Canakinumab - Ilaris; interleukin-1 beta monoclonal antibody; ACZ885
Status – Approved by FDA in June 2009; approved in EU in Oct. 2009
Organizations involved:
Novartis AG – Manuf.; R&D; Tech.; Int. mark.
Novartis Pharmaceutical Corp. – USA mark.
Chiron Corp. – Former
Medarex Inc. - Tech.
Bristol-Myers Squibb Co. - Parent
Description: Ilaris is a lyophilized (freeze-dried) formulation of canakinumab, a recombinant fully human IgG1/k (k = kappa) isotype subclass monoclonal antibody glycoprotein with binding specificity for human interleukin-1beta expressed by a expressed in a murine Sp2/0-Ag14 fused hydridoma cell line. Canakinumab is comprised of two 447- (or 448-) residue heavy chains and two 214-residue light chains, and has a molecular mass of 145.157 kDa when deglycosylated. Both heavy chains of canakinumab contain oligosaccharide chains linked to the protein backbone at asparagine 298 (Asn 298). The molecular formula for canakinumab is based on the amino acid composition without posttranslational glycosylation, but including N-terminal pyroglutamate formation and lysine residues at the C-terminals of the heavy chains.
ILARIS is packaged in a sterile, single-use, colorless, 6 mL glass vial with coated stopper and aluminum flip-off cap. Reconstitution with 1 mL of preservative-free Sterile Water for Injection is performed prior to subcutaneous administration of the drug. Reconstituted canakinumab is a 150 mg/mL solution, with a volume of up to 1 mL withdrawn for delivery of 150 mg/mL canakinumab for subcutaneous administration. Each vial contains 180 mg of canakinumab as a white, preservative-free, lyophilized powder; sucrose; L-histidine; L-histidine HCL monohydrate; polysorbate 80 (Tween 80), and when reconstituted, Sterile Water for Injection. No preservatives are used. Ilaris is stored refrigerated at 2-8°C (36-46°F).
Biological.: Canakinumab a fully human monoclonal antibody that rapidly and selectively blocks IL-1ß. Canakinumab binds to serum IL-1beta, eliminating its biological activity.
The biological activity of canakinumab is measured by comparing its inhibition of IL-1-dependent expression of the reporter gene luciferase to that of a canakinumab internal reference standard, using a stably transfected cell line.
Nomenclature: Interleukin-1 Mab, rDNA [BIO]; Ilaris [TR]; canakinumab [USAN; FDA]; immunoglobulin G1, anti-(human interleukin 1) (human clone ACZ885 heavy chain V region) [CAS]; immunoglobulin G1, anti-(human interleukin-1 beta (IL-1)) human monoclonal ACZ885; (1Glu>Glp)-1 heavy chain (221-214’)-disulfide with kappa light chain, dimer (227-227’’:230-230’’)-bisdisulfide [CAS]; 914613-48-2 [CAS RN]; CZ885 [SY]; interleukin-1 beta monoclonal antibody [SY]; interleukin-1 Mab, rDNA [SY]; NDC 0078-0582-61 [NDC]
Biological.: This fully human antibody was developed using UltiMAb technology from Medarex Inc., which was later acquired by Bristol-Myers Squibb Co. (BMS). HuMAb-Mouse transgenic mice can secrete antibodies that are fully human (100% human protein sequences). In these transgenic mice, mouse antibody gene expression is suppressed and effectively replaced with human antibody gene expression. HuMAb-Mouse transgenic mice can be inoculated with an antigen to develop fully-human, mouse-derived recombinant antibodies, with the murine antibody genes spliced into CHO or other cells for recombinant Mab manufacture. Because the human genes in the HuMAb-Mouse are stable, they are passed on to offspring of the mice. Mice secreting human antibodies can be bred indefinitely at relatively low cost and without additional genetic engineering. HuMAb-Mouse can generate fully human antibodies with affinities in the picomolar range, as high as 1012. Because these mice contain genes encoding human antibodies, the monoclonal antibodies generated are more likely to have favorable safety profiles and be eliminated less rapidly from the human body, potentially reducing the frequency and amount of dosing required.
