trametinib repurposed (SNR1611) / GENUV - LARVOL DELTA

[PREPRINT] Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel in KRAS-mutated colorectal cancer (bioRxiv) - "HTS identified paclitaxel as being synergistic with trametinib. In vitro validation showed that, compared with monotherapies, this drug combination demonstrated strong inhibition of cell growth, reduced colony formation, and enhanced apoptosis in multiple KRAS-mutated CRC cell lines. Mechanistically, combining trametinib with paclitaxel led to alterations in signaling mediators that block cell cycle progression and increases in microtubule stability that resulted in significantly higher defects in the mitosis. Finally, the combination of trametinib with paclitaxel exhibited significant inhibition of tumor growth in several KRAS-mutant patient-derived xenograft mouse models."

Preclinical • Preprint • Colorectal Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

GENUV announces clinical results of new targeted Lou Gehrig treatment at the American Academy of Neurology [Google translation] (Pharm News) - "GENUV...will discuss degenerative diseases at the Society for Neuroscience (SfN) annual academic conference 'Neuroscience 2023', which will be held in Washington, D.C. from the 11th to the 15th. It was announced on the 10th that the clinical and preclinical results of the neurological disease treatment drug 'SNR1611 (ingredient name: trametinib)' will be announced. GENUV plans to disclose the clinical results of Phase 1/2a interim analysis data of 'SNR1611' for amyotrophic lateral sclerosis...clinical trial through an oral presentation session at this event. In addition, we plan to announce the results of research on treatment efficacy and mechanisms, such as extension of survival period, delay in motor function decline, and recovery of motor neurons and muscle cells confirmed in preclinical tests on ALS-induced animal models."

P1/2 data • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders

Trametinib activates endogenous neurogenesis and recovers neuropathology in a model of Alzheimer's disease. (PubMed, Exp Mol Med) - "The most potent hit from an FDA-approved drug library was SNR1611 (trametinib), a selective MEK1/2 inhibitor. Finally, trametinib induced neurogenic differentiation of NSCs derived from AD patient iPSCs, which suggests its potential therapeutic application. Altogether, we suggest that restoration of endogenous adult neurogenesis by trametinib may be a promising therapeutic approach to AD."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • NEUROG2

A MEK1/2 inhibitor trametinib for the treatment of amyotrophic lateral sclerosis - Interim analysis of a Phase 1/2a clinical trial (Neuroscience 2023) - P1/2 | "Mean changes from baseline of the Korean version of Amyotrophic Lateral Sclerosis Rating Scale-Revised (K-ALSFRS-R) scores of SNR1611 groups (SNR1611 0.5 mg, SNR1611 1 mg) seemed similar to those of Riluzole group despite the large age differences between the SNR1611 groups and Riluzole group of over 13 years (SNR1611 0.5 mg: 63.38±6.55, SNR1611 1 mg: 63.25±6.30, Riluzole: 50.00±11.80 years). As older age at onset is related to faster progression, trametinib may show significant efficacy in age-stratified, well-powered clinical trials, warranting its further development for ALS."

Clinical • P1/2 data • Amyotrophic Lateral Sclerosis • CNS Disorders

High content phenotypic screening platform ATRIVIEW® for compounds that induce neurogenesis and neuroprotection mechanisms in the neurodegenerative environment (Neuroscience 2023) - "As a new therapeutic approach for treating neurodegenerative diseases, we have identified the importance of neuro-regeneration and neuroprotection by mechanistic studies: those leading to pathophysiological rescues by inducing neurogenesis/neuroprotection with SNR1611(trametinib, active pharmaceutical ingredient of Mekinist®) in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS)...Thus, the rapid and advanced ATRIVIEW®-AI platform increases screening efficiency by dramatically reducing the resources and time required for image analysis while enhancing acuity. Furthermore, it allows evaluation of biomarkers underlying the processes of neurogenesis/neuroprotection in the primary cell culture, increasing the potential of identifying drug candidates for the treatment of neurodegenerative disease."

