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 that start of the trial (“time zero”), all of the patients had a biopsy in which a tiny sliver of muscle is 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 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.”