olodanrigan (EMA401) / Novartis - LARVOL DELTA

The angiotensin II type 2 receptor antagonists, PD123,319 ((S-( +)-1-[(4-(dimethylamino)-3-methylphenyl)methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid), EMA300 (5-(2,2-diphenylacetyl)-4-[(4-methoxy-3-methylphenyl)methyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylic acid) and EMA401... (PubMed, Inflammopharmacology) - "Animals with PWTs ≤ 8 g received single doses of PD123,319 (0.03-3 mg/kg), EMA300 (0.3-5 mg/kg), EMA401 (0.03-1 mg/kg), gabapentin (10-60 mg/kg), amitriptyline (5-30 mg/kg), morphine (0.1-3 mg/kg), meloxicam (5-20 mg/kg) or vehicle and PWT versus time curves were generated. In conclusion, the anti-allodynic efficacy of EMA401 in a VZV-rat model of neuropathic pain is aligned with its analgesic efficacy in a Phase 2a clinical trial in patients with PHN. This model has utility for anti-allodynic efficacy assessment of novel AT2 receptor antagonists from drug discovery."

Journal • Preclinical • Herpes Zoster • Infectious Disease • Neuralgia • Pain • Varicella Zoster

Intraplantar EMA401 Abolished Angiotensin II-Evoked Mechanical Allodynia in the Mouse Hindpaw (IASP 2024) - "co-injection of the AT2 receptor antagonist, PD123319, but not the angiotensin II type 1 (AT1) receptor antagonist, losartan. Single i.pl. doses of Ang II (100 pmol) administered unilaterally into the mouse hindpaw evoked a prolonged period of mechanical hypersensitivity (48 h) in the hindpaw. I.pl."

Preclinical • Immunology • Neuralgia • Pain

Asymmetric Phase-Transfer Alkylation of Readily Available Aryl Aldehyde Schiff Bases of Amino Acid Ethyl Esters. (PubMed, Org Lett) - "Asymmetric phase-transfer alkylation of the N-(arylmethylene)-α-alkylamino acid ethyl esters and N-(arylmethylene)glycine ethyl esters was found to be catalyzed by the (R)- or (S)-Simplified Maruoka Catalyst with high efficiency and excellent enantioselectivity. This approach was successfully applied to the enantioselective formal synthesis of the angiotensin II type 2 receptor (AT2R) antagonists Olodanrigan and LX9211, and the practical aspect is demonstrated by the kilogram-scale synthesis of a key intermediate for the synthesis of LX9211."

Journal

Angiotensin II type 2 receptor signalling as a pain target: Bench, bedside and back-translation. (PubMed, Curr Opin Pharmacol) - "EMA401 was selected as the drug candidate based upon its suitable preclinical toxicity and safety profile and good pharmacokinetics. Herein, we provide an overview of the discovery, preclinical and clinical development of EMA401, for the alleviation of peripheral neuropathic pain."

Journal • Review • Neuralgia • Pain • Peripheral Neuropathic Pain

Functional assay for assessment of agonistic or antagonistic activity of angiotensin AT receptor ligands reveals that EMA401 and PD123319 have agonistic properties. (PubMed, Biochem Pharmacol) - "While testing the assay, we made several novel findings, including: a) C21 is a full agonist at the ATR (with the same efficacy as angiotensin II); b) C21 has no intrinsic activity at the receptor Mas; c) ATR-transfected HEK-293 cells are unresponsive to ATR stimulation; d) EMA401 and PD123319, which are commonly regarded as ATR antagonists, are partial agonists at the ATR. Collectively, we have developed and tested an assay based on the measurement and quantification of NO release in HAEC or in ATR-CHO cells that is suitable for the characterisation of novel and established ATR ligands."

Journal

Investigational Drugs for the Treatment of Postherpetic Neuralgia: Systematic Review of Randomized Controlled Trials. (PubMed, Int J Mol Sci) - "A total of 18 clinical trials were selected evaluating 15 molecules with pharmacological actions on nine different molecular targets: Angiotensin Type 2 Receptor (AT2R) antagonism (olodanrigan), Voltage-Gated Calcium Channel (VGCC) α2δ subunit inhibition (crisugabalin, mirogabalin and pregabalin), Voltage-Gated Sodium Channel (VGSC) blockade (funapide and lidocaine), Cyclooxygenase-1 (COX-1) inhibition (TRK-700), Adaptor-Associated Kinase 1 (AAK1) inhibition (LX9211), Lanthionine Synthetase C-Like Protein (LANCL) activation (LAT8881), N-Methyl-D-Aspartate (NMDA) receptor antagonism (esketamine), mu opioid receptor agonism (tramadol, oxycodone and hydromorphone) and Nerve Growth Factor (NGF) inhibition (fulranumab). AT2R antagonism, AAK1 inhibition, LANCL activation and NGF inhibition are considered first-in-class analgesics. Hopefully, these trials will result in a better clinical management of PHN."

