Ilaris (canakinumab)

P2, N=10, Terminated, University of Leipzig | It is not considered likely that the CANFIRE trial will be able to reach the target number of patients. Clinical responders will be further treated within the trial (expected duration: 3 years after stop of enrollment).

The cumulative incidence of at least one reported malignancy was lower for patients with TET2 mutations treated with canakinumab vs those treated with placebo. These findings support a potential role for canakinumab in cancer prevention and provide evidence of IL-1β blockade cooperating with CH mutations to modify the disease course.

P2, N=24, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=138 --> 24

P2, N=34, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Terminated by sponsor

This interim analysis showed a good maintenance of canakinumab treatment 2 years after initiation and confirmed its safety profile in real-life practice in France in patients diagnosed with FMF, MKD and TRAPS. The high variety of dose and interval combinations observed in canakinumab treated patients let suppose that physicians adapt the posology to individual situations rather than a fixed treatment plan.

P1/2, N=41, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Feb 2024 --> Jun 2024 | Trial primary completion date: Feb 2024 --> Jun 2024

Overproduction of pro-inflammatory cytokines and the hyperactivation of NOD2-mediated signaling pathways were found in the NOD2 variant Q902K patient with YAOS. NOD2-RIP2-MAPK pathway might play a pivotal role in the pathogenesis of YAOS. These results provide new perspectives for targeted therapies in YAOS.

Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.

P1/2, N=41, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Phase classification: P1b/2 --> P1/2

Adding canakinumab to docetaxel did not provide additional benefit for patients with advanced NSCLC who had progressed after PDC and immunotherapy.

No abstract available

However, the variations in CRP levels, that depend on sex, ethnicity, hormonal status, and some peculiarities of the measurement assays, must be taken into consideration when deciding to implement CRP as a useful biomarker in the study and treatment of atherosclerotic cardiovascular disease. This review aims to offer an updated vision of the importance of measuring CRP levels as a biomarker of cardiovascular risk beyond the traditional factors that estimate the risk of atherosclerotic disease.

This study provides one of the largest epidemiologic datasets for CAPS. While early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS following canakinumab treatment.

P2, N=138, Recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2025 --> Jun 2024 | Trial primary completion date: Oct 2025 --> Jun 2024

Cholesterol-inflammation lowering agents (statins), monoclonal antibodies targeting IL-1 and IL-6 (canakinumab and tocilizumab), disease-modifying antirheumatic drugs (methotrexate), sodium-glucose transport protein-2 (SGLT2) inhibitors, colchicine and xanthene oxidase inhibitor (allopurinol) have shown promising results in reducing inflammation, regressing atherogenic plaque and modifying the course of CAD. Here, we review the complex interplay between inflammatory, endothelial, smooth muscle and foam cells. Moreover, the putative role of inflammation in atherosclerotic CAD, underlying mechanisms and potential therapeutic implications are also discussed herein.

Intestinal BD may flare up after surgical treatment and require multiple surgeries. Introducing pharmacotherapy as soon as possible after surgical treatment is important to control the disease.

P3; Trial completion date: Jul 2024 --> Jun 2027

The patient was ultimately treated with canakinumab (Il-1 inhibitor), with near resolution of symptoms. This case demonstrates the importance of a broad differential diagnosis and maintaining a high clinical suspicion for rare diseases when presented with a complex form of an otherwise common condition.

The addition of canakinumab to first-line pembrolizumab and CT did not prolong PFS or OS in patients with NSCLC.

The blockade of interleukine-1 (anakinra and canakinumab) is a well-known highly effective tool for monogenic autoinflammatory diseases (AIDs), such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, hyperimmunoglobulinaemia D syndrome, and cryopyrin-associated periodic syndrome, but this treatment has not been assessed for patients with undifferentiated AIDs (uAIDs)...Initial treatment before canakinumab consisted of non-biologic therapies: non-steroidal anti-inflammatory drugs (NSAID) (91%), corticosteroids (88%), methotrexate (38%), intravenous immunoglobulin (IVIG) (34%), cyclosporine A (25%), colchicine (6%) cyclophosphamide (6%), sulfasalazine (3%), mycophenolate mofetil (3%), hydroxychloroquine (3%), and biologic drugs: tocilizumab (62%), sarilumab, etanercept, adalimumab, rituximab, and infliximab (all 3%)...The treatment of patients with uAIDs using canakinumab was safe and effective. Further randomized clinical trials are required to confirm the efficacy and safety.

P4, N=1000, Recruiting, Jeffrey Curtis | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: May 2023 --> Feb 2024

Additionally, 33% and 56% were refractory to lenalidomide and luspatercept therapy, respectively. The combination of canakinumab and darbepoetin was safe and well tolerated and 300mg of canakinumab is the RP2D. Canakinumab inhibited inflammasome activation as evidenced by a reduction of ASC specks although this did not translate to clinical responses. Phase 2 of the study will focus on patients with lower transfusion burden and molecular subsets with highest IL-1β expression (e.g.

Continuous vaso-occlusive (VO) and inflammatory processes in the vasculature are most likely the principal cause of such lesions, and there is little evidence, to date, that long-term hydroxyurea therapy (the standard of care for SCD) reduces organ damage in SCD adults. Inhibition of P-selectin activity, using crizanlizumab, has shown some success for reducing VO crisis frequency in SCD. Furthermore, interleukin (IL)-1β blockade, in the form of canakinumab administration, was well tolerated in young patients with SCD and associated with inflammatory marker reduction...Combination treatments, however, especially in the kidney and liver, had more complex effects. We suggest that future preclinical and clinical studies should investigate the potential of anti-inflammatory/adhesion approaches (alone or in combination) for preventing damage to multiple organs, in addition to preventing VO events.