History: Dr. Tim Wright, Novartis, is reported as deserving much of the credit for Novartis' development of Ilaris. Novartis had previously tested CZ885 in rheumatoid arthritis, with disappointing results. Wright, formerly chief of rheumatology at the University of Pittsburgh, joined the company in 2004 and promoted testing CZ885 for Muckle-Wells. The first four patients received the drug in February 2005. As is now common, within five hours of a single injection, the patient's symptoms had visibly improved, within a day they were gone, by the end of the week the disease was barely detectable in the blood, and patients remained symptom-free for the next six months. As is common in large companies, development then languished until in early 2006, Novartis CEO Da--n Vasella, intervened. Development began in earnest in early 2007 cryopyrin-associated periodic syndromes (CAPS), which include Muckle-Wells. This delay essentially allowed Regeneron Pharmaceuticals to get to market first, in Feb. 2008, with Arcalyst for CAPS (see related entry). Dr. Vasalla has noted, "It took way too long, much longer than necessary."
Companies.: Ilaris was developed and is manufactured and marketed by Novartis AG. Canakinumab was apparently originally invented by Chiron Corp., now merged into Novartis.
The U.S product insert cites manufacture by Novartis Pharma Stein AGT (Stein, Switzerland).
The EMEA EPAR states the the "biological active substance" is manufactured by Novartis Pharma S.A.S., Huningue, France. Canakinumab 150 mg Powder for solution for injection is manufactured by Novartis Pharma Stein AG, Switzerland.
Manufacture: Canakinumab is produced from murine Sp2/0 cells. The murine cell line secretes the monoclonal antibody into a serum-free cell culture medium and subsequently the monoclonal antibody is purified and formulated to produce bulk drug substance (BDS). The fermentation process is performed as standard fed-batch culture. The drug substance is purified from the harvested cell culture fluid by centrifugation and clarification, and is then subjected to a sequence of chromatographic steps, virus inactivation treatment and filtrations. The drug substance bulk is frozen for long term storage.
At least for EU approval, a new reference material, ACZ885.04REF, was used. Comparability with previous reference preparations was demonstrated.
No animal or human materials are used in the commercial manufacturing process of the drug substance. The fermentation process of the monoclonal antibody Canakinumab is in a culture medium without addition of human or animal derived components.
The cells used for production of canakinumab have been extensively screened for viruses. These tests failed to demonstrate the presence of any viral contaminant in the cells used for production with the exception of intracellular A-type and C-type retroviral particles. uch particles are well known to be present in murine Sp2/0 cells. This was acceptable (to EMEA), since there is sufficient capacity within the manufacturing process of canakinumab for reduction of this type of viral particles. The purification process includes several steps for inactivation/removal of enveloped viruses. The effectiveness of these steps, has been sufficiently demonstrated. The removal capacity of small non-enveloped viruses is based on the chromatography and the nanofiltration. This was be accepted, as screening for viruses including a rodent parvovirus test is routinely performed at the end of the fermentation runs.
FDA class: Biologic BLA
Appprovals: Date = 20090617
Indications: [full text of the "Indications and USAGE" section of product insert/labeling]:
ILARIS (canakinumab) is an interleukin-1a blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children 4 years of age and older including:
• Familial Cold Autoinflammatory Syndrome (FCAS)
• Muckle-Wells Syndrome (MWS)
Status: FDA approved the BLA on June 17, 2009 with orphan designation. FDA granted priority review to the Ilaris BLA based on its potential to meet an important clinical need for patients with CAPS.
As of July 2009, Novartis had also filed for regulatory approval in the European Union (EU), Switzerland and Australia. Ilaris has received orphan designation in the EU.
On Oct. 28, 2009, the EMEA/EU granted accelerated approvals with orphan status to Ilaris to treat adults and children as young as four years old with cryopyrin-associated periodic syndrome (CAPS). Ilaris became the only medicine approved in the EU for CAPS patients as young as four years old, and for patients with the most debilitating form of CAPS, neonatal-onset multisystem inflammatory disease (NOMID). The EU approval was granted under exceptional circumstances, a common practice with orphan drugs. The situation wit Ilaris will bereviewed every year until the European Medicines Agency (EMEA) is able to grant a normal approval.
