Developing Therapeutics To Combat ALS
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Amyotrophic lateral sclerosis (ALS) is a rare progressive neuromuscular disease that is characterized by degeneration of motor neurons that causes a loss of voluntary muscle control. The exact cause of ALS is currently unknown, with evidence suggesting that both environmental factors and genetics can play a role in its development. Current therapeutics available to manage ALS focus on controlling symptoms to make living with the disease easier, but do not prevent or reverse neuronal damage.
Currently, ALS is fatal, with patients usually surviving for around three to five years after symptoms appear, although about 10% of people with ALS survive for 10–20 years. The poor prognosis of the disease highlights the urgent need for new treatments.
Katie Brighton (KB): Firstly, for our readers who might not be aware, what is amyotrophic lateral sclerosis? How is it currently treated or managed?
Alon Ben-Noon (ABN): “Amyotrophic” comes from the Greek language and means "no muscle nourishment” and when a muscle has no nourishment, it "atrophies" or wastes away. "Lateral" refers to the areas in a person's spinal cord where portions of the nerve cells that signal and control the muscles are located. As this “lateral” area progressively degenerates, it results in scarring or hardening ("sclerosis") of the tissue.
ALS represents one of the most extremely debilitating and progressive neuromuscular diseases. It was first identified in 1869 by French neurologist Jean-Martin Charcot. ALS, however, is more widely known as Lou Gehrig’s disease after it ended the career of one of Major League Baseball’s most beloved players in 1939.
There are approximately 17,000 people in the United States living with ALS and unfortunately, the exact cause of the disease is still unknown, with about 10–15% of cases having known genetic causes while the remaining cases have no clear cause. Most people who develop ALS are between the ages of 40 and 70, although the disease can occur at a younger age. The loss of motor neurons in people with ALS eventually results in loss of life, often within three to five years following diagnosis.
This shocking and dreadful prognosis is what made Lou Gehrig’s words famous during a speech on July 4, 1939, when he said: “I consider myself the luckiest man on the face of the earth”. These words demonstrated his positivity, resilience and humility despite his ALS diagnosis and still resonate amongst the sporting and ALS communities today.
KB: What are the current approaches to developing treatments for ALS? How do NeuroSense’s strategies differ?
ABN: A significant increase in public awareness of the devastating effects caused by ALS, marked by the ice-bucket challenge and other fundraising efforts in the last decade, has substantially accelerated drug development in ALS. Scientific and technological breakthroughs have given drug developers better tools to understand and potentially combat this devastating disease.
NeuroSense is among the leading companies developing ALS treatments, including Amylyx Pharmaceuticals which is currently awaiting an FDA decision expected this fall on its NDA for AMX0035, an oral fixed-dose combination of sodium phenylbutyrate and taurursodiol. AMX0035 also recently received approval in Canada.
Currently, five drugs are FDA-approved to treat ALS and its symptoms: Rilutek® (riluzole) was the first drug approved for ALS in 1995, Radicava™ (edaravone), approved in 2017, Tiglutik®, a thickened liquid form of riluzole approved in 2018, Exservan™, an oral film formulation of riluzole approved in 2019, and Nuedexta® (dextromethorphan HBr and quinidine sulfate), approved in 2011 and used to treat pseudobulbar affect, a condition that occurs in some people with ALS. Although these drugs are being routinely used for treatment, these options still have a limited impact on function and survival in ALS patients.
There are many shared pathological mechanisms between neurodegenerative diseases, some of which include neuroinflammation, protein aggregation, mitophagy, excitotoxicity, oxidative stress, iron accumulation and dysregulation of microRNAs (miRNAs). We believe that a disease-modifying drug for one neurodegenerative disease can lay the foundations for effective drugs to treat other neurodegenerative diseases.
While most drugs aim to address ALS by targeting only one pathological mechanism, at NeuroSense we are taking a different approach by pursuing three direct targets and addressing oxidative stress and glutamate excitotoxicity in the downstream processes. NeuroSense’s lead drug, PrimeC, which has received orphan drug designation in both the US and Europe, is a novel formulation composed of unique doses of two FDA-approved drugs, ciprofloxacin and celecoxib, which aim to synergistically inhibit the progression of ALS by regulating microRNA synthesis, reducing neuroinflammation and influencing iron accumulation.
KB: Can you explain how PrimeC works?
ABN: Besides its antibiotic mechanisms, ciprofloxacin has been shown to upregulate the expression of miRNAs by inducing Dicer enzyme activity and is a moderate iron chelator. Celecoxib, a non-steroidal anti-inflammatory drug, is designed to treat pain through the inhibition of cyclooxygenase-2, or COX-2, and the reduction of inflammatory processes, thereby affecting glutamate excitotoxicity and oxidative stress, among others.
