The disease is characterized by pain or discomfort related to the bladder with accompanying lower urinary tract symptoms such as frequency, urgency, and nocturia, in the absence of malignancy, endometriosis, chronic prostatitis, and bladder outlet obstruction. It can also cause recurring discomfort in the pelvis. The urinary bladder wall gets inflamed and in extreme cases, inflammation of the wall may result in scarring and stiffening of the urinary bladder needing extensive surgery.
Otrimed Research Center is currently participating in a Phase 1b multicenter, randomized, double-blind, placebo-controlled, crossover study to investigate the effect of oral administration of 1 mg/day of an investigational product in female subjects with a diagnosis of interstitial cystitis/bladder pain syndrome as compared to placebo. The primary objective of the study is to find out the efficacy of the investigational product in controlling pain. The product is not expected to cure the disease per se.
● Female, 18 – 64 yrs.● Capable of voiding independently. ● Nonpregnant, and able to comply with acceptable methods of contraception. ● Have a diagnosis of IC/BPS in accordance with AUA Guidelines that was documented in the subject’s medical records at least 6 months prior to screening. ● Have bladder pain/discomfort with accompanying lower urinary tract symptoms that meet the following criteria at screening:a. Bladder pain/pressure/discomfort for greater than 6 months accompanied by other lower urinary tract symptoms for more than 6 months.b. Subject has bladder pain/interstitial cystitis symptoms scale total score of more than 19.c. Subject’s daily average bladder pain/discomfort score during the past week is greater than 4 and less than 9 as rated by the subject using an 11-point NRS.d. Subject micturition frequency is estimated to be greater than 11 and less than 30 voids per 24 hours in the last week. ● Has had cystoscopy findings obtained within 9 months of screening, that exclude other conditions that cause bladder pain discomfort (e.g., transitional cell carcinoma of the bladder, endometriosis of the bladder). Note: a subject is not required to have Hunner’s lesion on bladder cystoscopy for inclusion into the study. ● The subject should: Not have received pharmacologic treatment for IC/BPS in past 30 days: or, maybe on oral pharmacologic treatment for IC/BPS at a stable dose /regimen for the past 30 days and in the judgment of PI, is expected to remain on the same stable dose/ regimen throughout the study. ● Meet study inclusion criteria despite a history of previous or continuing treatments including conservative treatment, which may include one or more of the following: a. imed voiding and behavioral modification therapy, b. Dietary restrictionsc. Stress reductiond. Despite oral therapy with any of the following: antidepressants, antihistamines, antimuscarinic and anticholinergic agents, alpha-adrenergic blockers, analgesics, and pentosan polysulfate.● Should be otherwise healthy.
The Investigational product VII7957 is a selective partial agonist of the Nociceptin/orphanin -FQ peptide receptor. This receptor is widely distributed in the peripheral and central nervous system (Kiguchi et al, page 219), it is also expressed in the ventral and dorsal horn of the spinal cord which integrates sensory processing (Neal et al 1999b).
Unlike classic opioid receptors, the NOP receptor does not display opioid pharmacology. The hydrophobic and hydrophilic parts of the binding pockets of the NOP receptor and other Opioid receptors are distinctly different. This product lacks major side effects that are commonly seen associated with MOP receptor agonists and displays a much wider therapeutic window (Lin & Ko, 2013). The cellular mechanism of action is the same as that of the classic opioid receptors. NOP receptor coupled to pertussis toxin-sensitive Gi/o proteins, inhibits adenylate cyclase and voltage-gated calcium channels and activates inward potassium channels. (Hawes, Graziano, & Lambert, 2000; Ma et al., 1997; Margas, Sedeek, & Ruiz-Velasco, 2008).
These cellular events following NOP receptor activation reduce synaptic transmission, by either reducing neurotransmitter release via presynaptically located NOP receptors or inhibiting neuronal excitability via postsynaptically located NOP rectors (Connor, Vaughan, Cheng, & Christie, 1996). Even though the cellular mechanism is almost the same, however, the effects on pain modulation are more complicated. Depending on the route of administration, and the type species, it can be pronociceptive or antinociceptive (Schrӧder et al. 2014). NOP receptor activation inhibits the release of transmitters such as Gaba aminobutyric acid, glutamate, substance P, and norepinephrine in the CNS.
● Grainer. S, Manglik, A., Kruse, A.C., Kbilka, T.S et al. Structure of the delta-opioid receptor bound to naltrindole. Nature, 485(7398), 400-404).
● Kiguchi et al, Central N/OFQ-NOP Receptor System in Pain Modulation, Advances in Pharmacology Volume 75 Page 217- 243.
● Calo, G., Guerrini, R., et al, 2013. Medicinal chemistry, pharmacology, a biological action of peptide ligands selective for Nociceptin/orphanin FQ receptor. In M.C. Ko & S.M. Husbands (Eds.), ACS symposium series: Vol 1131. Research and development of opioid-related ligands (pp.275-325). Washington, DC: American Chemical Society.
● Lin, A.P., Ko, M.C. (2013). The therapeutic potential of Nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability. ACS Chemical Neuroscience 4(2), 214-224.
● Hawes, B.E., Graziano, M.P., & Lambert. D.G. (2000). Cellular action of Nociceptin: Transduction mechanism. Peptides, 21(7), 961-967.
● Margas, W, Sadeek, K. et al (2008). Coupling specificity of NOP opioid receptors to pertussis-toxin-sensitive G alpha proteins in adult rat stellate ganglion neurons using small interference RNA. Journal of Neurophysiology, 100(3), 1420-1432.
● Schrӧder, W., Lambert, D.G., et al (2014). Functional plasticity of the N/OFQ-NOP receptor system determines the analgesic properties of the NOP receptor agonist. British Journal of Pharmacology, 171(16), 3777-3800.