edaravone oral (FNP122) / Treeway, Ferrer International, Specialised Therap - LARVOL DELTA

ASURE: Alzheimer Study Using oRal Edaravone (clinicaltrials.gov) - P2 | N=61 | Completed | Sponsor: Treeway B.V. | Trial completion date: Mar 2025 ➔ Dec 2024

Trial completion date • Alzheimer's Disease • CNS Disorders • Aβ42

ASURE: Alzheimer Study Using oRal Edaravone (clinicaltrials.gov) - P2 | N=61 | Completed | Sponsor: Treeway B.V. | Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders • Aβ42

Post-hoc analysis of the adore study: an international, Phase 3 trial to investigate the efficacy and safety of daily oral edaravone (FNP122) in ALS (ALS-MND 2024) - "The primary analysis model included factors for treatment, time, treatment-by-time interaction, stratification factor concomitant use of riluzole (yes/ no), baseline ALSFRS-R score and stratification factor slope of disease progression (<1.0, 1.0) as fixed effects. Overall, 302 subjects were included in the mITT population for the main primary and post-hoc analyses. No changes were observed in the primary analysis after adjusting for baseline NfL and TRICALS Risk Profile as covariates. The mean difference between arms was not statistically significant (0.9 points, 95% CI (1.231–2.981), p = 0.41)."

Clinical • P3 data • Retrospective data • NEFL

Main results from the ADORE study: An international Phase 3 trial to investigate the efficacy and safety of daily oral edaravone (FNP122) in ALS (ALS-MND 2024) - "Objective: To present the main outcomes of the ADORE study: a phase 3 trial that assessed the efficacy and safety of daily edaravone in a new oral formulation, for the treatment of ALS. 304 participants from 37 sites were randomized to receive FNP122 (N 1⁄4 206) or placebo (N 1⁄4 98). Demographic characteristics: sex (61.3% male, 38.7% female), age (mean 59.3 years), race (91.1% white) were similar across treatment groups. Most participants were treated with riluzole (95.0%) and had a median ALS symptom duration of 14.0 months at baseline."

Clinical • P3 data

ADORE: Study to Investigate the Efficacy and Safety of FAB122 (Daily Oral Edaravone) in Patients With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P3 | N=313 | Completed | Sponsor: Ferrer Internacional S.A. | Active, not recruiting ➔ Completed | Trial completion date: Jun 2024 ➔ Oct 2023 | Trial primary completion date: Jun 2024 ➔ Oct 2023

Trial completion • Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

ASURE: Alzheimer Study Using ORal Edaravone (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: Treeway B.V. | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2024 ➔ Mar 2025 | Trial primary completion date: Jan 2024 ➔ Dec 2024

Enrollment closed • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Aβ42 • CHI3L1 • GFAP

ADOREXT: A Multicenter, Open-label Extension Study to Investigate the Long-term Safety of FAB122 in Patients With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P3 | N=206 | Terminated | Sponsor: Ferrer Internacional S.A. | Trial completion date: Jun 2026 ➔ Feb 2024 | Recruiting ➔ Terminated | Trial primary completion date: Jun 2026 ➔ Jan 2024; After the analysis of the main ADORE study it is concluded that there is no clinical benefit for the patients.

Trial completion date • Trial primary completion date • Trial termination • Amyotrophic Lateral Sclerosis • CNS Disorders

Ferrer’s ALS Agent FAB122 Fails to Meet Primary, Secondary End Points (NeurologyLive) - P3 | N=300 | ADORE (NCT05178810) | Sponsor:Ferrer Internacional S.A | "...FAB122...did not meet primary or key secondary end points in patients with amyotrophic lateral sclerosis (ALS). The company also announced the open-label extension ADOREXT study (NCT05866926) will be now concluded, based on the lack of efficacy of FAB122...AB122 did not display significant benefit compared with placebo in slowing disease progression after 48 weeks of daily dosing, as measured by change from baseline in the ALS Functional Rating Scale-Revised (ALSFRS-R) scale score...also did not observe improvement over placebo on long-term survival with FAB122 as measured by Combined Assessment of Function and Survival (CAFS) score at 48 weeks and 72 weeks in a subgroup of patients. Despite these findings, FAB122 was safe and well-tolerated."

