Tinostamustine is a first-in-class, new chemical entity that combines two potentially synergistic mechanisms of action, bifunctional alkylating activity and pan histone deacetylase inhibition (or HDAC inhibition). Tinostamustine is under investigation in patients with glioblastoma multiforme.
Available for partnering.
Available for partnering.
Preclinical
Phase I
Phase II
Phase III
Registration
INDICATION: Glioblastoma
Disease and Medical Need
GBM is a highly aggressive brain cancer with one of the highest unmet medical needs in oncology. Most patients die from progressive disease with a median survival of 14.6 months (Stupp 2005).
Rationale
Tinostamustine combines the dual activities of a bifunctional alkylating agent and a HDACi that crosses the blood brain barrier. Histone deacetylase inhibitors are recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well recognized mechanisms of HDACi lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, and promotion of apoptosis. Multiple lines of recent data suggest that biologically important synergy exists between alkylating agents and HDACi. For example, in one study the combination of bendamustine, an alkylating agent, and entinostat, a HDACi, synergistically inhibits proliferation of multiple myeloma (MM) cells via induction of apoptosis and DNA damage response (Cai 2013).
Key Scientific/Clinical Evidence
Tinostamustine has demonstrated both preclinical and early phase clinical evidence supporting promising activity for both MGMT promoter gene methylated and unmethylated glioblastoma phenotypes when administered following surgical resection and chemoradiation with temozolomide (Qiu 2018, Festuccia 2018, DeGroot 2023).
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996.doi:10.1056/NEJMoa043330. Cai B, Lyu H, Huang J, et al. Combination of bendamustine and entinostat synergistically inhibits proliferation of multiple myeloma cells via induction of apoptosis and DNA damage response. Cancer Lett. 2013;335(2):343-350. doi:10.1016/j.canlet.2013.02.046 Qiu Y, Zhimin L, Copland JA, Mehrling T and Tun HW. Combined alkylation and histone deacetylase inhibition with EDO-S101 has significant therapeutic activity against brain tumors in preclinical models. Oncotarget. 2018;9(46):28155-28164. Published 2018 Jun 15. doi:10.18632/oncotarget.25588. Festuccia C, Mancini A, Colapietro A, et al. The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma. [published correction appears in J Hematol Oncol. 2018 Mar 14;11(1):38]. J Hematol Oncol. 2018;11(1):32. Published 2018 Feb 27. doi:10.1186/s13045-018-0576-6. deGroot J. Tinostamustine; A novel alkylator – first data in glioblastoma. 2023 2nd Annual GBM Summit, Boston Ma. Mar 15, 2023.
Sunobinop is a first-in-class, new chemical entity that potently and selectively activates nociceptin/orphanin-FQ (NOP) receptors. Sunobinop is currently under investigation across a number of potential indications including alcohol use disorder, interstitial cystitis and overactive bladder.
All indications available for partnering.
All indications available for partnering.
Preclinical
Phase I
Phase II
Phase III
Registration
INDICATION: AUD/IAAC
Disease and Medical Need
Alcohol use disorder (AUD) is a common medical condition characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. AUD is a chronic, relapsing disorder that can increase the risk of certain cancers, lead to liver diseases and can damage the brain and other organs. Alcohol also increases the chances of developing sleep problems, depression, and other mental health problems.
Rationale
Preclinical studies have shown that activation of NOP receptors in AUD animal models reduces the reinforcing and motivating effects of ethanol (alcohol) (Kuzmin 2007; Ciccocioppo 1999). In humans, lower NOP activity in the brain (measured by PET imaging) has been associated with an increased risk of relapse in 22 recently abstinent patients with severe AUD who were followed for 12 weeks (Tollefson 2023).
Key Scientific/Clinical Evidence
Sunobinop studies have suggested improvements in various sleep measurements (Whiteside 2024) including in abstinent patients with AUD (NCT04035200) building on these data, Imbrium is conducting a two-part, randomized, double-blind, placebo-controlled, parallel-group Phase 2 study to evaluate the impact of sunobinop given at bedtime on alcohol consumption (NCT06545916), as well as alcohol craving. (NCT06545929)
Kuzmin A, Kreek MJ, Bakalkin G, Liljequist S. The nociceptin/orphanin FQ receptor agonist Ro 64-6198 reduces alcohol self-administration and prevents relapse-like alcohol drinking. Neuropsychopharmacology. 2007;32(4):902-10. Ciccocioppo R, Panocka I, Polidori C, Regoli D, Massi M. Effect of nociceptin on alcohol intake in alcohol-preferring rats. Psychopharmacology. 1999;141(2):220-4. Kuzmin A, Sandin J, Terenius L, Ogren SO. Acquisition, expression, and reinstatement of ethanol-induced conditioned place preference in mice: effects of opioid receptor-like 1 receptor agonists and naloxone. J Pharmacol Exp Ther. 2003;304(1):310-8. Tollefson S, Stoughton C, Himes ML, et al. Imaging Nociceptin Opioid Peptide Receptors in Alcohol Use Disorder With [11C]NOP-1A and Positron Emission Tomography: Findings From a Second Cohort. Biol Psychiatry. 2023;94(5):416-423. doi:10.1016/j.biopsych.2022.12.022
INDICATION: Interstitial Cystitis Pain
Disease and Medical Need
Interstitial cystitis / bladder (IC/BPS) pain syndrome is a chronic condition that causes bladder pain, discomfort and pressure as well as discomfort along with frequent and urgent need to urinate during the day and night (Kanter 2017). IC/BPS is not well understood and there are limited treatment options.
