Background Analysis: US FDA Advisory Committee to Review Novel Opioid Proposed by Nektar Therapeutics – JAN 14, 2020 (AADPAC-DSRM)

Announcement

The US FDA has scheduled a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) and the Drug Safety and Risk Management (DSRM) Advisory Committee meeting for Tuesday, January 14, 2020. The committees will discuss a new drug application (NDA) for oxycodegol, submitted by Nektar Therapeutics (Nektar), for the management of chronic low back pain in certain adult patients. The committees will be asked to discuss the safety and efficacy data as well as the overall risk-benefit profile of the product.

Regulatory Overview

This will be the first FDA advisory committee review of a proposed opioid since the Agency issued new draft guidance on the framework to assess the risk-benefit of opioids. The June 2019 guidance emphasized that FDA usually assesses drugs in the context of their proposed indication, however, due to the widespread misuse and abuse of opioids, the broader public health effects must also be considered when assessing opioids. This includes risks related to misuse, abuse, opioid use disorder, accidental exposure, and overdose, for both patients and others. The guidance summarizes the information that should be included in an opioid NDA to address the FDA’s considerations. Subsequent to issuing the new guidance, the FDA also convened a public meeting in September 2019 on the topic of approval standards for opioids, as well as ways to incentivize novel therapeutics for pain and addiction.

The topic of the upcoming advisory committee meeting is oxycodegol (a.k.a., NKTR-181), a full mu-opioid receptor that was designed to enter the brain slower than standard opioids, which is intended to reduce CNS-mediated side effects (e.g., sedation and euphoria) and confer less addiction and abuse liability. It is formulated as an oral pill to be taken twice daily. The NDA is based primarily on the outcomes of a Phase 3 program named SUMMIT, which included the SUMMIT-07 efficacy study (N=610), the SUMMIT-LTS long-term safety study (N=638), and a human abuse potential (HAP) study (N=54). Nektar is currently recruiting a magnetic resonance imaging (MRI) study (N=24) to evaluate the effect of oxycodegol on brain activity. If approved, Nektar plans to commercialize oxycodegol through a wholly owned subsidiary, Inheris Biopharma, Inc., with one or more potential capital partners to support commercial launch.

The Prescription Drug User Fee Act (PDUFA) goal date for the FDA to decide on whether to approve oxycodegol was August 29, 2019. However, prior to the PDUFA goal date, the Agency sent Nektar a letter which said they were postponing product-specific advisory committee meetings for opioid analgesics “while they continue to consider a number of scientific and policy issues relating to this class of drugs,” which postponed an advisory committee meeting that was planned for oxycodegol on August 21, 2019. The letter noted that the postponement could cause the Agency not to meet its PDUFA goal date.

Background

Clinical Trials

The NDA is based primarily on outcomes from the Phase 3 program named SUMMIT, which included the SUMMIT-07 efficacy study (ClinicalTrials.gov Identifier: NCT02362672, results not yet posted), the SUMMIT-LTS long-term safety study (ClinicalTrials.gov Identifier: NCT02367820, results not yet posted) and a human abuse potential (HAP) study (not posted at ClinicalTrials.gov). Top-line results of these studies are presented below based on information provided in press releases made by the company and information posted at ClinicalTrials.gov. A more comprehensive summary of the data package in the NDA will be made available two days prior to the AADPAC-DSRM meeting, in briefing materials posted online by the FDA. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

SUMMIT-07

The SUMMIT-07 study compared twice-daily oral dosing of NKTR-181 tablets to placebo in the treatment of 610 patients with moderate to severe chronic low back pain who were opioid-naïve. The study evaluated four doses of NKTR-181 (100 mg, 200 mg, 300 mg and 400 mg). Patients achieved an average pain score reduction of over 65% (from 6.73 at screening to 2.32 at randomization) during the dose titration period. The primary efficacy endpoint of the study (change in pain scores from baseline to Week 12 of the treatment period) demonstrated significantly improved chronic back pain relief with NKTR-181 compared to placebo (p=0.0019). Key secondary endpoints of the study also achieved statistical significance. Nektar also says the study demonstrated that NKTR-181 had a favorable safety profile and was well tolerated.

SUMMIT-LTS

SUMMIT-LTS was a 52-week long term safety study. The study evaluated the long-term safety and tolerability of NKTR-181 in 638 patients (opioid-naïve and opioid-experienced) with moderate to severe chronic low pain or chronic non-cancer pain. Nektar also says the study showed that NKTR-181 had a favorable safety profile with analgesic effect maintained over 52-weeks.

HAP Study

The HAP study was designed to confirm and assess the relative oral abuse potential of NKTR-181 at its maximum analgesic or therapeutic dose (400 mg) and at a supratherapeutic dose (3 times to 12 times greater than its analgesic dose range of 100 mg to 400 mg) compared to oxycodone in healthy non-dependent recreational drug users.

The study was powered to detect a relative peak (Emax) drug liking score difference between oxycodone at 60 mg and NKTR-181 at 1,200 mg.  Liking was based on a subject-reported 100-point bipolar liking/disliking visual analog scale (VAS). Secondary endpoints were Area Under Effect (AUE) for Drug Liking in the first 1, 2 and 3 hours after dosing as well as retrospective subject-reported unipolar VAS ratings for Drug High and bipolar VAS ratings for Take Drug Again. The results for each endpoint are listed below.

