FDA rulings advance biosimilar drugs
Will the marketplace welcome “generic” Lucentis and others?
By Jerry Helzner, Contributing Editor
If the term biosimilar drug isn’t in your daily lexicon, it soon will be. While some technical regulatory issues are still being resolved, biosimilars, when approved, will likely claim a growing percentage of future therapeutic options. Recent favorable FDA decisions — including the first two U.S. biosimilar approvals and FDA endorsement of simple biosimilar labeling — are helping to rapidly advance this new class of therapies into the marketplace.
Biosimilars can be likened to generic drugs, except that they are meant to mirror biologics rather than be copies of small-molecule, chemically formulated medications. One major difference between generic drugs and biosimilars is that a generic can have the exact chemical formulation of its branded reference drug, while a biosimilar is judged equivalent only in function and safety; it is not identical to the branded drug. An IMS Health report published in March suggests that stakeholders would require some education about biosimilars before there is widespread acceptance.1 An Economics of Biosimilars article from 2013 says that the biosimilar market, because of numerous factors including pricing and physician acceptance, will make the “biosimilar market develop different [sic] from the generic market.”2
Unlike traditional chemical drugs, biologics, made from living cells, are costly and difficult to replicate because of their complex molecular structure. Thus, the discount to the branded drug offered by a biosimilar manufacturer must be much smaller than the steep discounts achieved with generics. While manufacturers offer generics at a fraction of branded drug prices, biosimilars receive a 15% to 25% discount. However, for chronic diseases that require regular treatment with a specific drug, biosimilars have greater appeal as an alternative to branded products.
A look at some biosimilar prospects.
| CHEMICAL DRUGS* | BIOLOGICS |
|---|---|
| Made from: chemical synthesis | Living cells |
| Structure: defined | Heterogeneous structure
Related molecular mixtures |
| Characterization: easy | Difficult |
| Stability: relatively stable | Variable |
| Administration: usually oral | Usually an injectable |
| Prescriber: GP** | Prescriber: GP** |
| *Adapted from: Duke University School of Medicine. Chow, SC. Spot the difference. European Biopharmaceutical Review. Summer 2011. http://www.samedanltd.com/magazine/12/issue/155/article/2980
**General practitioner |
|
A prime biosimilar target
Biosimilar manufacturers are already targeting retinal therapeutic Lucentis (ranibizumab, Genentech) and its more than $4 billion in annual worldwide sales. The key U.S. patents for Lucentis expire in 2019.
Sustained-release could sustain Lucentis sales
One risk a biosimilar manufacturer takes is that by the time it completes the costly process of getting its copy of the branded drug approved, a better drug or method of delivery might have entered the marketplace.
Such may be the case with Lucentis. Genentech has a potentially strong defense of its Lucentis franchise through the development of new drugs now in the pipeline and also by means of a refillable, sustained-release implant that could greatly reduce office visits and eliminate the need for frequent intravitreal injections. The tiny device, the size of a grain of rice, is implanted in a standard surgical procedure. It can be refilled in the office using a specially designed refill needle. If the implant successfully completes its clinical trials and gains approval, “it would allow patients to receive the maximum benefits of treatment with Lucentis while reducing the number of office visits and injections they require,”says Jill Hopkins, MD, associate group medical director, Genentech Ophthalmology.
Last year Genentech initiated a phase 2 clinical trial investigating this device, called the Ranibizumab Port Delivery System (RPDS) implant, in patients with wet AMD. The aim of the 220-patient study, called LADDER (Long-Acting Delivery of Ranibizumab), is to assess the efficacy and safety of this refillable implant for the sustained delivery of the drug. Another goal is to determine the optimum duration of treatment the implant can provide before it needs to be refilled.
Genentech researchers have long believed that ranibizumab could be successful in a sustained-release format because the drug has the stability to remain effective when placed in an implant.
In a previous phase 1 study, the RPDS implant was well tolerated and showed an improvement in BCVA comparable to monthly injections, establishing proof of concept for the system. Genentech’s RPDS implant also recently received fast track designation from the FDA.
“Inconsistency in treatment adherence can sometimes result in vision loss,” says Richard F. Dreyer, MD, LADDER clinical investigator. “If successful, the RPDS implant could become a useful tool to better manage wet AMD by providing a consistent level of treatment and potentially result in better long-term visual outcomes.”
LADDER is an interventional, randomized, double-blind, active comparator, multicenter study.
Pfenex, now a partner of the Hospira division of pharmaceutical giant Pfizer, recently announced plans that it would begin a phase 3 clinical trial for its ranibizumab biosimilar sometime this year. The company, which has eight biosimilars in the pipeline, says one of its major advantages is its partnership with Pfizer, which also has made a commitment to developing biosimilars.