Rationale
Preclinical and clinical studies have shown that activating NOP in the bladder increases micturition threshold and bladder capacity (Lecci 200; Lazzeri 2003). Furthermore, clinical data shows activation of NOP receptors can reduce pain in IC/BPS patients (del Popolo 2011).
Key Scientific/Clinical Evidence
As Sunobinop’s primary route of elimination is renal, high concentrations are achieved in the bladder (Cipriano 2024). Sunobinop inhibits pain in the cyclophosphamide animal model of acute cystitis (Whiteside 2023). Imbrium is conducting a multicenter, randomized, double-blind, placebo-controlled single sequence Phase 1b crossover study in IC/BPS patients. (NCT06285214)
Kanter G, Volpe KA, Dunivan GC, et al. Important role of physicians in addressing psychological aspects of interstitial cystitis/bladder pain syndrome (IC/BPS): a qualitative analysis. Int Urogynecol J. 2017;28(2):249-256. Lecci A, Giuliani S, Meini S, Maggi CA. Nociceptin and the micturition reflex. Peptides. 2000; 21(7):1007-21. Lazzeri M, Calò G, Spinelli M, Guerrini R, Salvadori S, Beneforti P, Sandri S, Regoli D, Turini D. Urology 2003; 61(5):946-50. Lazzeri M, Calò G, Spinelli M, Malaguti S, Guerrini R, Salvadori S, Beneforti P, Regoli D, Turini D. Daily intravesical instillation of 1 mg nociceptin/orphanin FQ for the control of neurogenic detrusor overactivity: a multicenter, placebo controlled, randomized exploratory study. J Urol 2006; 176(5):2098-102. Del Popolo G, Celso M, Mencarini M, Neli F, Del Corso F, Lazzeri M. Intravesical Instillation of Nociceptin/Orphanin FQ (N/OFQ) in Patients with Interstitial Cystitis/Painful Bladder Syndrome(IC/BPS): results from a Pilot Study. Presented at: International Continence Society Meeting 2011. ((accessed 6-Dec 2024))
INDICATION: Overactive Bladder
Disease and Medical Need
Overactive bladder syndrome (OAB) is a condition that causes sudden urges to urinate that may be hard to control. There is often a need to pass urine many times during the day and night and there can be a loss of urine that isn't intended, called urge incontinence.
Rationale
Preclinical and clinical studies have shown that activating NOP in the bladder increases micturition threshold and bladder capacity (Lecci 200; Lazzeri 2003). Furthermore, clinical data shows activation of NOP receptors can reduce incontinence in OAB patients (Lazzeri 2006).
Key Scientific/Clinical Evidence
As Sunobinop’s primary route of elimination is renal, high concentrations are achieved in the bladder (Cipriano 2024). Unlike existing treatment that are directed to the neuromuscular junction, sunobinop targets the sensory neurons. Sunobinop inhibits the micturition reflex in an isovolumetric cystometry animal model (Whiteside 2023) and a Phase 1b clinical study with sunobinop in OAB patients has suggested an improvement in multiple OAB symptoms. (NCT06024642).
Lecci A, Giuliani S, Meini S, Maggi CA. Nociceptin and the micturition reflex. Peptides. 2000; 21(7):1007-21. Lazzeri M, Calò G, Spinelli M, Guerrini R, Salvadori S, Beneforti P, Sandri S, Regoli D, Turini D. Urology 2003; 61(5):946-50. Lazzeri M, Calò G, Spinelli M, Malaguti S, Guerrini R, Salvadori S, Beneforti P, Regoli D, Turini D. Daily intravesical instillation of 1 mg nociceptin/orphanin FQ for the control of neurogenic detrusor overactivity: a multicenter, placebo controlled, randomized exploratory study. J Urol 2006; 176(5):2098-102.
The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the investigational agents will successfully complete clinical development or gain approval from the United States Food and Drug Administration or other health authorities.