JZP150 / Jazz, EMD Serono - LARVOL DELTA

Pharmacotherapies for cannabis use disorder. (PubMed, Cochrane Database Syst Rev) - "There is incomplete evidence for all the clinically-important pharmacotherapies investigated and, for half of their outcomes, the quality of the evidence was low (44%) or very low (11%). Given the limited evidence of efficacy, those pharmacotherapies should still be considered experimental for treating cannabis use disorder. The greater withdrawal from treatment due to adverse effects seen with anticonvulsants and mood stabilisers may limit their therapeutic value."

Clinical • Journal • Review • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry • Substance Abuse

Mitigation of cisplatin-induced acute kidney injury through oral administration of fatty acid amide hydrolase inhibitor PF-04457845. (PubMed, J Pharmacol Exp Ther) - "SIGNIFICANCE STATEMENT: Oral administration of the fatty acid amide hydrolase (FAAH) inhibitor, PF-04457845, reduced cisplatin-induced DNA damage response, tubular damage, and kidney dysfunction. Inhibition of FAAH represents a promising approach to prevent cisplatin-induced nephrotoxicity."

Journal • Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • CDKN1A • KIM1 • LCN2

Endocannabinoid contributions to the perception of socially relevant, affective touch in humans. (PubMed, Neuropsychopharmacology) - "In study 2, healthy individuals were randomized to receive an inhibitor of fatty acid amide hydrolase (FAAH; PF-04457845) to increase AEA levels (n = 16) or placebo (n = 29)...In contrast to our hypothesis, elevated AEA was associated with reduced pleasantness ratings of CT-optimal, affective touch. This provides novel, in-human data linking AEA to social processing, adding nuance to the rationale for its use as a potential novel therapeutic target in disordered in social processing."

Journal

Mitigation of cisplatin-induced acute kidney injury through oral administration of FAAH Inhibitor PF-04457845. (PubMed, J Pharmacol Exp Ther) - "Significance Statement Oral administration of FAAH inhibitor, can reduce cisplatin-induced DNA damage response, tubular damages, and kidney dysfunction. Inactivation of FAAH could be a potential strategy to prevent cisplatin-induced nephrotoxicity."

Journal • Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Oncology • Renal Disease • Reperfusion Injury • CDKN1A • KIM1

Emerging pharmacotherapy for the treatment of cannabis use disorder. (PubMed, Expert Opin Pharmacother) - "Superiority over control of cannabidiol, gabapentin, galantamine, nabilone plus zolpidem, nabiximols, naltrexone, PF-04457845, quetiapine, varenicline, and topiramate were observed through the cannabinoid, glutamatergic, γ-aminobutyric acidergic, serotonergic, noradrenergic, dopaminergic, opioidergic, and cholinergic systems. Considering sample size, follow-up, and effect size, further studies using objective tools are necessary. The future of CUD treatment is promising."

Journal • Review • CNS Disorders • Immunology • Mental Retardation • Psychiatry • Substance Abuse

A Neuroanatomic and Pathophysiologic Framework for Novel Pharmacological Approaches to the Treatment of Post-traumatic Stress Disorder. (PubMed, Drugs) - "Indeed, investigations and drug development are proceeding in a number of these alternative, non-serotonergic pathways in an effort to improve the management of PTSD. In this manuscript, the authors introduce novel and emerging treatments for PTSD, including drugs in various stages of development and clinical testing (BI 1358894, BNC-210, PRAX-114, JZP-150, LU AG06466, NYV-783, PH-94B, SRX246, TNX-102), established agents and known compounds being investigated for their utility in PTSD (brexpiprazole, cannabidiol, doxasoin, ganaxolone, intranasal neuropeptide Y, intranasal oxytocin, tianeptine oxalate, verucerfont), and emerging psychedelic interventions (ketamine, MDMA-assisted psychotherapy, psilocybin-assisted psychotherapy), with an aim to examine and integrate these agents into the underlying pathophysiological frameworks of trauma-related disorders."

Journal • Review • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

FAAH-I MULTI: Fatty Acid Amide Hydrolase (FAAH) Inhibitor Treatment of Cannabis Use Disorder (CUD) (clinicaltrials.gov) - P2 | N=228 | Completed | Sponsor: Yale University | Phase classification: P2b ➔ P2

Phase classification • Substance Abuse

A Study of JZP150 in Adults With Posttraumatic Stress Disorder (clinicaltrials.gov) - P2 | N=282 | Completed | Sponsor: Jazz Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

Dual fatty acid hydrolase and TRPV1 inhibitor reduces inflammation and post-traumatic headache like symptoms induced by repetitive traumatic brain injury (Neuroscience 2023) - "Mice (n=6/group) were randomly assigned to treatment with either dual FAAH/TRPV1 inhibitor N-arachidonoyl-serotonin (AA-5-HT) or FAAH inhibitor PF-04457845 or vehicle...06). The results from this study suggest that reversal of TBI induced inflammation in the trigeminal regions and PTH-like symptoms by AA-5-HT is likely in part through augmentation of endocannabinoid (anandamide) and desensitization of TRPV1 neurons involved in nociception."

