What Are Biosimilars? Top Facts You May Not Know
Medically reviewed on Nov 8, 2018 by L. Anderson, PharmD
What Is A Biosimilar?
Similar to our European neighbors, biosimilar approvals are now making forward strides in the U.S.
But what is a biosimilar? A biosimilar is a biological product that is very similar to a reference biologic and for which there are no clinically meaningful differences in terms of safety, purity, and potency.
An example of an approved biosimilar is Amjevita (adalimumab-atto), the first biosimilar approved for the blockbuster Humira (adalimumab) used to treat rheumatoid arthritis and psoriasis, among many other uses.
However, a biosimilar is not considered a “generic” in the same way that a traditional drug is determined to be a generic.
- As with generics, biosimilar cost savings for healthcare systems and the consumer are expected to be significant.
- According to the RAND Corporation, biosimilars could save the U.S. health system close to $44 billion in the next ten years.
What is a Biologic?
If a biosimilar is a biologic, then what is a biologic?
Biological products can include a wide range of products including:
- blood components
- gene therapy
- proteins, like monoclonal antibodies and cell signaling proteins.
Unlike most chemically-derived small-molecule drugs, biological products are generally derived from a living organism, such as humans, animals, microorganisms or yeast. Clinically, they are used to treat patients with cancer, kidney diseases and autoimmune diseases, such as rheumatoid arthritis and Crohn's disease.
These products are very expensive, often in the tens-of-thousands of dollars per year, due to costs linked to complicated development and manufacturing. Often, patients will need to access these medications through a specialty pharmacy.
Are Biosimilars Exactly The Same As The Biologic?
Biosimilars are just that; similar because they do not have to be exact copies of the active ingredient, as with small-molecule drug generics.
In 2010, the President signed into law an abbreviated approval pathway for biologics to encourage production, create competition, increase treatment options and reduce healthcare costs. Under the new law, a biological product may be demonstrated to be “biosimilar” if data show that the product is “highly similar” to an already-approved biological product.
The law, known as the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), aligns with the FDA’s longstanding policy of permitting appropriate reliance on drug science that has already been established, thereby saving time, resources and unnecessary duplication of animal testing or human clinical trials.
Zarxio and Nivestym: Biosimilars to Neupogen
- Filgrastim is a recombinant granulocyte colony-stimulating factor used to boost white blood cells after cancer treatments that deplete these necessary infection-fighting cells.
- Zarxio is highly similar to the brand biologic and has no clinically meaningful differences with Neupogen in terms of safety, purity, and potency.
- The FDA stated that “robust” pharmacokinetic and pharmacodynamic comparative studies supported biosimilarity with the original filgrastim.
- Nivestym is used for the treatment of neutropenia due to chemotherapy as well as the other same approved conditions for the reference product Neupogen.
- As with other biosimilars, the FDA approval was based on a review of a comprehensive data package demonstrating a high degree of similarity of Nivestym compared to Neupogen.
Inflectra: A Biosimilar to Remicade
After Zarxio, Inflectra (infliximab-dyyb) by Celltrion was the second biosimilar approved in the U.S. Inflectra, a tumor necrosis factor (TNF) blocker, is biosimilar to Janssen’s Remicade (infliximab) originally approved in 1998.
Inflectra can be prescribed for the same indications as Remicade, including:
- rheumatoid arthritis
- Crohn’s disease
- ankylosing spondylitis (spine arthritis)
- ulcerative colitis
- psoriatic arthritis
- plaque psoriasis.
In April, 2017 the FDA approved Renflexis (infliximab-abda), the second biosimilar to Remicade from Samsung Bioepis. And a third biosimilar for Remicade is now approved as of December 2017 - Ixifi from Pfizer.
Erelzi: A Biosimilar to Enbrel
In August 2016 the third biosimilar, Sandoz's Erelzi (etanercept-szzs), was FDA-approved.
- Erelzi is biosimilar to Amgen’s tumor necrosis factor (TNF) blocker Enbrel.
- Erelzi is the first approved biosimilar for etanercept, and is used for the same five indications for Enbrel: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.
It’s important to note that Erelzi has been approved as a biosimilar, not as an interchangeable product, as with all other U.S. biosimilars as of Nov. 2018.
Physicians must write the prescription specifically for Erelzi, as pharmacists cannot automatically substitute Erelzi for Enbrel.
