Kiniksa Pharmaceuticals, Ltd. (NASDAQ: KNSA) reported final data from an open-label Phase 2 clinical trial of rilonacept, a weekly, subcutaneously-injected, recombinant fusion protein that blocks IL-1α and IL-1β signaling. The data were included in a poster presentation at theAmerican Heart Association(AHA) Scientific Sessions 2019.
"The final Phase 2 data showed the potential for rilonacept to improve clinically meaningful outcomes associated with unmet need in recurrent pericarditis," said Sanj K. Patel, Chief Executive Officer and Chairman of the Board of Kiniksa. "Rilonacept treatment in the Phase 2 trial led to a rapid resolution of recurrent pericarditis episodes that was sustained throughout the 6-month study as well as an improvement in overall quality of life scores. Treatment with rilonacept also led to a decrease in the annualized incidence of pericarditis episodes and importantly supported the discontinuation of corticosteroids without pericarditis recurrence. These data further confirm our confidence in the design of RHAPSODY, our pivotal Phase 3 trial of rilonacept in recurrent pericarditis, for which we expect top-line data in the second half of 2020."
Dr. Allan Klein, MD, of Cleveland Clinic and co-principal investigator for the trial, presented Efficacy and Safety of Rilonacept in Recurrent Pericarditis: A Multicenter Phase 2 Clinical Trial. The materials are available through the Science section of Kiniksa's website (www.kiniksa.com).
The Phase 2 trial evaluated the treatment response to rilonacept in a range of pericarditis populations and was divided into five parts across two cohorts.
Symptomatic recurrent pericarditis patients:
Part 1: Symptomatic patients with recurrent pericarditis and C-reactive protein (CRP) > 1 mg/dL;
Part 2: Symptomatic patients with recurrent pericarditis and CRP ≤ 1 mg/dL but pericardial inflammation confirmed by magnetic resonance imaging (MRI); and
Part 4: Symptomatic patients with post-pericardiotomy syndrome (PPS) and CRP > 1 mg/dL.
Corticosteroid-dependent recurrent pericarditis patients:
Part 3: Asymptomatic patients with recurrent pericarditis who were dependent upon or unable to wean off corticosteroids; and
Part 5: Asymptomatic patients with PPS who were dependent upon or unable to wean off corticosteroids.
In this study, all patients received a loading dose of rilonacept 320 mg subcutaneously (SC) followed by 160 mg SC weekly maintenance on top of any combination of co-administered nonsteroidal anti-inflammatory drugs (NSAIDs) and/or colchicine and/or corticosteroids during a 6-week base treatment period. There was an optional 18-week extension treatment period, during which physicians were given the option to wean patients off concomitant NSAIDs, colchicine, and/or corticosteroids. The assessed efficacy outcomes measures included an 11-point pain Numerical Rating Scale (NRS), CRP, electrocardiogram, and size of pericardial effusion. The co-principal investigators were Dr. Allan Klein of Cleveland Clinic and Dr. David Lin of Minneapolis Heart Institute Foundation.
25 unique patients enrolled in the 6-week base treatment period across Parts 1 through 5 of the Phase 2 trial, and 23 patients continued into the optional 18-week extension treatment period and completed 24 weeks of treatment.
The Phase 2 data provided first evidence that rilonacept treatment improved clinically meaningful outcomes associated with the unmet medical need in recurrent pericarditis.
Resolution of Pericarditis Episodes
Symptomatic recurrent pericarditis patients with CRP > 1mg/dL (Parts 1 and 4; n = 13), who were failing standard of care management with NSAIDs, colchicine, and/or corticosteroids, are expected to be most relevant to the enrollment population for the ongoing Phase 3 clinical trial (RHAPSODY). There was a rapid reduction in both reported pain and inflammation after the first dose as well as a persistent and clinically meaningful response throughout the study for these patients.
Mean patient-reported pericardial pain on an 11-point NRS decreased from 4.5 at baseline to 0.5 at 24 weeks;
mean CRP decreased from 4.6 mg/dL at baseline to 0.2 mg/dL at 24 weeks; mean time to CRP normalization was 9 days; and
pericardial signs resolved or improved in all patients, including pericardial effusion (6/7 patients), PR depression (2/3 patients), widespread ST elevation (2/2 patients) and pericardial rub (2/2 patients).
