Nerventra (laquinimod) / Active Biotech - LARVOL DELTA

Beta Interferon 1a and Laquinimod Differentially Affect Coagulation-Related Gene Expression in Multiple Sclerosis Patients: Implications for Clinical Efficacy and Side Effects. (PubMed, Int J Mol Sci) - "Laquinimod (LAQ) and interferon-β1a (IFN-β1a, Rebif) are immunomodulatory therapies for relapsing-remitting multiple sclerosis (RRMS) that may also influence vascular and hemostatic pathways. Both therapies modulate transcriptional regulators of vascular homeostasis, revealing a potential molecular interface between immune modulation and hemostatic balance in RRMS. These findings are exploratory and hypothesis-generating, warranting further functional and clinical validation."

Adverse events • Journal • CNS Disorders • Immune Modulation • Immunology • Multiple Sclerosis • ANXA2 • F13A1 • IFNB1 • PROS1 • SERPINA1 • SERPINE1

Laquinimod treatment attenuates EAU by inhibiting both the inductive and effector phases in an APC-dependent manner. (PubMed, bioRxiv) - "LAQ protects against EAU by acting on AhR-expressing antigen-presenting cells to impair both priming and reactivation of pathogenic T cells. Its active metabolite DELAQ does not suppress T cells directly, but re-programs dendritic cells toward a tolerogenic, IDO-expressing phenotype that promotes immune regulation."

IO biomarker • Journal • Immunology • Infectious Disease • Ocular Inflammation • Ophthalmology • Tetanus • Uveitis • AHR • FOXP3 • IDO1 • IDO2

What Is the Evidence on Immunomodulators and Immunosuppressants for Progressive Multiple Sclerosis? - A Cochrane Review Summary with Commentary. (PubMed, NeuroRehabilitation) - "Also, rituximab, natalizumab, siponimod, and ocrelizumab probably do not increase the risk for treatment discontinuation due to AEs, while laquinimod may not increase the risk treatment discontinuation due to AEs.ConclusionsCompared with placebo, two-, and three-year treatment with rituximab or interferon beta-1b, respectively, probably slightly reduce relapses in PMS people. A slight increase of treatment discontinuation due to AEs has been reported for rituximab, interferon beta-1b, interferon beta-1a, immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab. No reliable evidence is available for disability progression and SAEs with available DMTs compared to placebo."

Journal • CNS Disorders • Multiple Sclerosis

Efficacy and safety of laquinimod versus placebo in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials. (PubMed, J Int Med Res) - "These findings support the efficacy of laquinimod in managing RRMS but necessitate careful monitoring during treatment."

Clinical • Journal • Retrospective data • Review • CNS Disorders • Multiple Sclerosis

Mapping the Efficacy Landscape: A Network Meta-Analysis of Pharmacological Interventions in Huntington's Disease (MDS Congress 2024) - "UHDRS TMS scores for Laquinimod 1.5mg OD showed a significant mean difference of 9.7 (95% CI: 2.55 to 16.85). RO7234292 ODC 120 mg once every 4 weeks showed a mean difference of 4.55 (95% CI: 1.59 to 7.5)... Rivastigmine incremental dose (1.5-3 mg BID) , Creatinine (40mg), HUFAs mixture (400mg), and Riluzole (200mg) show significant improvements with regards to UHDRS TMS score, in order of decreasing efficacy. Further research is required to validate these results. Fig."

Retrospective data • CNS Disorders

Immunomodulators and immunosuppressants for progressive multiple sclerosis: a network meta-analysis. (PubMed, Cochrane Database Syst Rev) - "The number of people with PMS with relapses is probably slightly reduced with rituximab at two years, and interferon beta-1b at three years, compared to placebo. Both drugs are also probably associated with a slightly higher proportion of withdrawals due to adverse events, as are immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab; we have high confidence that this is the case with interferon beta-1a. We found only low or very low certainty evidence relating to disability progression for the included disease-modifying treatments compared to placebo, largely due to imprecision. We are also uncertain about the effect of interventions on serious adverse events, also because of imprecision. These findings are due in part to the short follow-up of the included RCTs, which lacked detection of less common severe adverse events. Moreover, the funding source of many included studies may have introduced bias into the results. Future research on..."

Clinical • Immunomodulating • Journal • Retrospective data • Review • CNS Disorders • Multiple Sclerosis

Disease-modifying therapy in progressive multiple sclerosis: a systematic review and network meta-analysis of randomized controlled trials. (PubMed, Front Neurol) - "Among them, mitoxantrone, siponimod, and ocrelizumab are superior to other drug options in delaying disease progression (high certainty)...In terms of adverse events (AEs), rituximab (RR 1.01), and laquinimod (RR 1.02) were more effective than the placebo (high certainty). In terms of serious adverse events (SAEs), natalizumab (RR 1.09), and ocrelizumab (RR 1.07) were safer than placebo (high certainty). DMTs can effectively control disease progression and reduce disease deterioration during the treatment of PMS. https://inplasy.com/?s=202320071, identifier: 202320071."

