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The SARfaris: GPCR, Kinase, ADME

Sunday, 21 June 2009

New Drug Approvals - Pt. VII - Canakinumab (Ilaris)

Next in our series of posts on new FDA drug approvals this year is Canakinumab, approved on the 18th of June. Canakinumab is a Interleukin-1 beta (IL-1β) blocker indicated for the treatment of various auto-immune diseases - specifically described by the term Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS) (alternatively known as familial cold urticaria) and Muckle-Wells Syndrome (MWS). These are rare (albeit debilitating) genetic diseases, and are usually caused by mutations in the NLRP-3 gene - here is the link to the OMIM entry for NLRP-3.

Canakinumab is the third Il-1β blocker to reach the market, and as the INN/USAN suggests it is a human (the 'u' before mab) derived monoclonal antibody (the 'mab' part). The earlier IL-1β blockers were Anakinra (Kineret), and Rilonacept (Arcalyst); both of these earlier therapies are not antibody therapies, and have different detailed mechanisms of action. Canakinumab binds directly to IL-1β, and is reported to not bind to the related IL-1α and IL-1ra proteins. Rilonacept similarly binds directly to IL-1β, but also binds to the related IL-1α and IL-1ra proteins with modest selectivity (with binding constants ~3 and ~12 fold down relative to IL-1β respectively).

Canakinumab (previously known as the research code ACZ885) is a human monoclonal antibody that exhibits multiple glycoforms with a deglycosylated molecular weight of ca. 145 kDa. Canakinumab has a good subcutaneous (s.c.) absorption (ca. 70% bioavailable), a plasma half-life of ca. 4 weeks, a volume of distribution of ca. 86 mL/kg and a systemic clearance of 2.5 mL/day/kg. The recommended dosage of 150 mg is administrated by subcutaneous injection just once every two months. The full prescribing information can be found here.

The CAPS set of diseases are rare (about 1 in a million in the US), and Ilaris will unlikely have significant commercial impact, despite the high prices that are often charged for this type of 'orphan' drug (for example, Cerezyme is about $200,000 per patient p.a.). However, the commercial strategy of getting initial approval for a orphan disease is quite interesting and common. Basically it is to target a tightly defined genetic disease, get a drug that works against that mechanism (as detailed above, it does not have to be the gene that is mutated in the disease itself, just some member of the signalling pathway/mechanism that involves that gene), get approval, and then study new potential indications (the key target, IL-1β, has been implicated, and clinically shown, to be important in many, many human diseases - for example, type-2 diabetes (which is a big and growing disease), gout, and juvenile idiopathic arthritis). If the studies show utility in these more common diseases, there is great potential to 1) develop genuinely innovative medicines against more frequent diseases and 2) grow revenues. There are some issues with this strategy though.... but that is for another day.

Canakinumab molecular formula: C6452H9958N1722O2010S42

Canakinumab CAS registry: 914613-48-2

The license holder for Canakinumab is Novartis. and the product website is

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