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Introduction
Fulcrum Therapeutics (NASDAQ:FULC) is a biopharmaceutical company that specializes in the development of innovative therapies for the treatment of genetic diseases. One of the company’s most promising experimental drugs is losmapimod, which is being developed as a treatment for facioscapulohumeral muscular dystrophy, a rare and progressive genetic disorder that affects the muscles of the face, shoulder blades, and upper arms.
The following article will focus on losmapimod’s prospects for the treatment of facioscapulohumeral muscular dystrophy.
Financials
Before we dive in, let’s review Fulcrum’s most recent financial report. The financial results for the third quarter of 2022 show that the company had $221.8 million in cash, cash equivalents, and marketable securities, an increase from $218.2 million at the end of 2021. This increase is primarily due to an equity offering in August 2022, but it was partially offset by operating expenses. Collaboration revenue for the quarter was $1.2 million, a decrease of $3.7 million from the same quarter in 2021, due to the winding down of a collaboration agreement with Acceleron Pharma Inc. Total operating expenses for the quarter were $25.5 million, with a decrease in R&D expenses offset by an increase in G&A expenses. The net loss for the quarter was $23.7 million, compared to a net loss of $20.7 million in the third quarter of 2021. Fulcrum predicts that its current cash reserves will be sufficient to support its operating expenses and capital expenditures into late 2024. As of writing (February 13, 2023), Fulcrum is valued at $785 million (market capitalization).
FSHD Pathophysiology/Symptoms
Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder that significantly impairs the lives of around 1 in 24,000 individuals worldwide. It is among the most prevalent types of muscular dystrophy. The condition is caused by a genetic mutation that leads to an overabundance of a protein known as DUX4, which contributes to the degeneration of muscle cells and the consequent weakening, wasting, and shrinking of the muscles.
The symptoms of FSHD can vary greatly, but most sufferers experience the progressive weakening and wasting of their muscles, particularly those located in the face, shoulders, and upper arms. As the disease advances, patients may struggle with routine tasks such as eating, speaking, and walking, further hindering their quality of life.
One aspect of FSHD that is particularly important to consider is the patient’s reachable workspace. The reachable workspace refers to the area within the patient’s immediate environment that they can reach with their limbs and hands. As the disease progresses and muscle weakness sets in, the reachable workspace can become smaller and smaller, making it increasingly difficult for patients to perform everyday activities, such as reaching for objects on a shelf or brushing their teeth. This highlights the importance of designing interventions that aim to maximize the reachable workspace for FSHD patients, helping them to maintain their independence and independence for as long as possible.
FSHD Current Treatment and Limitations
At present, FSHD remains incurable and without any approved interventions to slow down or arrest the progression of the disease. The available management options for patients are primarily focused on symptom relief and quality of life improvement through physical therapy, rehabilitation, and the use of assistive devices. Commonly used drugs include nonsteroidal anti-inflammatory medications such as ibuprofen to enhance mobility and antidepressants or antiepileptic drugs to alleviate chronic pain. Although these treatments can provide some degree of symptom relief, they do not target the root cause of FSHD and hence do not have any impact on slowing down or stopping the progression of the disease.
Experimental Attempts to Improve Function
With the absence of a clear understanding of the underlying mechanisms of the disease, early therapeutic efforts aimed at enhancing muscle function, but were not targeted and relied on the use of anabolic and anti-inflammatory drugs. The outcomes of these treatments were inconsistent and, in some instances, the use of myostatin inhibitors to increase muscle mass did not result in any significant functional improvement.
Common clinical endpoints include biomarkers (e.g. inflammatory markers, DUX4), mobility (e.g. ability to extend/raise arms), imaging (e.g. MRIs to quantitate fatty infiltration of muscles), and patient-reported outcomes (assessing quality of life).
Losmapimod – Mechanism of Action
Losmapimod is a p38 MAPK inhibitor. It is unique in that it is the first compound to target the underlying mechanism of FSHD by inhibiting DUX4. The significance of this compound and its related pathway was discovered by a research group while investigating signaling pathways involved in the repression of DUX4 by β2-agonists. Given that β2-agonist signaling activates p38 MAPK, it was initially believed that inhibitors of p38 MAPK would prevent β2-agonists from suppressing DUX4. However, it was discovered that targeting this pathway independently inhibits DUX4 expression, regardless of the presence of β2-agonists.
Losmapimod – Data Prior to FSHD Experimentation
Before its acquisition by Fulcrum Therapeutics in 2019, losmapimod had undergone several clinical trials, including trials with over 3,600 patients, for the treatment of various conditions such as cardiovascular and pulmonary diseases. The trials indicated that losmapimod was well-tolerated and had a positive safety profile, however, it failed to meet efficacy criteria.
Despite its prior limitations for common diseases, losmapimod is considered a significant advancement in FSHD clinical experiments compared to earlier, untargeted drugs. With its targeted approach and the presence of supportive preclinical data and larger sample sizes, losmapimod offers higher prospects of a conclusive outcome, making it a highly anticipated compound in the quest for effective treatments for FSHD.
Losmapimod – Phase 1 & 2 FSHD Data
Phase 1 – safety, tolerability, pharmacokinetics, and target engagement
A phase 1 study assessed the safety, tolerability, pharmacokinetics, and target engagement of losmapimod in healthy and FSHD volunteers. The findings of the study indicated that losmapimod was well received and produced results that aligned with the established safety and tolerability profile. The study revealed that losmapimod reached its intended target in skeletal muscle at concentrations proportional to the dose and effectively suppressed p38 α/β in both blood and muscle. These concentrations were in line with previous preclinical research, which demonstrated a significant reduction in DUX4 expression.
