RENEW OR SUBSCRIBE TO PPM
Subscription is FREE for qualified healthcare professionals in the US.
14 Articles in Volume 19, Issue #1
Analgesics of the Future: NKTR-181
Antidote to CDC Guideline; Plantar Fasciitis; Patient Input
Assessing and Treating Migraine in Women and Men
Demystifying Opioid-Induced Hyperalgesia
Editorial: Have We Gone Too Far? Can We Get Back?
How to Compel Patients to Complete Home Exercises
Inflammation Targeted Nanomedicine
Intravenous Stem Cell Administration for Ileitis
Invasive Surgery: Effective in Relieving Chronic Pain?
Pain Catastrophizing: What Practitioners Need to Know
Pain Therapy Options for the Home
Regenerative Medicine
The Future of Pain Management: An Experts' Roundtable
Whole Body Vibration: Potential Benefits in the Management of Pain and Physical Function

Analgesics of the Future: NKTR-181

In this new column, the unique properties and potential of Nektar Therapeutics’ new abuse-deterrent opioid are shared. Plus, PPM Editors rate the NCE, indicated for chronic low back pain.
Pages 41-44

 

Nektar Therapeutics’ new abuse-deterrent opioid, NKTR-181, is unique from typical abuse-deterrent formulations due to its slow central nervous system (CNS) entry characteristics. This uniqueness is attributed to the drug’s PEGylated side chain, similar to that seen in Movantik (AstraZeneca Pharmaceuticals), a drug formulation that, unlike NKTR-181, has virtually no CNS permeability; the novel mechanism prevents physical manipulation from altering its abuse deterrence. Traditional opioid uptake into the CNS results in rapid activation of dopamine reward pathways associated with increased euphoria; an opioid manipulated to foster slower uptake is expected to have less abuse potential.

The FDA has granted the investigational medicine NKTR-181 Fast Track designation for the treatment of moderate to severe chronic pain. NKTR-181 was studied in Phase 3 for patients with chronic low back pain and in Phase 2 for patients with osteoarthritis (OA) knee pain. As of January 2019, there are no other abuse-deterrent opioids on market or in the pipeline with a similar mechanism to deter abuse or misuse.1, 2

 (See details of the star rating and review by Jeffrey Fudin,  PharmD, and Jeff Gudin, MD, at end of article.)

The Data

SUMMIT-07 was a Phase 3, enriched-enrollment, randomized, double-blind, placebo-controlled study that assessed the efficacy, safety, and tolerability of NKTR-181 in opioid-naïve patients with moderate to severe chronic low back pain. SUMMIT-07 began with a screening period, in which participants had to have:

  • a clinical diagnosis of moderate to severe, chronic non- neuropathic low-back pain for ≥ 6 months
  • failed outcomes with non-opioid analgesics
  • a daily dose of ≤10 mg morphine equivalents
  • a pain inventory baseline of 5 to 9 points on an 11-point numerical scale (see Table I)

Subjects that met inclusion criteria (n = 1,189) were transitioned to the open-label titration period and administered NKTR-181 beginning at 100 mg twice daily, titrated over 3 to 7 weeks to a maximum dose of 400 mg twice daily. As part of the enriched-enrollment process, only subjects that showed improvement, defined as reporting a 7-day average pain inventory score of ≤ 4, termed pre-randomization pain score (see Table I), were randomized to receive either NKTR-181 or placebo for 12 weeks. Out of the total subjects that received NKTR-181 during titration, 610 subjects were randomized to NKTR-181 (n = 309) or placebo (n = 301); Nektar did not clarify whether subjects excluded from randomization were solely excluded based on pre-randomization pain scores or other factors.

The primary outcome was the least-squares mean difference from pre-randomization pain score to average pain score after the 12-week treatment period. Secondary outcomes included percent of participants with pain scores ≥ 30% and ≥ 50% lower than their screening pain score, and the percentage of patients that characterized themselves as either “improved” or “very improved” after 12 weeks of treatment using the Patient Global Impression of Change (PGIC) scale. The 12-week change in the Medical Outcomes Study (MOS) Sleep Scale—Revised evaluated sleep quality. Withdrawal and abuse-potential were evaluated using the Clinical Opiate Withdrawal Scale (COWS), and the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS), respectively.3-5

Results for SUMMIT-07 are displayed in Table II. For the primary outcome, the mean difference in pain scores at Week 12 were slightly increased from the pre-randomization score. During the first two weeks after randomization, patients were allowed 5 mg hydrocodone/300 mg acetaminophen for breakthrough pain; after two weeks, only acetaminophen was permitted. The details for use of rescue were not provided; however, researchers stated that it was used less in the NKTR-181 group. The 12-week change in the MOS Sleep Scale scores were significantly improved for those in the NKTR-181 treatment group in the following categories: sleep disturbance, sleep problems, sleep adequacy, and sleep quantity. Respiratory impairments and daytime sleepiness assessed by the MOS Sleep Scale was not significantly different from placebo. The most frequent adverse effects reported are displayed in Table III.3,4

After the titration period with NKTR-181, patients randomized to placebo were not tapered off NKTR-181, so it would be expected to see increased withdrawal at randomization or at end of Week 1 of treatment; however, at the end of Week 1, only 2.4% of placebo randomized subjects were classified as mild classification according to COWS scores compared to 1.0% of NKTR-181 subjects. After the 12-week treatment, there was a 1-week taper off NKTR-181 and placebo. At the end of taper, 2.3% of NKTR-181 subjects were classified as mild withdrawal according to COWS scores, compared to 0.5% of placebo. Only five subjects had an event classified as abuse. Of the five cases, two occurred in the placebo group and three cases occurred during NKTR-181 titration, and were adjudicated to abuse because of missing pills.4,6

Nektar presented data on two additional studies analyzing the abuse potential of NKTR-181 compared to oxycodone and placebo; however, only one has been published to date. Both studies had three phases: screening, qualification, and treatment. The screening phase was the same for both studies; researchers screened for non-dependent recreational opioid users and participants had to pass a naloxone challenge.