Symptomatic recurrent pericarditis patients with CRP ≤ 1mg/dL (Part 2; n = 3), who were failing standard of care management with NSAIDs, colchicine, and/or corticosteroids, showed a reduction in both reported pain and inflammation after the first dose as well as a persistent and clinically meaningful response throughout the study.
Mean patient-reported pericardial pain on an 11-point NRS decreased from 4.7 at baseline to 0.0 at 24 weeks; and
mean CRP decreased from 0.46 mg/dL at baseline to 0.32 mg/dL at 24 weeks.
Tapering and Discontinuation of Corticosteroids without Pericarditis Recurrence
15 recurrent pericarditis patients on corticosteroids at baseline enrolled in the 6-week base treatment period, and 13 continued into the optional 18-week extension treatment period and completed 24 weeks of treatment. During the optional 18-week extension treatment period, investigators were given the option to wean patients from concomitant medications while continuing weekly rilonacept treatment. All patients on corticosteroids stopped or tapered corticosteroids during this part of the study without experiencing a recurrent pericarditis episode.
11 recurrent pericarditis patients discontinued corticosteroids completely: 4 symptomatic patients across Parts 1 and 2 as well as 7 corticosteroid-dependent patients across Parts 3 and 5.
The corticosteroid dose was successfully tapered in the 2 remaining recurrent pericarditis patients by the end of the 24-week study period: 1 symptomatic patient in Part 2 and 1 corticosteroid-dependent patient in Part 3.
Reduction in Recurrences of Pericarditis Episodes
A comparison of the annualized incidence of pericarditis episodes during the study while receiving rilonacept versus patients' own natural history in the period prior to the study demonstrated a decrease in annualized incidence of pericarditis episodes across all parts from 3.9 episodes/year prior to the study to <0.18 episodes/year.
Improved Quality of Life Scores
Rilonacept treatment resulted in improvement of Patient Reported Outcomes Measurement Information System (PROMIS) Global Health scores for Physical and Mental Global Health (U.S. mean score = 50.0; standard deviation = 10).
In symptomatic recurrent pericarditis patients (Parts 1, 2, and 4), the mean Physical and Mental Global Health baseline scores were 39.9 and 44.5, respectively, and improved to 51.3 and 50.5, respectively, at 24 weeks.
In corticosteroid-dependent recurrent pericarditis patients (Parts 3 and 5), the mean Physical and Mental Global Health baseline scores were 43.3 and 46.5, respectively, and improved to 46.8 and 50.7, respectively, at 24 weeks.
Rilonacept was generally well-tolerated in the study, with adverse events consistent with the U.S. Food and Drug Administration (FDA)-approved label for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome and Muckle-Wells Syndrome. The most common adverse events were mild, transient injection site reactions that did not cause discontinuation. There was one treatment-related serious adverse event which resulted in discontinuation: a skin abscess which responded to medical treatment. Infections are reported in the rilonacept label for CAPS.
"Recurrent pericarditis is a debilitating autoinflammatory disease with a clear unmet need," said Dr. Allan Klein, MD, of Cleveland Clinic. "The final Phase 2 data show a sustained clinical response over 6 months of treatment, supporting tapering of corticosteroids while on treatment and affirming the efficacy of the interim analysis reported at the American College of Cardiology's (ACC) Annual Scientific Sessions in March 2018. I look forward to further investigation of rilonacept in the ongoing Phase 3 trial, RHAPSODY."
Kiniksa is enrolling RHAPSODY, a global, randomized withdrawal (RW) design, pivotal Phase 3 clinical trial in the U.S., Australia, Israel, and Italy. The primary efficacy endpoint is time-to-first pericarditis-recurrence in the RW period. The Clinical Endpoint Committee will adjudicate all suspected pericarditis recurrences for inclusion in the primary efficacy endpoint analysis. Top-line data are expected in the second half of 2020.