·       Primary Endpoint of Drug Liking:

o   NKTR-181 400 mg had a significantly lower rating of peak (Emax) liking compared to oxycodone 40 mg (62.0 vs. 76.6, p < 0.0001).

o   NKTR-181 400 mg had a significantly lower rating of peak (Emax) liking compared to oxycodone 60 mg (62.0 vs. 81.5, p < 0.0001).

o   NKTR-181 600 mg had a significantly lower rating of peak (Emax) liking compared to oxycodone 40 mg (67.9 vs. 76.6, p < 0.0001).

o   NKTR-181 600 mg had a significantly lower rating of peak (Emax) liking compared to oxycodone 60 mg (67.9 vs. 81.5, p < 0.0001).

o   NKTR-181 1200 mg had a significantly lower rating of peak (Emax) drug liking compared to oxycodone 60 mg (76.7 vs. 81.5, p=0.0071). This dose was not statistically different from oxycodone 40 mg.

Note: Nektar says the peak liking score for NKTR-181 400 mg oral tablet in this study confirmed the same peak liking score for NKTR-181 400 mg oral solution evaluated in the company's prior HAP study (62.0 vs 62.3).

·       AUE for Drug Liking Following Dosing (0-1 Hours, 0-2 Hours, 0-3 Hours):

o   NKTR-181 400 mg had significantly lower AUE for all timepoints compared to both oxycodone 40 mg and 60 mg (p < 0.0001).

o   NKTR-181 600 mg had significantly lower AUE for all timepoints compared to both oxycodone 40 mg and 60 mg (p < 0.0001).

o   NKTR-181 1200 mg had significantly lower AUE for all timepoints compared to both oxycodone 40 mg and 60 mg. For AUE (0-1 Hours), p=0.0002 and p<0.0001, respectively; for AUE 0-2 Hours, p=0.001 and p < 0.0001, respectively; for AUE 0-3 Hours, p=0.0396 and p=0.0003, respectively). 

·       Secondary Endpoint of Drug High:

o   NKTR-181 400 mg had significantly lower ratings of peak (Emax) Drug High compared to both oxycodone 40 mg and 60 mg (p < 0.0001).

o   NKTR-181 600 mg had significantly lower ratings of peak (Emax) Drug High compared to both oxycodone 40 mg and 60 mg (p < 0.0001).

o   NKTR-181 1200 mg had a significantly lower rating of peak (Emax) Drug High compared to 60 mg oxycodone (p=0.0071).

Note: Nektar says the peak Drug High score for NKTR-181 400 mg oral tablet in this study confirmed the peak Drug High score in the first HAP trial, which evaluated 400 mg NKTR-181 as an oral solution (21.3 vs 22.59).

·       Secondary Endpoint of Take Drug Again:

o   NKTR-181 400 mg had significantly lower ratings of peak (Emax) Take Drug Again compared to the 40 mg and 60 mg oxycodone (p < 0.0001).

o   NKTR-181 600 mg had significantly lower ratings of peak (Emax) Take Drug Again compared to the 40 mg and 60 mg oxycodone (p=0.0004 and p < 0.0001, respectively).

o   NKTR-181 1200 mg had a significantly lower rating of peak Take Drug Again compared to 60 mg oxycodone (p=0.011).

Magnetic Imaging Study

According to ClinicalTrials.gov, Nektar is currently recruiting a study (ClinicalTrials.gov Identifier: NCT03802227) to evaluate the effect of oxycodegol on brain activity in healthy, non-physically dependent recreational opioid users. The study is estimated to complete on March 30, 2020. It is a single-center study in which approximately 24 subjects will be randomized to either oxycodegol or immediate-release oxycodone. The primary outcome is the functional magnetic resonance imaging (MRI) blood oxygenation level dependent (BOLD) signal in brain following administration.

Regulatory History

US Regulatory History

September 17, 2019 – The FDA held a public hearing entitled, “Standards for Future Opioid Analgesic Approvals and Incentives for New Therapeutics to Treat Pain and Addiction.”

August 29, 2019 – PDUFA goal date

July 23, 2019 – Nektar filed a Form 8-K with the US Securities and Exchange commission. The form noted as follows (in part):

On July 23, 2019, Nektar Therapeutics, a Delaware corporation (“Nektar”), received a General Advice letter (“Letter”) from the U.S. Food and Drug Administration (“FDA”) regarding Nektar’s New Drug Application (“NDA”) for NKTR-181, a novel mu-opioid analgesic drug candidate.

In the Letter, the FDA stated that it is postponing product-specific advisory committee meetings for opioid analgesics, including the one previously scheduled for August 21, 2019 to discuss the NDA for the NKTR-181 product, while the agency continues to consider a number of scientific and policy issues relating to this class of drugs. The Letter stated that the FDA’s reason for postponing the advisory committee meeting for NKTR-181 is not unique to the NKTR-181 product. The Letter further stated that the FDA will continue to review the NDA for NKTR-181 according to the existing Prescription Drug User Fee Act (“PDUFA”) timeline and will request additional information from Nektar, as needed. However, the FDA did indicate in the Letter that it is possible the agency may not be able to meet the PDUFA goal date of August 29, 2019, due to the postponement of the advisory committee meeting.

June 2019 – The FDA issued Draft Guidance For Industry: Opioid Analgesic Drugs: Considerations for Benefit Risk Assessment Framework.

May 28, 2019 – Initial PDUFA date, per Nektar’s announcement of the NDA submission on July 30, 2018. At some point, the PDUFA was extended by 3 months, to August 29, 2019.

July 30, 2018 – Nektar announced the NDA submission (NDA 211802).

Ex-US Regulatory History

Tarius did not find any reports in the public domain pertaining to ex-US development of oxycodegol.

What’s Next?

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 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: Nektar Therapeutics Drug Name: oxycodegol 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.