Novel, Non-Addictive Opioid Dimer DMX-101 Targets Peripheral Opioid Receptors for Treatment of Chronic Pain without Risks Associated with Traditional Opioids

Although opioids are effective for chronic severe pain, they are associated with significant CNS-mediated side effects such as sedation, addiction, hyperalgesia, and tolerance [1]. Despite a large proportion (up to 80%) of opioid receptors located outside the CNS also mediating opiate analgesic effects [2], drug developers have failed to capitalize on peripheral opioid receptors for the effective management of chronic pain. The exclusive targeting of peripheral opioid receptors while avoiding CNS opioid receptors would provide safe and effective management of chronic pain [3,4].

DMX-101 is a new chemical entity created by covalently linking two molecules of buprenorphine. After oral administration, DMX-101 is rapidly absorbed and distributed, but its high molecular weight prevents its crossing the blood-brain barrier, avoiding the negative side effects resulting from CNS involvement.

Purpose/Objectives: Preclinical and clinical studies were conducted to evaluate the safety and analgesic efficacy of DMX-101 and to confirm the lack of CNS effects. Results of these studies determined whether DMX-101 should be further investigated for the treatment of chronic pain.

Method:

Preclinical: DMX-101 was evaluated utilizing a neuropathic pain model induced by spinal nerve ligation (Chung Model), widely considered to be the standard for studying potential pain medications. Thirty male Sprague-Dawley rats were tested for baseline allodynia. After ligation of the left L5 and L6 spinal nerves under anesthesia, the rats were tested pre-dose and were randomized into cohorts receiving either vehicle, subcutaneous DMX-101 10, 25, 50, 75, 100, 200mg/kg, or oral gabapentin 100mg/kg (positive control). Allodynia was evaluated 1 and 3 hours after dosing by applying von Frey filaments to the left hind paw and measuring pressure needed to elicit brisk withdrawal or flinching as a pain response.

Clinical: DMX-101 pharmacokinetics and safety, including possible CNS effects, were assessed in two randomized, placebo-controlled, double-blind studies in healthy adult subjects. DMX-101 was administered in single doses up to 800mg (SAD study) and up to 400mg daily for 7 days (MAD study).

Results:

In the Chung model study, a dose-dependent reduction in pain was seen with subcutaneous DMX-101 100 and 200mg/kg, comparable to that of gabapentin 100mg/kg. Plasma levels at which pain efficacy was seen were equivalent to ~700ng/mL in humans. Thus, we determined 700ng/mL to be the efficacy threshold in humans.

In the SAD and MAD studies DMX-101 blood levels were as high as 3,000ng/mL, with Cmax achieved in 7-8 hours. No pupillary constriction indicative of opioid-like effects was observed at any dose in either study.

No serious AEs occurred in any patient at any dose during either study.

Conclusions: DMX-101, dimer of buprenorphine, demonstrated potent anti-hyperalgesic effects in the Chung neuropathic pain model spinal nerve ligation study and relieved peripheral neuropathic pain in rats with efficacy comparable to that of gabapentin. No safety issues were noted during the study. It was determined that the human equivalent dose of 700ng/mL was the analgesia efficacy threshold for the treatment of pain in humans. In the human single and multiple dose studies, DMX 100mg and 200mg doses reached this hypothesized efficacy threshold at approximately 3 hours post-dose and maintained that level >12 hours. There were no signs of CNS involvement in the rat or human studies. In the human PK studies, DMX-101 was well tolerated with no significant safety issues.

If developed and approved, DMX-101 would be the first opioid that is well absorbed after oral dosing, selectively acting at peripheral opioid receptors throughout the body but not penetrating the CNS. DMX-101 has the potential to change the landscape of pain management and end the tide of opioid use disorder and fatal opioid overdoses.

References: 1. Iwaszkiewicz, K. S., Schneider, J. J. & Hua, S. Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions. Front Pharmacol 4, 132 (2013). doi:10.3389/fphar.2013.00132. PMCID:PMC3807052.
2. Stein, C. et al. Peripheral mechanisms of pain and analgesia. Brain Res Rev 60, 90-113 (2009). doi:10.1016/j.brainresrev.2008.12.017. PMCID:PMC2730351.
3. DeHaven-Hudkins, D. L. & Dolle, R. E. Peripherally restricted opioid agonists as novel analgesic agents. Curr Pharm Des 10, 743-757 (2004). doi:10.2174/1381612043453036.
4. Vadivelu, N., Mitra, S. & Hines, R. L. Peripheral opioid receptor agonists for analgesia: a comprehensive review. J Opioid Manag 7, 55-68 (2011). doi:10.5055/jom.2011.0049.