Phase 2 – DUX4 expression and secondary endpoints
The results of the phase 2 clinical study indicated that losmapimod did not effectively reduce DUX4-driven gene expression, which was the primary endpoint, compared to the placebo. This failure is attributed to the difficulties in detecting changes over time due to the dynamic and limited nature of DUX4 expression. The expression of DUX4 can fluctuate by 1000 times and is only found in about 1 in 1000 muscle nuclei, making it a challenge to track its presence. The use of needle biopsy, which only examines a small portion of muscle tissue from a diverse cell environment, adds further variability both between and within patients, making it challenging to detect any effects of the treatment. The imprecision of the needle biopsy procedure across multiple trial sites only exacerbates these difficulties, making it difficult to determine the efficacy of losmapimod in the clinical setting.
The drug did succeed in three ways relative to placebo:
- Statistically significant change in Muscle Fat Infiltration within intermediate muscles (p=0.01)
- Statistically significant improvements in three of the four reachable workspace (RWS) assessments (p≤0.05) – a key function
- Statistically significant improvements in Patients’ Global Impression of Change (PGIC) (p=0.02) – a key patient-reported outcome
Losmapimod, however, failed in several other aspects. It did not enhance other indicators of muscle health apart from reducing fat infiltration. Moreover, it did not result in an improvement in the facioscapulohumeral muscular dystrophy-health index, which is a patient-reported outcome. Lastly, functional assessments such as the timed up and go test, which evaluates a patient’s capability to stand up from a seated position and walk, showed no improvement.
Subsequent to the few successes, Fulcrum is now evaluating its drug in a phase 3 trial with RWS as a primary endpoint and MFI and PGIC as secondary endpoints.
FSHD Market
According to Fulcrum’s estimates, the US population affected by FSHD is between 16,000 and 38,000 individuals. The healthcare costs directly linked to FSHD can reach up to $23,000 per year, depending on the severity of the illness. With no cure or approved treatments available, the market for FSHD treatments presents a significant opportunity. If losmapimod proves to be effective in a phase 3 trial, demonstrates significant benefits, and gains FDA approval, Fulcrum could price it competitively due to the rarity of the disease and the lack of existing treatments.
For example, if losmapimod is priced at $50,000 per year and is able to reach 60% of the affected population (16,000 individuals), Fulcrum could generate $480 million in annual revenue. Additionally, as losmapimod has been granted Orphan Drug Designation, Fulcrum would have at least seven years of market exclusivity before generic versions become available.
My Analysis
Losmapimod has the advantage of having already demonstrated its safety and tolerance in thousands of patients. Despite showing disease-modifying potential in preclinical studies, as indicated by its ability to decrease DUX4 expression, this effect was not observed in FSHD patients. Fulcrum attributes this to the challenges associated with detecting changes over time, such as variability and biopsy limitations, and the experimental nature of the biomarker.
Losmapimod did not improve many outcomes in phase 2 but did hit on important ones, such as muscle health (muscle fat infiltration), function (RWS), and patient-reported outcomes. These are important achievements for a population like FSHD and the FDA has been, and will likely continue to be, accommodating given the critical need for treatments. The question now becomes can losmapimod redemonstrate these benefits with larger numbers.
The improvement in muscle fat infiltration is likely due to the inhibition of p38 MAPK, rather than being a consequence of reduced DUX4 activity.
FSHD patients, in general, tend to be overweight because of various factors such as a genetic predisposition and a lack of physical activity. In the phase 2 trial of losmapimod, the average baseline Body Mass Index (BMI) of the participants was 25.71. Inhibition of p38 MAPK has been linked to improved glucose uptake in insulin-resistant fat cells, and losmapimod has been shown to be active in muscle.
A study on p38 MAPK inhibition in patients recovering from rotator cuff repair also supports this:
Inhibition of p38 MAPK was found to have a significant decrease in intramuscular lipid accumulation and fibrosis that is usually seen in the degenerative cascade of rotator cuff tears, without having negative effects on the contractile properties of the rotator cuff muscle tissue.
Reduction of muscle fat infiltration improves range-of-motion/reachable workspace
Reduction in muscle fat infiltration, or adipose reduction, can potentially improve range of motion (ROM). Fat infiltration in muscle can cause stiffness and impair movement, so reducing the fat content can lead to improved flexibility and mobility. However, this improvement in range of motion may vary depending on the individual and the specific condition being treated. It is important to note that other factors, such as muscle strength and nerve function, can also impact range of motion, so a comprehensive approach to treatment is often necessary.
Improvements in ROM/RWS increase quality of life
Patients’ Global Impression of Change scale asks the following of patients after treatment:
Since beginning treatment …, how would you describe the change (if any) in ACTIVITY LIMITATIONS, SYMPTOMS, EMOTIONS and OVERALL QUALITY OF LIFE, related to your … ?
Notice the first outcome: activity limitations.
Conclusion
The challenge of finding an effective treatment for FSHD persists, as there are currently no approved interventions to halt or slow down the progression of the condition. Despite this, losmapimod presents a potentially promising therapeutic approach for FSHD patients, as it aims to address the root cause of the disease through the inhibition of DUX4 expression. However, there are concerns about the true disease-modifying properties of losmapimod, as the modest benefits observed in a phase 2 trial may be attributed to improved glucose uptake in insulin-resistant fat cells rather than reduced DUX4 activity, as Fulcrum hopes. Nevertheless, losmapimod may still prove beneficial for FSHD patients, given its safety and tolerability profiles. The results of the phase 2 study are inconclusive and more research is needed to determine the efficacy of losmapimod as a treatment for FSHD. My rating for Fulcrum’s stock is a “hold”, and caution and appropriate allocation is advised for investors as they await the results of phase 3 trials.
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