Amjevita, Cyltezo, and Hyrimoz: Biosimilars to Humira
Amgen’s Amjevita (adalimumab-atto) was the first U.S. biosimilar approved for adalimumab (Humira) in September 2016.
- It is used for the treatment of seven inflammatory diseases, including rheumatoid arthritis, ulcerative colitis, Crohn's disease, and plaque psoriasis.
- Amjevita is an anti-TNF-α monoclonal antibody that has the same amino acid sequence as adalimumab.
- The pharmacist needs direction from the prescribing doctor to substitute Amjevita for Humira, as it is not approved as an interchangeable product.
- Common side effects include increased risk of infections and injection site reactions.
- Amjevita is available in a pre-filled syringe or auto-injector.
Cyltezo (adalimumab-adbm), another Humira biosimilar, was approved in August 2017.
- Cyltezo is also used for the treatment of various inflammatory diseases including rheumatoid arthritis, psoriatic arthritis, and plaque psoriasis, but is not interchangeable with Humira at the pharmacy level.
- It is available in a pre-filled syringe and can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).
In October 2018 Sandoz's Hyrimoz (adalimumab-adaz) was cleared by the FDA as the third U.S. biosimilar to AbbVie’s Humira.
Renflexis: A Second Remicade Biosimilar
In April 2017, the FDA approved Renflexis (infliximab-abda), a tumor necrosis factor (TNF) blocker from Samsung Bioepis that is biosimilar to Remicade (infliximab).
The first biosimilar to Remicade, Pfizer’s Inflectra (infliximab-dyyb) was approved by the FDA in April, 2016.
Renflexis is used for the treatment of Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis.
The biosimilar must be shown to have no clinically meaningful differences in terms of safety and effectiveness from the reference product Remicade.
Only minor differences in clinically inactive components are allowable in biosimilar products.
Mvasi: The First Cancer Biosimilar
Mvasi is indicated for the treatment of multiple types of cancer, including adult patients with certain metastatic colorectal cancers, non-squamous non-small cell lung cancer, brain cancer (glioblastoma), metastatic renal cell carcinoma (kidney cancer) and cervical cancers. It has been approved as a biosimilar, not as an interchangeable product.
The FDA's approval of Mvasi is based on review of safety and effectiveness data that shows Mvasi is biosimilar to Avastin. Common expected side effects of Mvasi include nose bleeds, headache, high blood pressure, inflammation of the nasal cavity, among others.
Ogivri: The Second Cancer Biosimilar
In December 2017 the FDA approved Mylan and Biocon's Ogivri (trastuzumab-dkst), a biosimilar to Herceptin (trastuzumab), for the treatment of patients with HER2+ breast cancer or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma).
Ogivri is a HER2/neu receptor antagonist. It is not interchangeable with Herceptin, meaning if you -- or your healthplan -- wants to use Ogivri, your doctor will need to specifically order that medication instead of Herceptin.
Side effects with Ogivri can vary, but may include:
- difficulty sleeping (insomnia)
- worsening of neutropenia (white blood cells)
Ixifi: The Third Biosimilar to Remicade
Ixifi is approved as a biosimilar for all 8 eligible indications of the reference product, including rheumatoid arthritis, Crohn's disease, and ulcerative colitis.
- In Phase III studies, researchers evaluated the safety, efficacy, and immunogenicity of Ixifi versus Remicade administered intravenously in combination with methotrexate to treat patients with moderate to severely active RA who have had an inadequate response to methotrexate therapy.
- The study met its primary endpoint of ACR20 response (≥20% improvement by American College of Rheumatology criteria) at Week 14, and was supported by data at week 30.
- Ixifi is not designated as interchangeable, unless specified by the prescriber.
Retacrit is First Epoetin Alfa Biosimilar for Anemia
- chronic kidney disease
- use of zidovudine in patients with HIV
- and for reduction of allogeneic red blood cell transfusions in patients undergoing elective, noncardiac, nonvascular surgery.
Retacrit, an erythropoiesis-stimulating agent (ESA), was approved based on data showing that it is highly similar to Epogen and Procrit. It has no clinically meaningful differences in terms of safety, purity and potency when evaluated based on these drugs.
However, even the new biosimilars still have the same safety concerns: as with other ESAs, a boxed warning informs of the risk of death, heart attack, stroke, blood clots and cancer progression or recurrence.
