Background/Purpose

In the last 5 years, the number of biosimilars in development for the treatment of immunologic diseases has increased as innovator etanercept (ETA), infliximab (IFX), adalimumab (ADA) and rituximab (RTX) near expiry of their original patents. Adequate clinical data may be achieved for a biosimilar with a single Phase (Ph) III study in a representative indication if the mode of action for the various proposed indications is similar. Disease prevalence, effect sizes for treatment response, regulatory and marketing considerations all may play a role in the indication(s) chosen for evaluation. In 2013, an IFX biosimilar, CT-P13, was the first mAb biosimilar approved in the EU on the basis of an extensive nonclinical and clinical comparative data package. Included clinical data demonstrated noninferiority to innovator IFX in just 2 indications, ankylosing spondylitis (AS) and rheumatoid arthritis (RA); approval was obtained for all pediatric and adult indications (8 in total) of innovator IFX. The US has yet to approve a biosimilar via the Public Health Service 351(k) pathway that is designated for biosimilar approval.

Methods

We performed a systematic review of ClinicalTrials.gov (CT.gov) to assess the evolution of the biosimilar trial landscape for immunologic indications. A cutoff date of 31 May 2014 was used to identify studies of biosimilars of innovator ETA, ADA, IFX and RTX, excluding oncologic studies for RTX.    

Results

Overall, there were 14 unique biosimilars in development: 12 in Ph III and 2 in Ph I or I/II only; 4 each were ADA or ETA, 3 each, IFX or RTX. Thirty-one biosimilar studies were registered on CT.gov over the last 5 years, with none reported as being initiated prior to 2010. Fifteen (55%) were Ph III, double-blind, randomized controlled trials (DBRCT). Of these, 12 (80%) were or planned to be started in 2013 to 2014.  Four DBRCT each evaluated ADA or IFX biosimilars (27% each); 5, ETA (33%); and 2, RTX (13%). Listed indications for the Ph III DBRCT were RA (10 studies, 67%), psoriasis (PsO; 4, 27%), and Crohn’s disease (CD; 1, 7%). Only 3 biosimilars had Ph III DBRCT in > 1 indication each: RA and PsO for both an ADA and ETA biosimilar, and RA and CD for CT‑P13. PsO was used only for evaluation of ADA or ETA biosimilars. RA was used to also assess RTX biosimilars in Ph I, due to regulatory authorities not permitting RTX use in normal healthy volunteers. Only 7 of the Ph III DBRCT (47%) included US sites.

Conclusion

Biosimilar development has increased significantly in the last 5 years, with the majority of the Ph III studies having been or planned to be started from 2013 onward. Most biosimilars appear to be evaluating efficacy, safety and immunogenicity against the innovator in only 1 indication. The common use of RA and/or PsO as indications may reflect disease prevalence, effect sizes and actual innovator use for these indications in clinical practice. RTX biosimilar Ph I studies in RA may not translate into eventual development in RA for Ph III. Less than half of the Ph III studies involve US sites. It is unclear whether the development programs proposed will be adequate to achieve approval of a biosimilar mAb in the US for the treatment of rheumatic conditions as well as extrapolation to other indications approved for the innovator product.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-biosimilar-landscape-a-systematic-review-of-its-current-status/