CNS Disorders • Pain • Vascular Neurology • AIF1 • C1QA

Modulation of TRPV1 activity by endocannabinoid anandamide in the development and treatment of posttraumatic headache (Neuroscience 2023) - "Unexpectedly, treatment with the FAAH inhibitor PF04457845 did not attenuate inflammation in the trigeminal system and had little effects on periorbital allodynia...These results suggest that TRPV1 signaling mediated by AEA is likely exaggerated by deletion of FAAH, and blockade of the TRPV1 activity can boost the pain suppressive effects of AEA in the FAAH KO mice. We are currently under investigation if the therapeutic effect of SB-366791 in the FAAH KO mice is also attributed to activation of cannabinoid receptors."

CNS Disorders • Migraine • Pain • Vascular Neurology • CD68 • FABP7 • GFAP • TRPV1

A Study of JZP150 in Adults With Posttraumatic Stress Disorder (clinicaltrials.gov) - P2 | N=270 | Active, not recruiting | Sponsor: Jazz Pharmaceuticals | N=719 ➔ 270

Enrollment change • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

A Study of JZP150 in Adults With Posttraumatic Stress Disorder (clinicaltrials.gov) - P2 | N=719 | Active, not recruiting | Sponsor: Jazz Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=270 ➔ 719 | Trial completion date: Jun 2023 ➔ Dec 2023 | Trial primary completion date: Jun 2023 ➔ Dec 2023

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

Therapeutic Effects of Combined Treatment with the AEA Hydrolysis Inhibitor PF04457845 and the Substrate Selective COX-2 Inhibitor LM4131 in the Mouse Model of Neuropathic Pain. (PubMed, Cells) - "Consistently, the increased proinflammatory cytokines IL-1β, IL-6, and chemokine MCP-1 in the CCI mouse spinal cord and sciatic nerve were also significantly reduced by combination of low doses of PF04457845 and LM4131 treatment. Therefore, our study suggests that simultaneous blockage of endocannabinoid hydrolysis and oxygenation by using the substrate-selective COX-2 inhibitor, which avoids the cardiovascular and gastrointestinal side effects associated with the use of general COX-2 inhibitors, might be a suitable strategy for the treatment of inflammatory and neuropathic pain."

Journal • Preclinical • Cardiovascular • CNS Disorders • Gastrointestinal Disorder • Inflammation • Neuralgia • Pain • IL1B • IL6

JZP150: Expiry of composition-of-matter patents in US/ex-US in 2029 (Jazz Pharma) - Annual Report 2022

Patent • CNS Disorders • Parkinson's Disease

Safety and Efficacy of a FAAH-Inhibitor to Treat Cannabis Withdrawal (clinicaltrials.gov) - P2 | N=70 | Completed | Sponsor: Yale University | N=120 ➔ 70

Enrollment change

Genetic Knockout of Fatty Acid Amide Hydrolase (FAAH) Ameliorates Cisplatin-induced Nephropathy in Mice. (PubMed, Mol Pharmacol) - "Notably, a selective FAAH inhibitor (PF-04457845) did not interfere with or perturb the antitumor effects of cisplatin in two head and neck squamous cell carcinoma cell lines, HN30 and HN12. Significance Statement Mice lacking the Faah gene are protected from cisplatin-induced inflammation, DNA damage response, tubular damages and kidney dysfunction. Inactivation of FAAH could be a potential strategy to mitigate cisplatin-induced nephrotoxicity."

Journal • Preclinical • Acute Kidney Injury • Head and Neck Cancer • Immunology • Inflammation • Nephrology • Oncology • Renal Disease • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CDKN1A • IL1B • NF-κβ • RELA

FAAH-I MULTI: Fatty Acid Amide Hydrolase (FAAH) Inhibitor Treatment of Cannabis Use Disorder (CUD) (clinicaltrials.gov) - P2b | N=235 | Completed | Sponsor: Yale University | Recruiting ➔ Completed | Trial completion date: Dec 2022 ➔ Jul 2022 | Trial primary completion date: Dec 2022 ➔ Jul 2022

Trial completion • Trial completion date • Trial primary completion date • Substance Abuse

Inhibition of FAAH suppresses RANKL-induced osteoclastogenesis and attenuates ovariectomy-induced bone loss partially through repressing the IL17 pathway. (PubMed, FASEB J) - "Moreover, intragastric administration of the FAAH inhibitor PF-04457845(PF) ameliorated ovariectomy (OVX)-induced bone loss in mice...RNAseq indicated that the IL17 pathway was blocked by PF, and administration of recombinant murine IL17 protein could partially restore osteoclastogenesis and activate NF-κB and MAPK pathways. To sum up, our findings demonstrate that targeting FAAH could be a promising candidate strategy for treating osteoclast-related diseases, especially osteoporosis."

Journal • Immunology • Inflammation • Osteoporosis • Rheumatology • IL17A • TNFSF11

Multisite Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy, Safety and Tolerability of the Fatty Acid Amide Hydrolase (FAAH) Inhibitor JZP150 (PF-04457845) in Adults With Cannabis Use Disorder (CUD) (ACNP 2022) - "Conclusions JZP150 is safe and well-tolerated. The efficacy results of the study will be discussed."

