Oncology Pipeline Bursting With Biosimilars

Mark Ginestro, a principal with KPMG

Mark Ginestro

After years of regulatory and legal wrangling, the development of biosimilars is starting to advance rapidly in the United States, particularly in the oncology sector where multiple versions of the most widely used cancer drugs are moving forward.

Thus far, the FDA has approved 5 biosimilars, including 1 supportive care drug for patients with cancer.¹ Biosimilar versions of 4 major anticancer therapies are either undergoing regulatory review by the FDA or have completed clinical trials designed to secure their final approval (Table). The FDA is likely to make decisions on biosimilar versions of trastuzumab (Herceptin) and bevacizumab (Avastin) within the next year.

Table. Evolving Biosimilar Landscape in United States

^aLaunched in Canada in March 2016.

^bGained EMA approval in February.

^cApproved by Ministry of Health of Russian Federation in November 2016.

^dUnder review by the EMA.

CLL indicates chronic lymphocytic leukemia; CRC, colorectal cancer; DLBCL, diffuse large B-cell lymphoma; EGFR+, epidermal growth factor receptor 2-positive; EMA, European Medicines Agency FL, follicular lymphoma; GEJ, gastroesophageal junction; HER2+ indicates human epidermal growth factor receptor 2-positive; MBC, metastatic breast cancer; mCRC, metastatic colorectal cancer; NSCLC, non—small cell lung cancer; RCC, renal cell carcinoma.

Although each biosimilar product has the potential to save patients and payers hundreds of millions of dollars per year and ease the upward pressure on cancer care costs, efforts to maximize those potential savings face many hurdles. Experts say these challenges include:

• Current regulations require developers of biosimilar medications to provide more evidence than generic drug manufacturers to prove equivalency to reference products.
• Performing the studies needed to generate such support is no guarantee of success. The FDA has rejected 3 biosimilar candidates from companies that thought their applications met regulatory requirements.
• Even biosimilar medications that do reach the market cannot be substituted for reference products as readily as generic drugs can be substituted for the brands with which they compete.
• The complexity of biologic drugs has enabled the makers of reference products to win dozens of patents for each medication and court battles have ensued over whether approved biosimilars can be marketed.
• The difficulty of bringing each new biosimilar product to market limits price competition. The 2 biosimilar medications currently available in the United States only cost about 15% less than their reference products cost before their arrival.

Nevertheless, the market for biological medications is so large that deep-pocketed competitors are spending billions of dollars to bring biosimilars to market. Nearly every blockbuster that’s close to losing its main patent protection faces the threat of several biosimilar competitors. Additionally, there is evidence from other countries that laws and regulations similar to those in the United States will eventually create competition. The European Medicines Agency (EMA) has approved 28 biosimilars², and prices for the most duplicated medications have fallen by more than 30%—substantially more, in some cases.

"The long-term outlook for a competitive market that significantly reduces the prices of older medications is still good," Mark Ginestro, a principal with KPMG who follows the biosimilar market said in an interview. “It’s just that most of the evidence we see now suggests it’s going to take significantly longer for that market to develop than many people had hoped.”

The financial stakes could not be higher. Analysts estimate that biologic drugs generate $200 billion globally in total annual revenue and are expected to account for up to 28% of the worldwide pharmaceutical market by 2020.^3,4 As a class, these drugs are more expensive than branded small-molecule therapeutics. A 2011 study found that the average daily price of all treatments was $1 for branded small-molecule drugs and $22 for biologics.⁵

However, developing biosimilars is more complex than developing and testing generic versions of small-molecule drugs. A biologic medi- cation such as a monoclonal antibody can be 1000 times larger and more complex than a small-molecule medication such as aspirin. It is also a fragile living organism that can only survive in carefully controlled environments that are expensive to create and challenging to maintain.⁶ Additionally, potential biosimilar makers cannot simply copy the originals because they have no access to the cultures used to grow their reference product. They must create their own cultures and hope those cultures produce a structurally similar and functionally equivalent medicine.

Figure. FDA Requirements for Biosimilarity⁷

Competition Shapes Up

The difficulty of duplicating medications that are grown rather than manufactured has prompted the FDA to require a higher standard of proof of safety and efficacy for biosimilars than it does for generics. The generic approval process typically requires a chemical analysis. The current biosimilar approval process requires not only chemical analysis but also trial data showing that a candidate behaves the same as its reference product, both in animals and in actual patients (Figure).⁷Nevertheless, many companies are seeking to develop and test biosimilar medicines for widely used therapeutic and supportive care oncology drugs. The interest in leukocyte growth factors for patients who develop neutropenia or are at risk of infection from myelosuppressive anticancer therapies is robust; filgrastim-sndz (Zarxio), a version of Neupogen, was the first biosimilar that the FDA approved in 2015. Applications for another filgrastim biosimilar and a version of the longer-acting pegfilgrastim are pending.

