Oral NKTR-118 and Oral NKTR-119

Market information
Oral NKTR-118 is a peripheral opioid antagonist in development for the treatment of opioid-induced constipation (OIC) and other manifestations of opioid bowel dysfunction (OBD). Depending on the population studied and the definitions used, constipation has been shown to occur in up to 90% of patients taking opioids. Over 200 million opioid prescriptions are filled in the U.S. annually with worldwide sales of opioids reaching $7.5 billion in 2007. There is a significant need for an oral therapy to address the debilitating side effects of chronic opioid use.

Oral NKTR-118 Clinical Data and Product Profile
Oral NKTR-118 applies Nektar's advanced polymer conjugate technology platform with naloxol, a derivative of the opioid-antagonist drug, naloxone. The drug is under development for the treatment of opioid-induced constipation (OIC). Oral NKTR-118 is designed to target peripheral opioid receptors to alleviate constipation associated with opioid therapy, while limiting naloxol's penetration across the blood-brain barrier to preserve the analgesic effects of opioids.

Phase 1 clinical trials have shown:

• A terminal half-life of Oral NKTR-118 was approximately eleven hours as compared to a known half-life of between 45 and 100 minutes for naloxone.
• Single doses of Oral NKTR-118 antagonized morphine-induced delay in GI transit time demonstrating the potential of the drug to relieve constipation. Further, no diminution of morphine-induced constriction of the pupil, a CNS effect, was observed at single doses of Oral NKTR-118 of 125 mg or less.
• Oral NKTR-118 were generally well-tolerated at generally well-tolerated at doses up to 250 mg twice daily, with no serious or severe adverse events and at single doses up to 1,000 mg.

Topline results from a Phase 2, multi-center, placebo-controlled, dose-escalation trial were announced in March 2009 and presented at the ACG:

• The study achieved a statistically significant change from baseline in spontaneous bowel movements (SBMs) during the first week of NKTR-118 treatment with the 25 mg dose and the 50 mg dose versus placebo (p < 0.01 for all comparisons).
• The increase in SBMs versus placebo was maintained over the 28-day treatment period (p <0.01). More importantly, there was no reversal of opioid-mediated analgesia in any of the dose groups as measured by change in Numerical Rating Scale (NRS) pain scores and no increase in mean daily opiate use.
• The most commonly reported side effects from this Phase 2 study of NKTR-118 were dose dependent gastrointestinal-related effects. The majority of side effects for both the 5 and 25 mg dose cohorts were graded as mild by the investigators. Side effects included diarrhea (13% at 25 mg and 31% at 50 mg, versus 4% and 5% for the placebo arms), nausea (13% for 25 mg and 20% for 50 mg, versus 19% and 8% for the placebo arms) and abdominal pain (30% for 25 mg and 17% for 50 mg, versus 7% and 0% for the placebo arm). No treatment-related serious adverse events (SAE) for the 5 or 25 mg cohorts were observed. Only one patient experienced an SAE of hospitalization due to abdominal cramping in the 50 mg cohort.

The Phase 2 study for NKTR-118, in 208 pain patients experiencing OIC, was an international, multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial.

The primary endpoint of the study was a change in SBMs from a two-week baseline period during which the patient had to demonstrate significant constipation in the absence of laxatives, to the change in SBMs at the end of the first week of randomized study drug. Patients in the study were being treated for moderate to severe pain with 30 to 1,000 morphine equivalent units. Under the study protocol, patients were randomly assigned to placebo or one of three different dose cohorts (5 mg, 25 mg, and 50 mg given as a single daily oral dose) for a treatment period of four weeks. In addition to measures of SBMs, patients also recorded daily use of opiates and pain NRS scores. The most frequent side effects observed in the study that led to discontinuation of medication were diarrhea, nausea and abdominal cramping. These side effects were most frequent in the 50 mg dose group.

Oral NKTR-119 Clinical Data and Product Profile
Oral NKTR-119 is an investigational drug candidate that is a co-formulation of Oral NKTR-118 and an opioid analgesic. The product is designed to fulfill a significant unmet medical need and provide adequate analgesic properties in the chronic treatment of moderate to severe pain patients while preventing the debilitating side effects that are common in opioid use, such as constipation and bowel dysfunction.

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