In Study 1, the qualification phase verified that subjects could tolerate oxycodone 15 mg and differentiate it from placebo. The treatment phase consisted of each subject receiving single doses of 100, 200, and 400 mg NKTR-181, oxycodone 15 mg, and placebo in a randomized, double-blind, crossover fashion with a 72-hour washout period between administrations.

In Study 2, the qualification phase verified that subjects could tolerate oxycodone 40 mg and differentiate it from placebo. The treatment phase consisted of each subject receiving single doses of 400, 600, and 1,200 mg NKTR-181, oxycodone 40 and 60 mg, and placebo in a randomized, double-blind, crossover fashion with a ≥ 5-day washout period between administrations. Each study evaluated Mean Drug Liking using the 0 to 100 mm, bipolar Drug Liking Visual Analog Scale (VAS), where 50 mm represented neutral response and Mean Drug High using the 0 to 100 mm, unipolar Drug High VAS. NKTR-181 400 mg twice daily is the current maximum recommended and studied dose for the treatment of chronic low back pain, and both studies reported outcomes and adverse events for the 400 mg dose, therefore the results reported for Study 2 are representative of what is seen in Study 1, and displayed in Table IV.7-10

Discussion

For the treatment of chronic low back pain, NKTR-181 is used at doses of 100 to 400 mg twice daily, therefore the results for “drug liking” and “drug high” (ie, euphoria) for doses ≤ 400 mg would be most generalizable to the doses seen in future pain management. However, at doses ≤ 600 mg, there were less adverse events reported, significantly less drug liking and drug high compared to oxycodone 40 and 60 mg, and similar drug liking as seen in placebo.

In both abuse potential trials, NKTR-181 was studied as single doses, and therefore they may not account for the potential adverse events that may be more prevalent with long-term use, however, the adverse events seen in the SUMMIT-07 trial may be more generalizable to the adverse events seen with long-term NKTR-181 use. NKTR-181 had similar respiratory impairment and daytime sleepiness when compared to placebo, supporting the relatively low risk associated with the new drug. SUMMIT-07 provides the only efficacy data for NKTR-181 as an analgesic.

In SUMMIT-07, the only criteria disclosed for subjects being excluded from randomization after the open-label titration phase was that participants did not report a pain score ≤ 4. The subjects excluded from randomization (n = 579) are almost half of the subjects that enrolled in the open-label titration period and, without disclosing the reasons for attrition, it is difficult to fully assess. More evidence related to efficacy is needed. On the basis of an efficacy study against placebo, clinical differences were modest. To date, there are no published efficacy studies for the management of chronic pain comparing NKTR-181 to active-control (eg, opioid analgesics).

 

PPM Editors-at-Large Weigh In on NKTR-181: 4 out of 5 Stars*

with Jeff Gudin, MD, and Jeffrey Fudin, PharmD

(*Star-rating system described below)

The prospect of having a new extended-release opioid which has a lower drug liking at therapeutic doses compared to oxycodone is pretty amazing. According to published data, even high doses of up to 400 mg of NKTR-181 had likability similar to placebo.

Note that the large therapeutic dose of NKTR-181 in comparison to oxycodone is due to the large chemical side-chain. The higher dose of NTKR-181 compared to oxycodone, therefore, should not be misconstrued as an inferior potency. Traditional oxycodone activates opioid receptors, then dopamine is produced within the ventral tegmental area and saturates the nucleus accumbens which, in turn, causes a pleasurable response. The concept that a slowed CNS influx of NKTR-181 may reduce immediate dopamine release and cause less euphoria is, without a doubt, a very desirable attribute that contributes to our rating.

From an analgesic standpoint, this particular agent seems to perform in line with other mu-opioid agonists that have received approval for chronic pain. The benefits come from slow entry into the CNS and slow binding to the opioid receptors. According to the HAP studies, these properties appear to contribute to decreased drug liking when tested in known opioid abusers.

So what are the pitfalls? Simply put, NKTR-181 is still an opioid in a rather unfriendly opioid climate where opponents will certainly focus on the potential negatives. As clinicians, we recognize that many patients fail nonpharmacologic and non-opioid therapies, and opioids still deserve a place in our pharmacologic armamentarium.

Overall, we applaud Nektar Therapeutics’ effort to develop an analgesic with incremental benefits to those currently available. We give NKTR-181 a score of 4 out of 5 STARS* for being an innovative opioid product with extremely innovative pharmacokinetics and an enhanced tolerability profile, while acknowledging that long-term safety data is pending publication.

As part of this new monthly column, Analgesics of the Future, PPM Editors-at-Large Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB, and Jeff Gudin, MD, will rate investigational medicines/techniques on a 5-star scale. For this particular review, Dr. Gudin discloses that he has been involved with the development of NKTR-181 as an advisor.

*Potential analgesics of the future are rated based on: novelty, risk-benefit ratio, clinical utility, scientific rigor of studies, and market potential, along with the reviewers’ expertise and opinion.

Last updated on: February 4, 2019
Continue Reading:
Assessing and Treating Migraine in Women and Men
close X
SHOW MAIN MENU
SHOW SUB MENU