Summary Basis of Decision for Korsuva

 

As described above, the New Drug Submission for Korsuva was reviewed as part of the New Active Substance Work Sharing Initiative. Australia’s Therapeutic Goods Administration (TGA) completed the review of the clinical components of the NDS for Korsuva. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently. Additionally, the clinical component of the NDS for Korsuva was reviewed as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

The pathophysiology of chronic kidney disease‑associated pruritus is thought to be multifactorial, including systemic inflammation and an imbalance in the endogenous opioid system (e.g., overexpression of mu opioid receptors and concomitant downregulation of kappa opioid receptors [KORs]). Opioid receptors are known to modulate itch signals and inflammation, with KOR activation reducing itch and producing immunomodulatory effects.

Difelikefalin (the medicinal ingredient in Korsuva) is a targeted KOR agonist. It has low central nervous system (CNS) penetration and no binding or functional activity at mu opioid receptors, which mostly avoids mu-associated side effects such as constipation, euphoria, dependence, and respiratory depression. The physicochemical properties of difelikefalin (hydrophilic, synthetic D‑amino acid peptide with high polar surface area and charge at physiological pH) minimize its passive diffusion (permeability) and active transport across membranes (blood‑brain barrier [BBB]), thus limiting penetration into the CNS.

The activation by difelikefalin of KORs on peripheral sensory neurons and immune cells is considered mechanistically responsible for the antipruritic and anti‑inflammatory effects.

Pharmacokinetics

Difelikefalin exhibited dose‑proportional pharmacokinetics following administration of single and multiple doses ranging from 0.5 mcg/kg to 2.5 mcg/kg (1 to 5 times the recommended dosage) in patients with chronic kidney disease and who were undergoing hemodialysis. Steady‑state was reached after the second dose and the mean accumulation ratio was up to 1.6.

Plasma protein binding of difelikefalin is low to moderate (24% to 32%) and remains unaffected by renal impairment. Following the intravenous administration of difelikefalin ranging from 1 mcg/kg to 6 mcg/kg in patients undergoing hemodialysis, plasma protein binding ranged from 23% to 28%. Difelikefalin is not metabolized by cytochrome P450 (CYP) enzymes, human hepatic microsomes or hepatocytes, or kidney microsomes. In an in vivo absorption, distribution, metabolism, and elimination (ADME) study in humans, difelikefalin was the predominant component in plasma samples, accounting for more than 99% of the circulating radioactivity in both healthy volunteers and patients undergoing hemodialysis.

Hemodialysis reduced plasma concentrations of difelikefalin by 70% to 80%, and difelikefalin was not detectable in plasma after two dialysis cycles. Following administration of difelikefalin to hemodialysis patients, 11.2% of the dosage was excreted in urine, 58.8% in feces, and 19.5% in dialysate fluid.

Difelikefalin is not an inhibitor or substrate of clinically relevant enzymes or transporters based on the results of in vitro studies. Additionally, difelikefalin has minimal to no potential for induction of human CYP1A2, CYP2B6, or CYP3A4 enzymes. These findings suggest that difelikefalin is not likely to interact with co‑administered drugs.

The results of population pharmacokinetic analyses did not reveal any clinically significant differences in the pharmacokinetics of difelikefalin based on age, sex, and race/ethnicity.

The available data in hemodialysis patients indicated that no dosage adjustment is needed in patients with mild to moderate hepatic impairment. However, the clinical data in patients with moderate hepatic impairment is limited. Difelikefalin is not recommended for patients with severe hepatic impairment, as the effects of this condition on the pharmacokinetics of difelikefalin have not been evaluated.

Patients with mild renal impairment have a comparable pharmacokinetic profile to that of healthy subjects based on the available data. Total body clearance of difelikefalin in subjects with severe renal impairment is reduced relative to healthy, matched, control subjects and plasma concentrations of difelikefalin in subjects undergoing hemodialysis remain relatively constant until cleared during dialysis.

Pharmacodynamics

The penetration of difelikefalin into the CNS (brain) is restricted by its physicochemical properties, which minimize passive diffusion or active transport across membranes.

