Opioids produce potent pain relief and thus remain the cornerstone of treatment for moderate to severe pain. Each year, roughly 45 million U.S. hospital patients receive an I.V. opioid for acute pain treatment (asamonitor.pub/36htwuR). Many of these patients have complex medical conditions that can be difficult to treat, such as old age, obesity, or renal impairment. The number of complex patient cases is reportedly growing, representing an increasing burden on the health care system (Clin Drug Investig 2015;35:53-59).

Although opioid analgesics are necessary, their overuse in clinical settings, diversion, and abuse has led to a difficult public health crisis. Additionally, many opioid side effects may complicate adequate dose exposure for analgesia, which can in rare instances be life-threatening. Most opioid overdose deaths in the U.S. occur from illegal heroin, fentanyl, and fentanyl analogs; however, prescription opioid medications are also a major source of morbidity and mortality (asamonitor.pub/2HJbDen). A majority of the prescription opioids misused or abused are oral medications dispensed directly to patients (asamonitor.pub/2Gh3aOK).

“Addressing the opioid crisis remains a top priority for the FDA. Importantly, the FDA will only approve new drug applications, including those for opioid medications, following a rigorous review to evaluate the risks and benefits and ultimate determination that the data support safety and effectiveness,” stated Douglas Throckmorton, MD, deputy director for regulatory programs in the FDA's Center for Drug Evaluation and Research (asamonitor.pub/36hicPx).

One emerging strategy to address the opioid crisis is the development of mu opioid receptor (MOR) ligands that preferentially signal the G-protein versus β-arrestin pathway. Conventional I.V. opioid agonists (e.g., morphine, fentanyl, hydromorphone) bind to the MOR, a type of G protein coupled receptor (GPCR), leading to G protein post-receptor signaling and analgesia. But they also activate the β-arrestin pathway, a signaling pathway associated with opioid-related adverse events including respiratory depression and gastrointestinal (GI)-related effects.

A novel mechanism of action

Recently, researchers have discovered that “biased” ligands could selectively engage some signaling pathways while avoiding, or even inactivating, other signaling pathways mediated by the same receptor (Front Neurosci. 2017;11:17). Trevena, Inc. (Trevena), was founded to translate these discoveries into developing new GPCR-targeted medicines that could offer improved benefit-risk profiles over existing therapies (asamonitor.pub/36g3PuM).

Oliceridine (OLINVYK™) injection, an opioid agonist that was discovered by Trevena scientists in 2010, hopes to address the significant unmet need in the acute pain management landscape: a mechanism to offer opioid-level analgesia while reducing opioid side effects compared with conventional I.V. opioids (asamonitor.pub/36hl4fa). Oliceridine is the first of a new class of biased ligands with a novel mechanism of action at MOR. This novel pharmacology was designed to selectively activate the G protein pathway, with markedly reduced, but not elimination, of β-arrestin post-receptor activation. Nonclinical evidence revealed reduced respiratory and GI dysfunction were observed in oliceridine-treated rodents at doses providing equivalent analgesic activity compared with morphine (J Pharmacol Exp Ther 2013;344:708-17).

FDA approval

In August 2020, the FDA approved oliceridine for the management of adults with acute pain severe enough to require an I.V. opioid analgesic and for whom alternative treatments fail (asamonitor.pub/2Gb25s3). The indication is for short-term I.V. use in hospitals or other controlled clinical settings, without allowance for take-home prescription.

Oliceridine's FDA approval was based on results from two pivotal phase 3 studies that evaluated the efficacy of oliceridine in 790 adult patients with moderate to severe acute pain following orthopedic surgery-bunionectomy (APOLLO-1) and plastic surgery-abdominoplasty (APOLLO-2) (asamonitor.pub/33b2L9A; asamonitor.pub/2Gim3kv). Findings from both studies showed a statistically greater analgesic effect in the oliceridine treatment groups versus placebo. Additionally, an open-label, phase 3 study (ATHENA), involving 768 patients found oliceridine to be safe and well tolerated in a medically complex patient population, including elderly and obese patients, and those with comorbid conditions (e.g., diabetes, sleep apnea)(asamonitor.pub/2G9XpTi).

At the approved doses, the therapy was associated with decreased rates of reported pain among post-operative patients compared with patients who received placebo. Investigators reported a safety profile of oliceridine like that of other opioids: most common side effects (≥10%) were nausea, vomiting, dizziness, headache, and constipation.

