Baricitinib Derailed by FDA Review Save

Eli Lilly and Co disclosed today that upon further discussions with the US Food and Drug Administration (FDA) there would be a delay in further regulatory decisions regarding baricitinib, a JAK inhibitor, that is being developed for use in rheumatoid arthritis (RA).  

Specifically, the FDA is calling for an additional clinical trial to address the risk of thromboembolic disease.  Analyses gleened from over 3100 RA patients in 6 large clinical trials, demonstrated an "imbalance in thromboembolic events during the placebo-controlled period."

During the placebo controlled trials, there were no thromboembolic events (including DVT and pulmonary embolism) in patients receiving placebo or the 2 mg baricitinib dose - but 5 cases were noted in the 4 mg bariticinib population.

Pending further data analysis and clinical trial study, the timeline for resubmission would be delayed by a minimum of 18 months.  This has lead some to estimate the potential launch of baricitinib to be sometime around 2021. 

Baricitinib (Iluminant) is currently approved in the European Union, Japan, Switzerland and Kuwait, where this issue of thromboembolic events has been reviewed and resulted in additions to the drug safety profile in the product label. 

The issue here is whether this imbalanced risk seen in the high dose group but not the placebo treated patients is a small but significant drug specific risk or is related to the background risk of venous thromboembolic events (VTE) seen in RA.

There are no risks or warnings for VTE or vascular events with tofacitinib (Xeljanz).

RA (and many other autoimmune disease) patients have a constitutively higher risk of VTE (http://buff.ly/2tAHGRO) that is unrelated to the use of DMARDs or TNF inhibitors.  An ACR Drug Safety Quarterly article from 2012 (http://buff.ly/2tAEu8t) reviewed this issue and came to the same conclusion.  The RA incidence ratio for VTE was about 5-6 VTE per 1000 person years; which is more than 2 times the risk of non-RA patients.  We concluded that inflammation in RA indirectly increased the rate of VTE. 

Lilly has plans to study baricitinib in atopic dermatitis and lupus, but will delay its phase III trial in psoriatic arthritis iuntil next year.