P3 data • Trial termination • Amyotrophic Lateral Sclerosis

Mitsubishi Tanabe Pharma America Spotlights ALS Research at the XXVI World Congress of Neurology (PRNewswire) - "Mitsubishi Tanabe Pharma America, Inc...today announced the presentation of five abstracts in amyotrophic lateral sclerosis (ALS) at the XXVI World Congress of Neurology (WCN), being held virtually and in-person in Montreal, Quebec, October 15-19....A real-world analysis describing patient demographics, clinical characteristics and treatment outcomes in people with ALS being treated with intravenous (IV) RADICAVA, based on data collected from a U.S. provider of home and alternate-site infusions, will be presented....Study design details from the global, multi-center, double-blind, Phase 3b MT-1186-A02 study comparing two dosing regimens for oral edaravone to evaluate its long-term efficacy and safety in ALS, and its extension study, MT-1186-A04, will be shared. Additionally, 48-week safety results from the global Phase 3 multi-center, open-label clinical trial (MT-1186-A01) evaluating RADICAVA ORS in people with ALS will be presented."

Clinical protocol • P3 data • Real-world evidence • Amyotrophic Lateral Sclerosis • CNS Disorders

Specialised Therapeutics acquires commercialisation rights to new oral MND therapy (PRNewswire) - "Independent biopharmaceutical company Specialised Therapeutics Asia Pte Ltd (ST) will partner with Netherlands based biotechnology company Treeway BV to commercialise a new therapy to treat Amyotrophic Lateral Sclerosis (ALS) – the most common form of Motor Neurone Disease (MND) - in Australia and New Zealand. The therapy is known as TW001 and is a unique oral formulation of edaravone which works by reducing the oxidative damage associated with neuron death in ALS....Under the terms of the licensing agreement, ST will be responsible for all marketing, regulatory and distribution activities of TW001 for ALS/MND in Australia and New Zealand."

Licensing / partnership • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Tauopathies And Synucleinopathies

Ferrer Initiates its ADOREXT Extension Study in Amyotrophic Lateral Sclerosis (ALS) (Businesswire) - "Ferrer has announced the extension of its phase III clinical trial ADORE (ALS trial with Daily ORal Edaravone), with FNP122 in amyotrophic lateral sclerosis (ALS). The ADOREXT study offers the possibility of receiving FNP-122 to all ADORE participants that complete the full study period. Patients who stopped treatment (for other than safety reasons) but completed the study period will be also invited to participate in ADOREXT. All participants will remain in active treatment...It is expected that participants from additional countries will be enrolled in the coming months."

Trial status • Amyotrophic Lateral Sclerosis • CNS Disorders

ADOREXT: A Multicenter, Open-label Extension Study to Investigate the Long-term Safety of FAB122 in Patients With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P3 | N=225 | Recruiting | Sponsor: Ferrer Internacional S.A.

New P3 trial • Amyotrophic Lateral Sclerosis • CNS Disorders

ASURE: Alzheimer Study Using oRal Edaravone (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Treeway B.V. | Not yet recruiting ➔ Recruiting

Enrollment open • Alzheimer's Disease • CNS Disorders

A study to investigate the safety of FAB122 in patients with Amyotrophic Lateral Sclerosis on the long term. (clinicaltrialsregister.eu) - P3 | N=225 | Ongoing | Sponsor: Ferrer Internacional, S.A.

New P3 trial • Amyotrophic Lateral Sclerosis • CNS Disorders

ADORE: Study to Investigate the Efficacy and Safety of FAB122 (Daily Oral Edaravone) in Patients With Amyotrophic Lateral Sclerosis (clinicaltrials.gov) - P3 | N=300 | Active, not recruiting | Sponsor: Ferrer Internacional S.A. | Recruiting ➔ Active, not recruiting

Enrollment closed • Amyotrophic Lateral Sclerosis • CNS Disorders

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Pharmacodynamics and Pharmacokinetics of TW001 in Alzheimer Patients (CTAD 2022) - "Although the primary objective of this highly innovative study design is to investigate the effect of oral edaravone on a series of disease and target engagement (e.g., oxidative stress) biomarkers, the study will also explore the early effect of edaravone on a variety of individual biomarkers and surrogate endpoints such as EEG, to define a potential composite biomarker that can be used in subsequent long-term clinical studies. In addition, a newly developed and highly sensitive clinical assessment tool (Cognitive-Functional Composite - CFC), developed by the Alzheimer Center of Amsterdam, will be tested in the study as a clinical outcome measure to potentially detect early changes in cognitive function."

