Regulatory Decision Summary for Korsuva

Korsuva (difelikefalin) is a targeted kappa opioid receptor agonist proposed for the treatment of moderate to severe pruritus associated with chronic kidney disease (CKD) (also known as chronic kidney disease associated pruritus [CKD-aP]) in adult patients on hemodialysis (HD). Korsuva is a new active substance and first-in-class drug and is intended for use only in HD centres and by health care professionals trained in HD administration. There are currently no approved drug therapies in Canada for the indication proposed for Korsuva.

The clinical presentation of CKD-aP varies between patients and may fluctuate over time. Severity of the condition may range from mild itching with no to minimal impact on daily activities, to extreme itching that leads to restlessness, sleep disruption, fatigue, symptoms of depression, reduction in quality of life and missed dialysis sessions. Results from observational studies have suggested that moderate-to-severe pruritus is associated with a higher mortality risk among hemodialysis patients, even after adjusting for other risk factors, and this relationship is thought to be at least partly due to poor sleep quality.

The physicochemical properties of difelikefalin limit its penetration into the CNS, and difelikefalin has no binding or functional activity at mu-opioid receptors, which avoids mu-associated side effects, such as constipation, euphoria, dependence, and respiratory depression.

The efficacy and safety of Korsuva at the proposed dose for marketing were evaluated in two randomized, multicenter, double-blind, placebo-controlled trials (KALM-1 and KALM-2) that enrolled a total of 851 patients 18 years of age and older undergoing HD and who had moderate-to-severe pruritus not attributable to a cause other than end stage renal disease (ESRD). Patients received either placebo or 0.5 microgram/kg Korsuva intravenously 3 times a week following HD for 12 weeks. If an extra dialysis session was performed, the study drug was administered after each additional dialysis session up to a maximum of 4 times per week. Patients who received at least 30 doses of study drug (either placebo or active) during the 12-week double-blind treatment period and who continued to meet other eligibility criteria had the option to receive open-label Korsuva for up to an additional 52 weeks, regardless of the treatment received during the 12-week double-blind period.

The primary efficacy endpoint for KALM-1 and KALM-2 was the proportion of patients who achieved at least a 3-point reduction (improvement) from baseline in the patient-reported daily 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS) at 12 Weeks. The WI-NRS is a validated numerical rating scale that has been widely used for evaluation of chronic itch, including CKD-aP. The key secondary endpoints in both trials included an assessment of the percentages of patients with an improvement in the WI-NRS of at least 4 points after 12 weeks (a more conservative threshold compared to the primary endpoint), and changes in itch-related quality of life (QoL) as measured by the total Skindex-10 and 5-D Itch Scale. In both KALM-1 and KALM-2, Korsuva significantly improved itch severity over 12 weeks, based on the results for the primary endpoint, and the results for the key secondary endpoints were also considered supportive of the efficacy of Korsuva.

In pooled placebo-controlled analyses, the main safety concerns identified for Korsuva included somnolence, dizziness, mental status changes (including confusional state), gait disturbances including falls (possibly a consequence of concurrent dizziness and somnolence in some patients), headache, hyperkalemia (with greater incidence in patients who took concomitant opioids), paraesthesia, nausea, and diarrhea. There was a greater incidence of somnolence in patients 65 years of age and older who took Korsuva compared to younger patients, and there is a potential increased risk of somnolence and dizziness in patients using concomitant sedating antihistamines, opioid analgesics or other CNS depressants. These safety concerns have been described in the Product Monograph (PM).

An intact blood-brain barrier (BBB) is important for minimizing difelikefalin uptake into the CNS. As such, patients with clinically important disruptions to the BBB (e.g., primary brain malignancies, CNS metastases or other inflammatory conditions, active multiple sclerosis, advanced Alzheimer’s disease) may be at risk for difelikefalin entry into the CNS. The PM therefore includes a statement indicating that Korsuva should be prescribed with caution in such patients, taking into account whether the benefits of Korsuva outweigh the potential risks for the individual, and ensuring observation for potential CNS effects.

In the placebo-controlled analyses from the two 12-week pivotal studies, there was a numerical imbalance observed in the incidence of cardiac failure events and cardiac arrhythmia events, including atrial fibrillation in patients treated with Korsuva vs. placebo, in particular among patients with a medical history of atrial fibrillation, some of whom had discontinued or missed their atrial fibrillation treatment. The clinical significance of these findings is not known based on the available data as a causal relationship to Korsuva for these events was not established. There were no other safety signals identified regarding major adverse cardiovascular events (MACE) and difelikefalin was not found to prolong the QT interval. Evaluation of additional open-label, uncontrolled safety data in patients exposed to Korsuva for up to 52 weeks did not suggest any additional serious safety concerns.

The results from dedicated abuse, dependence and withdrawal studies indicated that difelikefalin was found to have low extra-medical (abuse) potential and its use was not associated with opioid withdrawal symptoms. As well, across all clinical studies of difelikefalin, there were no adverse event reports related to misuse, abuse, diversion, or dependence with IV difelikefalin at doses up to 80-fold of the proposed clinical dose.

There was no identified signal for serious hepatotoxicity. As Korsuva has not been studied in patients with severe hepatic impairment, it is not recommended for use in this population.

Taking into consideration the lack of approved drug treatments for the proposed indication, the benefit-harm-uncertainty profile for use of difelikefalin in patients with moderate to severe pruritus associated with chronic kidney disease in adult patients on hemodialysis is considered positive. It is anticipated that the close medical monitoring of hemodialysis patients receiving Korsuva three times per week should facilitate early detection and medical management of the potential adverse effects associated with Korsuva. It was determined that the safety issues identified for Korsuva can be appropriately addressed with product labelling and post-market surveillance as specified in a Risk Management Plan.