New Drug Candidate Aims To Treat Both Pain and Opioid Addiction Interview with:

Richard M. Mangano, PhD Chief Scientific Officer at Relmada Therapeutics

Dr. Richard Mangano

Richard M. Mangano, PhD
Chief Scientific Officer at Relmada Therapeutics

Dr. Mangano has extensive experience leading global R&D programs in both large and small pharmaceutical companies including positions in discovery and clinical research at Hoffmann-La Roche, Lederle Laboratories, Wyeth Research and Adolor Corporation. He served as acting Therapeutic Area Director for Neuroscience at Wyeth before joining Adolor as Vice President of Clinical Research and Development. Dr. Mangano’s expertise includes multiple IND/CTC submissions and NDA/MAA approvals in psychiatry, neurology and gastrointestinal therapeutic areas. Dr. Mangano is also an adjunct professor in the Department of Pharmacology and Physiology at the Drexel University School of Medicine. He lectures in the Drug Discovery and Development Program and in the Psychiatry Department’s Resident Training Program.  He has authored 30 peer reviewed publications and over 120 abstracts and presentations. Dr. Mangano holds a B.S degree in Chemistry from Iona College and a PhD degree in Biochemistry from Fordham University. Prior to joining the pharmaceutical industry, he was a research faculty member of the Maryland Psychiatric Research Institute at the University of Maryland School of Medicine.

Dr. Mangano discusses the opioid addiction and the development of abuse-resistant medications. What is the background for the development of abuse-resistant medications? How extensive is the problem of opioid addiction?

Dr. Mangano: Recognizing the growing incidence of opioid abuse, misuse, and overdose in the United States, pharmaceutical companies, with the guidance of the FDA, are developing products that can mitigate abuse, while recognizing the importance of maintaining the availability of opioid analgesics for the millions of patients in this country who suffer from pain.

Approximately two million people in the U.S. are addicted to opioids. The market for products that treat opioid dependence has grown significantly due to the rapidly escalating problem of prescription opioid misuse and abuse, a recent resurgence of heroin use, and the growing number of physicians treating opioid dependence.

One of our product candidates, REL-1028 (BuTab), is a proprietary formulation of buprenorphine designed to treat both opioid addiction and moderate to severe chronic pain. Although there is the potential for addiction to buprenorphine, the risk is lower because it is a “partial agonist” of the mu opioid receptor compared with “full agonist” opioids like heroin, morphine, oxycodone, and hydrocodone. As a result, products containing buprenorphine, such as BuTab, should have reduced risk of abuse and physical dependence and would be controlled in Schedule III of the Controlled Substances Act (as opposed to the more restrictive Schedule II). We are also considering a formulation that would include an opioid antagonist that would not interfere with analgesia when taken orally as prescribed but would block the action of buprenorphine if it were to be inhaled or injected. What is neuropathic pain?  How might d-Methadone be useful yet avoid typical opioid side effects?

Dr. Mangano: Neuropathic pain is defined as a disorder of the sensorimotor system as opposed to nociceptive pain, which is the result of trauma, injury, or inflammation. According to the Neuropathy Association, neuropathic pain affects more than 20 million people in the U.S. Our new chemical entity, d-Methadone (dextromethadone, REL-1017), is a novel, N-methyl-D-aspartate (NMDA) receptor antagonist in development for the treatment of neuropathic pain. The activation of NMDA receptors has been associated with neuropathic pain and d-Methadone has the potential to block this activity and thus help provide pain relief to patients. Clinical trials have also shown that d-Methadone, as a single isomer of racemic methadone, demonstrates virtually no opioid activity at the expected therapeutic doses. In contrast, racemic methadone is a long-acting narcotic producing typical opioid side effects, such as nausea, addiction and constipation.

In January 2016, we reported results from our Multiple Ascending Dose (MAD) study that successfully demonstrated a potential therapeutic dosing regimen for d-Methadone with a very favorable side effect and tolerability profile. This study helped us identify doses and plasma concentrations that were devoid of any opioid and ketamine-like adverse events. We are currently planning a subsequent Phase II proof-of-concept study in patients with neuropathic pain.