The Generics and Biosimilars Institute, an information service that tracks the industry, reports multiple clinical development programs for 4 widely used oncologic monoclonal antibodies: 22 for rituximab (Rituxan), 16 for Herceptin, 15 for Avastin, and 4 for cetuximab (Erbitux).⁸

Although many of those biosimilars likely will never reach patients in the United States, there are an increasing number of therapeutic oncology drugs that have advanced to late-stage development. The FDA is reviewing applications for Myl-1401O, a biosimilar version of Herceptin, and ABP-215, a copy of Avastin, according to the companies developing the drugs. In February, Truxima, a biosimilar version of Rituxan, became the first anticancer therapeutic to gain approval from the European Medicines Agency. Celltrion, which manufactures Truxima, said it plans to file applications for regulatory approval with the FDA in 2017 for Truxima and Herzuma, a biosimilar version of Herceptin.⁹ There are additional versions of these branded drugs that have reached phase III development for the US market but have not yet generated biologics drug applications: at least 4 of bevacizumab, 3 of trastuzumab, and 4 of rituximab.¹⁰

The list of potential cetuximab (Erbitux) competitors appears less extensive. Sorrento Therapeutics has announced positive results for its pivotal biosimilar trial, but 3 other would-be biosimilars appear to be in earlier phases of development.¹¹

Clinical Trial Evidence

Applicants expect that the combination of structural analysis and successful trials in animals and humans will be enough to win approval for their biosimilars, but an application no more guarantees approval for a biosimilar than it does for a new drug. To date, the FDA has sent complete response letters, which indicate that an application will not be approved as submitted, to the maker of at least 1 Neupogen biosimilar¹², 1 Neulasta biosimilar¹³, and 1 biosimilar of the anemia treatment Epogen.¹⁴The main patent on trastuzumab does not expire until 2019, but Mylan has already submitted a biosimilar license application (BLA) for its version of the product, which produced $7 billion in annual revenues last year.

In the Heritage study, investigators randomized 458 women with untreated metastatic HER2-positive breast cancer to receive a taxane chemotherapy with either the biosimilar Myl-1401O or Herceptin. The overall response rate at 24 weeks, the primary endpoint of the trial, was 69.6% (95% CI, 63.62-75.51) for the biosimilar versus 64.0% (95%CI, 57.81-70.26) for Herceptin.¹⁵ At 48 weeks, investigators said, there was no statistically significant difference between the 2 drugs in time to tumor progression, progression-free survival, or overall survival, and adverse event profiles were comparable.

Also pending is an application for ABP-215, a biosimilar version of Avastin that Amgen and Allergan are developing. The companies said a BLA submitted in November was based on data from a phase III trial demonstrating comparable efficacy, safety, and immunogenicity between the ABP-215 and Avastin in adult patients with nonsquamous non—small cell lung cancer.¹⁶ Further details have not been disclosed.

Interchangeability Issues

One question that has emerged about biosimilars is whether findings from an equivalency trial in 1 indication can be extrapolated into an approval for other disease settings in which the reference product has been approved. For instance, Zarxio, the biosimilar version of Neupogen, has been approved for the same indications as the original drug, while patent protections have prevented similarly extensive labeling for copies of at least 2 other branded drugs, according to Friends of Cancer Research.¹⁷Although would-be biosimilar candidates might be able to demonstrate statistically identical perfor- mance on trials with hundreds of patients, that evidence is not enough to win biosimilars the sort of approval that many observers think they need to bring real competition to the biologic market: approval as interchangeable agents. Under the pathway for biosimilars approved in 2009, the FDA rst determines whether candidates must meet technical and clinical standards as “highly similar” products and then decides whether they are interchangeable.

Thus far, none of the biosimilars approved in the United States can be freely substituted for reference products the way that generic drugs can be freely substituted for name brand drugs in most states because they have not been deemed to be interchangeable. If a doctor prescribed “Neupogen,” a pharmacist cannot look at a patient’s drug plan and give the patient “Zarxio” to reduce the co-pay. Even if the doctor prescribes the theoretically generic “filgrastim” the pharmacist cannot use the biosimilar because the differences in its structure led it to receive a slightly different generic name, “filgrastim-sndz.”

In January, the FDA released long-awaited draft guidance on what it will likely take to earn interchangeable approvals: additional trials that involve patients switching back and forth between the reference drug and the biosimilar.¹⁸

“In order to meet the higher standard of interchangeability, a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product,” FDA spokeswoman Sandy Walsh wrote in an email.