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders

Combined treatment with trametinib and riluzole improves motor function by enhancing autophagy in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. (Neuroscience 2023) - "In motor neurons of trametinib+riluzole administrated SOD1-G93A mice, the level of cathepsin D and the co-localization of LC3 and LAMP1 increased, while abnormal p62 accumulation was significantly reduced, indicating improvement of autophagic flux. Altogether, these data suggest that low dose trametinib+riluzole combination therapy is pharmacologically superior to monotherapy in the ALS mouse model and could serve as a promising clinical combination for the improvement of current neuroprotective treatment strategies of ALS."

Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • CTSD • LAMP1

GENUV “Confirmed a 2.7-fold increase in cranial nerve regeneration in preclinical studies of candidate substance for Alzheimer’s disease” [Google translation] (Health Korea News) - "GENUV...announced on the 5th that it has discovered that the expression of specific genes involved in brain nerve cell differentiation increases brain nerve regeneration by more than 2.7 times and improves memory by about 2-fold. GENUV's preclinical test results for 'SNR1611 (ingredient name: trametinib)'...showed that it inhibits MEK1/2 protein signaling, one of the overactivated cytoplasmic enzymes 'mitogen-activated protein kinase (MAPK)'. It was confirmed that the expression of genes related to neuronal differentiation specifically increased....When 'SNR1611' was administered to an Alzheimer's disease-induced animal model, nerve regeneration in the dentate gyrus, the inner region of the hippocampus responsible for memory, and the subventricular zone, the lower region of the paraventricular system, increased compared to the non-administered group. They increased by about 176.3% and 295.2%, respectively."

Preclinical • Alzheimer's Disease • CNS Disorders

Combination of Dabrafenib, Trametinib, and Navitoclax Shows Promise in Metastatic Melanoma (Targeted Oncology) - P1/2 | N=75 | NCT01989585 | "The phase 2 CTEP-P9466 trial (NCT01989585) evaluating the combination of dabrafenib (Tafinlar) with trametinib (Mekinist) and navitoclax met its co-primary end point for complete response (CR) rate vs historical controls in patients with BRAF V600–mutant metastatic melanoma...the study missed its other co-primary end point of maximal tumor shrinkage for patients treated with the combination of dabrafenib, trametinib, and navitoclax vs those given dabrafenib plus trametinib...patients who received the triplet combination (n = 25) experienced an overall response rate (ORR) of 84%, consisting of a 20% CR rate and a 64% partial response (PR) rate....At a median follow-up of 27.4 months, the median PFS was 20.9 months (95% CI, 11.3–not reached [NR]) with the triplet and 21.7 months (95% CI, 9.6-NR) with the doublet (log-rank P = .7)."

P2 data • Melanoma • Oncology • Solid Tumor

Trial of Safety, Tolerability and Efficacy of Trametinib (SNR1611) in Patients With Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P1/2 | N=23 | Terminated | Sponsor: Genuv Inc. | Trial completion date: Dec 2024 ➔ Apr 2023 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Apr 2023; Terminated as it is considered that necessary data have been collected

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

Pancancer Activity of Dabrafenib Plus Trametinib in Patients with BRAFV600E-Mutated Rare Cancers (ESMO.org) - "The encouraging tumour-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers according to Dr. Vivek Subbiah..."

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Naporafenib Plus Trametinib in Advanced NRAS-Mutant Melanoma (THE ASCO POST) - "The investigators concluded, 'Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.'"

Lung Cancer: How a Drug Combination May Help Reduce Tumors (Healthline) - "Dr. Ranee Mehra...agreed with taking a cautious approach. 'For patients, we hope a reduction in tumors will help them to live longer,' she told Healthline. 'But we cannot make that assumption from laboratory studies done in mice.' Ultimately, though, 'this data does provide more justification for considering further studies,' Mehra noted....'NSCLCs can have mutations associated with them that drive the growth of the cancer,' stated Mehra."