A thorough QT study was conducted in which healthy volunteers were administered difelikefalin as a single intravenous 0.5 mcg/kg dose (the clinical dose) or as a single 3.0 mcg/kg dose (6 times the clinical dose). The outcomes of this study indicated that difelikefalin did not prolong the corrected QT (QTc) interval to a clinically relevant extent.

A dose‑dependent increase in serum prolactin concentrations was observed in Phase I and II studies. Although it was not assessed in Phase III studies, one treatment‑emergent adverse event (TEAE) of increased blood prolactin was observed in the pooled Phase III safety analyses in a patient treated with Korsuva. However, no TEAEs were reported which were potentially indicative of clinical effects of hyperprolactinaemia in hemodialysis patients exposed to Korsuva for up to one year. The clinical relevance of these observations remain unknown.

Dose‑dependent decreases in serum thyroid stimulating hormone (TSH) and free thyroxine levels were observed in a Phase II study in Japanese patients, with a return to baseline levels following treatment discontinuation. Decreased TSH and decreased free thyroxine levels were both observed as TEAEs in patients following intravenous administration of difelikefalin, while these events were not observed in patients administered the placebo. Although TSH and free thyroxine were not assessed in Phase III studies, one TEAE of decreased free thyroxine was detected in the pooled Phase II/III safety analyses in a patient treated with Korsuva. This TEAE was considered by the investigator to be related to the study treatment. However, there was no overall imbalance in thyroid‑related adverse events between patients treated with Korsuva or placebo in the Phase III studies. The clinical relevance of these observations remain unknown.

For further details, please refer to the Korsuva Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Evidence of the clinical efficacy of Korsuva (difelikefalin) was provided through two pivotal Phase III placebo‑controlled studies, KALM‑1 (CLIN3102; 378 patients) and KALM‑2 (CLIN3103; 473 patients). Both studies included a 12‑week double‑blind phase in which patients received either Korsuva at a dose of 0.5 mcg/kg of dry body weight or placebo three times per week. In the KALM‑1 study, the double‑blind treatment period was followed by a 2‑week discontinuation period designed to assess potential signs or symptoms of drug withdrawal. Patients did not receive any study drug during this period and were monitored for signs or symptoms of physical dependence. In both studies, patients who received at least 30 doses of either Korsuva or placebo during the 12‑week double‑blind phase had the option to receive open‑label Korsuva at a dose of 0.5 mcg/kg of dry body weight three times per week for an additional 52 weeks.

Patients included in the two pivotal studies were required to be at least 18 years of age, be undergoing hemodialysis three times per week for end stage renal disease (ESRD), and have a mean baseline score of >4 (in KALM‑1) or ≥5 (in KALM‑2) on the patient‑reported daily 24‑hour Worst Itching Intensity Numerical Rating Scale (WI‑NRS). The WI‑NRS is a validated numerical rating scale for the evaluation of the intensity of chronic itch, ranging from 0 (no itching) to 10 (worst itching imaginable). Patients were permitted to continue their current antipruritic therapies, provided there had been no change within 14 days prior to screening. Patients receiving ongoing ultraviolet B therapy were excluded.

The primary efficacy endpoint, which was met in both pivotal studies, was a responder analysis of the proportion of patients who self‑reported an improvement of ≥3 points on the 24‑hour WI‑NRS at Week 12 in the Korsuva group versus (vs.) the placebo group. Justification for this endpoint as a clinically meaningful threshold was based on a published psychometric analysis and results from the supportive Phase II safety study, CR845‑CLIN2101. Statistically significant differences were identified in the intent‑to‑treat (ITT) analyses in both pivotal studies (851 patients in total). The least‑squares mean percentages of patients reporting an improvement from baseline of ≥3 points on the 24‑hour WI‑NRS at Week 12 were greater in the group treated with Korsuva than in the group that received placebo. In the KALM‑1 study, the least‑squares mean percentages were 51.0% in the Korsuva group vs. 27.6% in the placebo group (odds ratio of 2.72, p<0.001). In the KALM‑2 study, the least‑squares mean percentages were 54.0% in the Korsuva group vs. 42.2% in the placebo group (odds ratio of 1.61, p = 0.020). In both studies, a treatment effect was noted by Weeks 2 to 3, and was maintained throughout the 12‑week double‑blind treatment period.