By mitigating the degeneration and inflammatory response of motor neurons, we believe that PrimeC can improve motor performance and recover the morphology of motor neurons, neuromuscular junction structures and microglial cells. Furthermore, using two previously approved drugs gives us the advantage of being able to use the FDA’s 505(b) regulatory pathway, allowing us to rely in part on earlier agency findings of safety and efficacy, thereby reducing the time to market.
In preclinical testing, using a zebrafish model of ALS, PrimeC has significantly outperformed conventional treatments and was shown to improve motor performance and recover the morphology of neurons. More recently, results from our Phase 2a clinical study in Israel with 15 ALS patients studied over 12 months demonstrated that PrimeC was well tolerated, reduced functional and respiratory deterioration and resulted in significant changes in ALS-related biomarkers, indicating the biological activity of PrimeC.
In June of this year, we announced that the first patient has been enrolled in our Phase 2b PARADIGM trial. PARADIGM will enroll 69 people living with ALS in Israel, Italy and the U.S. The double-blind, placebo-controlled, multicenter trial will randomize participants at a 2:1 ratio to receive PrimeC or placebo, respectively. The clinical trial endpoints include assessment of ALS-biomarkers, evaluation of clinical efficacy and improvement in quality of life to demonstrate an attenuation in disease progression. We expect to complete enrollment by the end of 2022 and to report top-line results in the first half of 2023.
NeuroSense’s patient-centric study will be carried out in collaboration with cutting-edge technology partners on an extensive panel of biomarkers to elucidate PrimeC’s mechanism of action, as they believe this could enable patient stratification and increase the likelihood of success in a pivotal Phase III study, which they expect to commence in Q4 2023.
KB: What are the challenges behind developing ALS treatments?
ABN: Over the past decades, almost all clinical trials aiming to develop a successful therapy for ALS have failed, mostly due to genetic complexity, inadequate animal models, poor clinical trial design, lack of sensitive biomarkers, as well as diagnostic delays.
About 90–95% of all reported ALS cases are sporadic, without any known family history and identifiable risk factors, whereas familial ALS accounts for about 10% of all cases. Therefore, understanding the genes involved in ALS is critical for the development of therapeutic drugs. However, given the predominant sporadic occurrence and rarity of this disease, gene mapping and identification of causative genes have been challenging. As a result, patients with variable clinical subtypes are often pooled in the same study group leading to significant statistical differences.
Whilst multiple drugs have been tested in phase 2 or 3 clinical trials, none of these drugs have emerged as an effective therapeutic agent. Issues with trial designs have also hindered the development of an effective drug, mostly due to inappropriate trial rationale (from misleading positive results reported in mice), pharmacological issues, short study duration and variability of disease presentation in the patient population.
To address these challenges, reliable progression biomarkers can make it possible to conduct shorter trials on a smaller number of patients, thereby opening up the prospect of more diversified trials. Despite intensive research spanning the past 20 years, there are currently no practical diagnostic biomarkers for ALS, which often leads to diagnostic delays before the appropriate treatment is administered.
KB: NeuroSense is conducting biomarker studies for ALS, how do you identify the biomarkers of interest? How do biomarker studies help progress understanding of neurodegenerative diseases?
ABN: Our mission is to develop combined therapies for complex diseases, synergistically targeting multiple mechanisms, whilst utilizing regulatory pathways to bring these drugs to market within short timelines.
Biomarkers are measurable substances that change in quantity or can appear or disappear with the presence of a disease, such as chemical changes in the blood, urine or cerebral spinal fluid. We are currently conducting a collaborative biomarker study with Massachusetts General Hospital (MGH) following two prior successful studies conducted with the novel neuron-derived exosomes platform, also completed in collaboration with MGH. The initial study identified ALS biomarkers that are indicative of the mechanism of action for PrimeC in blood samples obtained from healthy people and people living with ALS. The second study analyzed blood samples from patients treated with PrimeC in NeuroSense's NST002 trial and examined the longitudinal effect of PrimeC administration on those identified biomarkers. Following 12 months of treatment with PrimeC, we observed statistically significant changes in key ALS-related biomarkers such as TDP-43, neuroinflammation and lysosomal trafficking. Moreover, there was a correlation between clinically meaningful outcomes and changes in these biomarkers.
Our current study aims to provide further insight into these biomarkers and their correlation to the progression of ALS symptoms, by evaluating the same biomarkers longitudinally in patients who have not been treated with PrimeC. This enhanced understanding of the underlying mechanism of action for PrimeC, and its impact on disease progression, will support the use of PrimeC as a drug for treating ALS and will assist NeuroSense in optimizing the clinical trials that are planned for FDA approval and commercialization.
We know that biomarkers play an increasingly important role in the understanding of ALS disease progression and the mode of action of PrimeC. Therefore, the data generated from these studies will provide additional insights and will also shape the design and outcome measures of upcoming clinical trials.
Alon Ben-Noon was speaking to Katie Brighton, Scientific Copywriter for Technology Networks.