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Background Analysis: US FDA Advisory Committee to Review Trevena’s Oliceridine for Acute Pain Management – OCT 11, 2018 (AADPAC)

Announcement

The US FDA has scheduled a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) for Thursday, October 11, 2018. The committee will discuss new drug application (NDA) 210730, for oliceridine 1 milligram/milliliter injection, submitted by Trevena, Inc. (Trevena), for the management of moderate-to-severe acute pain in adult patients for whom an intravenous opioid is warranted. The committee will be asked to discuss the efficacy and safety data and benefit-risk considerations.

Background

Description of Indication

Acute pain is pain that occurs as a sensation to alerts us to possible injury. Acute pain typically lasts less than 3 to 6 months, or pain that is directly related to soft tissue damage. It gradually resolves as the injured tissues heal. Acute pain is relatively more sharp and severe than chronic pain.

Description of Drug Class

Opioids are a class of small molecule drugs that are commonly prescribed to treat moderate to severe pain. Opioids work by reducing the perception of pain through binding to opioid receptors found in the brain, spinal cord, gastrointestinal tract, and other organs in the body. The FDA has approved several opioid-containing products, which include the following active ingredients: fentanyl, oxymorphone, hydromorphone, morphine, hydrocodone, and oxycodone.

FDA Considerations for the Drug Class

The US is currently experiencing an epidemic of overprescribing, misuse and abuse of opioid drugs. Because opioids affect regions of the brain that are involved in reward mechanisms, many people experience a euphoric response. Abusers may take higher or more frequent opioid doses than prescribed or tamper with opioid products in order to administer them in ways that were not intended (e.g., manipulating an oral opioid for injection or to snort it) in an attempt to increase the euphoric affect, which is referred to as dose-dumping. Such misuse and abuse can lead to fatal respiratory depression. The US Centers for Disease Control and Prevention (CDC) has reported that, in 2015, drug overdoses accounted for 52,404 US deaths, including 33,091 (63.1%) that involved an opioid.

Several US agencies have been undergoing efforts to evaluate and attempt to curb the opioid crisis.

In response to the epidemic, in January 2018, the FDA announced its 2018 Strategic Policy Roadmap, which detailed several proposed actions within the Agency’s Opioid Policy Work Plan, including:

• Re-examine and modernize FDA’s framework for evaluating the pre- and post-market safety of opioid products based on risk and benefit considerations; including an evaluation of a product’s potential risks for illicit use or its potential for abuse.

• Address inappropriate prescribing of prescription opioids with new modifications to REMS programs that require, for example: training on non-opioid pain alternatives; training for prescribing related to immediate-release formulations of opioid drugs; and, broader training that covers more health care providers who help manage patients with pain.

• Support development of abuse-deterrent formulations of opioids by exploring new methods for analyzing, evaluating abuse-deterrent features; evaluating the nomenclature used to describe these abuse-deterrent features; facilitating development of science for generic development of these drugs; and, taking new steps to encourage the conversion of the market to effective, abuse-deterrent formulations.

• Finalize policies to enable the OTC availability of naloxone.

• Generate further opportunities for stakeholder input with public hearings and workshops on opioid issues while FDA explores new steps through innovations in regulation, packaging, and prescribing to reduce overall exposure to opioid drugs and address misuse and abuse. This could result in a new, comprehensive approach – using education, packaging, labeling and other tools – to encourage more appropriate prescribing and dispensing of opioid drugs.

• Advance policies to enable more product innovation in the development of non-addictive pain remedies; as well as the development of improved medication-assisted treatment (MAT).

• Implement a new and more robust approach to the oversight of illicit controlled substances and foreign unapproved drugs imported into the US through international mail facilities (IMFs). Among other things, the FDA will pursue new resources in these facilities and will expand its efforts through the formation of a new Enforcement Task Force.

• Launch a public campaign to drive more widespread, appropriate adoption of medication-assisted treatment and take new steps to address the stigma and other obstacles to more widespread availability and appropriate prescribing of MAT.

