With the FDA expected to decide in September on Amylyx Pharmaceuticals’ amyotrophic lateral sclerosis (ALS) treatment known as AMX0035, perhaps no one will be watching what the agency does more closely than Alon Ben-Noon.
Ben-Noon is the co-founder and CEO of NeuroSense Therapeutics, a developer of drugs for ALS and other neurodegenerative diseases. NeuroSense’s pipeline is led by its oral ALS candidate PrimeC, for which the company was granted U.S. Patent No. 10,980,780 last year for its novel formulation of a fixed-dose combination drug combining the broad-spectrum fluoroquinolone antibiotic ciprofloxacin and celecoxib, a non-steroidal anti-inflammatory drug (NSAID) marketed as Celebrex® but also available as a generic.
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 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.
Using two previously approved drugs gives NeuroSense the advantage of being able to use the FDA’s 505(b)(2) regulatory pathway, allowing the company to rely in part on earlier agency findings of safety and efficacy, thereby reducing the time to market.
Earlier this month, NeuroSense enrolled the first patient in its Phase IIb PARADIGM trial (NCT05357950), assessing PrimeC’s safety, tolerability, and efficacy in people living with ALS. PARADIGM will enroll 69 people with ALS in Israel, Italy, and the U.S., in a double-blind, placebo-controlled, multicenter trial that will randomize participants 2:1 to receive PrimeC or placebo.
NeuroSense expects to complete enrollment in PARADIGM by year’s end, with topline results set to be reported in the second quarter of 2023. The trial’s primary endpoints include assessment after six months of ALS-biomarkers, evaluation of clinical efficacy, and improvement in quality of life to demonstrate an attenuation in disease progression.
PARADIGM is one of two studies in progress on PrimeC for ALS. The other is a pharmacokinetic study (NCT05232461) designed to evaluate the effect of food on the bioavailability of PrimeC, compared with the bioavailability of co-administered ciprofloxacin tablets and celecoxib capsules in 12 healthy adults in the U.S. The open-label, randomized, single-dose, three-treatment, three-period crossover study is being carried out under an FDA-cleared IND protocol, with data set to be reported in Q3 2022.
Data from the pharmacokinetic study and PARADIGM will help NeuroSense design a pivotal Phase III trial of PrimeC, which has been granted Orphan Drug Designation by the FDA and the European Medicines Agency (EMA).
Amylyx decision postponed
NeuroSense is among companies developing ALS treatments. Among leading companies in the specialty is Amylyx, which is awaiting an FDA decision expected this fall on its NDA for AMX0035 (sodium phenylbutyrate [PB] and taurursodiol [TURSO; also known as ursodoxicoltaurine].
The FDA has set a PDUFA (Prescription Drug User Fee Act) target date of September 29 for a decision on AMX0035, an oral fixed-dose combination of two small molecules: sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine). PB is a small molecular chaperone designed to reduce the unfolded protein response (UPR), preventing cell death resulting from the UPR, while TURSO is a Bax inhibitor designed to reduce cell death through apoptosis.
The PDUFA date was extended three months from June 29 after Amylyx submitted to the FDA additional analyses of data from its clinical studies. The agency said the additional data constituted a major amendment to Amylyx’s NDA, hence the extension.
“We are confident in the potential of AMX0035 to help people living with ALS and other neurodegenerative diseases, and we continue to work closely with the FDA as they complete their review,” Amylyx’s co-CEOs and co-founders, Justin Klee and Joshua Cohen, said in a statement.
AMX0035’s road to approval suffered a setback in March, when the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee (PCNSDAC) recommended 6-4 against agency approval of the ALS combination drug. The adcomm majority concluded that data from Amylyx’s single 137-patient clinical study, the Phase II CENTAUR trial (NCT03127514), did not meet the panel’s standard for substantial evidence and persuasiveness.
The majority cited the rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) 24 weeks after treatment.
Amylyx insists its primary endpoint was met, reporting that participants treated with AMX0035 scored, on average, 2.32 points higher than placebo patients on ALSFRS-R over 24 weeks.