The key secondary efficacy endpoints included a WI‑NRS responder analysis based on the proportion of patients achieving an improvement of ≥4 points (a more conservative threshold than the primary endpoint), and other validated patient‑reported outcomes evaluating the impact on quality of life. The least‑squares mean percentages of patients reporting an improvement from baseline of ≥4 points on the WI‑NRS at Week 12 were greater in the group treated with Korsuva than in the group that received placebo. In both studies, this difference was statistically significant. In the KALM‑1 study, the least‑squares mean percentages were 38.9% in the Korsuva group vs. 18.0% in the placebo group (odds ratio of 2.89, p<0.001). In the KALM‑2 study, the least‑squares mean percentages were 41.2% in the Korsuva group vs. 28.4% in the placebo group (odds ratio of 1.77, p = 0.010). Results of the additional validated quality of life measures (i.e., change from baseline in 5‑D Itch Scale and total Skindex‑10 Scale scores at Week 12) were also generally supportive of the efficacy of Korsuva in the target patient population.

Indication

Health Canada approved the following indication:

• Korsuva (difelikefalin) is indicated for the treatment of moderate to severe pruritus associated with chronic kidney disease in adult patients on hemodialysis.

For more information, refer to the Korsuva Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Data from three randomized Phase II studies (CR845-CLIN2005, CR845-CLIN2101, and PR-13A9-P2-A) were submitted and evaluated as supportive safety studies. Based on observations from these studies, the 0.5 mcg/kg dose of difelikefalin was determined to have the most favourable benefit risk profile and was the dose used for further evaluation in Phase III studies. The results of the supportive studies did not raise any efficacy concerns. The safety data were consistent with safety findings from the pivotal Phase III studies and did not raise any additional safety concerns.

The main evidence of the clinical safety of Korsuva was obtained from the primary safety pool, which includes data from 848 patients who were treated with either Korsuva or placebo (424 patients each) during the 12‑week placebo‑controlled phases of the pivotal Phase III studies, KALM‑1 and KALM‑2 (described in the Clinical Efficacy section). Patients in the primary safety pool were undergoing hemodialysis and had moderate‑to-severe pruritus as defined by baseline WI‑NRS scores.

Results from a larger safety pool were also evaluated, which included the exposure provided by the KALM‑1 and KALM‑2 studies and their respective open‑label extension periods, along with the exposure provided by two additional open‑label supportive Phase III studies, CLIN3101 and CLIN3105. This larger safety pool included 1,306 patients undergoing hemodialysis who had moderate‑to‑severe pruritus. Patients in this pool were treated with Korsuva at the recommended dose of 0.5 mcg/kg of dry body weight, with 711 patients having been continuously exposed to Korsuva for at least 6 months, and 400 patients having been continuously exposed for at least 12 months.

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 (pooled term including paraesthesia, hypoesthesia, paresthesia oral and hypoesthesia oral), nausea, and diarrhea. A greater incidence of somnolence was observed in patients 65 years of age and older who took Korsuva compared to younger patients. Additionally, there is a potential increase in the risk of somnolence and dizziness in patients using concomitant sedating antihistamines, opioid analgesics, or other CNS depressants.

The somnolence, dizziness, and mental status changes observed in the Phase III clinical studies are particularly notable, as the non‑clinical data indicated minimal CNS penetration of difelikefalin (the medicinal ingredient in Korsuva). The identification of these events in the clinical studies suggests that there is some penetration of difelikefalin into the CNS at clinical doses. Although the pathogenesis of the CNS‑related adverse events was not known at the time of authorization, based on the results from dedicated abuse, dependence, and withdrawal studies, difelikefalin is anticipated to have no meaningful abuse and dependence potential and was not associated with opioid withdrawal symptoms. In addition, across all clinical studies of difelikefalin, there were no adverse event reports related to misuse, abuse, diversion, or dependence with intravenously administered difelikefalin at doses of up to 80‑fold higher than the proposed clinical dose. Evaluation of the available longer‑term safety data did not raise any additional major safety concerns.

An intact blood-brain barrier is important for minimizing difelikefalin uptake into the CNS. As such, patients with clinically important disruptions to the blood‑brain barrier (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 Product Monograph therefore states 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.

For more information, refer to the Korsuva Product Monograph, approved by Health Canada and available through the Drug Product Database.