Journal • Review • Neuralgia • Pain

Computational investigation of the impact of potential ATR polymorphism on small molecule binding. (PubMed, J Biomol Struct Dyn) - "Our analysis of native and mutant AT2R and their complexes with C21 and EMA401 indicated that the occurrence of these mutations affects the conformation of the protein and has affected the binding of these ligand molecules. The study's findings will aid in the development of better, more versatile medications in the near future, and also in vitro and in vivo studies might be planned in accordance with recent findings.Communicated by Ramaswamy H. Sarma."

Journal • RAS

Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma (SNO 2022) - "Standard of care consists of surgical debulking followed by radiation and temozolomide, but the tumor invariably recurs, and median survival is only ~18 months. Conjugation of EMA401 to angiopep-2 enhanced its blood brain barrier passage and reduced tumor volume in an orthotopic xenograft model of GBM. Targeting AT2R is a novel therapeutic strategy to treat GBM that should be explored in patients."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CASP3 • CASP7

The ACE Inhibitor Lisinopril Stimulates Melanoma Cell Invasiveness by Inducing MMP2 Secretion. (PubMed, Cell Physiol Biochem) - "Lisinopril stimulates MV3 cell invasion by increasing the expression and secretion of MMP2."

Journal • Cardiovascular • Hypertension • Melanoma • Oncology • Solid Tumor • MMP2

Nonopioid analgesics discovery and the Valley of Death: EMA401 from concept to clinical trial. (PubMed, Pain) - "Based on these data, a proof-of-concept clinical trial of oral EMA401 was undertaken in patients with postherpetic neuralgia. This 4-week trial showed that EMA401 evoked superior relief of postherpetic neuralgia relative to placebo and there were no serious adverse events in the EMA401 group."

Journal • Neuralgia • Pain

Inhibition of the angiotensin II type 2 receptor ATR is a novel therapeutic strategy for glioblastoma. (PubMed, Proc Natl Acad Sci U S A) - "To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2-tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM."

Journal • Brain Cancer • Glioblastoma • Oncology • Pain • Solid Tumor • ATR

Targeting Angiotensin Receptor Signaling for Neuropathic Pain: Clinical Trials and the Development Landscape (IASP 2022) - "The Lancet 2014;383:1637-1647 _x005F_x000D_ Rice ASC, Dworkin RH, Finnerup NB, Attal N, Anand P, Freeman R, Piaia A, Callegari F, Doerr C, Mondal S, Narayanan N, Ecochard L, Flossbach F & Pandhi S. Efficacy and safety of EMA401 in peripheral neuropathic pain: Results of two randomised, double-blind, phase 2 studies in patients with postherpetic neuralgia and painful diabetic neuropathy. PAIN 2021;162:2578-2589 ._x005F_x000D_"

Clinical • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain

Nonopioid Analgesics Discovery and the Valley of Death – EMA401 from Concept to Clinical Trial (IASP 2022) - P2 | "Subsequent work by us and others showed these molecules evoked pain relief in models of antiretroviral toxic neuropathy4, prostate cancer induced bone pain5, chronic inflammatory pain6, vestibulodynia7, spared nerve injury8,9 and acute paclitaxel-induced neuropathic pain10. Whether 2nd generation, small molecule AT2 receptor antagonists will be devoid of hepatotoxicity in longterm animal toxicity studies, remains to be determined. This Session is Available in Virtual Congress"

Clinical • Diabetic Neuropathy • Genito-urinary Cancer • Hepatology • Musculoskeletal Pain • Neuralgia • Oncology • Pain • Peripheral Neuropathic Pain • Prostate Cancer • Solid Tumor

EMA401, an angiotensin II type 2 receptor antagonist blocks visceral hypersensitivity and colonic hyperpermeability in rat model of irritable bowel syndrome. (PubMed, J Pharmacol Sci) - "EMA401 blocked visceral hypersensitivity and colonic hyperpermeability in these models, and naloxone reversed the effects by EMA401. These results suggest that EMA401 may improve gut function via opioid signaling in IBS."