Clinical • Substance Abuse

Endocannabinoid Contributions to Affective Touch Processing in Humans With or Without Trauma Exposure Histories (ACNP 2022) - "In study 2, we further demonstrated the role for AEA in affective touch processing by using PF-04457845 (now known as JZP150) to enhance AEA levels via reduced enzymatic degradation in healthy adults... Overall, we find that increases in the stress-buffering endocannabinoid ligand AEA may play a critical role in mediating the perceived pleasantness of affective touch, as evidence both by individual variation in AEA levels and pharmacological intervention. This data suggests that when AEA is high, the impact of the stress buffering qualities of affective, CT-optimal touch may be minimal. As such, it is possible that individuals with lower AEA, or states that induce decreases in AEA (i.e., following stress exposure), may be particularly responsive to the stress buffering qualities of socially relevant, affective touch, providing insight into populations who may most benefit from social support via affective touch."

Mood Disorders

Clinical Research on Novel Pharmacologic and Immunologic Approaches to Treating Cannabis Use Disorder and Opioid Use Disorder (ACNP 2022) - "Haney will present Phase 1-2a studies testing the pregnenolone analogue, AEF0117, a signaling specific inhibitor of the cannabinoid type 1 receptor...D’Souza, will describe findings from a near-completed multi-site Phase 2b trial testing the effects of PF-04457845, an orally active, longacting, potent, and selective inhibitor of fatty acid amide hydrolase (FAAH), the primary enzyme degrading the endocannabinoid, anandamide...Comer will present the safety, immunogenicity, and preliminary efficacy data from a Phase 1a/1b study to evaluate an opioid vaccine targeting oxycodone in non-treatment-seeking participants with OUD, as well as preclinical data that were used to support the clinical research. Snyder will present unpublished data describing the preclinical pharmacological profile of ITI-333 in animal models of opioid withdrawal and craving and the clinical translation of ITI-333 into Phase I SAD study."

Clinical • Addiction (Opioid and Alcohol) • Substance Abuse

Chemical Probes to Control and Visualize Lipid Metabolism in the Brain. (PubMed, Acc Chem Res) - "Activity-based protein profiling and chemical proteomics were essential to guide the drug discovery and development of compounds targeting MAGL and FAAH, such as ABX-1431 (Lu AG06466) and PF-04457845, respectively. It is anticipated that the combination of chemical probes, highly selective inhibitors, and sensors with advanced (super resolution) imaging modalities, such as PharmacoSTORM and correlative light-electron microscopy, will uncover the fundamental basis of lipid signaling at nanoscale resolution in the brain. Furthermore, chemical biology approaches enable the translation of these fundamental discoveries into clinical solutions for brain diseases with aberrant lipid signaling."

Journal • CNS Disorders • Immunology • Inflammation • Metabolic Disorders • Mood Disorders • Multiple Sclerosis • Pain • Post-traumatic Stress Disorder • Psychiatry

FAAH served a key membrane-anchoring and stabilizing role for NLRP3 protein independently of the endocannabinoid system. (PubMed, Cell Death Differ) - "Interestingly, select FAAH inhibitors, in particular URB597 and PF-04457845, disrupted NLRP3-FAAH interaction and induced autophagic NLRP3 degradation, leading to diminished inflammasome activation in mouse macrophage cells as well as in peripheral blood mononuclear cells isolated from CAPS patients. Our results unraveled a novel NLRP3-stabilizing mechanism and pinpointed NLRP3-FAAH interaction as a potential drug target for CAPS and other NLRP3-driven diseases."

Journal • Inflammation • NLRP3

Cannabinoids in the Treatment of Cannabis Use Disorder: Systematic Review of Randomized Controlled Trials. (PubMed, Front Psychiatry) - "Cannabinoid receptor agonists, i.e., dronabinol and nabilone, showed only limited or no therapeutic potential in the treatment of CUD. In contrast, modulators of endocannabinoid activity, i.e., nabiximols, cannabidiol and PF-04457845, demonstrated broader efficacy which covered almost all aspects of CUD. Endocannabinoid modulation appears to be a promising treatment approach in CUD, but the evidence to support this strategy is still small and future research in this direction is needed."

Review • Substance Abuse

Inactivation of fatty acid amide hydrolase protects against ischemic reperfusion injury-induced renal fibrogenesis. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Correspondingly, a selective FAAH inhibitor, PF-04457845, inhibited the transforming growth factor-beta 1 (TGF-β1)-induced profibrogenic markers in human proximal tubular cell line (HK-2 cells) and mouse primary cultured tubular cells...Further, AEA-COX-2 metabolite, prostamide E2 exerted anti-fibrogenesis effect. These findings suggest that FAAH activation and the consequent reduction of AEA contribute to the renal fibrogenesis, and that FAAH inhibition protects against fibrogenesis in renal cells independently of CB receptors via the AEA-COX-2 pathway by the recovery of reduced AEA."

Journal • Cardiovascular • Fibrosis • Immunology • Renal Disease • Reperfusion Injury • TGFB1