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Repurposing of Trametinib in the SOD1-G93A mouse model of amyotrophic lateral sclerosis (Neuroscience 2022) - P1/2 | "Previously, we selected a MEK inhibitor, trametinib (SNR1611), as the most neuroregenerative and neuroprotective substance among FDA-approved small molecule drugs through a phenotype-based screening using neural stem cells...The combined data provide clear evidence that MEK inhibition by trametinib slows disease progression of the ALS model mice by enhancing autophagy and thus protecting motor neurons, as we have shown in AD models. Currently, trametinib is a repurposed drug candidate in clinical trial (Phase I/IIa) for the indication of ALS in Korea (ClinicalTrials.gov identifier: NCT04326283)."

Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders

Trametinib rescues neurodegeneration by enhancing TFEB-dependent autophagic lysosomal function in Alzheimer’s Disease model mice (Neuroscience 2022) - "We observed that a MEK1/2 inhibitor, trametinib (GSK1120212, SNR1611), reduced Aβ deposition in the 5XFAD mice (2.5 month-oral administration to 5-month-old) and thus protected against Aβ-mediated apoptotic neuronal death...Finally, we showed that the level of pTFEB is higher in AD patient brains than in age-matched normal brains, indicating the relevance of our studies in human disease. Altogether, we have demonstrated that MEK inhibition by trametinib provides neuronal protection from Aβ burden through increased autophagic lysosomal activity and present it as a potential therapeutic strategy for AD."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • CTSB • TFEB

Inhibition of MEK1/2 promotes endogenous neurogenesis and improves cognitive deficits in models of Alzheimer’s disease (Neuroscience 2022) - "Using an adult neural stem cell (NSC)-based phenotypic screening platform (ATRIVIEW®), we identified that SNR1611 (trametinib, Mekinist®; a selective MEK1/2 inhibitor) was the most potent hit among the small molecule drugs approved by US FDA...Finally, we present human relevance for the therapeutic potential of trametinib by confirming its neurogenic differentiation effect in NSCs derived from AD patient-induced pluripotent stem cells. Overall, these data suggest that trametinib enhances adult neurogenesis and replenishes neurons in brain areas where neurodegeneration most affects AD and that further evaluation of activating neurogenesis as a potent treatment for AD and other neurodegenerative diseases is warranted."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Efficacy of trametinib in patients with multiple myeloma with NRAS and KRAS mutations (YouTube) - "Meral Beksac, MD...talks on the efficacy of trametinib in patients with triple-class refractory multiple myeloma who are KRAS or NRAS-mutated. This interview took place at the 19th International Myeloma Society Meeting (IMS) held in Los Angeles, CA."

Interview • Video

Trial of Safety, Tolerability and Efficacy of Trametinib (SNR1611) in Patients With Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P1/2 | N=30 | Recruiting | Sponsor: Genuv Inc. | Trial completion date: Dec 2022 ➔ Dec 2024 | Trial primary completion date: Dec 2022 ➔ Dec 2024

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

Publication in Nature Molecular Psychiatry Supports Genuv’s Alternate Theory for Treatment of Alzheimer’s Disease (Businesswire) - “Genuv Inc…announced the publication of a manuscript in Molecular Psychiatry…published by Springer Nature Group. The new research provides important validation for the company’s six-year effort to develop new treatments for neurodegenerative diseases including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS)….The article presents findings from Genuv’s preclinical experiments treating a mouse model of Alzheimer’s with SNR1611, a commercially available MEK 1/2 inhibitor. Treating the mice with SNR1611 was found to protect neurons by inducing autophagic lysosomal activity, which in turn led to reductions in the amyloid beta plaques that are the physiological hallmark of the disease.”

Preclinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders

MEK1/2 inhibition rescues neurodegeneration by TFEB-mediated activation of autophagic lysosomal function in a model of Alzheimer's Disease. (PubMed, Mol Psychiatry) - "Here, we showed that inhibiting MEK/ERK signaling using a clinically available MEK1/2 inhibitor, trametinib (GSK1120212, SNR1611), induces the protection of neurons through autophagic lysosomal activation mediated by transcription factor EB (TFEB) in a model of AD. From these observations, we concluded that MEK inhibition provides neuronal protection from the Aβ burden by increasing autophagic lysosomal activity. Thus, MEK inhibition may be an effective therapeutic strategy for AD."