Retrospective data • Review • CNS Disorders • Multiple Sclerosis

Nerventransfers bei Kindern mit nicht traumatischer AmyoplasieNerve Transfers in Children with Non-traumatic Amyoplasia. (PubMed, Handchir Mikrochir Plast Chir) - "This work shows that the treatment of non-traumatic amyoplasia in children with selective nerve grafts is a successful method. Nerve transfers allow patients to gain or regain important functions for managing independent everyday life. The surgical methods have been established in the treatment of traumatic nerve injuries. They are well-known and can be carried out safely. We believe that this is an important treatment option for paediatric patients with paralysis associated with TM or AMC, which should also be known to the treating physicians."

Journal • CNS Disorders • Obstetrics • Orthopedics • Pediatrics

Laquinimod attenuates oxidative stress-induced mitochondrial injury and alleviates intervertebral disc degeneration by inhibiting the NF-κB signaling pathway. (PubMed, Int Immunopharmacol) - "Collectively, the findings of this study provide new insights into the therapeutic potential of Laquinimod as a treatment for oxidative stress-induced IVDD."

Journal • Back Pain • Inflammation • Lumbar Back Pain • Musculoskeletal Pain • Pain

Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study. (PubMed, Lancet Neurol) - P2 | "Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington's disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments."

Journal • P2 data • Cardiovascular • CNS Disorders • Fatigue • Huntington's Disease • Infectious Disease • Influenza • Insomnia • Movement Disorders • Multiple Sclerosis • Musculoskeletal Pain • Pain • Respiratory Diseases • Sleep Disorder

Laquinimod, Huntington's disease, and disease modification. (PubMed, Lancet Neurol) - No abstract available

Journal • Huntington's Disease • Movement Disorders

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. (PubMed, Cochrane Database Syst Rev) - "We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate..."

Immunomodulating • Journal • Retrospective data • Review • CNS Disorders • Multiple Sclerosis

Adverse effects of immunotherapies for multiple sclerosis: a network meta-analysis. (PubMed, Cochrane Database Syst Rev) - "We found mostly low and very low-certainty evidence that drugs used to treat MS may not increase SAEs, but may increase withdrawals compared with placebo. The results suggest that there is no important difference in the occurrence of SAEs between first- and second-line drugs and between oral, injectable, or infused drugs, compared with placebo. Our review, along with other work in the literature, confirms poor-quality reporting of adverse events from RCTs of interventions. At the least, future studies should follow the CONSORT recommendations about reporting harm-related issues. To address adverse effects, future systematic reviews should also include non-randomized studies."

Adverse events • Journal • Retrospective data • Review • CNS Disorders • Multiple Sclerosis

Improving Precision Medicine for Multiple Sclerosis with Uncertainty-Aware Causal Models (MSMilan 2023) - "For example, the fraction of individuals with a true favorable outcome (< 2 NE-T2 lesions) on laquinimod, a drug that showed minimal effectiveness in clinical trials, increased from 0.72 (SD 0.201) when the model is 50% confident about its prediction, to 0.82 (SD 0.146) when the model is 75% confident (difference 0.1; 95% CI, 0.036-0.164; p-value, 0.002)... The proposed model can predict future NE-T2 lesion counts on different treatments and identify responders to treatment, while also providing an estimate of predictive uncertainty. Using the model's uncertainty to guide decision-making can lead to better clinical outcomes for populations treated based on its predictions."

CNS Disorders • Multiple Sclerosis

Re-Interpreting Data of a Randomized Controlled Trial in Multiple Sclerosis using Prioritization of Outcomes and Win Statistics (MSMilan 2023) - " To show the potential of the method** we applied it to 2 RCT testing laquinimod vs placebo (ALLEGRO and BRAVO). This application demonstrates that the proposed approach can give a personalized estimation of treatment effects, based on each patient's preference. It also provides greater statistical power to detect and quantify a treatment difference by using all available information contained in the component outcomes."

Clinical • CNS Disorders • Multiple Sclerosis

AI PREDICTION OF INDIVIDUAL TREATMENT RESPONSE TO ENABLE PHASE 2 TRIALS IN PROGRESSIVE MS (WCN 2023) - "Crucially, responsiveness to treatment is measured by standard clinical disability scores, and therefore this method can increase a trial's effect size without relying on surrogate outcome measures. I will discuss validation experiments using historical data from randomized control trials that studied the effect of anti-CD20 antibodies and laquinimod, and how this strategy could be deployed in future clinical trials to accelerate drug development for progressive MS."