We also announced recently the results of an in vivo study in rats showing that administration of d-Methadone results in antidepressant-like effects comparable to those achieved in this and similar treatment models using ketamine. The encouraging results of this in vivo study support our belief that d-Methadone warrants further evaluation in a Phase II study as an effective treatment for depression. How does REL-1028 (BuTab) differ from the sublingual and transdermal formulations of Buprenorphine?  

Dr. Mangano: Buprenorphine is a partial opioid agonist that has been widely administered via the sublingual and transdermal routes, but oral administration was believed to be ineffective due to low bioavailability. REL-1028’s (BuTab) proprietary formulation of buprenorphine is designed to overcome the significant first pass metabolism in the upper gastrointestinal tract to allow for oral administration in traditional capsule or tablet form. Last fall we announced topline results of a proof-of-concept pharmacokinetic study in healthy volunteers using prototype oral formulations of BuTab. The absolute bioavailability of BuTab relative to intravenous (IV) administration exceeded published data with non-modified buprenorphine when administered orally and compares favorably with a currently marketed transdermal patch. The data generated by this study will guide formulation optimization and inform the design of subsequent clinical pharmacology studies. How does REL-1015 (LevoCap ER) differ from morphine, oxycodone, and other strong opioids? Does it have a similar tendency to addiction risk?

Dr. Mangano: LevoCap ER (REL-1015), is an extended release, abuse deterrent, and proprietary formulation of the opioid analgesic levorphanol, which is pharmacologically differentiated from morphine, oxycodone, and other strong opioids for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment. In particular, levorphanol binds to all three opioid receptor subtypes involved in analgesia (mu, kappa, and delta), the N-methyl-D-aspartate (NMDA) receptor and the norepinephrine and serotonin reuptake pumps, whereas morphine is relatively selective for the mu subtype. Due to the selectivity of morphine for mu receptors compared to levorphanol’s ability to interact more potently with other relevant receptor subtypes, levorphanol could achieve analgesia in patients resistant to other strong opioids. In clinical studies, it has demonstrated a remarkably broad spectrum of analgesic activity against many different types of pain including neuropathic pain, post-surgical pain, and chronic pain in patients refractory to other opioids. As a strong opioid, levorphanol would have a similar tendency to addiction risk. This will be evaluated in the course of a Phase 3 clinical trial. What should clinicians and patients take away from your d-Methadone report?

Dr. Mangano: Results from our Phase I trial of d-Methadone (dextromethadone, REL-1017) show that it is safe and well tolerated in patients suffering from chronic pain and has the potential to treat a number of pain syndromes with virtually no opioid-related effects. It’s important for clinicians to understand that there is an unmet medical need for more effective and better-tolerated therapies for chronic neuropathic pain. Based on clinical data we expect d-Methadone to address this market. Is there anything else you would like to add?

Dr. Mangano: A large number of people in the US suffer from chronic pain, recent estimates place the prevalence at 11% of the adult population. The challenge for clinicians is providing patients with appropriate treatment based on a careful consideration of the benefits and risks of treatment options. The Centers for Disease Control recently published new guidelines for treating chronic pain.[i]

It is also important to recognize that abuse-deterrent opioid products are not abuse-proof. Most of the abuse-deterrent technologies developed to date are intended to make manipulation more difficult or less rewarding. The most common form of abuse is still swallowing a number of intact capsules or tablets to achieve a feeling of euphoria. Since opioid products have to deliver the opioid to the patient, there may always be some abuse of these products.

Despite the availability of multiple pain medications, only about 50 percent of U.S. patients say that their pain is under control. Relmada’s development programs hope to deliver choices to clinicians and physicians so effective treatment can be provided with a reduced risk of physical dependence and abuse potential. Thank you for your contribution to the community.


[1] Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016. JAMA. 2016;315(15):1624-1645. doi:10.1001/jama.2016.1464.

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on May 11, 2016 by Marie Benz MD FAAD