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Background Analysis: US FDA Advisory Committee to Review AcelRx’s Sufentanil Sublingual Tablets for Pain Management – OCT 12, 2018 (AADPAC)

Announcement

The US FDA has scheduled a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) for Friday, October 12, 2018. The committee will be asked to discuss new drug application (NDA) 209128 for sufentanil sublingual tablets, submitted by AcelRx Pharmaceuticals, Inc. (AcelRx), for the management of moderate-to-severe acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate, in adult patients in a medically supervised setting. The committee will be asked to discuss risk-benefit considerations and whether this product should be approved.

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

Sufentanil is a µ-opioid agonist. It was first synthesized by Janssen in 1974, and approved by the FDA for intravenous (IV) delivery in 1984. It was later approved for epidural delivery as an analgesic in combination with bupivacaine.

AcelRx says that the subject of the submitted NDA, the sufentanil sublingual tablet (SST), with a proposed trade name of DSUVIA in the US, has shown rapid (6 minutes) plasma-central nervous system equilibration time and predictable off-set and uses a noninvasive delivery route, making it appropriate for temporary pain management. The system consists of 30 µg sufentanil in small sublingually absorbed tablets that are delivered via a disposable, pre-filled, single-dose applicator (SDA).

Note that, separate from the subject of this NDA and related AADPAC meeting, AcelRx also has developed a drug/device combination product designed to deliver 15 µg sufentanil, formulated in a proprietary non-invasive sublingual dosage form via a novel hand-held, pre-programmed, patient-controlled analgesia system, for use in hospital settings. With the trade name of Zalviso, this product is approved in the European Union, but not in the US. In November 2013, AcelRx filed an NDA with the FDA, but received a Complete Response Letter (CRL) in 2014. In response to the CRL and in consultation with the FDA, AcelRx developed a protocol for a fourth Phase 3 study designed to evaluate the overall performance of the Zalviso System.

Clinical Trials

AcelRx says that the sufentanil sublingual system NDA is based on three clinical trials. The first trial, SAP301 (ClinicalTrials.gov Identifier: NCT02356588), is a multi-center, double-blind, placebo-controlled Phase 3 trial in patients with moderate-to-severe acute pain following ambulatory abdominal surgery. AcelRx reported in September 2015 that DSUVIA met primary and secondary endpoints in this study. They reported that the results of SAP301 demonstrated that patients receiving DSUVIA experienced significantly greater pain reduction compared to placebo, as measured by the time-weighted Summed Pain Intensity Difference to baseline over the first 12 hours of treatment (SPID-12) (p<0.001). Adverse events reported in the study were typical of opioid therapy and were similar for patients treated with DSUVIA and placebo, the most common of which were nausea, headache and vomiting.

The second trial, SAP302 (ClinicalTrials.gov Identifier: NCT02447848), is a multi-center, open-label Phase 3 trial of DSUVIA for the treatment of adult patients who present to the emergency department with moderate-to-severe acute pain associated with trauma or injury. SAP302 enrolled patients in two cohorts: 1) 40 adults who were administered a single dose of DSUVIA; and 2) 36 adults who were eligible to receive up to four doses of DSUVIA, given hourly as needed for pain. The company says that, overall, the 76 adults treated with DSUVIA in this study experienced a mean pain intensity difference to baseline (PID) of 2.9 on a 0-10 numeric rating scale at 60 minutes. Patients treated in the first cohort experienced a mean decrease from baseline of 2.7 after a single dose of DSUVIA; and patients in the second cohort reported a mean decrease from baseline of 3.1. DSUVIA showed 79% of patients reporting no adverse events, with the most commonly reported adverse events being nausea (9%), somnolence (5%) and vomiting (4%). A cognitive impairment assessment using the validated Six-Item Screener was also conducted within SAP302, and demonstrated that DSUVIA was not associated with drug-induced cognitive impairment.

The third trial, SAP303 (ClinicalTrials.gov Identifier: NCT02662556), is a multi-center, open-label Phase 3 trial for the treatment of moderate-to-severe acute pain in patients who had undergone short-stay in-patient or out-patient surgery. SAP303 enrolled 140 patients aged ≥40 years, 17% of whom where aged ≥65 years and 29% of whom had baseline renal and/or hepatic impairment. In this study, treatment with DSUVIA was associated with improvements in pain intensity as early as 30 minutes after the start of DSUVIA dosing, a 49% reduction in mean pain intensity from baseline (from 6.19 to 3.17 on a 0-10 numeric rating scale) during the first 2 hours, and maintenance of that reduction for the duration of the 12-hour study period. Safety results showed the most frequently reported adverse events in the total population were nausea (27%) and headache (6%). Overall, safety and efficacy findings were similar among patients regardless of age and renal or liver function.

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 3, 2018 – PDUFA date

May 24, 2018 – AcelRx announces US FDA’s acceptance of its NDA resubmission for sufentanil sublingual tablets.

October 2017 – AcelRx received a Complete Response (CR) Letter from the US FDA. AcelRx said that the two primary recommendations within the CRL were: 1) while the safety database was suitable in number of patients, the collection of additional data was requested on at least 50 patients to assess the safety of DSUVIA dosed at the maximum amount described in the proposed labelling; and 2) to ensure proper administration of the tablet with the single-dose applicator, the FDA recommended certain changes to the Directions for Use to address use-related errors, including dropped tablets, to be validated through a human factors study. AcelRx said that they considered the recommendations stated in the CRL to be manageable and would move toward resubmission of the NDA.

December 2016 – NDA for sufentanil sublingual tablets submitted to the US FDA.

Ex-US Regulatory Background

June 27, 2018 – The European Commission (EC) approved sufentanil sublingual tablets (brand name DZUVEO) for the management of acute moderate-to-severe pain in adults in medically monitored settings.

March 2017 – Marketing Authorization Application (MAA) filed with the European Medicines Agency (EMA).

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: AcelRx Pharmaceuticals, Inc.  Drug Name: sufentanil Drug Class: opioid Indication: pain


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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.