NKTR-181 failed its Phase II efficacy study but in an unusual way.
First, some background. Most drugs are evaluated for efficacy in multi-armed, randomized, double blind placebo controlled studies. Multi-armed and randomized means that people entering the study are broken into groups at random. For example, a study may have three groups, one gets a low dose of the drug, another a high dose of the drug, another gets placebo. Double blind means that neither the patient nor the physician knows what the patient is getting. Data is collected during the study. After the study is complete, the data is sent to a monitoring committee (who do know what the patient was given) and statistical analysis performed. The idea is to eliminate all forms of bias in the study.
However, this design often works poorly in opioid studies. The reason is that many people cannot tolerate opioids. In the past, so many patients assigned to an opioid group have dropped out due to side effects to render the study statistically worthless. Opioid drugs are now evaluated using a withdrawal study design. In a withdrawal study, all patients are given the opioid drug in increasing doses until sufficient pain relief is achieved and maintained, called the titration phase. The patients are then randomized in a double blind manner. Some patients are maintained on the opioid and others are switched to placebo. The idea is that pain will return to patients switched to the placebo. After a period of time (called the withdrawal phase), the pain scores of the patients are evaluated. Success is measured by the difference in pain between patients remaining on the opioid to those switched to placebo. This eliminates the dropout problem from patients who cannot tolerate opioids. They are dropped during the titration phase prior to the evaluation.
The NKTR-181 Phase II study was with osteoarthritis patients who could not achieve adequate pain relief using NSAID's. Patients were given NKTR-181 in increasing doses until 40% pain relief was achieved and maintained. 40% pain relief is considered clinically significant. The patients were randomized to continue NKTR-181 or switch to placebo in a double blind manner. They were evaluated over a six week period. The endpoint was the difference in pain scores between the two groups after six weeks.
During the titration phase, only 18% of the patients dropped out due to side effects, which is very low for an opioid. 97% of patients achieved and maintained 40% pain relief or better after titration. The unusual results occurred during the withdrawal phase. After six weeks, the pain scores of patients who continued on NKTR-181 improved another 6%. However, the
patients who were switched to placebo maintained their 40% improvement in pain six weeks after being taken off NKTR-181. There was no statistically significance difference in pain scores between the two groups, so the study failed.
What does it mean? Is it all placebo effect? Is six weeks long enough for a withdrawal period? Is there some additional long lasting benefit that NKTR-181 provides in osteoarthritis? The company is looking at options about how to proceed. Stay tuned.
Links.
Press release:
http://finance.yahoo.com/news/nektar-announces-preliminary-topline-results-201000567.html
Conference call transcript:
http://seekingalpha.com/article/171...r-nktr-181-conference-transcript?source=yahoo
R&D Day presentation:
http://www.nektar.com/pdf/NKTR-R&D_Day_2013_Pain.pdf
R&D Day transcript:
http://seekingalpha.com/article/173...-amp-d-day-conference-transcript?source=yahoo
