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Biosimilars -- Bargain or Boondoggle?

We've been hearing a lot lately about new "biosimilar" drugs being approved for rheumatoid arthritis (RA) and other autoimmune diseases. While these drugs promise to be a potentially less expensive alternative to older biologics like Humira, don't confuse the term "biosimilar" with "generic." And don't think they'll be a bargain.

Biosimilar medications are not cheaper "generic" versions of existing biologic drugs.

Here's what you need to know:

The three new anti-rheumatic biosims approved by the FDA -- Amjevita, Inflectra,and Erelzi – copycats of adalimumab (Humira), Remicade (Infliximab), and etanercept (Enbrel) – all target the same inflammatory molecule tumor necrosis factor-alpha (TNF-α) and are approved to treat the same autoimmune and arthritic conditions as the original biologics:

• Amjevita (adalimumab-atto): a subcutaneous injection approved for moderate to severe rheumatoid arthritis (RA), Crohn's disease and ulcerative colitis, as well as psoriatic arthritis (PsA), ankylosing spondylitis (AS), and moderate to severe plaque psoriasis.1

• Erelzi (etanercept-szzs): an intravenous injection approved for treating polyarticular juvenile idiopathic arthritis (JIA) and RA, as well as PsA, AS, and moderate to severe plaque psoriasis.2

• Inflectra (infliximab-dyyb): intravenous infusion approved for adults and children two years old and over with moderate to severe Crohn's disease or ulcerative colitis for whom conventional therapies were not effective, for AS, PsA, chronic severe plaque psoriasis, and for treating RA in combination with methotrexate.3

Because these drugs are "similar" but not exact copies of older TNF-α inhibitors, your pharmacy can't just swap them without consulting your doctor as they can with other brand-name prescription drugs and their generic versions.

Biosimilars vs. Interchangables vs. Generics

The FDA approves biological drugs in two categories: "biosimilar" and "interchangeable."

To be approved as a biosimilar a drug must "highly similar" to an already FDA-approved biological drug ("reference drug") and have "no clinically meaningful differences" in purity, potency, safety and effectiveness.4

A biosimilar must also have the same "mechanism of action," route of administration, dosage form, and strength as the reference drug. They can only be prescribed for the same indications and conditions of use as the original drug.4

To be FDA-approved as an interchangeable biological, the drug must also "produce the same clinical result as the reference product in any given patient" and pose no greater risk in terms of safety and effectiveness if alternated or switched with the original.4 This is important, because many patients with RA, Crohn's disease, and other autoimmune conditions are switched from one biologic to another if the first drug produces an inadequate response.

Generic drugs must have exactly the same active chemical components, dosage form, and route of administration as the brand-name, and produce the same effects. In pharma-speak, they're "bioequivalent."

Because biological drugs are very complex, it's simply not possible to make exact copies of a drug like Remicade to produce a generic. According to the FDA, biologics are "large molecule" drugs, lab-produced proteins derived from living sources including humans, microorganisms, and yeast. In contrast, conventional prescription drugs are considered "small molecules" and compounds made from chemical formulas.4

Manufacturing a biologic medication is also more complicated. The process involves gene splicing and other techniques to produce a drug engineered to home in on and disable a specific protein that causes inflammation in the body, in this case TNF-α.

Amjevita, Erelzi and Inflectra are approved as biosimilars and not as "interchangeables." They must be specifically prescribed by name and can't be substituted for the original drug without permission from your rheumatologist.

Prescribing information for two of the new biosim drugs doesn't indicate whether they are interchangeable or not.1,2 For Inflectra, information on switching medications cautions only that "Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection."3

The American College of Rheumatology (ACR) is calling on the FDA to specify on drug labels whether or not a biological has official interchangeable status -- and set up rules to protect patients, including guidelines for substituting medications.

"Substituting non-interchangeable biosimilars, especially without notifying the prescribing provider, poses uncertain safety risks to rheumatology patients due to the complexity of these drugs and the possibility of patients being forced to switch," warned Angus Worthing, MD, incoming chair of the ACR's Government Affairs Committee.5

Positive Trials Data and Price Points

All three drugs passed muster with the FDA after years of positive clinical trials among thousands of patients.

