Results are coming in from clinical trials of biosimilar drugs for rheumatoid arthritis (RA) and concerns are being raised about their potential and pitfalls.
A multi-center comparative study of a biosimilar to adalimumab (Exemptia) shows the drug is just that – biosimilar to regular adalimumab (Humira) in efficacy, tolerability and safety in patients with moderate to severe RA.(1)
The prospective, randomized, double-blind, active controlled parallel arm study, published in the July 14, 2015 issue of the International Journal of Rheumatic Diseases, enrolled 120 RA patients in India. It showed that bi-weekly injections of test adalimumab produce statistically similar American College of Rheumatology (ACR) response rates to reference adalimumab at 12 weeks, investigators report.
Led by Rajendrakumar H. Jani, PhD, of the Zydus Research Centre in India, the researchers concluded that the drugs were "quite comparable in their aggregates and had similar folding properties, as has been separately reported."
Equal numbers of the patients, a majority of them women with a mean age of 45, were allocated to receive the test or reference version of the tumor necrosis alpha (TNF-α) inhibitor.
At three months, 82% of the patients treated with 40 mg subcutaneous Exemptia every other week had 20% ACR responses compared with 79.2% of those given reference Humira -- and similar proportions of both groups had ACR50 and ACR70 improvements and fewer swollen and tender joints.
The two drugs also achieved statistically similar improvements in C-reactive protein and disease activity in 28 joints (DAS28-CRP) scores, declining 2.1 points in both groups, the investigators say.
As for safety, both preparations were safe and well-tolerated; with only three serious adverse events and no deaths.
Earlier this year, the drug maker Amgen announced phase III results for its adalimumab biosimilar (ABP 501), saying it met “clinical equivalence” in safety and effectiveness at and similar endpoints at 24 weeks.(2)
The story was reported in the Wall Street Journal and elsewhere, but the trial results have not been formally published.
Adalimumab is among the first of the RA drugs that will lose patent protection in the next few years, opening the door for use of biosimilar medications.
Another adalimumab biosimilar, ONS-3010, is in phase I clinical trials in Europe(3), two biosimilars to the TNF-blocker infliximab (Remicade) have already been approved by the European Medicines Agency, and Etacept, a Chinese-made biosimilar of the TNF-blocker etanercept (Enbrel) has been approved in India. The EMA-approved infliximab biosimilar Remsima has been submitted to the FDA for review. (4)
The first biosimilar drug was approved in the US by the FDA in March for certain cancers and bone marrow transplants.(5)
News of the FDA’s first biosimilar drug approval was greeted by cautionary statements by the American College of Rheumatology (ACR) previously reported in Rheumatology Network and the American Autoimmune and Related Diseases Association (AARDA), noting India’s lack of standards for approval of biosimilars.
Unlike generic drugs, which must be identical to branded drugs, the FDA only requires that biosimilars be “highly similar” to the original.
Both groups expressed concern that since generics are routinely substituted for branded drugs by pharmacy plans (which cost insurers less), often without informing patients, the same thing could happen with biosimilars.
“The ACR objects to compulsory switching of stable patients to a different medication 17 (including a biosimilar) of the same class for cost saving reasons without advance 18 consent from the prescribing provider,” the group said in its statement.
Based on Medicare claims, the annual cost of adalimumab is almost $20,000.(6) Prices for biosimilars currently hover around 70% of branded drugs.
“It is uncertain whether patients will respond to these drugs the same way they would to an original biologic, because biologics are very sensitive to manufacturing changes," ACR President E. William St.Clair MD, said in an ACR press release. “Even minor differences in a biosimilar’s molecular structure, purity or other chemical properties could change the way a patient responds to the drug.”
Ten states have already passed legislation requiring notification of substitution for biosimilar drugs and more are expected to follow.
Most legislation specifies that the biosimilars must be deemed interchangeable by the FDA, offer a "dispense as written" option to prescribing physicians, and mandate patient and physician notification of substitution.
The Mendiratta study published in the International Journal of Rheumatic Diseases was sponsored and funded by Cadila Healthcare Limited, the Zydus Group Company, India.
1. Jani RH, Gupta R, Bhatia G, et al., Prospective, randomized, double-blind, multicentre, parallel-group, active controlled study to compare efficacy and safety of biosimilar adalimumab (Exemptia; ZRC-3197) and adalimumab (Humira) in patients with rheumatoid arthritis. International Journal of Rheumatic Diseases. Article first published online: 14 JUL 2015. DOI: 10.1111/1756-185X.12711.
2. Stynes T., Amgen Biosimilar Rheumatoid Arthritis Therapy Shows Positive Results. Wall Street Journal, February 3, 2015.
3. Oncobiologics launches Phase I clinical trial for Humira biosimilar. Biosimilars News, June 13, 2014,
4. Lumpe A., FDA Approves First Bioisimilar Drug - What’s next for RA?, Rheumatoid Arthrtitis.net, March 10, 2015.
5. FDA approves first biosimilar product Zarxio. FDA news release, March 6, 2015.
6. Bonadfede M, Joseph GI, Shah N, Princic N, Harrison DJ. Cost of tumor necrosis factor blockers per patient with rheumatoid arthritis in a multistate Medicaid population. Clinical Economics and Outcomes Research. 2014; 5:381-388. DOI