Journal • Alzheimer's Disease • CNS Disorders • TFEB

Michael Atkins, MD, on Initial Immunotherapy vs Targeted Therapy for BRAF-Mutant Melanoma – Study compared nivolumab/ipilimumab followed by dabrafenib/trametinib with the converse (MedPageToday) - "In the following interview he discusses the study's highlights...Atkins: Based on the DREAMseq trial, combination nivolumab/ipilimumab should be the preferred initial treatment for patients with BRAF-mutant metastatic melanoma. And based on the CheckMate 204 trial and the ABC melanoma trial, this combination is also the preferred treatment approach for patients with asymptomatic melanoma brain metastases."

Interview

New Research Says Combination Immunotherapy Should be First-Line Therapy for Patients with BRAF-mutant Melanoma (Melanoma Research Alliance) - '"What this means is that response rates were consistent for patients when receiving targeted therapy as first or second line therapy, whereas response rates for immunotherapy were less effective if patients received targeted therapies first,' says Dr. Atkins."

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Immunotherapy Combination Most Effective as Initial Treatment for BRAF+ Melanoma (National Cancer Institute) - P3 | N=265 | DREAMseq (NCT02224781) | "According to Michael Atkins, M.D...who led the trial, the findings support an immediate change in clinical practice and will have 'a significant impact on clinical care.' Dr. Atkins presented results from the trial as part of the American Society of Clinical Oncology Virtual Plenary Series on November 16."

Media quote • P3 data

Trametinib restores memory deficits by activating endogenous neurogenesis in mouse model of Alzheimer's disease (Neuroscience 2021) - "Proposed treatments based on neurotoxic protein elimination, however, have brought disappointing results until recent controversial approval of Aduhelm TM , suggesting that new approaches should be explored...Using a FDA-approved drug library, we identified the most potent hit, SNR1611 (Trametinib), a selective MEK1/2 inhibitor...Altogether, these observations provide evidence that MEK inhibition by trametinib induces endogenous neurogenesis in the brain cortex as well as in the DG/SVZ and is a potential therapeutic approach for the recovery from neurodegeneration. Therefore, we are suggesting that trametinib is a new therapeutic candidate for AD.; Grant Support: Genuv Inc.; KHIDI grant HI18C1801"

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Trametinib protects motor neurons from degeneration by enhancing autophagy in the SOD1 G93A amyotrophic lateral sclerosis model mice (Neuroscience 2021) - P1/2 | "Previously, we screened a MEK inhibitor, trametinib (SNR1611) from a FDA-approved drug library by its neurogenerative and neuroprotective effect...The combined data provides clear evidence that MEK inhibition might be a novel therapeutical approach for ALS by enhancing autophagy and eliminate disease-causing mutant proteins. Currently, trametinib is a repurposed drug candidate in the clinical trial (Phase I/IIa) for the indication of ALS in Korea (ClinicalTrials.gov identifier: NCT04326283).; Grant Support: Genuv Inc."

Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • CTSD • LAMP1

Mek1/2 inhibition rescues neurodegeneration by activation of autophagic lysosomal function in alzheimer’s disease (Neuroscience 2021) - "Here, we showed that inhibition of MEK/ERK signaling using a clinically available MEK1/2 inhibitor, trametinib (GSK1120212, SNR1611) protected neurons in AD-model mice (5XFAD)...In addition, trametinib elevated autophagic lysosomal activity in 5XFAD cortex and primary cortical neurons cultured with Aβ oligomers. From these observations, we concluded that MEK inhibition provides neuronal protection by increasing autophagic lysosomal activity, and thus MEK inhibition might be effective therapeutic strategy for AD.; Grant Support: Genuv Inc.; KHIDI grant HI18C1801"

Alzheimer's Disease • CNS Disorders • Cognitive Disorders