In Aug. 2011, FDA followed the recommendations of its advisory committee and refused to approve canakinumab (ACZ885) for the treatment of gouty arthritis. A complete response letter (CRL) issued to the firm requested additional clinical data to evaluate the benefit/risk profile in refractory patients. The review committe had agreed to overall efficacy of canakinumab, but had some safety concerns, and had suggested that retreatment data would be needed in order to assess the overall safety profile of the drug.
Tech. transfer:
U.S. 7,566,772, "Antibodies against interleukin-1β," assigned to Novartis,
An application is pending (late 2012) for extension of 7,446,175, "Antibodies to human IL-1β," assigned to Novartis, by 177 days from its normal expiration date of Aug 20, 2021 into 2022.
EP 1313769, "ANTIBODIES TO HUMAN IL-1 BETA," assigned to Novartis, expires in 2021. EP 1248804, "Recombinant antibodies to human interleukin-1 beta," assigned to Novartis, expires in 2021.
Related patent applications originating from Chiron Corp., now Novartis, that may have recently issued include U.S. 20070065439, " Antibodies against interleukin-1 beta," claiming IL-1beta monoclonal antibodies. "Antibody 9.5.2" cited in this application appears to substantially be canakinumab. [This is a high-affinity (K.sub.D=204 fM for IgG2 and 181 fM for IgG4) IgG2.lamda. Mab that binds to N-terminal residues 1-34 of the IL-1.beta. molecule. The 9.5.2 mAb had in vitro and in vivo potencies superior to anakinra (see related entry)]. Chiron/Novartis has also filed U.S. 20090060923 and 20090060918, both titled "Method of treating or preventing an IL-1 related disease or condition," claiming treatment of a variety of diseases, including Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), systemic onset juvenile idiopathic arthritis, CIAS1 Associated Periodic Syndromes (CAPS), Stills disease, or Muckle-Wells syndrome, with IL-1beta antibodies or fragments.
Medarex/BMS receives royalties on sales of Ilaris from licensing of UltiMAb technology.
Trials: The Novartis research and development strategy for Ilaris included use of proof-of-concept studies or small-scale Phase I clinical trials in genetically well-defined diseases to determine how genes interact in molecular or 'signaling' pathways. The resulting clinical and biomarker data were then subjected to state-of-the-art modeling and simulation to yield new insights into the regulation of IL-1ß in patients. This approach allowed minimization of the number of clinical trials.
FDA approval of Ilaris was based on a three-part, one-year Phase III study involving 35 patients aged nine to 74 years old with varying degrees of disease severity. This 48-week study involved 35 patients aged nine to 74 years old. Results at one year were published in The New England Journal of Medicine on June 4, 2009 show that Ilaris produced a rapid, complete and sustained response in the majority of patients. In the first part of the study lasting eight weeks, 35 patients received a single dose of Ilaris (150 mg by subcutaneous injection). All but one patient (97%) showed a rapid and complete response. After this, 31 patients who maintained their response proceeded to part two, a randomized 24-week, double-blind placebo-controlled phase. Patients were treated every eight weeks with either Ilaris or placebo and if a relapse occurred, they entered part three. Part two of the study included the primary endpoint, a comparison between the number of patients treated every eight weeks with Ilaris who experienced disease relapse or 'flares' vs. those on placebo. Results showed that no patients in the Ilaris group experienced a disease flare compared to 13 out 16 patients in the placebo group (0% vs. 81%, p<0.001). These results supported interim data from earlier phases showing efficacy in 97-100% of patients. None of the patients in the Ilaris group (0 out of 15) experienced a disease flare compared to 13 out of 16 patients in the placebo group (0% vs. 81% respectively, p<0.001). Over 90% of patients studied did not experience any injection site reactions and those that did occur were of a mild-to-moderate nature.
Following either completion of part two or occurrence of a disease flare, patients proceeded to part three which involved at least two further doses of Ilaris for a minimum of 16 weeks. Out of 31 patients who entered part three, 28 completed this phase of the study without suffering a relapse (90%).
Overall, patients experienced a benefit within hours after receiving a single dose of Ilaris and only needed further treatment every two months to control their symptoms. In many respects, they were cured. Ilaris was generally well tolerated, with no consistent pattern of adverse events beyond an increase in all suspected infections. Two patients experienced serious adverse events, which were a lower urinary tract infection and vertigo[1]. The most common adverse events reported by patients treated with Ilaris were nasopharyngitis, diarrhea, influenza, headache and nausea. No impact on the type or frequency of adverse events was seen with longer-term treatment.
