability of the losmapimod study drug, unless the results of phase2 were remarkable and clearly convincing then we still have to likely get through one or two successful phase3 trials before the drug and trial results would be presented to the FDA. There are a variety of variables at play, but we’re probably talking low single digit numbers of year before the FDA approval would be considered along with successful trials, of course.
@Leslie… needle muscle biopsy for the trial was based on MRI analysis of leg muscles… quadricep, calf, tibialis (front of calf). Fulcrum chose to study leg muscle groups… and qualifying muscles had to fit Fulcrum’s criteria for specific level of disease. I believe Fulcrum was looking for a leg muscle that showed enough signs of FSHD that they could assume a good chance of DUX4 being expressed in the muscle, but not too much disease progression such that there’s little muscle to biopsy.
I’ve seen other studies where leg muscle is the source of needle muscle biopsy. I’m guessing, but I assume a part of the reason is that leg muscles are big so that likely makes the muscle easier to biopsy and more likely to get a good sample along with there likely being plenty to spare assuming the study or trial is going to repeat biopsies. By the way, needle muscle biopsies extract very small pieces of muscle and there is a very tiny incision that heals quickly and generally no lasting scar. A needle muscle biopsy is very different than the older style open-muscle biopsy that is far more invasive and leaves a permanent scar.
So, for this trial, needle muscle biopsies could come from a number of different leg muscle groups based on each participants’ MRI results.