Marketed OLINVYK carries a boxed warning regarding the risks of addiction, abuse, and misuse; life-threatening respiratory depression; neonatal opioid withdrawal syndrome; and risks from concomitant use with benzodiazepines or other central nervous system depressants. Moreover, the cumulative total daily dose should not exceed 27mg. The effect on QT prolongation at total cumulative daily doses >27mg has not been studied in a thorough QT study. Total cumulative daily doses exceeding 27mg/day may increase the risk for QTc interval prolongation. Trevena plans to make OLINVYK available in the fourth quarter of 2020.

“In August 2020, the FDA approved oliceridine for the management of adults with acute pain severe enough to require an I.V. opioid analgesic and for whom alternative treatments fail.”

The ASA Monitor spoke to Mark Demitrack, MD, Senior Vice President and Chief Medical Officer of Trevena to discuss the recent FDA approval of OLINVYK.

ASA Monitor: What are the principal advantages of OLINVYK, over other available opioid analgesics?

Dr. Demitrack: OLINVYK offers a novel product profile among available parenteral opioids, and due to several differentiated features, has the potential to be an important new therapeutic option for use in medically complex patients in the hospital setting. First, its chemical structure is distinct from I.V. morphine or hydromorphone. Second, its clinical analgesic effect is rapid, with a near-immediate 2-5-minute onset of action. Third, it has no active metabolites, and does not require dose adjustment in the setting of renal impairment, which may make dosing less challenging in the medically complex patient. Finally, the product labeling includes safety and tolerability of OLINVYK in a comprehensive series of phase 3 studies, specifically among them a large, multisite, real-world safety study in a diverse population of patients with multiple medical comorbidities across a wide array of surgical procedures.

ASA Monitor: Is the separation in potency for signaling via the G-protein versus β-arrestin pathways that is currently achievable limit the interpretation of whether Olinvyk preclinical results translate into improved clinical utility compared with currently utilized MOR agonists?

Dr. Demitrack: OLINVYK's nonclinical pharmacology has demonstrated it is uniquely and preferentially directed to signaling via the G-protein pathway, with relatively little downstream engagement of β-arrestin signaling within the cell. Animal data have shown that this pharmacology results in a reduced propensity to cause GI or respiratory adverse effects at doses that are equipotent in analgesic effect to conventional opioid drugs.

Translating these animal findings to clinical signals in human patients can indeed be challenging. We have examined respiratory and GI outcomes in our human studies, using morphine as a reference compound in that work. In all those studies, the directional pattern of evidence was consistent with the results observed in the early animal work. As an example, we studied OLINVYK and morphine in a Phase 1 experimental medicine model using hypercapnic respiratory drive and the cold pain test to measure respiratory physiology and establish analgesic equipotency directly. In a recent clinical utility function analysis of that data, Dr. Albert Dahan and his team verified that across the clinically relevant concentration range, OLINVYK showed a positive utility function, with the probability of analgesia exceeding the probability of respiratory depression, with the reverse pattern observed with morphine (Anesthesiology 2020;133:559-568). We believe these data are exciting and provide us insights into the pharmacology of OLINVYK and our approaches to future clinical studies. Still, clinicians always need to consider the possibility of respiratory depression and take caution when prescribing any opioid.

ASA Monitor: Were there any differences in how well the OLINVYK worked in clinical trials among sex, race, and age? Were there any differences in side effects among sex, race, and age?

Dr. Demitrack: Across the clinical development program, OLINVYK did not perform differently based on sex, race, or age. This program also included a large, multisite, real-world safety study with a diverse patient population, many of whom were medically complex – over one-third of patients were elderly, almost half of patients had a BMI >30, and multiple medical comorbidities were represented, including diabetes, obstructive sleep apnea, and COPD. Despite this more challenging patient population, OLINVYK performed very consistently, with only a 2% discontinuation rate due to adverse events and a 4% discontinuation rate due to lack of efficacy.

ASA Monitor: What are the future developmental programs for OLINVYK?

Dr. Demitrack: We have amassed a comprehensive set of clinical data for OLINVYK, with 22 peer-reviewed publications spanning the full OLINVYK development program. We have a very strong foundation of evidence in place to support the commercial launch. Looking ahead, there are several areas we identified based on the data from our clinical studies that might provide additional opportunities to demonstrate differentiation. Examples include expanding our examination of respiratory depression, studying the role of cognition in acute pain management and recovery, and further investigating the favorable GI tolerability profile of OLINVYK.

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