What Is A Biosimilar?
Similar to our European neighbors, biosimilar approvals are now making forward strides quickly 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:
vaccines
blood components
gene therapy
tissues
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. For example, Enbrel (etanercept) or Humira (adalimumab) are referred to as “large-molecule” drugs because they are larger and more complex in structure than small-molecule drugs. 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. In the U.S., biosimilar products continue to be available for FDA review in the next decade due to patent loss.
Zarxio and Nivestym: Biosimilars to Neupogen
In March, 2015 the FDA approved the first biosimilar for the U.S. market -- Sandoz’s Zarxio (filgrastim-sndz), the biosimilar to Amgen's 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.
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”. In July 2018, the FDA cleared Pfizer’s Nivestym (filgrastim-aafi), another biosimilar to Amgen’s Neupogen.
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).
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 and fourth biosimilar for Remicade are now approved: Ixifi from Pfizer and Avsola (infliximab-axxq) from Amgen.
Erelzi and Eticovo: Biosimilars to Enbrel
In August 2016, Sandoz's Erelzi (etanercept-szzs), was FDA-approved.
Erelzi is biosimilar to Amgen’s tumor necrosis factor (TNF) blocker Enbrel, was the first approved biosimilar for etanercept, and is used for the same five indications as Enbrel:
rheumatoid arthritis
polyarticular juvenile idiopathic arthritis
psoriatic arthritis
ankylosing spondylitis
plaque psoriasis.
In April 2019 the FDA cleared Eticovo (etanercept-ykro) from Samsung Bioepis, the second biosimilar to Enbrel and approved for the same uses.
These products are subcutaneous injections and contain a Boxed Warning alerting health care providers and patients of the increased risk of serious infections and malignancies.
Side effects can vary between patients, but in general the most commonly reported side effects of etanercept (in more than 5% of patients) include:
infections
injection site reactions.
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. The latest include Samsung Bioepis’ Hadlima (adalimumab-bwwd), Pfizer’s Abrilada (adalimumab-afzb), and Mylan's Hulio (adalimumab-fkjp).
Remicade Biosimilars The first biosimilar to Remicade, Pfizer’s Inflectra (infliximab-dyyb) was approved by the FDA in April, 2016. In April 2017, the FDA approved Renflexis (infliximab-abda), a tumor necrosis factor (TNF) blocker from Samsung Bioepis that is biosimilar to Remicade (infliximab). 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 U.S. Cancer Biosimilar
In September 2017, the first U.S. biosimilar for any cancer indication was approved by the FDA -- Amgen’s Mvasi (bevacizumab-awwb) -- a biosimilar to Genentech’s Avastin (bevacizumab).
Pfizer's Zirabev (bevacizumab-bvzr) followed Mvasi as the second biosimilar to Avastin.
Mvasi and Zirabev are FDA-approved for the treatment of multiple types of cancer, including adult patients with:
metastatic colorectal cancer
non-squamous non-small cell lung cancer (NSCLC)
brain cancer (glioblastoma)
metastatic renal cell carcinoma (kidney cancer)
cervical cancers
Research demonstrated biosimilar activity with no clinically meaningful differences compared to Avastin, the reference product. However, Mvasi and Zirabev are not approved for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer as found in the approved Avastin U.S. label. In addition, these new biosimilar products are not approved as interchangeable products with Avastin. While side effects with bevacizumab can vary among patients, they can include nose bleeds, headache, high blood pressure, rhinitis (runny, stuffy nose), and protein in the urine, among others.
Herceptin Cancer Biosimilars Expanding
Five biosimilars to Genentech's Herceptin (trastuzumab) are now cleared by the FDA:
Ogivri (trastuzumab-dkst) approved in Dec. 2017 (from Mylan GmbH)
Herzuma (trastuzumab-pkrb) approved in Dec. 2018 (from Celltrion and Teva)
Ontruzant (trastuzumab-dttb) approved in Jan. 2019 (from Samsung Bioepis)
Trazimera (trastuzumab-qyyp) approved March 2019 (from Pfizer)
Kanjinti (trastuzumab-anns) approved June 2019 (from Amgen)
All agents, with the exception of Herzuma, are approved for the same uses as the reference product Herceptin, which includes treatment of patients with HER2+ breast cancer and gastric (stomach) cancer whose tumors overexpress the HER2 gene (HER2+). Herzuma was only FDA-approved for the breast cancer indication.
