A Phase 3 Multicenter, Open-Label, 52-Week Study (SUMMIT-08 LTS) to determine the long-term safety and tolerability of NKTR-181 in patients with moderate to severe chronic low back pain or chronic noncancer pain.

Clinical Research 6 min 25

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Created On: 14/10/2020

A Phase 3 Multicenter, Open-Label, 52-Week Study (SUMMIT-08 LTS) to determine the long-term safety and tolerability of NKTR-181 in patients with moderate to severe chronic low back pain or chronic noncancer pain.

Opioids are the most effective treatment for pain so far. Approximately 92 million adults in the United States use prescription opioids each year.

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Key take away

NKTR-181, a novel mu-opioid receptor agonist, is effective and safe management option for patients with moderate to severe chronic low back pain (CLBP) or chronic non cancer pain (CNP).

Background

Opioids are the most effective treatment for pain so far. Approximately 92 million adults in the United States use prescription opioids each year. Along with higher efficacy in pain management, opiods use cause severe complications related to overdose, misuse and abuse, thereby hindering the utility of this drug. Complications associated with opioid use leaves limited management options for chronic pain patients. A survey data collected from United States in 2016 demonstrated misuse of prescription opiods in approximately >11 million people. The economic burden per yearly with the misuse of prescription opioids is estimated to be about $78.5 billion, including addiction treatment, lost productivity, and costs related to health care, and involvement of criminal justice.

To prevent the misuse of opioids, the Food and Drug Administration (FDA) has granted approval to 10 abuse-deterrent formulations (ADFs) of oral opioids in January 2019. These ADFs are equipped with chemical or physical barriers which makes them difficult to dissolve or crush in order to provide the active drug for intravenous use. These formulations can prevent the misuse of opioids but they are unable to address the abuse of intact product, presenting a critical need for novel treatment modalities.

NKTR-181 is such a novel mu-receptor agonist which has been designed to reduce the rate and entry of potential drug into central nervous system. The molecular structure of NKTR-181 is responsible for reduced entry into CNS rather than the use of ADFs. It also delays mu receptor binding which attenuated the rapid onset of euphoria related with the use of conventional opioids. Its long term exposure provides prolonged pain relief due to sustained mu-receptor occupancy. As per the data of various nonclinical studies, NKTR-181 has showed a sustained analgesic effect with a markedly slower CNS entry rate compared with oxycodone. Therapeutic doses of NKTR-181 had significantly reduce ratings for drug high and drug liking in comparison to oxycodone in recreational opioid users in a human abuse potential (HAP) study. It has also showed reduced incidence of CNS related side effects when compared with oxycodone in both animals and human studies. A prior randomized, double-blind, placebo-controlled 12-week phase 3 clinical trial, named as SUMMIT-07 patients have determined a greater pain reduction in NKTR-181 group in comparison with placebo/control group.

Rationale behind research

Prior trials have reported the efficacy of NKTR-181 in pain management but the data on safety and tolerability of NKTR-181 is still lacking. Therefore, this study was conducted to determine the safety and tolerability of NKTR-181.

Objective

The objective of this study is to demonstrate the long term safety and tolerability outcomes in addition with its efficacy in patients with CLBL and CNP.

Method

Study outcomes

The study outcomes included evaluation of:

Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
Opioid withdrawal rates using the 11-item COWS and the 16-item Subjective Opiate Withdrawal Scale (SOWS)
Potential abuse, dependence, or misuse-related events using Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS)
Suicidal ideation and behaviors using the electronic version of C-SSRS
Pain relief assessed using the pain intensity and interference scores in the Brief Pain Inventory Short Form (mBPI-SF)

Result

Outcomes

Baseline: There were no significant differences reported at baseline

Study outcomes

The most frequently reported TEAEs were constipation (26%) and nausea (12%) with serious TEAEs, reported in only 5% of patients
Only nine patients showed mild opioid withdrawal effects and only one patient showed moderate opioid withdrawal
Only a small number of patients reported potentially abuse-related events, including misuse, abuse, diversion, withdrawal, or addiction-related behaviors
Low numbers of suicide-related TEAEs were indicated by using C-SSRS
A sustained reduction in mBPI-SF pain intensity and pain interference from baseline was observed throughout treatment (Fig.2)

Conclusion

The findings of the present study demonstrated the safety and tolerability of NKTR-181 over a longer period (52 weeks) and at higher doses (500 and 600 mg BID) than previously tested in the phase 3 efficacy trials. The NKTR-181 was safe and well tolerable at higher doses with similar TEAEs as observed in previous SUMMIT-07 trial. Constipation and nausea were reported as the most frequently occurring TEAEs. Only 5% patients reported the incidence of serious TEAEs. The abuse related CNS effects were also rare. No cases of depression and death due to drug use were reported. The study reported low abuse potential and suicidal outcomes with use of NKTR0181 which were consistent with the results of SUMMIT-07 phase 3 clinical trial. These finding showed the success of study excluding potential subjects at elevated risk for substance use disorder, investigator adherence to the exclusion criteria of the study protocol, or lower intrinsic abuse liability of NKT-181.

Reductions in pain intensity were also maintained throughout the treatment period from baseline. Most patients both opioid experienced and opioid naïve were maintained on a stable dose throughout the treatment period. No substantial requirement for rescue medications for pain management was reported after the once daily stable use of NKTR-181 in this study. Only 2% of patients discontinued the study due to lack of efficacy outcomes. These findings suggest that NKTR-181 provides a novel alternative pain management option which is quite safe, effective and tolerable in management of CLBP and CNP.

Limitations

The study did not include any control or active comparator group
The participants taking >60 mg of MSE per day for seven or more days before consent were excluded, which were likely to develop tolerance
The study lacks the measures for risk of bias toward retention of patients with acceptable analgesic responses and acceptable safety and tolerability profiles

Clinical take-away

This study supports the long term use of NKTR-181 for chronic pain management in CLBP and CNP patients due to its established safety, tolerability, and analgesic effectiveness data. It provide a better and safe pain management option to clinicians as an alternative to conventional opioids suffering from serious complication related to misuse, abuse and addiction.

Source:

Pain Medicine

Link:

https://academic.oup.com/painmedicine/article/21/7/1347/5540711

Article:

Long-term Safety and Tolerability of NKTR-181 in Patients with Moderate to Severe Chronic Low Back Pain or Chronic Noncancer Pain: A Phase 3 Multicenter, Open-Label, 52-Week Study (SUMMIT-08 LTS)