The original BLA included data from approximately 833 subjects having been treated with Ilaris in blinded and open-label clinical trials in CAPS and other diseases, and healthy volunteers..
Disease: See the Interleukin-1 trap, rDNA (Arcalyst) entry for further information about cryopyrin-associated periodic syndromes (CAPS). There are believed to be approximately 300 cases in the U.S., but many patients may remain undiagnosed due to poor disease recognition.
Medical: Ilaris is the first treatment approved for patients as young as four years old suffering from two forms of CAPS: familial cold auto-inflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). CAPS is a life-long disease and the convenience of administration of medicine is very important for these patients. With rapid and sustained response, good tolerability, and a significantly less-frequent dosing schedule, Ilaris is portrayed as an important treatment advance for children and adults with CAPS.
The recommended dose is 150 mg for CAPS patients with body weight greater than 40 kg. For CAPS patients
with body weight between 15 kg and 40 kg, the recommended dose is 2 mg/kg. For children 15 to 40 kg with an inadequate response, the dose can be increased to 3 mg/kg. Ilaris is administered every eight weeks as a single dose via subcutaneous injection.
The dosing schedule for Ilaris is less frequent than for Aracalyst (see related entry) also approved for CAPS indications:, and Ilaris provides the longest dosing interval of any available treatment.
Market: Ilaris will compete with Arcalyst from Regeneron, which is also an Il-1beta antagonist and approved for CAPS indications:.
Ongoing: Ongoing trials are will support filings for Ilaris to treat gout, juvenile arthritis, rheumatoid arthritis, and neonatal onset multisystem inflammatory disease, which causes brain inflammation in newborns, type 2 diabetes.and chronic obstructive pulmonary disorder (COPD). The company is also exploring its use in chronic obstructive pulmonary disease and diabetes. Further development in rheumatoid arthritis (RA) has been abandoned.
Companies involvement:
Full monograph
214.5 Interleukin-1 Mab, rDNA
Nomenclature:
Interleukin-1 Mab, rDNA [BIO]
Ilaris [TR]
Canakinumab [USAN; FDA; INN]
immunoglobulin G1, anti-(human interleukin 1β) (human clone ACZ885 heavy chain V region) [CAS]
immunoglobulin G1, anti-(human interleukin-1 beta (IL-1β)) human monoclonal ACZ885; (1Glu>Glp)-γ1 heavy chain (221-214’)-disulfide with kappa light chain, dimer (227-227’’:230-230’’)-bisdisulfide [CAs]
914613-48-2 [CAS RN]
ACZ885 [SY]
interleukin-1 beta monoclonal antibody [SY]
Interleukin-1 Mab, rDNA [SY]
NDC 0078-0582-61 [NDC]
molecular weight (kDa) = 145.2
FDA Class: Biologic BLA
Year of approval (FDA) = 2009
Date of 1st FDA approval = 20090617
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2022, presuming pending application for extension of 7,446,175 is granted, 2021 if not granted |
U.S. Patent Expiration Year: | 2021 |
U.S. Biosimilars Data Exclusivity Expiration: | 2021 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2016 |
U.S. Biosimilars Launchability Year: | 2021 |
U.S. Biobetters Launchability Year: | 2021 |
Biosimilars/biobetters-related EU Patents: | 2021, based on EP 1313769 and EP 1248804 |
EU Patent Expiration Year: | 2021 |
EU Biosimilars Data Exclusivity Expiration: | 2019 |
EU Biosimilars Orphan Exclusivity Expiration: | 2019 |
EU Biosimilars Launchability Year: | 2021 |
EU Biobetters Launchability Year: | 2021 |
Index Terms:
biopharmaceutical products
monoclonal antibodies
monoclonal antibodies, recombinant
recombinant DNA
hP67.6, monoclonal antibody
hyaluronidase
murine serum proteins
U.S. Standard Rabies Vaccine
histidine
lyophilized (freeze-dried)
polysorbate 80 (Tween 80)
Sterile Water for Injection
sucrose
Complement-Fixation Test
orphan status
PrefGel
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM160 Controlled/Gov't Distribution in EU
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