Price Considerations

Meanwhile, regulations for substituting biosimilars for branded drugs on prescriptions, which are controlled at the state level, have been debated throughout the country and 27 states have now enacted laws, according to the National Conference of State Legislatures.19 Most states agree that the FDA must recognize a biosimilar as interchangeable before it can be substituted for a branded product and that the prescribing physician would be able to prevent substitution by specifying “dispense as written” or “brand medically necessary.”¹⁹Ginestro and other analysts believe that biosimilars cannot reach their full price-saving potential unless it is easy to substitute to the less expensive product at the point where it is dispensed. Physicians would be hard-pressed to keep track of which competing products would be the least expensive in any particular month and keep changing their scripts accordingly, particularly when the most cost-effective brand might vary from patient to patient, based upon each patient’s insurer.

“The field of oncology is a potential bright spot in this respect because most biologic medications are given in the office. Practices would have a strong incentive to shop around for the cheapest comparable product, just as they shop for the cheapest provider of paclitaxel rather than buying Taxol,” said Harold J. Burstein, MD, PhD, an oncologist at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School. “Cancer patients will get value-based care when the person writing the prescription is guided by the best medical information, and then chooses between equivalent options based on price.”

It might be some time before such options are available, not only because the approval process is lengthy and expensive, but also because the makers of reference products have fought aggressively against biosimilar products in the courts.

The court case that has generated the most attention so far, Sandoz v Amgen, is likely to affect every maker of biosimilars and reference products, analysts believe. At issue in the case, now before the US Supreme Court, is how much patent and marketing information the Biologics Price Competition and Innovation Act of 2009 requires biosimilar makers to share with reference product makers and whether the act effectively requires a 6-month gap between the approval and launch of a biosimilar.

That is far from the only biosimilar-related case, however. Reference product makers have turned to the courts to block the introduction of at least 4 biosimilars that have been approved by the FDA. The nature of each case varies but most of them hinge on patent infringement, an argument that reference product makers can pursue after the expiration a product’s exclusivity period because each company wins dozens of patents on each biologic product it makes.²⁰

This combination of legal and regulatory hurdles has kept the number of biosimilars available to American patients so far down to just 2: Zarxio and a biosimilar version of infliximab (Remicade) called infliximab-dyyb (In ectra). It has also limited the discounts. Zarxio launched at a 15% discount to Neupogen,²¹ and recent reports indicate no further price cuts.²² The infliximab biosimilar sells for the same 15% discount.²³

The best hope that biosimilars will eventually bring much deeper discounts comes from abroad. The EMA, which began approving biosimilars in 2006, has approved 7 filgrastim biosimilars and 5 epoetin versions. The number of competitors varies not just among reference products but among European countries, so discounts vary widely. In markets where there are only 2 competitors, discounts tend to be modest. In markets where there are more than 3 competitors and it is easy to pick the least expensive, discounts often exceed 50%, according to a recent study from IMS Health.²⁴ In some cases, the discounts can be far greater. The Finnish drug company Orion Oyj, which licenses a Remicade biosimilar from South Korea’s Celltrion, captured half the Norwegian market by offering a 70% discount on the arthritis drug, which has a list price of $10,600 a year.

“It definitely looks like it’s going to take some time to bring the sort of competition that everyone wants to the United States,” Burstein said. “But there are reasonable processes in place, so we should eventually get to where we want to be without compromising patient safety along the way.”

