Fulcrum halts losmapimod development
by June Kinoshita
This morning, we received news Fulcrum has decided to halt its development of losmapimod (see press release below). Fulcrum’s decision was based on analysis of data from the Phase 3 REACH trial.
The REACH data reported small improvements in Reachable Workspace (RWS) not only in people taking the drug but in those taking placebo. This contradicts data from more than five years of natural history studies of FSHD, which have never shown an improvement in RWS in untreated individuals. The Phase 2 ReDUX4 trial of losmapimod showed a decline in the placebo group versus improvement in the treated group. In addition, the Open-Label Extension (OLE) study showed sustained benefits of losmapimod up to 96 weeks in those who were on the drug in ReDUX4, and stable symptoms or improvements for those from the placebo group who began taking losmapimod after the ReDUX4 trial ended.
It will be important to dive deeper into REACH data before broader conclusions can be made. For example:
-
- Was the REACH cohort different at baseline (the start of the trial) than the ReDUX4 cohort?
- In ReDUX4, scores from each participant’s dominant arm and non-dominant arm were analyzed separately and showed a larger effect in the non-dominant arm.
- In contrast, the REACH analysis combined the scores from both arms.
- What impact did this have on the outcome?
The Society looks forward to exploring the data further with Fulcrum. We’ll be following developments closely and report back.
What does this mean for our community?
For patients, it’s important to remember that there are many promising therapies in development. Losmapimod reduced DUX4 through an indirect pathway. Other companies, such as Avidity Biosciences, Dyne Therapeutics, Arrowhead Pharmaceuticals, and miRecule, are pursuing approaches that knock down DUX4 directly. Avidity’s interim data are already highly encouraging, and the company plans to begin recruiting participants for the next set of clinical trials later this year and next spring.
Though this is a setback, there will be important lessons to learn, and Fulcrum’s work puts us closer to treatment.
Fulcrum’s press release
CAMBRIDGE, Mass., Sept. 12, 2024 (GLOBE NEWSWIRE) — Fulcrum Therapeutics, Inc.® (the “Company”) (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases, today announced that its Phase 3 REACH trial evaluating losmapimod in patients with FSHD, did not achieve its primary endpoint of change from baseline in RSA with losmapimod compared to placebo. In addition, secondary endpoints did not achieve nominal statistical significance. The safety and tolerability profile of losmapimod was consistent with previously reported studies. The Company will complete a full evaluation of the data it received this week and plans to share the results at an upcoming medical meeting.
“We are deeply disappointed that the REACH trial did not replicate the clinical results observed in the Phase 2 ReDUX4 trial,” said Alex C. Sapir, Fulcrum’s president and chief executive officer. “In light of these results, we plan to suspend the losmapimod program in FSHD. We would like to thank the FSHD patients who participated in losmapimod clinical trials, their families, the investigators, the FSHD Society, and the broader FSHD community for their unwavering support for this program.”
Top-line REACH study results:
- Reachable Workspace (RWS): Participants receiving losmapimod demonstrated a 0.013 (±0.007) improvement in RSA at week 48 compared to placebo patients who showed a 0.010 (±0.007) improvement in RWS (p-value = 0.75).
- Muscle Fat Infiltration (MFI) as measured by Magnetic Resonance Imaging (MRI): Participants receiving losmapimod demonstrated an increase of 0.42% in MFI at week 48 compared to participants receiving placebo who showed an increase of 0.576% in MFI (p-value = 0.16).
- Shoulder Abductor Strength as measured by Hand-Held Dynamometry: Participants receiving losmapimod demonstrated a 9.63% improvement in abductor strength at week 48 compared to a 2.24% improvement in abductor strength seen in the placebo arm of the study (p-value = 0.51).
- Patient Reported Outcomes (PRO): Across the two PRO secondary endpoints in the REACH study, Patient Global Impression of Change (PGIC) and the Neuro QoL Upper Extremity, there were no statistically significant differences observed.
- Safety and Tolerability: The rate of treatment-related adverse events was similar in the two treatment arms, and there were no treatment-related serious adverse events in participants receiving losmapimod.
“These results in patients receiving losmapimod when compared to baseline were similar to those observed in our Phase 2 study,” said Dr. Pat Horn, Fulcrum’s chief medical officer. “However, in contrast to what was seen in the ReDUX4 study as well as what has been reported in other FSHD studies, the patients receiving placebo in REACH did not show a decline in functional status as measured by RWS and shoulder dynamometry over the 48 weeks of the study. As the largest interventional study ever completed in FSHD, we intend to share the full trial results with patients, study investigators, and the broader FSHD community to ensure others developing treatments for FSHD can benefit from these data.”
See the full press release from Fulcrum
Aqeel Mahesri says
Companies doing clinical trials for FSHD drugs should rethink who they are targeting in their clinical trials. Fulcrum did a 1 year study on patients with an average age in their fifties. C’mon, even healthy people in their fifties are experiencing muscle loss. Ambulatory FSHD patients in their fifties are experiencing muscle loss only slightly faster. Any 1 year delta in muscle loss between treatment and placebo groups, even for a *highly effective* DUX4 suppressant (i.e. one that suppresses DUX4 to the level of a healthy person), is going to be hard to see in the statistical noise!
If these companies want to show positive results in a reasonable timeframe, they should target YOUNG people with RECENT diagnoses, especially those who have an indication (such as a D4Z4 repeat count below 4) indicating that they would experience a rapid progression. This is the population who would experience the largest benefit from treatment.
Anonymus says
I am on my 30s, my symptoms are not so strong yet and am part of the study on the open label. And it is helping, my shoulders improved significanty and it is visible that I have more muscle on my legs and byceps. Most importantly, I did not feel much worsen since starting with the drug.
Hence, this news is hard to accept, since it seems that they may could have this drug approved that does not cure, but really helps, if designed a different study…
Anonymous says
I wanted to know what is open lab? And who can be part of it.
Anonymous says
Open label. It means it was not a placebo.
jkinoshita says
The Open Label study involved people who had participated in the Phase 2 randomized, placebo controlled trial (RCT). After that trial was completed, all participants were offered the opportunity to take the drug. Nearly everyone did and has been followed for 96 weeks. Those data indicated that sustained improvements in those who had been on the drug during the RCT and a stablization or improvement on those who had been on placebo (and shown a decline on average).
Hanny Hoek says
Goodmorning,
I was one of the persons that used lomapimod in a open label. This adventure stopt. I hope soon that a joint another trial.
-My question is how many days must between different trials before a start.
-Is this in every country the same?
I live in the netherlands and they said that i must wait for a 1 year before a begins a new trail.
In America a read that it was 30 days after those days the losmapimod was out of the body.
Maybe you have an answer for me?
Thanks for your time
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Brian Jude Loiacono says
After being devastated by the news , I needed to take a step back, process everything I know, and decompressed. Basically, since being diagnosed with FSHD in 2019, I have been controlling my own narrative, specifically, rigorous Physical Therapy, Acupuncture and Chiropractic, in addition to daily walking. My journey has been very challenging of late, but I’m forging forward despite the increased challenges. Like many of us, I attended many zoom wellness calls, and got caught up with all of the enthusiasm of Losmapimod, but I’m hearing Avidity Biosciences has had some good results as well, so maybe we aren’t too far away. If there is a silver lining here, I have interfaced with the most amazing and wonderful people in the world, helping me cope with the struggles. We will all be ok, I feel it in my bones, and fingers crossed and Gods loving hand, we will see the finish line sooner than later. God bless all of us 🙏🙏🙏🙏🙏🙏❤️❤️❤️❤️❤️❤️❤️