Clinical • PK/PD data • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • Cardiovascular • CNS Disorders • Dementia • Ischemic stroke

Evaluation of Safety, Pharmacodynamics and Pharmacokinetics of TW001 in Alzheimer Patients Evaluatie van veiligheid, farmacodynamiek en farmacokinetiek van TW001 in Alzheimer patiënten (clinicaltrialsregister.eu) - P2 | N=150 | Ongoing | Sponsor: Treeway TW001AD B.V.

New P2 trial • Alzheimer's Disease • CNS Disorders • Mental Retardation • Psychiatry • CHI3L1 • CSF Neurogranin • CSF P-tau • CSF T-tau • GFAP • Plasma NfL • Plasma T-Tau

ASURE: Alzheimer Study Using oRal Edaravone (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Treeway B.V.

New P2 trial • Alzheimer's Disease • CNS Disorders

Ferrer announces first patient enrollment of FNP122 in ADORE Phase III trial for ALS treatment (Select Science) - "Ferrer...has today announced the next major milestone in its mission to develop transformative therapies for Amyotrophic Lateral Sclerosis (ALS) – marked by the first patient enrolled in the ALS Deceleration with ORal Edaravone (ADORE), FNP122 Phase III clinical trial....The ADORE Phase III clinical trial is being conducted with the support of TRICALS, the largest European research initiative to find a cure for ALS....This major milestone comes swiftly after Ferrer announced its license agreement with Treeway – a Dutch clinical-stage biotechnology company founded by ALS patients – for the development and commercialization of FNP122 for ALS in certain territories, including Europe and some Asian countries."

Licensing / partnership • Trial status • Amyotrophic Lateral Sclerosis • CNS Disorders

Expression regulation of multiple key genes to improve L-threonine in Escherichia coli. (PubMed, Microb Cell Fact) - "The genetic engineering through the expression regulation of key genes is a better strategy than simple deletion of these genes to improve L-threonine production in E. coli. This strategy has little effect on the intracellular metabolism in the early stage of the growth but could increase L-threonine biosynthesis in the late stage."

Journal

Rebalancing microbial carbon distribution for L-threonine maximization using a thermal switch system. (PubMed, Metab Eng) - "The system was tested in an L-threonine producer Escherichia coli TWF001, and the resulting strain TWF106/pFT24rp overproduced L-threonine from glucose with 111.78% molar yield. The thermal switch system was then employed to switch off the L-alanine synthesis pathway, and the resulting strain TWF113/pFT24rpa1 overproduced L-threonine from glucose with 124.03% molar yield, which is higher than the best reported yield (87.88%) and exceeds the maximum available theoretical value of L-threonine production (122.47%). This inducer-free genetic circuit design can be also developed for other biosynthetic pathways to increase product conversion rates and shorten production cycles."

Journal

Increasing L-threonine production in Escherichia coli by overexpressing the gene cluster phaCAB. (PubMed, J Ind Microbiol Biotechnol) - "In this study, L-threonine production in an L-threonine-producing Escherichia coli strain TWF001 was significantly increased by overexpressing the gene cluster phaCAB from Ralstonia eutropha...Transcription analysis showed that the key genes in the L-threonine biosynthetic pathway were up-regulated, the genes relevant to the acetate formation were down-regulated, and the gene acs encoding the enzyme which converts acetate to acetyl-CoA was up-regulated. The results suggested that overexpression of the gene cluster phaCAB in E. coli benefits the enhancement of L-threonine production."

Journal

Transcriptomic analysis of an L-threonine producing Escherichia coli TWF001. (PubMed, Biotechnol Appl Biochem) - "Many genes encoding 30S and 50S subunits of ribosomes were also up-regulated. The findings are useful for gene engineering to increase L-threonine production in E. coli."

Journal

Deletion of arcA, iclR and tdcC in Escherichia coli to improve L-threonine production. (PubMed, Biotechnol Appl Biochem) - "In addition, TWF018 could consume glucose more efficiently than TWF001 and produce less acetate. The results suggest that deletion of arcA, iclR and tdcC could efficiently increase L-threonine production in E. coli."

Journal