Therefore, we have amended the protocol of a phase 1/2 clinical trial evaluating the safety and activity of canakinumab in clonal cytopenia of unknown significance (CCUS) and low-molecular complexity MDS patients. Our results will clarify the role of IL-1β signaling in MDS initiation and progression.

A phase II clinical trial investigating the use of canakinumab in combination with azacitidine is currently studying the impact canakinumab may have on disease progression in relapsed/refractory low or intermediate risk MDS patients (NCT04239157). Accounting for 5% drop-out, this calculation assumes accrual of 89 patients over 3 years and a minimum follow-up of 5 years (or until withdrawal, death, or study closure; earliest event). To date, 5 patients have been randomized and enrolled on study (Table 1).

P2, N=60, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2026

P1, N=33, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=90 --> 33 | Trial completion date: Sep 2024 --> May 2024 | Trial primary completion date: Sep 2024 --> May 2024

P2, N=34, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=90 --> 34 | Trial completion date: Feb 2026 --> Mar 2024 | Trial primary completion date: Feb 2026 --> Mar 2024

CANOPY-A did not show a DFS benefit of adding canakinumab after surgery and adjuvant cisplatin-based chemotherapy in patients with resected, stage II-III NSCLC. No new safety signals were identified with canakinumab.

P2, N=75, Not yet recruiting, Peter Shields

The colony forming activity of healthy donor HSPCs exposed to monocytes from LR-MDS was increased by the IL-1β-neutralizing antibody canakinumab. This work reveals distinct inflammatory profiles in LR-MDS that are of likely relevance to the personalization of emerging anti-inflammatory therapies.

Introduction: CANOPY-1 (NCT03631199) was a Phase III study evaluating the efficacy and safety of pembrolizumab plus platinum-based doublet chemotherapy combined with canakinumab or placebo as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). The results of predefined exploratory biomarker analyses from CANOPY-1 indicated a positive trend towards treatment benefit with canakinumab in patients with low T-cell infiltration (low total count or immune desert phenotype). Preclinical studies and the neoadjuvant CANOPY-N trial recently showed that canakinumab combined with ICI could decrease immunosuppressive features and activate a CD8-driven antitumor response (Mok TSK, et al. ESMO Asia 2022), providing potential rationale for the findings from CANOPY-1 subgroup analyses.

P2, N=88, Terminated, Novartis Pharmaceuticals | Completed --> Terminated; Study early terminated due to low enrollment compared to the anticipated figures.

P3; Trial completion date: Sep 2023 --> Jul 2024

P3, N=245, Terminated, Novartis Pharmaceuticals | Completed --> Terminated; The study was early terminated due to the lack of efficacy of study treatment observed in the analysis of the primary endpoint of the randomized part

We describe a Puerto Rican family of three with Cryopyrin-associated Periodic Syndrome and varying degrees of severity that received Canakinumab...Many develop mental or cognitive impairment. Auditory Mild hearing loss Sensorineural hearing loss starting in adolescence Sensorineural hearing loss from infancy/childhood Ophthalmic Conjunctivitis during flares Conjunctivitis during flares Papilledema, uveitis, iritis, conjunctivitis, and vision loss Lymphatic Not noted May be noted May have enlarged lymph nodes Joints Arthralgia Arthralgia, stiffness, and swelling during flares Arthralgia, stiffness, and swelling during flares Laboratory values High ESR, CRP, SAA, and leukocytosis with flares High ESR, CRP, SAA, and leukocytosis with flares Chronically elevated ESR, CRP, SAA, and leukocytosis FCAS, Familial cold autoinflammatory syndrome; MWS Muckle Wells Syndrome; CINCA/NOMID, chronic infantile neurologic, cutaneous, and articular syndrome/neonatal-onset multisystem inflammatory disease.

The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) and colchicine trials suggest an important role of inflammasomes and their major product IL-1β (interleukin 1β) in human atherosclerotic cardiovascular disease. Recent studies in mice and humans point to a wider role of the AIM2 (absent in melanoma 2) inflammasome in promoting cardiovascular disease including in some forms of clonal hematopoiesis and diabetes. These developments suggest a precision medicine approach in which treatments targeting inflammasomes or IL-1β might be best employed in clinical settings involving increased inflammasome activation.

Current data on VEXAS treatment are limited and inhomogeneous. Treatment decisions should be individualized. For the devolvement of treatment algorithms clinical trials are needed. AEs remain a challenge, especially an elevated risk for venous thromboembolism associated to JAKi treatment should be carefully considered.

Seventeen patients (54%) received anakinra, 11 patients (35%) received canakinumab and 3 patients (10%) received etanercept with other immunosuppressive treatment. The incidence of infection was 54% in our study. Mean treatment duration of biological agent was 4.2 year was considered main reason for higher incidence of infection in our study.

This evaluation of CH mutation and the development of non-hematological malignancies revealed different ratesof cancer incidence in different CH subtypes with and without canakinumab treatment. These data may support the role of IL-1 β inhibition for cancer prevention in patients with specific CH mutation. Inflammation, Clinical outcome, Clonal hematopoiesis of indeterminate potential, Solid tumor