However Emily R. Freilich, MD, cross-disciplinary leader of FDA’s team of researchers reviewing Amylyx’s data, said the study population was small, the efficacy data modest, and imbalances between the cohorts could have affected the results: “The findings of the 24-week, double-blind CENTAUR study do not provide robust support for a treatment effect in patients with ALS,” Freilich said at the adcomm’s March 30 meeting, according to an FDA transcript.
The FDA usually follows the recommendations of its advisory committees but does not have to. Amylyx responded to the advisory panel’s negative recommendation with a statement from Jamie Timmons, MD, the company’s Head of Scientific Communications: “We remain confident in the data from the Phase 2 CENTAUR trial and the potential benefits of AMX0035 as a treatment option for people living with ALS.”
“Super informative”
Ben-Noon said Amylyx’s experience before the advisory committee or “adcomm” was “super informative”.
“We learned a lot from it, and we also learned that we are in the right path in the right way, so when the FDA will come to us, we will have the answers for the FDA and things will move smoothly.”
What did he and NeuroSense learn from the adcomm process?
“Execution of our study will be important, because of the criticisms they had about the way the Amylyx study went,” Ben-Noon said. “We are ensuring that we will not do the mistakes that, according to the FDA adcomm, Amylyx did. This is one thing that is important for us. And all the rest, we’ve actually addressed already in terms of running a robust biomarker study.”
“Luckily, we have also obtained statistically significant results in a large panel of biomarkers, and additional items that actually were already addressed from a regulatory perspective in the path that we’re going,” Ben-Noon added.
A search of ClinicalTrials.gov revealed 100 ALS-focused clinical trials as of June 16.
According to the ALS Association, five drugs are FDA- approved to treat ALS and its symptoms:
- Radicava™ (edaravone), first approved in 2017. An oral formulation, Radicava ORS, was approved on May 12 [marketed by Mitsubishi Tanabe Pharma America].
- Rilutek® (riluzole), the first drug approved for ALS in 1995, and now available as a generic [Sanofi]
- Tiglutik® (riluzole oral suspension), a thickened liquid form of riluzole approved in 2018 [ITF Pharma]
- Exservan™ (riluzole oral film), an oral film formulation of riluzole approved in 2019 [Mitsubishi Tanabe Pharma America].
- Nuedexta® (dextromethorphan HBr and quinidine sulfate), approved in 2011 and indicated for pseudobulbar affect which occurs in some people with ALS [Avanir Pharmaceuticals].
The clinical scramble to develop ALS candidates follows about a decade of heightened public awareness of the devastation caused by ALS, marked by the ice-bucket challenge and other fundraising efforts.
“Without the public attention, without more researchers in the field, maybe NeuroSense would never have been established,” Ben-Noon acknowledged.
He said that the attention, generated through patients and patient advocacy groups, “is a huge boost for us. It gives us energy. It gives us the sense that we are doing what we’re doing for a cause and we know who are the people that we are working for.
“Some amazing people that are our guiders,” Ben-Noon added. “And some, unfortunately are not with us anymore.”
Life-Changing relationship
Among those in the latter category was Shay Rishoni, an IRONMAN triathlete and the CEO of a sporting-events production company before contracting ALS. In 2013, RIshoni became CEO of Prize4Life, a nonprofit dedicated to supporting the discovery of treatments for ALS.
Rishoni’s fierce determination to spend his remaining days fighting the disease inspired Ben-Noon to change his life by launching NeuroSense. The two men met through Hagit Alon, PhD, an entrepreneur who worked with Rishoni to develop a digital health platform to assess ALS disease progression.
“Shay made me think that I’m not doing enough in my life basically,” recalled Ben-Noon, who at the time headed a consultancy working with dozens of biotech companies to assist them in advancing their pipelines. “Suddenly, I felt that if this guy, a super nice guy but completely paralyzed, can actually push mountains, why can’t I? And for this important cause?
“Seeing these miserable people in this miserable condition, one always probably thinks to himself that something needs to be done to change this condition, to change the future of patients, like Shay,” Ben-Noon said.
Rishoni passed away in 2018. Before he died, Ben-Noon showed him preliminary data from preclinical studies showing promise for PrimeC. The promise, according to Ben-Noon and NeuroSense, stems from PrimeC’s triple direct targeting of ALS, which entails regulating microRNA synthesis, influencing iron accumulation, and reducing neuroinflammation—all hallmarks of ALS pathologies.
