P-081 - SMART™ Opioids with Unprecedented Protection Against Abuse and Oral Overdose – Human Proof-of-Concept

Abstract Title: SMART™ Opioids with Unprecedented Protection Against Abuse and Oral Overdose – Human Proof-of-Concept


Background: The decades long effort to develop non-opioid analgesics with efficacy comparable to opioids has not been fruitful.

Opioid therapy continues to provide unmatched efficacy for the management of acute pain related to severe traumatic injuries, invasive surgeries typically associated with moderate to severe postoperative pain, and other severe acute pain.

When used as prescribed, opioid analgesics for acute pain are safe and effective.

Based on their pharmacology, opioids are subject to abuse. Concerns related to the abuse liability of opioids have resulted in under-prescribing to legitimate pain patients, leaving them with pain that cannot be effectively treated with non-opioid pain management strategies.
The vast majority ( >90%) of the abuse of currently prescribed short-acting opioid analgesics is via the ingestion of supra-therapeutic doses.¹

Abuse of short-acting opioid analgesics is reinforced by two key risk factors (i) a dosing regimen that necessitates a high number of prescribed tablets, and (ii) the dose-proportional reward incentive for abusers to ingest supra-therapeutic doses for increased euphoric effects,² often resulting in opioid use disorders and potentially lethal overdoses.

Safer opioids that address these inherent risks are needed.
Formulation-based attempts to develop abuse-resistant opioids focused on thwarting non-oral routes of abuse and have made little impact.

Purpose/Objectives: Elysium is developing a novel class of SMART™ Opioids for the treatment of acute pain that reduce the potential for abuse, diversion, and risk of oral overdose.

Elysium’s SMART opioid prodrugs leverage our O2P (Oral Overdose Protected) technology — novel prodrugs designed to effectively mitigate non-oral and oral abuse while safely delivering an FDA approved opioid agonist.

Elysium’s SMART opioids demonstrate a highly sought-after and unprecedented product profile, including:

• Safe and well-tolerated


• Efficient delivery of therapeutic opioid exposures at prescribed doses


• Reduced dose-proportional plasma exposures (e.g., C_max) when supratherapeutic doses are ingested


• Pharmacokinetics consistent with once-daily dosing


• Protection against non-oral abuse and overdose (i.e., opioid not released unless ingested)


• Robust chemical stability that renders O2P molecules highly tamper-resistant.

O2P opioid prodrug technology is broadly applicable to all currently prescribed oral opioid agonists.


Methods: Elysium conducted a phase 1, randomized, open-label, 2-part study to evaluate the safety and pharmacokinetics of oral O2P Hydrocodone vs. hydrocodone bitartrate (HCBT) in healthy adult subjects under fasted conditions under naltrexone blockade.

Key objectives of the study were to:

• Evaluate the safety, tolerability, and pharmacokinetics of oral O2P Hydrocodone relative to a HCBT comparator following single oral doses in healthy adult subjects.


• Demonstrate reduced maximum plasma exposures (C_max) of hydrocodone delivered from escalated oral doses of O2P Hydrocodone relative to an escalated comparator dose of HCBT (i.e. oral overdose protection).


• Identify appropriate doses of oral O2P Hydrocodone for subsequent clinical studies.

POPULATION:

• The population for this study included male and female subjects, 18 to 55 years of age, inclusive, who were in general good health.

STUDY

Design:

• 93 healthy adult subjects were enrolled for the study with each subject participating in 1 treatment period. Six subjects were included in each treatment period.


• Safety assessments included incidence of adverse events (AEs), physical examination findings, vital signs, electrocardiogram (ECG) parameters, and clinical laboratory tests.


• For safety, subjects were administered oral naltrexone pre- and post-dose for each treatment period.


• Blood sampling and subsequent PK analyses were performed during the study.

Results: SAFETY:

• Safety was assessed by evaluating physical examinations, vital signs (BP, heart rate, respiratory rate, oxygen saturation, and oral body temperature), 12-lead ECGs, clinical laboratory parameters (serum chemistry, hematology, and urinalysis), and AEs reported during the study.


• In all treatment periods O2P Hydrocodone was generally well tolerated in all subjects with no serious adverse events reported.


• Study drug related Treatment-Emergent Adverse Events (TEAEs) occurrence was 19.4% for the entire study population (n=93).


• All TEAEs were classified and mild or moderate.


• Study Drug Related TEAEs included nausea, emesis abdominal pain/distension, diarrhea, dizziness, headache, presyncope, anxiety, insomnia, and agitation.


• There were no clinically significant clinical laboratory values, ECG results, or out-of-range vital signs following treatments with O2P hydrocodone or HCBT.

PHARMACOKINETICS:

• Data from all subjects who completed selected treatments were included for pharmacokinetic analysis.


• Hydrocodone plasma concentration vs. time profiles were determined.


• Based on comparable Cmax values, 5 mg HCBT and 60 mg O2P hydrocodone represent Hydrocodone Equivalent Doses (HEDs).

ORAL OVERDOSE PROTECTION:

• Dose escalations of O2P hydrocodone and HCBT were conducted to evaluate the extent of oral overdose protection exerted with O2P hydrocodone.


• Pharmacokinetic parameters following escalating HEDs of O2P hydrocodone and HCBT were determined.


• Mean hydrocodone C_max values for escalating doses of O2P hydrocodone and HCBT were compared.


• Mean C_max values for O2P hydrocodone and HCBT were benchmarked against a potentially lethal hydrocodone plasma exposure of ~110 ng/ml.³


• The C_max value from highest dose of HCBT exceeded a potentially lethal hydrocodone exposure, while the C_max value produced with highest dose of O2P hydrocodone did not.

Conclusions/Implications for future research and/or clinical care: Significant Reduction in The Number of Prescribed Doses Mitigates Misuse, Abuse and Diversion

The sustained plasma exposure of hydrocodone demonstrated by O2P hydrocodone is consistent with a once-daily dosing regimen. Consequently, the number of prescribed tablets for O2P hydrocodone is significantly reduced vs. currently prescribed hydrocodone.



Limits the Number of Euphoric Experiences that May Serve to Initiate and Reinforce Abuse Behavior

Based on attenuated hydrocodone exposures when supratherapeutic doses are ingested and the reduced number of tablets per prescription, the number of euphoric experiences available from an O2P hydrocodone prescription is dramatically reduced vs. currently prescribed hydrocodone.



Significantly Reduces the Risk of Fatal Overdose

An 8-day prescription of currently prescribed hydrocodone contains 8-fold the potentially lethal dose of hydrocodone. In stark contrast, an 8-day prescription of O2P hydrocodone will not produce a potentially lethal plasma exposure of hydrocodone even if the entire prescription is taken as a single dose.


References: 1) Gasior, Maciej; Bond, Mary; Malamut, Richard (2016): Routes of abuse of prescription opioid analgesics. A review and assessment of the potential impact of abuse-deterrent formulations. In Postgraduate medicine 128 (1), pp. 85–96.

2) Walsh SL, Nuzzo PA, Lofwall MR, Holtman JR Jr. The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers. Drug Alcohol Depend. 2008 Dec 1;98(3):191-202.

3) Molina DK, Hargrove VM. What is the lethal concentration of hydrocodone? A comparison of postmortem hydrocodone concentrations in lethal and incidental intoxications. Am J Forensic Med Pathol. 2011 Jun;32(2):108-11.