Clinical • P2 data • CNS Disorders

In situ gel-forming oil as rectally delivering platform of hydrophobic therapeutics for ulcerative colitis therapy. (PubMed, Int J Pharm) - "The hydrophobic laquinimod (LAQ) as a model drug was easily dissolved in gel-forming oil and its solubility was reaching to 7 ± 0.1 mg/mL...Importantly, the gut mucosa barrier was largely repaired without any formation of fibrosis remodeling. Conclusively, in situ liquid gel may be a potential delivery system of hydrophobic medicines for ulcerative colitis."

Journal • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

Laquinimod Inhibits Microglial Activation, Astrogliosis, BBB Damage, and Infarction and Improves Neurological Damage after Ischemic Stroke. (PubMed, ACS Chem Neurosci) - "Therefore, this study demonstrated that LAQ post-treatment restricted microglial polarization, astrogliosis, and glial scar and improved BBB damage and behavioral function. LAQ may serve as a novel target to develop new therapeutic agents for ischemic stroke."

Journal • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Vascular Neurology

A PET-CT study on neuroinflammation in Huntington's disease patients participating in a randomized trial with laquinimod. (PubMed, Brain Commun) - P2 | "Over time, the patients treated with laquinimod did not show a significant clinical improvement. Data from the C-PBR28 PET-CT study indicate that laquinimod may not have affected regional translocator protein expression and clinical performance over the studied period."

Journal • Huntington's Disease • Inflammation • Movement Disorders

Therapeutic potential of targeting kynurenine pathway in neurodegenerative diseases. (PubMed, Eur J Med Chem) - "Currently, many agents have been discovered with significant improvement in animal models but only one aryl hydrocarbon receptor (AHR) agonist 30 (laquinimod) has entered clinical trials for treating Huntington's disease (HD). In this review, we describe neuroactive KP metabolites, discuss the dysregulation of KP in aging and NDs and summarize the development of KP regulators in preclinical and clinical studies, offering an outlook of targeting KP for NDs treatment in future."

Journal • Review • CNS Disorders • Huntington's Disease • Metabolic Disorders • Movement Disorders

Laquinimod combined with an essential fatty acid-rich diet enhances the neuroprotective effect in an acute rodent model of Huntington's disease (Neuroscience 2022) - "Our results show a synergic effect of the combined therapy, since there was a 45% reduction in rotatory behavior, beam balance performance was improved, and striatal oxidative damage was significantly diminished. We showed the neuroprotective effect that laquinimod combined with an EFA -rich diet induced in an acute model of HD."

Preclinical • CNS Disorders • IL6

Estimating individual treatment effect on disability progression in multiple sclerosis using deep learning. (PubMed, Nat Commun) - "The same model could also identify responders to laquinimod in another held-out test set of PPMS patients (n = 318). Finally, we show that using this model for predictive enrichment results in important increases in power."

Clinical • Journal • CNS Disorders • Multiple Sclerosis

Sphingosine 1-Phosphate Modulation in Inflammatory Bowel Diseases: Keeping Lymphocytes Out of the Intestine. (PubMed, Biomedicines) - "Of special interest are results from the use of oral sphingosine 1-phosphate (S1P) receptor modulators (ozanimod, etrasimod, fingolimod and laquinimod), based on S1P activities to target lymphocyte recirculation in the mucosa, acting as immunosuppressive agents. Cost-effectiveness studies and head-to-head trials are needed to better define their place in therapy. This review summarizes these emerging data published by PubMed and EMBASE databases and from ongoing clinical trials on the safety and efficacy of selectivity of S1P modulators in the treatment of IBD."

Journal • Review • Cardiovascular • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

Deep Learning Prediction of Response to Disease Modifying Therapy in Primary Progressive Multiple Sclerosis (AAN 2022) - "These placebo-controlled trials investigated ocrelizumab, rituximab and laquinimod, respectively. Subgroups of individuals with PPMS who respond favourably to DMTs can be identified based on their baseline characteristics, even when no significant treatment effect can be found at the whole-group level. Doing so allows for predictive enrichment of future clinical trials and personalized treatment selection in the clinic."

CNS Disorders • Multiple Sclerosis

Carboxamide Derivatives Are Potential Therapeutic AHR Ligands for Restoring IL-4 Mediated Repression of Epidermal Differentiation Proteins. (PubMed, Int J Mol Sci) - "Therapeutics targeting the aryl hydrocarbon receptor (AHR), such as coal tar and tapinarof, are effective in AD, yet new receptor ligands with improved potency or bioavailability are in demand to expand the AHR-targeting therapeutic arsenal. We found that carboxamide derivatives from laquinimod, tasquinimod, and roquinimex can activate AHR signaling at low nanomolar concentrations...Partial agonist activity by other derivatives was less efficacious. The previously reported beneficial safety profile of these novel small molecules, and the herein reported therapeutic potential of specific carboxamide derivatives, provides a solid rationale for further preclinical assertation."

Journal • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • FLG • IL4