Ogivri was the first biosimilar approved in the U.S. for the treatment of breast cancer or stomach cancer and the second biosimilar approved in the U.S. for the treatment of cancer of any type (after Mvasi).
Side effects with trastuzumab and biosimilars can vary, but may include:
headache
fatigue
diarrhea
anemia
nausea
fever, chills
infection
difficulty sleeping (insomnia)
worsening of neutropenia (low white blood cells)
All agents are HER2/neu receptor antagonists, like Herceptin. However, these products are not yet interchangeable with Herceptin, meaning if you -- or your healthplan -- want to use one of these biosimilars in place of Herceptin, a doctor will need to specifically order that biosimilar medication by name. The pharmacist cannot make the switch automatically at the pharmacy.
Ixifi: The Third Biosimilar to Remicade
In December 2017 the FDA approved Pfizer's Ixifi (infliximab-qbtx), a chimeric human-murine mAb against tumor necrosis factor.
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
In May 2018, the FDA approved Hospira's Retacrit (epoetin alfa-epbx), a biosimilar to Epogen and Procrit (epoetin alfa), for treatment of anemia caused by:
chronic kidney disease
chemotherapy
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. Ziextenzo (pegfilgrastim-bmez), from Sandoz, was approved in November 2019 and Nyvepria (pegfilgrastim-apgf) was cleared in June 2020. Like Neulasta, all products 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.
Rituxan, Truxima, Ruxience and Riabni
In November 2018, the FDA approved Truxima (rituximab-abbs) injection from Celltrion as the first biosimilar to Rituxan (rituximab) for the treatment of adult patients with CD20-positive, B-cell non-Hodgkin’s lymphoma (NHL). Truxima is also the first US biosimilar overall to be approved for the treatment of non-Hodgkin’s lymphoma.
Truxima is used as a single agent or in combination with chemotherapy in patients with various grades of NHL, based on previous treatments. The most common side effects of Truxima include:
infusion reactions
fever
low level of lymphocytes (a type of white blood cell)
chills
infection
weakness (asthenia).
Rituxan, from Genentech, is used for the treatment of various forms of non-Hodgkin’s lymphoma, plus several other conditions in adults patients, including: Chronic Lymphocytic Leukemia (CLL), Rheumatoid Arthritis (RA), Granulomatosis with Polyangiitis, and Pemphigus Vulgaris (PV). In July 2019, Pfizer's Ruxience (rituximab-pvvr), the second biosimilar to Rituxan was approved. This was followed by the FDA approval of Amgen's Riabni (rituximab-arrx) in Dec. 2020
Byooviz: 1st US-Approved Biosimilar for Eye Conditions
In Sept. 2021, the FDA approved Byooviz (ranibizumab-nuna), a vascular endothelial growth factor (VEGF) inhibitor biosimilar to Lucentis. VEGF therapy helps to slow the growth of blood vessels that leads to worsening vision or blindness. Byooviz is administered as an injection inside the eye once per month.
Byooviz is approved to treat 3 ophthalmic (eye) conditions:
neovascular (wet) age-related macular degeneration (abnormal growth of blood vessels in the back of the eye which may leak fluid, blood and cause swelling)
macular edema (fluid build-up) following retinal vein occlusion (blockage of veins in the retina)
myopic choroidal neovascularization (a vision-threatening complication of nearsightedness).
However, unlike Lucentis, Byooviz is not approved to treat diabetic macular edema (DME) or diabetic retinopathy (DR). Byooviz may cause serious side effects such as endophthalmitis (infection inside the eye) and retinal detachments; increases in intraocular (inside the eye) pressure; and thromboembolic events (obstruction of a blood vessel by a blood clot). Common side effects include conjunctival hemorrhage (broken blood vessels), eye pain, vitreous floaters (black spots that drift across the eye), and increased intraocular fluid pressure. Byooviz is manufactured by Samsung Bioepis and will not be commercially available until June 2022.
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 Reference Brand?
Not yet. None of the approved biosimilars 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% 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?
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