A systematic review conducted by researchers at Johns Hopkins University and Brigham and Women's Hospital in Boston, evaluated 19 studies (including 13 clinical trials) of biosimilars to Remicade and Humira in patients with rheumatoid arthritis and inflammatory bowel disease. Phase 3 clinical trials suggest the biosims and their reference drugs produced similar clinical responses. The authors also note that four studies of patients switched from reference drugs to biosimilars suggested similar efficacy and safety outcomes.6

The analysis, published online August 2nd in the Annals of Internal Medicine, concluded that, so far, these biosim TNF blockers and their brand-name "reference drugs" do appear to be interchangeable.6

A clinical trial of an etanercept copycat, marketed in Europe asBenepali (etanercept SB4), came to the same conclusion. That 52-week study found that the drug could be safely switched in patients with moderate to severe RA. An open label extension trial lasting almost two years suggests patients could safely and effectively switch from reference etanercept to etanercept (SB4).7

While Inflectra is expected to come on the market shortly, patent disputes, especially over Humira, may delay Amjevita and Erelzi for at least five years.

Meanwhile, other questions remain to be answered.

For one thing, the three biosimilars haven't been tested in every disease for which their reference drugs are approved. In the case of Amjevita, clinical trial results in RA and plaque psoriasis were reportedly extrapolated so the drug could be approved for all the conditions for which Humira is currently indicated.8 While experts are optimistic, there's no way to know how these biosims will actually perform in a variety of real-world autoimmune patients outside the controlled confines of clinical trials.9

In light of that, the ACR's Dr. Worthing called on the FDA at a public hearing October 20th, to set up a post-marketing surveillance program to watch for any adverse events related to non-interchangeable substitutions.5

Then there's the issue of drug pricing. While industry experts expect the biosims to be priced just below the original drugs,10 it's unclear if autoimmune patients will benefit. These days, even generic drugs can end up costing as much -- or even more -- than their brand-name equivalents.

According to a May report in the "pharmaceutical companies have been raising prices on biotech drugs about to lose patent protection to squeeze out more revenue before competition arrives… And makers of the knockoffs are setting their prices just below those marked-up ones."10

In the case of Humira, whose patent expires December 31, WSJ.com says maker AbbVie, Inc., increased the drug's list price eight times in the past three years -- by a total of 73% -- to $49,362 for one year's treatment.10

So what will Amjevita cost when it's finally launched? WSJ.com quotes an AbbVie spokesman as saying the company "prices its medicines based on the value that those medicines bring to patients and the competitive environment."

Judging from the current pharmaceutical marketplace, that often means whatever the market will bear.


1 FDA approves Amjevita, a biosimilar to Humira. FDA News Announcement, September 23, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522243.htm.

2 FDA approves Erelzi, a biosimilar to Enbrel, FDA News Announcement, August 20, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518639.htm

3 FDA approves Inflectra, a biosimilar to Remicade. FDA News Announcement, April 5, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm

4 FDA, Information for Consumers (Biosimilars). http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm

5 ACR Calls for Clearer FDA Guidelines and Increased Congressional Funding to Ensure Safe and Effective Adoption of Biosimilars in the U.S. American College of Rheumatology News Release, October 20, 2016.

6 Chingcuanco F, Segal JB, Kim SC, et al . Bioequivalence of Biosimilar Tumor Necrosis Factor-α Inhibitors Compared With Their Reference Biologics: A Systematic Review. Ann Intern Med. 2016;165(8):565-574. Published online 2 August 2016 doi:10.7326/M160428.

7 Burness CB and Duggan ST, Etanercept (SB4): A Review in Autoimmune Inflammatory Diseases. BioDrugs. 2016; 30(4):371-378. doi:10.1007/s40259-016-0188-z.

8 Clarke T. "FDA panel backs Amgen copy of AbbVie arthritis drug Humira." Reuters Health News, July 12, 2016. http://www.reuters.com/article/us-amgen-humira-fda-idUSKCN0ZS2NC Accessed August 20, 2016.

9 Lupkin, S, "Study Bodes Well For Biosimilars, But Highlights Need For More Research." Kaiser Health News, August 1, 2016. http://khn.org/news/study-bodes-well-for-biosimilars-but-highlights-need-for-more/ Retrieved August 20, 2016.

10 Rockcoff JD. Knockoffs of Biotech Drugs Bring Paltry Savings. Wall Street Journal. May 5, 2016. http://www.wsj.com/articles/knockoffsofbiotechdrugsbringpaltrysavings1462458209
Retrieved August 20, 2016.

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