In August 2022, the Food and Drug Administration (FDA) approved Cimerli™ (ranibizumab-eqrn) as a biosimilar for Lucentis® (ranibizumab). In a time when high prescription costs can mean unaffordable out-of-pocket costs for patients, the potential implications are far-reaching.
Cimerli became the 37th of 38 (as of this writing) biosimilar drugs approved by the agency and the third as an interchangeable. It was also the first drug to be approved as an interchangeable without costly switching studies, which are designed to demonstrate that the risk of switching to a biosimilar or back again does not increase the risk of diminished efficacy or safety compared with remaining on the original drug.
Biologics Price Competition and Innovation Act
Inside the 2010 Patient Protection and Affordable Care Act, the Biologics Price Competition and Innovation Act (BPCI) established an abbreviated approval pathway for biologics that are biosimilar, or “highly similar to the reference product.”
Over the next few years, the FDA worked out a process for a new biologic to get approval as a biosimilar. Generally, the new drug must be shown to be significantly similar in terms of structure, function, and bioactivity, and have “no clinically meaningful differences” to an already approved drug.
The BPCI also created an additional category called “interchangeable” that may be applied if the new biologic meets additional requirements. Although pharmacy laws vary from state to state, an interchangeable product can generally be substituted at the pharmacy without consulting the prescribing physician. In order to attain the interchangeable designation, evidence needs to be provided that shows the new biologic “is expected to produce the same clinical result” and establishes the efficacy and safety of switching, or alternating, between the products. So-called switching studies, or interchangeability studies, are clinical trials that investigate how patients fare when switched back and forth between the approved drug and the proposed biosimilar drug.
Lucentis and Cimerli
Ranibizumab was developed by Genentech and approved for medical use in the United States in June 2006. Sold under the brand name Lucentis, this biologic is indicated for the treatment of five conditions:
- Neovascular (Wet) Age-Related Macular Degeneration (AMD)
- Macular Edema Following Retinal Vein Occlusion (RVO)
- Diabetic Macular Edema (DME)
- Diabetic Retinopathy (DR)
- Myopic Choroidal Neovascularization (mCNV)
These diseases have a common feature. They are all marked by retinal damage or the blocking of light to the retina, the light-collecting structure in the eye, due to the formation of new blood vessels and/or leaking of fluids from existing blood vessels. Untreated progression can frequently lead to blindness.
Vascular endothelial growth factor (VEGF) is a protein that binds to a VEGF receptor and stimulates the formation of blood vessels. This process occurs in normal human development during the initial formation of the embryonic vascular system (called vascularization) and when growing new blood vessels from existing ones (called angiogenesis). Abnormal production of VEGF or abnormal activation of the VEGF receptor can cause blood vessels to form in excess and/or to become leaky. When this occurs in the eye, the changes to the blood vessels can cause or exacerbate the five conditions for which ranibizumab has been approved.
Lucentis and Cimerli are both fragments of monoclonal antibodies that bind to and inhibit VEGF. By inhibiting the protein’s function, new blood vessels are not created. This activity can halt or revert disease progression.
Interchangeable Approval of Cimerli
The FDA granted the first two interchangeable biosimilar statuses in 2021 to Semglee® (insulin glargine-yfgn)and Cyltezo® (adalimumab-adbm). Applications for both drugs included results from switching studies that showed how patients responded to switching back and forth between the existing, approved drug and the new biosimilar drug.
The approval of Cimerli was groundbreaking not only for patients who may now enjoy alternative and potentially cheaper treatments for the five eye disorders but also because Cimerli was the first to get approval as an interchangeable without performing costly switching studies. In addition, Cimerli is the first drug to get interchangeability for all indications for which the reference drug has approval.
Biosimilars and Generics
The concept of biosimilars may sound similar to generic drugs. Both biosimilars and generic drugs benefit from an abbreviated FDA approval process, but there are important differences. With generic drugs, the active ingredient must be identical. This contrasts with biosimilars, where evidence needs to be provided that the approved and new drug are similar to each other in structure, function, safety, and efficacy. Biosimilar dugs can have minor differences in the components of their active ingredients. In addition, a biosimilar drug needs to also be classified as interchangeable in order to enjoy the free substitution at a pharmacy without consulting a physician, similar to generics. A biosimilar without interchangeable status can only be substituted with a specific prescription from a physician.
The Future of Biosimilars
The approval of Cimerli without switching studies has potentially lowered the cost barrier of interchangeability. For patients, this lowered cost could translate to decreased prescription costs and interchangeable drugs being brought to the market more quickly. While the FDA has said that they approach all interchangeable applications on a case-by-case basis, they stated that a switching study would not be informative between Lucentis and Cimerli due to the “comprehensive and robust analytical assessment that compared the structural and functional characteristics.” The future need for switching studies in biosimilar interchangeable applications remains unclear.
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