“We believe that biosimilars are the future of affordable health care,” says Pfenex in a statement. “Pfenex’s protein production platform and bioanalytical approach to developing biosimilars enables the potential for a fingerprint-like identity to a reference product limiting the need for expensive and costly clinical trials.” The company says its recombinant protein production platform permits rapid development. (The company declined to be interviewed for this article.)
German partners Formycon AG and bioeq GmbH also announced plans to soon begin their global phase 3 pivotal trial for a Lucentis biosimilar known as FYB 201. In addition, Formycon also plans to launch a biosimilar of the anti-VEGF retinal disease drug Eylea (aflibercept, Regeneron) in partnership with the German pharmaceutical company Santo Holding. All of this is stirring interest despite the existence of low-cost, off-label bevacizumab (Avastin, Genentech): a low-priced — albeit off-label — alternative to Lucentis already available in the U.S. market. The downside: it must be prepared by a compounding pharmacy for ocular use. International markets with stricter rules regarding the use of unapproved drugs may prove a more fertile ground for Lucentis biosimilars.
Biosimilars: A pathway to approval
The U.S. biosimilars industry dates back to March 2010 when President Obama signed the Biosimilars Act as part of the Affordable Care Act. At that time, five of the 15 top-selling pharmaceuticals were biologics, according to statistics compiled by IMS Health. Today, eight of the top 20 are biologics. To be approved, a biosimilar must demonstrate safety, purity and potency. The FDA allows minor differences to the branded product in inactive components.
Manufacturers of the branded product can traverse several avenues to defend their market share from a competing biosimilar. These include:
• Applying for patent extensions
• Filing patent infringement suits
• Emphasizing the small price differential between their product and the biosimilars, and
• Creating doubt in the minds of physicians and patients about possible differences between their branded product and the biosimilar.
Challenges to biosimilars
Regulatory, manufacturing and acceptance hurdles all present key issues for biosimilars, especially for smaller companies with limited funding, which may allow development of only one or two key biosimilar drugs. In the case of Lucentis, another potential obstacle is the numerous credible challengers to Lucentis currently in clinical trials — some of which may prove superior to the current standard of anti-VEGF monotherapy. In addition, Genentech has new drugs in the pipeline and a sustained-release format for Lucentis in clinical trials. These factors entail the risk of the branded drug being surpassed by other therapeutic agents or a better method of delivery by the time the biosimilar is ready to come into the marketplace.
Biosimilars find favor with the FDA
The FDA has already approved two biosimilars, beginning last year with Zarxio, a Sandoz equivalent of the chemotherapy drug Neupogen (Amgen). Selling at only a 15% discount to Neupogen, Zarxio has yet to make a dent in the marketplace. However, Sandoz is not deterred; company spokesman Sreejit Mohan says U.S. sales of Zarxio have been in line with expectations. The company expected a “gradual uptake in a physician-driven market.”
In April, the FDA approved the 2018 launch of Inflectra (Celltrion/Pfizer), a biosimilar version of Johnson & Johnson’s monoclonal antibody Remicade, a treatment for Crohn’s disease, ulcerative colitis and rheumatoid arthritis.
Johnson & Johnson mounted a negative public awareness campaign about biosimilars.
When Inflectra was approved in April, Johnson & Johnson highlighted the fact that the two drugs were not the same, potentially raising doubts among physicians and patients. Jay Siegel, MD, the company’s chief biotechnology officer and the head of scientific strategy and policy, said at the time, “Celltrion’s infliximab-dyyb is a biosimilar but not identical to Remicade. … The FDA has not approved Celltrion’s infliximab-dyyb as being interchangeable with Remicade.”
Dr. Siegel also said in a company release that for the FDA to determine if a biosimilar is interchangeable with its reference product, a manufacturer must show that the biosimilar is expected to produce the same clinical result as the reference product in any given patient. In addition, the manufacturer must demonstrate the risk of alternating or switching between the reference product and biosimilar is no greater than the risk of using the reference product.”
Several more biosimilars, including the Coherus Biosciences version of the oncology drug Neulasta (Amgen) are wending their way through the FDA approval process. These rapid developments, in combination with the April endorsement by the FDA of the simple product labeling favored by the biosimilar industry group Biosimilars Council, would seem to indicate that the federal government wants this new class of money-saving drugs, still in its infancy, to move ahead.
The combination of a difficult manufacturing process, regulatory hurdles, patent protection, potential physician/patient resistance to biosimilars, possible product obsolescence, and the level of discount to branded biologics, could factor in how much of an impact biosimilars make in the ophthalmic arena. Only time will tell. OM
REFERENCES
1. IMS Health Predicts Significant Growth of Biosimilars by 2020. Published online March 31, 2016. http://www.ajmc.com/newsroom/imh-health-predicts-significant-growth-of-biosimilars-by-2020#sthash.eM68AmBQ.dpuf. Last accessed June 3, 2016.
2. Blackstone EA, Joseph, PF Jr. The Economics of Biosimilars. Amer Health & Drug Benefits. 2013. Sep-Oct: 6;8.
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