Product Background

Description of Product

Oliceridine is a μ-opioid receptor biased agonist. In in vitro research, oliceridine elicits G protein signaling, with potency and efficacy similar to that of morphine, but with the possibility of fewer adverse effects than morphine.

Clinical Trials of Proposed Indication

Trevena announced positive topline results from two Phase 3 studies of oliceridine for the treatment of moderate-to-severe acute pain. The first trial, APOLLO-1 (ClinicalTrials.gov Identifier: NCT02815709), was a multicenter, randomized, double-blind, placebo- and active-controlled trial evaluating the efficacy of oliceridine for 48 hours following bunionectomy. The second trial, APOLLO-2 (ClinicalTrials.gov Identifier: NCT02820324), was a multicenter, randomized, double-blind, placebo- and active-controlled trial evaluating the efficacy of oliceridine 24 hours following abdominoplasty. In both trials, patients received a loading dose of placebo, morphine 4 mg or oliceridine 1.5 mg, followed by on-demand doses of morphine 1 mg or oliceridine 0.1 mg, 0.35 mg, or 0.mg. If more pain control was needed, patients could request an additional 0.75 mg oliceridine injection or 2 mg morphine, no more than once an hour. Patients also could receive an oral nonsteroidal anti-inflammatory agent (NSAID).

The primary endpoint was analgesic efficacy of oliceridine compared to placebo, as measured by responder rate. Responders were defined as patients who experienced at least a 30% reduction in their sum of pain intensity difference at the end of the treatment period without early discontinuation or use of rescue medication. Secondary endpoints included comparisons of efficacy, safety, and tolerability of oliceridine to morphine, including incidence of nausea and vomiting and respiratory safety measures.

In February 2017, Trevena announced that APOLLO-1 results showed that all three doses of oliceridine demonstrated statistically greater efficacy than placebo (p<0.0001) and both the 0.35 mg and 0.5 mg oliceridine doses showed non-inferior efficacy to morphine based on responder rate (P<0.005), with comparable rescue analgesic usage. APOLLO-2 results showed that all three oliceridine doses demonstrated statistically superior responder rates vs. placebo (adjusted P<0.05 for 0.1 mg; adjusted P<0.001 for 0.35 mg and 0.5 mg). Both the 0.35 mg dose and the 0.5 mg dose showed non-inferior efficacy to morphine (P<0.005 for 0.35 mg), with comparable rates of rescue analgesic use.

Trevena said that both studies found oliceridine to be generally safe and well-tolerated, with the most common adverse events found to be nausea, vomiting, headache, and dizziness.

In addition, Trevena conducted a large, Phase 3, open label safety study, ATHENA (ClinicalTrials.gov Identifier: NCT02656875), designed to model "real world" use in a wide spectrum of surgical and medical acute pain conditions. The study was conducted in more than 750 patients undergoing a variety of procedures including general, gastrointestinal (GI), orthopedic, and plastic surgeries. The patients receiving oliceridine injection included those considered at higher risk of opioid-related adverse events such as elderly patients and those with higher body mass index (BMI). Oliceridine injection was given in post-anesthesia care units by IV bolus and on surgical/medical floors by IV bolus and/or patient-controlled analgesia. Trevena has said that results of the trial showed that oliceridine can be successfully substituted for conventional IV opioids to manage moderate to severe acute pain.

Comprehensive data from the NDA, including detailed analyses by the company and by the FDA, as well as specific FDA questions for the Committee, will be presented in briefing materials that will be posted ahead of the meeting. The briefing materials for the meeting will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

Regulatory Background

US Regulatory Background

November 2, 2018 – PDUFA date

January 2, 2018 – NDA 210730 FDA acceptance date

Fast track, breakthrough therapy designation

Ex-US Regulatory Background

Tarius has not found any publicly-available information regarding ex-US regulatory submissions for oliceridine.

What’s Next? (With Subscription)

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Trevena, Inc.  Drug Name: oliceridine Drug Class: opioid Indication: painbiase


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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.