“Many failed in the past, trying to address ALS with the only one target. From the beginning, we understood that we cannot take the same path,” Ben-Noon said. We are going with three direct targets and in the cascade, we are addressing oxidative stress and glutamate excitotoxicity in the downstream processes.”
By mitigating the degeneration and inflammatory response of motor neurons, NeuroSense reasons, PrimeC can improve motor performance, and recover the morphology of motor neurons, neuromuscular junction structures, and microglial cells—results first seen in preclinical studies in zebrafish models of ALS.
Last year, NeuroSense reported positive results from its Phase IIa NST002 trial (NCT04165850) showing that PrimeC was both safe and tolerable in 15 ALS patients studied over 12 months. The company also reported that initial clinical signals were seen, as overall disease decline was slower than expected compared with historical controls. NST002 was conducted in the ALS clinic at Tel-Aviv Sourasky Medical Center (TASMC).
Stock Surges, Then Falls
“I’m not an analyst. I cannot analyze the stock price. I was surprised by the reaction and also was surprised that it was reduced so drastically,” Ben-Noon said. “I think that some people recognized or heard about the Amylyx story, and they understood the huge potential that we have here with PrimeC when we presented amazing biomarker results, which Amylyx doesn’t have in their hands—and yet they’re worth so much more in valuation.
NeuroSense went public on the Nasdaq Capital Market in December 2021, through an initial public offering (IPO) that generated approximately $9.9 million in net proceeds. The company sold 2 million units—each consisting of one ordinary share and a warrant representing the right to purchase one ordinary share at the IPO price—plus 300,000 additional warrants, the latter being a partial exercise of the underwriter’s 45-day purchase option.
From an IPO price of $6 a share, NeuroSense’s stock price has dropped 73%. Despite the decline, Ben-Noon says he has no second thoughts about NeuroSense going public.
“We’re well financed, and that’s what counts. We can execute our program as we want to, as we think is the right way to move forward. We are not compromising about anything, and that’s what’s important,” Ben-Noon said.
Also in NeuroSense’s pipeline are two preclinical candidates also based on novel formulations of the ciprofloxacin-celecoxib combination: StabiliC for Parkinson’s disease, and CogniC for Alzheimer’s disease. Both are expected to conclude preclinical studies in the second half of this year and be IND-ready by the beginning of 2023.
Ben-Noon said NeuroSense envisions adding “maybe two or three more employees” to its workforce of 12, though the company addresses many of its needs through outside consultants.
“It’s not that we don’t care about the stock. But then, the situation is not very good in the market in general,” Ben-Noon observed. “I think it will improve at some point. We have lots of time to work in advance our programs, so once it improves the market can clearly appreciate what we’re doing, and once we have the results coming from the Phase IIb study, that will be an amazing inflection point for the company.”
ALS Drugs in the Clinic and Some Recent Failures
NeuroSense is among companies with clinical candidates in development for ALS. Among other developers:
- Alector and GlaxoSmithKline (GSK) earlier this year closed enrollment in a Phase IIa biomarker trial (NCT05053035) of the progranulin-elevating monoclonal antibody latozinemab (AL001) in people with ALS who carry a C9orf72 mutation, in what the companies called a strategic, non-safety related decision. They are considering a Phase IIb study of latozinemab in patients with all forms of ALS, including the C9orf72 mutation.
- Amylyx Pharmaceuticals is awaiting FDA review of its BLA for AMX035, an oral fixed-dose combination of sodium phenylbutyrate and taurursodiol. The FDA’s target decision date is September 29. In March, an FDA advisory panel recommended against agency approval of AMX035, citing concerns with the company’s pivotal study. (See above).
- Biogen and Ionis Pharmaceuticals on June 3 reported positive data from the Phase III VALOR trial (NCT02623699) and its open-label extension (NCT03070119) showing that immediate initiation of tofersen (BIIB067) in people with superoxide dismutase 1 (SOD1) ALS slowed declines in clinical function, respiratory function, muscle strength, and quality of life compared with initiation six months later. The positive secondary endpoint results emerged eight months after the companies acknowledged that VALOR missed its primary endpoint of ALSFRS-R change from baseline to week 28.