Journal • Preclinical • Gastrointestinal Disorder • Immunology

Efficacy and safety of EMA401 in peripheral neuropathic pain: results of two randomised, double-blind, phase 2 studies in patients with postherpetic neuralgia and painful diabetic neuropathy. (PubMed, Pain) - "The least square mean reduction in NRS pain score was numerically in favour of EMA401 100 mg arm in both EMPHENE (TD: -0.5 [95%CI: -1.6, 0.6; p value: 0.35]) and EMPADINE (treatment difference [TD]: -0.6 [95%CI: -1.4, 0.1; p value: 0.10]) at the end of Week 12. However, as the studies were terminated prematurely, no firm conclusion could be drawn but the consistent clinical improvement in pain intensity reduction across these two studies in two different populations is worth noting."

Clinical • Journal • P2 data • Diabetes • Diabetic Neuropathy • Hepatology • Metabolic Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain

"❇️Hargdegger and co-workers from @Novartis reported the ✨#Synthesis of #Olodanrigan✨. 🔷Highlighted by Philip Kocienski as Synfact of the Month🔷 👉 https://t.co/B1QA0Ub1fd" (@thiemechemistry)

Angiotensin Type 2 Receptors: Painful, or Not? (PubMed, Front Pharmacol) - "It is also important to consider that Novartis terminated their phase II clinical trial (EMPHENE) to validate that ATR antagonist EMA401 mitigates post-herpetic neuralgia...Moreover, early data from the trial did not show statistically significant positive outcomes. These facts suggest that may ATR not be the proper drug target for neuropathic pain in humans and its inhibition can be harmful."

Journal • Review • Diabetes • Immunology • Inflammation • Metabolic Disorders • Neuralgia • Oncology • Pain • Peripheral Neuropathic Pain • ATR

Blockade of Bradykinin Receptors or Angiotensin II Type 2 Receptor Prevents Paclitaxel-Associated Acute Pain Syndrome in Mice. (PubMed, Eur J Pain) - "Our results demonstrated the involvement of bradykinin receptors B1 and B2 as well as AT2R in the induction of P-APS in mice and suggest the use of AT2R antagonists as a potential therapy for the prevention of P-APS in humans."

Journal • Preclinical • Lung Cancer • Musculoskeletal Pain • Oncology • Ovarian Cancer • Pain • Solid Tumor

EMPADINE: Safety and Efficacy of EMA401 in Patients With Painful Diabetic Neuropathy (PDN) (clinicaltrials.gov) - P2; N=142; Terminated; Sponsor: Novartis Pharmaceuticals; Completed ➔ Terminated; Study was terminated due to animal toxicity data

Clinical • Trial termination • Diabetes • Diabetic Neuropathy • Gene Therapies • Pain

Emerging therapies in clinical development and new contributions for neuropathic pain. (PubMed, Rev Esp Anestesiol Reanim) - "New drugs that act on different therapeutic targets are currently in preclinical development or in their first phases of clinical development. In this review, focus will be directed specifically on new pharmacological treatments for neuropathic pain for which clinical data are already available, including older and known drugs with new data on their anti-neuropathic activity."

Clinical • Journal • Neuralgia • Pain

EMPHENE: Dose Response Study of EMA401 in Patients With Post-herpetic Neuralgia (PHN) (clinicaltrials.gov) - P2; N=130; Terminated; Sponsor: Novartis Pharmaceuticals; Completed ➔ Terminated; The study was terminated early due to pre-clinical toxicity data that became available after start of trial

Clinical • Trial termination • CNS Disorders • Neuralgia • Pain

Non-Clinical Characterization of the Disposition of EMA401, a Novel Small Molecule Angiotensin II type 2 Receptor (AT2R) Antagonist. (PubMed, Biopharm Drug Dispos) - "Independent of the dosing route, the S-enantiomer EMA401 showed a good in vivo chiral stability. Overall, the present study provides the first full characterization of the disposition of EMA401 in preclinical species."

Clinical • Journal

EMPADINE: Safety and Efficacy of EMA401 in Patients With Painful Diabetic Neuropathy (PDN) (clinicaltrials.gov) - P2; N=142; Completed; Sponsor: Novartis Pharmaceuticals; Terminated ➔ Completed

Clinical • Trial completion

EMPHENE: Dose Response Study of EMA401 in Patients With Post-herpetic Neuralgia (PHN) (clinicaltrials.gov) - P2; N=130; Completed; Sponsor: Novartis Pharmaceuticals; Terminated ➔ Completed

Clinical • Trial completion

An Electroencephalography Bioassay for Preclinical Testing of Analgesic Efficacy. (PubMed, Sci Rep) - "We report mostly parallel trends in the reversal of theta power and PWL in response to administration of pregabalin and EMA 401, but not minocycline. We also note divergent trends at non-optimal doses and following prolonged drug administration, suggesting that EEG theta power can be used to detect false positive and false negative outcomes of the withdrawal reflex behavior, and yielding novel insights into the analgesic effects of these drugs on spontaneous nociceptive states in rats."

Journal • Preclinical