References

1. CDER list of licensed biological products. US Food and Drug Administration. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM549201.pdf. Updated April 21, 2017. Accessed April 26, 2017.
2. European public assessment reports. European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?mid=WC0b01ac058001d124&searchType=name&taxonomyPath=&genericsKeywordSearch=Submit&searchGenericType=biosimilars&keyword=Enter+keywords&alreadyLoaded=true&curl=pages%2Fmedicines%2Flanding%2Fepar_search.jsp&status=Authorised&treeNumber=&searchTab=searchByAuthType&pageNo=1. Accessed April 26, 2017.
3. Morgan Stanley Research. Biosimilars: disrupted profits. Published April 5, 2017.
4. Aitken M. Delivering on the potential of biosimilar medicines: the role of functioning competitive markets. IMS Health Institute for Healthcare Informatics. http://www.imshealth.com/files/web/IMSH%20Institute/Healthcare%20Briefs/Documents/IMS_Institute_Biosimilar_Brief_March_2016.pdf. Published March, 2016. Accessed April 26, 2017.
5. McCamish M, Woollett G. Worldwide experience with biosimilar development. MAbs. 2011;3(2):209-217. doi: 10.4161/mabs.3.2.15005.
6. Chhina M. Overview of biological products. US Food and Drug Administration. www.fda.gov/downloads/aboutfda/transparency/basics/ucm356666.pdf. Published June 17, 2013. Accessed April 25, 2017.
7. Christl L. FDA’s Overview of the regulatory guidance for the development and approval of biosimilar products in the US. US Food and Drug Administration. www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm428732.pdf. Published January, 2015. Accessed April 25, 2017.
8. Generics and Biosimilars Initiative. http://gabionline.net/. Accessed April 26, 2017.
9. Truxima™, the first biosimilar mAb in oncology, granted EU marketing authorization [news release]. Incheon, Korea: Celltrion; February 22, 2017. https://www.celltrion.com/en/pr/reportDetail.do?seq=409. Accessed April 26, 2017.
10. Mullard A. Bracing for the biosimilar wave. Nature Rev Drug Discov. 2017;16(3):152-154. doi: 10.1038/nrd.2017.36.
11. Biosimilars of cetuximab. Generics and Biosimilars Initiative. gabionline.net/Biosimilars/General/Biosimilars-of-cetuximab. Updated April 1, 2016. Accessed April 25, 2017.
12. Sutter S. Biosimilars in 2017: crowded US FDA review queue, key legal decisions. Pink Sheet Pharma Intelligence. pink.pharmamedtechbi.com/PS119882/Biosimilars-In-2017-Crowded-US-FDA-Review-Queue-Key-Legal-Decisions. Published January 24, 2017. Accessed April 25, 2017.
13. Dangi-Garimella S. FDA rejects Novartis' biosimilar application for pegfilgrastim, seeks additional information. AJMC website. www.ajmc.com/newsroom/fda-rejects-novartis-biosimilar-application-for-pegfilgrastim-seeks-additional-information. Published July 20, 2016. Accessed April 25, 2017.
14. Cohen AD, Royzman I. FDA rejects Hospira’s EPO biosimilar application. Biologics Blog. www.biologicsblog.com/fda-rejects-hospiras-epo-biosimilar-application. Published November 5, 2015. Accessed April 25, 2017.
15. Rugo HS, Barve A, Waller CF; et al; Heritage Study Investigators. Effect of a proposed trastuzumab biosimilar compared with trastuzumab on overall response rate in patients with ERBB2 (HER2)—positive metastatic breast cancer a randomized clinical trial. JAMA. 2017;317(1):37-47. doi: 10.1001/jama.2016.18305.
16. Amgen and Allergan submit biosimilar biologics license application for ABP 215 To U.S. Food and Drug Administration [news release]. Thousand Oaks, CA: Amgen; November 15, 2016. http://wwwext.amgen.com/media/news-releases/2016/11/amgen-and-allergan-submit-biosimilar-biologics-license-application-for-abp-215-to-u-s--food-and-drug-administration/. Accessed April 26, 2017.
17. The future of the U.S. biosimilars market: development, education, and utilization. Friends of Cancer Research. https://www.focr.org/publications/future-us-biosimilars-market-development-education-and-utilization-0. Published October 21, 2016. Accessed April 27, 2017.
18. US Food and Drug Administration. Considerations in demonstrating interchangeability with a reference product. www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm537135.pdf. Published January 2017. Accessed April 25, 2017.
19. State laws and legislation related to biologic medications and substitution of biosimilars. National Conference of State Legislatures website. http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx#News. Updated March 31, 2017. Accessed April 27, 2017.
20. SUS biosimilar litigation news. Big Molecule Watch website. GoodwinProcter LLP. http://www.bigmoleculewatch.com/category/u-s-biosimilar-litigation-news/. Published April 25, 2017. Accessed April 26, 2017.
21. Hirschler B, Shields M. Novartis launches first U.S. ‘biosimilar’ drug at 15 percent discount. Reuters website. www.reuters.com/article/us-novartis-drug-idUSKCN0R30C220150903. Published September 3, 2015. Accessed April 25, 2017.
22. Gray N. Biosimilar update: Zarxio one year later. BioPharmaDive website. www.biopharmadive.com/news/biosimilar-update-zarxio-one-year-later/417797/. Published April 20, 2016. Accessed April 26, 2017.
23. Pfizer announces the U.S. availability of biosimilar Inflectra (infliximab-dyyb) [news release]. New York, NY: Pfizer Inc; October 17, 2016. www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_the_u_s_availability_of_biosimilar_inflectra_infliximab_dyyb. Accessed April 25, 2017.
24. Palmer E. Deep discounts allow Remicade biosimilar to grab 50% of Norway's market. FiercePharma website. www.fiercepharma.com/m-a/deep-discounts-allow-remicade-biosimilar-to-grab-50-of-norway-s-market. Published April 22, 2015. Accessed April 25, 2017.