Biosimilars for Neulasta Now Approved
In 2018, the first U.S. biosimilars for Neulasta (pegfilgrastim) were given the go-ahead by the FDA.
In June 2018, the FDA approved Mylan's and Biocon’s Fulphila (pegfilgrastim-jmbd). In November 2018, Udenyca (pegfilgrastim-cbqv), from Coherus BioSciences, received clearance from the FDA.
Like Neulasta, both biologics are PEGylated growth colony-stimulating factors used to reduce the duration of febrile neutropenia (fever or other signs of infection with a low count of white blood cells) in patients treated with chemotherapy in certain types of cancer.
These agents help lower the risk of infection due to a low white blood cell count.
How Are Biosimilars Named?
In January 2017 the FDA issued a guidance on naming conventions for biosimilars. According to the guidance the nonproprietary name designated "will be a proper name that is a combination of the core name and a distinguishing suffix that is devoid of meaning and composed of four lowercase letters. FDA is continuing to consider the appropriate suffix format for interchangeable products.
- In the current naming convention, the FDA has designated guidelines for approved biosimilar nonproprietary names that incorporates four lowercase letters (a suffix).
- FDA has stated drug companies can propose up to 10 suffixes for each new biosimilar.
- Currently, the licensed biosimilars (none of which are deemed interchangeable by the FDA) have gained the unique 4-letter suffix.
- Some older biosimilars are linked with the manufacturer (filgrastim-'sndz' for Sandoz), and some random (infliximab-dyyb); going forward they will be random and not linked with the manufacturer's name.
Can Pharmacists Automatically Substitute a Biosimilar for a Brand?
Not yet, as of November 2018 no products are deemed as "interchangeable" by the FDA. Biosimilars cannot be dispensed in place of another biological product unless a physician or other healthcare professional specifically prescribes the biosimilar product by name.
- According to the FDA, automatic substitution can happen once a product is deemed interchangeable.
- If the product has been determined to be interchangeable, then it is biosimilar to the reference product AND will produce the same clinical result as the reference product in any given patient.
- Interchangeable also means the original biologic and the new biosimilar can be switched back and forth in patients without a risk of diminished safety or efficacy.
Pharmacists will be responsible for knowing which biological products are interchangeable, and can check The Purple Book to find these products, once they are approved that way.
The Purple Book
The Purple Book is the go-to resource for pharmacists and other health care providers interested in making an interchange between a reference biologic and a biosimilar. But as mentioned, no biosimilars can yet be interchanged automatically at the pharmacy.
Similar to The Orange Book used to compare generic products to their brand name counterparts, The Purple Book has been developed by the FDA to list each reference biological product and the corresponding biosimilar and interchangeable biological product.
Those biosimilars designated as interchangeable will have no clinically important differences from the original product. Variation in formulation, delivery device, indications, and routes of administration may be acceptable.
The Cost of Biosimilars
The size of the molecule is not the only thing large about biologics. Seven of the top 10 drugs by sales in the U.S. in 2014 were biologics. In fact, AbbVie’s global Humira sales in 2016 was close to $10.5 billion, the number one seller for the company.
And as reported in The Economist, biologics could encompass over 30 percent of total big pharma sales by 2023.
How payers - and patients - will handle the burgeoning cost of biologics and biosimilars is a question that must be answered.
- Insurance groups and the government are pushing back on the price tags, and for patients who lack adequate insurance, potentially life-saving biologic therapy can be completely out of reach.
- As reported by SeekingAlfa, Hospira has noted biosimilars in the U.S. will most likely will be sold at discounts of 10 to 40 percent from the branded competitors.
Are There Other Questions With Biosimilars?
Biosimilars have been available in Europe for years, and there have been some product-related and clinical issues raised with biosimilars. For example:
- Will use of biosimilars for unapproved or “off-label” indications based on extrapolated data raise safety issues?
- Should post-marketing, phase IV safety studies be initiated to actively monitor for previously unreported side effects?
- Will clinicians be concerned that biosimilars are not identical to the innovator product, limiting prescribing?
- Could new types of immunogenicity be seen with biosimilars due to newly introduced substances during the manufacturing process?
Which Biosimilars May Be Up for Approval Next?
In the U.S., several more biosimilar products may be available for FDA review in the next decade due to patent loss.
