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PNB 081

PNB-081 for Opiate Pain Management and Pancreatitis


Therapeutic target Cholecystokinin Receptors A, CCK1
Therapeutic indication Pain management in combination with opioids
Secondary indications Pancreatitis

Information about target and disease: Opiate addition is epidemic in the US and CCK antagonists work best in opiate potentiation. Anatomical studies have shown that the distribution of CCK-8 and CCK receptors parallels that of endogenous opioids and opioid receptors in the pain-processing regions in both the brain and the spinal cord. This overlapping distribution triggered numerous investigations on the role of CCK in nociception. Thus, several groups described a naloxone-reversible antinociceptive effect of CCK-8 or its analogs in relevant antinociceptive tests, such as the hot-plate, writhing, and tail-flick tests. Interestingly, the combination of opioids with selective CCK1 receptor antagonists enhanced the analgesic effects of morphine in rodents, which was confirmed by many groups. In a phase 2 trial, the CCK1 antagonist devazepide (Devacade), but not the CCK2 antagonist Polykade, significantly improved pain relief at a higher dose in 50% of patients.

Preclinical studies: In the hot plate paw withdrawal model, 0.5 mg/kg PNB-081 analog was administered intraperitoneally in conjunction with 40 mg/kg tramadol, a widely used opioid, subcutaneously to mice and the latency time was measured one hour after administration of the drugs. PNB-081 potentiated the analgesic effect of tramadol into the analgesic efficacy of morphine. Subsequent experiments were performed to determine the dose and time response of PNB-081 analog to understand the longevity of the effect. Mice administered with PNB-081 analog at 1 mg/kg and 2 mg/kg of morphine demonstrated a sustained pain tolerance and these effects were either comparable or superior to the effect observed with a high morphine dose (8, 16 mg/kg). In order to confirm the prevention of opiate tolerance, PNB-081 analog was orally administered at 1 mg/kg in mice and 4 mg/kg of morphine. The analgesic effect of morphine faded out within days and PNB-081 1 mg/kg concomitantly administered with 4 mg/kg of morphine showed an unchanged response time over many days. No tolerance to morphine was observed.

Further extended studies clearly demonstrated, that PNB-081 at 1 mg/kg P.O. was very effective in preventing opiate tolerance and is orally bioavailable. PNB-081 was also tested in preclinical models of colon and pancreatic cancers and pancreatitis. Oral administration of PNB-081 completely inhibited the growth of colon and pancreatic cancer xenografts. In addition, PNB-081 was also effective in preclinical models of pancreatitis, depression and anxiety. PNB-081 was found highly efficient in vitro and in vivo in mice in the treatment of experimentally induced pancreatitis by oral administration. Cholecystokinin is physiologically leading to the release of pancreatic enzymes in the target organ – the pancreas and the CCK antagonist PNB-081 offers the first targeted efficient treatment for acute and chronic pancreatitis. Pancreatitis is an unmet medical need and a low hurdle approach through the regulatory approval. Recently pancreatitis was recognized as emerging disease in India, with rates of incidences of 20 in 100 000 in the general population and significantly higher in Indians in the USA.

Preclinical development studies: PNB-081 is in terms of binding profile equivalent to devazepide, but has excellent pharmacokinetics with >40% oral bioavailability, as well as very high membrane penetration. DMPK studies with PNB-081 indicated, that similar to PNB-028, PNB-081 was highly stable in rat, dog, and human liver microsomes. PNB-081 was also highly available in rats with good bioavailability. Other studies, including CaCo2 permeability and plasma protein binding demonstrated favorable druggable properties of PNB-081.