- Biohaven Pharmaceuticals is set to report topline data later this year on its first-in-class brain-penetrant, irreversible myeloperoxidase (MPO) enzyme inhibitor verdiperstat, one of several candidates being studied in Massachusetts General Hospital’s Phase II/III HEALEY ALS Platform Trial (NCT04436510). Biohaven is being acquired by Pfizer for $11.6 billion.
- Clene Nanomedicine is developing CNM-Au8®, a gold nanocrystal suspension for ALS as well as multiple sclerosis and Parkinson’s disease. At the European Network to Cure ALS (ENCALS) Meeting 2022, held June 1-3 in Edinburgh, Scotland, Clene presented interim survival data from its ongoing RESCUE-ALS long-term open label extension study showing that early treatment (decreased risk of mortality by 62% compared to either no treatment or delayed treatment. CNM-Au8 is also under study in the HEALEY trial.
- Eledon Phrmaceuticals on May 31 announced positive topline results for its lead compound tegoprubart (formerly AT-1501) in ALS showing it met its primary endpoints of safety and tolerability in a 12-week, 54-patient Phase IIa trial (NCT04322149). Dose-dependent target engagement was shown at the 4 and 8 mg / kg dosing levels using CD40L and CXCL13 biomarkers related to T cell and B cell function, respectively. ALS-associated pro-inflammatory biomarkers were seen and reduced.
- Neuvivo published positive Phase IIb data in February showing that its NP001, a multifactorial immune system regulator, demonstrated a 36% slower rate of decline in ALSFRS-R scores and a 51% slower rate of decline of respiratory function in a subset of 117 evaluable patients aged 40-65 over six months.
- Novartis is assessing the CSF-1R inhibitor sotuletinib (formerly BLZ945) in a Phase II trial (NCT04066244) designed to evaluate safety, tolerability and brain microglia response, to identify a dosage that measurably decreases translocator protein binding in the brain. The study’s estimated primary completion date is February 5, 2024.
- Wave Life Sciences is evaluating WVE-004 in C9orf72-associated ALS and/or frontotemporal dementia in the Phase Ib/IIa FOCUS-C9 trial (NCT04931862). In April, Wave published positive preclinical data showing that WVE-004 reduced C9orf72 transcriptional variants and poly(GP) dipeptide repeat proteins in mice for six months after only two doses. Clinical data from FOCUS-C9 is expected later this year.
However, the road to ALS drug development is littered with failures. Biogen earlier this month terminated a 4-1/2 year old, up-to-$217 million collaboration with Karyopharm Therapeutics to develop the oral selective nuclear export inhibitor KPT-350 for ALS, Karyopharm disclosed in a regulatory filing, a year after completion of a Phase I trial for which no results have been posted.
And in March, Biogen and Ionis in March halted their development of BIIB078 (IONIS-C9Rx), an antisense oligonucleotide (ASO) for people with C9orf72-associated ALS, after it failed a Phase I trial (NCT03626012) by not showing clinical benefit and not meeting any secondary efficacy endpoints.
Besides tofersen, Biogen and Ionis have a second ALS candidate in the clinic—BIIB105/ION541, an antisense treatment targeting ataxin 2 (ATXN2) RNA that is in a Phase I study (NCT04494256)
Also among ALS failures in recent years is Alexion’s Ultomiris® (ravulizumab), which is FDA-approved to treat adults and children (one month of age and older) with paroxysmal nocturnal haemoglobinuria (PNH). Alexion, the rare disease business unit of AstraZeneca, last year halted the Phase III CHAMPION-ALS trial (NCT04248465) at the recommendation of the study’s Independent Data Monitoring Committee (IDMC), which cited a lack of efficacy.
And in 2020, BrainStorm Cell Therapeutics acknowledged that its NurOwn® (MSC-NTF cells) failed a Phase III trial (NCT03280056) by not showing statistical significance in the primary endpoint, the proportion of participants who experienced a 1.25 points per month improvement in ALSFRS-R. That proportion was 34.7% in NurOwn patients (in line with the 35% assumption) but 27.7% for placebo patients, nearly double the projected 15%.