While the biologics Neupogen (filgrastim) and Granix (tbo-filgrastim) are both filgrastim products, they each went through the full BCPI Act approval process and therefore are not considered “biosimilar”.
Companies such as Teva, Hospira and Sandoz are now rapidly working in this area and developing biosimilar products.
The Case of Granix (tbo-filgrastim)
There's always an exception, and this is no different with biosimilars. Teva's Granix (tbo-filgrastim) is not technically considered a biosimilar to Neupogen (filgrastim) because it was filed with a full BLA and clinical trials to determine effectiveness before the the publication of FDA’s new biosimilar pathway.
- FDA approved Granix to treat neutropenia, low white blood cells caused by receiving cancer treatment with chemotherapy.
- Even though Granix and Neupogen differ slightly in structure, their differences in effectiveness and safety are not significant.
- Tbo-filgrastim's effectiveness was evaluated in a clinical study of 348 adult patients with advanced breast cancer receiving treatment with the anti-cancer drugs doxorubicin and docetaxel.
Granix's "tbo" suffix is used to distinguish it's nonproprietary name from the reference biological product Neupogen (filgrastim).
Finished: What Are Biosimilars? Top Facts You May Not Know
- FDA Approves Fulphila (pegfilgrastim-jmdb), the First Biosimilar to Neulasta. Drugs.com. Accessed Nov. 8, 2018 at https://www.drugs.com/newdrugs/fda-approves-fulphila-pegfilgrastim-jmdb-first-biosimilar-neulasta-4759.html
- FDA Approves Hyrimoz (adalimumab-adaz), a Biosimilar to Humira. Drugs.com. Accessed Nov 7, 2018 at https://www.drugs.com/newdrugs/fda-approves-hyrimoz-adalimumab-adaz-biosimilar-humira-4852.html
- FDA Approves Udenyca (pegfilgrastim-cbqv), a Biosimilar to Neulasta. Drugs.com. Accessed Nov. 8, 2018 at https://www.drugs.com/newdrugs/fda-approves-udenyca-pegfilgrastim-cbqv-biosimilar-neulasta-4857.html
- Ogivri Product Labeling. 2017. Mylan Pharmaceuticals. Accesed Nov. 8, 2018 at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761074s000lbl.pdf
- Davies N. The FDA’s Take on Biosimilars. The Pharma Letter. Accessed Nov. 8, 2018 at https://www.thepharmaletter.com/article/the-fda-s-take-on-biosimilars
- The Economist. Business. Pharmaceuticals. Going large. p.47-48. Accessed Nov. 8, 2018 at https://www.economist.com/news/business/21637387-wave-new-medicines-known-biologics-will-be-good-drugmakers-may-not-be-so-good
- U.S. Food and Drug Administration (FDA). Biosimilars: More Treatment Choices and Innovation. Accessed Nov. 8, 2018 at https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm436399.htm
- U.S. Food and Drug Administration (FDA). Background Information: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations. Accessed Nov. 8, 2018 at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411424.htm
- IMS Institute for Healthcare Informatics. Assessing biosimilar uptake and competition in European markets. October 2014. Accessed Nov. 8, 2018.
- FiercePharma. The Top 10 patent losses of 2015. Stanton T. Accessed Nov. 8, 2018 at https://www.fiercepharma.com/special-reports/top-10-patent-expirations-2015
- U.S. Food and Drug Administration (FDA). Drugs. Implementation of the Biologics Price Competition and Innovation Act of 2009. Accessed Nov. 8, 2018 at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm
- Seeking Alfa. Amgen and Its Biosimilar Competition. Accessed Nov. 8, 2018 at https://seekingalpha.com/article/846451-amgen-and-its-biosimilar-competitors
- EvaulatePharma. Budget Busters: The shift to high-priced innovator drugs in the USA. Accessed Nov. 8, 2018.
- Weise M. Bielsky M. De Smet K. et al. Biosimilars: What clinicians should know. Blood. 2012;120:5111-17. Accessed Nov. 8, 2018.
- Biosimilars pose problems for Medicare beneficiaries. Formulary Journal. April 25, 2016. Accessed Nov. 8, 2018.
- Nonproprietary Naming of Biological Products. Guidance for Industry. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). January 2017. Accessed Nov. 8, 2018 at https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459987.pdf