Comparing biologic agents for the treatment of RA:

Do we already have enough data?

Yusuf Yazıcı, MD

Assistant Professor of Medicine,NYU School of Medicine

Director, Seligman Center for Advanced Therapeutics & Behcet’s Syndrome Evaluation, Treatment and Research Center

NYU Hospital for Joint Diseases

Which biologic?

• No head to head trials– ATTEST– Metaanalysis of MTX IR, TNF IR

• Different populations, • No standard definition of “IR”• No consistency of DMARDs used• Head to head trials too expensive, too many people

needed• And probably not necessary for efficacy purposes

NNT

• NNT analysis is a useful tool for putting RCT efficacy results into perspective in patient care.

• For clinical decision making, the NNT is a useful measure to convey statistical and clinical significance to the doctor.

• Furthermore, it can be used to extrapolate published findings to patients in the real world.1

Cook RJ, Sackett DL. BMJ 1995;310:452–454

NNH / OR

• Odds Ratio (OR) analyses are useful tools for putting RCT safety and treatment risks into clinical perspective.

• These measures convey statistical and clinical significance and may be used to extrapolate published findings to patients in the real world.

Analysis NNT• PubMed was searched for randomized double-blind (DB),

MTX-controlled studies of biologics in MTX-naive pts with early RA.

• Response rates (RR) for primary and secondary outcomes specified by each RCT were used to assess NNT of biologic (active) versus MTX (control)

• number of patients needed to treat to achieve 1 additional response compared to control

• where NNT=[1/(RRactive-RRcontrol)]*100. • Outcomes assessed included ACR responses, major clinical

response (MCR; defined as ACR70 for at least 6 consecutive months) and DAS28 defined remission (DAS28 <2.6). Response rates at end of Year 1 were used for the analysis

Analysis OR• Randomized double-blind, MTX-controlled

studies of biologics in MTX-naive patients with early RA were identified through a PubMed search.

• Event rates (ER) specified by each RCT were used to assess unadjusted ORs of biologic agent (active) versus MTX (control).

• ERs assessed included overall discontinuation (DC), DC due adverse event (AE), DC due to lack of efficacy, and rate of serious infection.

• Results at end of the first year were used for the analysis.

Demographics

• Four published RCTs were identified.– Emery P et al. Lancet 2008;– Breedveld F et al. A & R 2006:– St. Clair EW et al. A & R 2004; – Westhovens R et al. Ann Rheum Dis 2009;

• Baseline demographics and disease characteristics were similar across the four studies (average age 50-52 yrs; 71-79% female; mean disease duration 6.2-10.8 months; mean DAS28=6.2-6.7; and mean HAQ=1.5-1.7).

Results NNH/OR• Overall DC rates for combination therapies

ranged from 9.4% (abatacept, ABA) to 24.3% (adalimumab, ADA), and were similar to or lower than that of MTX in each RCT.

• OR (95% CI) vs MTX were 0.57 (95% 0.39, 0.85) for etanercept (ETA), 0.61(0.42, 0.90) for ADA, 0.85 (0.58, 1.26) for infliximab (INF), and 0.90 (0.5, 1.62) for ABA.

• Compared with MTX, no differences were seen in rates of DC due to AEs when MTX was combined with ETA (OR=0.78 [0.46, 1.33]), ADA (OR=1.7 [0.94, 3.08]), or ABA (OR= 0.8 [0.33, 1.97]).

Results NNH/OR (2)• Combination infliximab plus MTX treatment had a higher

rate of DC due to AEs (9.1%) than MTX (3.0%),  an increase of greater than 3 times  in odds (OR=3.22 [1.52, 6.83]).

• No differences in rates of serious infections were seen between ETA (OR=0.6 [0.2, 1.87]), ADA (OR=1.24 [0.46, 3.38]), or ABA (OR=0.99 [0.28, 3.46]) in combination with MTX versus MTX.

• Increased odds of higher risk of serious infection (OR=2.84 [1.13, 7.14]) was observed with INF + MTX compared to MTX alone.

• All biologics in combination with MTX had lower odds  of DC due to lack of efficacy than MTX alone (ETA:OR= 0.35 [0.16, 0.76]; ADA:OR=0.23 [0.12, 0.44]; INF:OR=0.19 [0.08, 0.45]; and ABA: OR=0.06 [0, 0.98]).

Conclusions• No major difference in ACR20, 50 and 70

responses

• Possible differences in more robust, MCR and DAS28 remission rates

• Possible differences for serious infections and DC due to AE

• In the absence of head-to-head RCTs, NNT, NNH/OR for selected efficacy and safety outcomes can be useful for determining relative risks and benefits of biologic therapy for RA in the real world.