Recent Approval of Trastuzumab Biosimilar, Ogivri, Has Implications for Patients and Industry

Nearly 20 years after Genentech set a new standard for treatment of patients with breast cancer whose tumors overexpress human epidermal growth factor receptor 2 (HER2),¹ the FDA approved Mylan and Bio- con’s trastuzumab biosimilar MYL-14010 in December 2017,² referenced on the drug trastuzumab (Herceptin).

Mylan’s biosimilar, which will be marketed in the United States as Ogivri,² will compete with 1 of the most profitable cancer therapies in the world: Her- ceptin’s global sales were reported to be $6.7 billion in 2016.³ A report in FiercePharma noted that Herceptin has 90% market share for HER2-positive breast cancer, which affects 15% to 20% of patients,4 and various sources listed the drug’s price at $64,000 to $70,000 a year in 2016.^5,6

A study published by the Journal of Clinical Oncology last fall found that Herceptin’s price had climbed 78% between 1996 and 2012, although a commenter said the study failed to account for the effects of the 340B drug discount program.⁷

But the situation could be changing. The FiercePharma report projected that Herceptin sales would fall to $3.98 billion by 2022.4 Early in 2018, at least 1 national payer, Humana, has moved Herceptin to a less favorable formulary position in some markets⁸; at press time, a spokesperson for the insurer had not responded to inquiries from Evidence-Based OncologyTM (EBO^TM) whether the change was related to the anticipated availability of Ogivri.

“I think biosimilars for trastuzumab in general are an incredibly important advance,” Hope Rugo, MD, clinical professor in the Department of Medicine and director of Breast Oncology Clinical Trials at the University of California, San Francisco, said in an interview with EBO^TM. She conducted a clinical trial of Ogivri and made a presentation in support of the drug on behalf of Mylan and Biocon before the FDA’s Oncologic Drugs Advisory Committee.

“The reduced cost will improve the pool of money available for new agents as they come out, because we can’t continuously just increase and increase costs. This way, for us, where we have insurance, [it] will allow insurers to potentially continue to insure patients, and also to provide the funding for new agents when they come out. For the rest of the world, it will allow people access to trastuzumab because there will be competition in terms of providing the drug at a lower price.”

A "Milestone" in Breast Cancer Treatment

When Herceptin was approved by the FDA in September 1998, it was the first treatment of its kind: a targeted therapy, in this case for patients with HER2- overexpressing metastatic breast cancer. It was approved as a single agent for those who have received at least 1 prior chemotherapy regimen for metastatic disease; or, in combination with paclitaxel, for those who have not received prior treatment for their metastatic disease.¹ Then, in 2006, Herceptin was approved for use in the adjuvant setting—for women who had received surgery or radiation for localized breast cancer—with the goal of preventing recurrence.⁹

As Jose Baselga, MD, and co-authors noted in 2006, 4 distinct trials involving trastuzumab in the adjuvant setting for early breast cancer showed that the drug reduced the risk of 3-year recurrence by about half, marking a “milestone” in the treatment of women with HER2-positive disease.¹⁰

These developments resulted in the National Comprehensive Cancer Network including HER2 testing and the use of the targeted agent Herceptin in their guidelines for treatment of early breast cancer back in 2005, and it has remained the standard of practice ever since.¹¹

However, the cost of 12 months of adjuvant trastuzumab therapy, the standard duration of treatment, as well as the cost associated with indefinite use in a metastatic setting, raises questions of patient access to this life-saving drug.

In 2012, the FDA approved pertuzumab (Perjeta), which was designed for use in combination with Herceptin. Herceptin and Perjeta are aimed at different regions of the HER2 receptor, improving chances of survival.¹²

Peter Clark, MD, a practicing oncologist and chair of the Cancer Drugs Fund of the National Health Service in the United Kingdom, said that Perjeta, in combination with chemotherapy and Herceptin, provides a 16-month survival advantage in breast cancer, and provides patients “a whopping benefit, but it will cost a fortune.”¹³

In the United States, this combination therapy was likely to cost about $115,000 for a year’s worth of treatment in 2012.¹² By 2017, the cost of the same treatment rose to $158,000 with patients often staying on the regimen for more than a year, exacerbating costs further.¹⁴

A 2015 report from the American Society of Clinical Oncology estimated the global cost of cancer at $1.16 trillion.¹⁵ This price tag includes not only drugs but the costs of diagnosis, radiotherapy, imaging, pathology, surgery, and end- of-life care. Richard Sullivan, MD, PhD, director of the Kings Institute of Cancer Policy and professor, Cancer Policy & Global Health, King’s College London, said that medicines account for just 4% to 5% of total improvements in patient outcomes, with most control and cure through surgery and radiotherapy, yet medicines dominate public policy and media attention.¹³

Will Biosimilars Offer Relief in Pricing?

Approval of Ogivri comes after the FDA’s Oncologic Drugs Advisory Committee voted unanimously in July 2017 to approve the biosimilar for all indications

of the reference, Herceptin.¹⁶ When FDA granted final approval in December, Ogivri became the first biosimilar approved in the United States for the treatment of breast cancer or stomach cancer and only the second biosimilar approved in the United States for the treatment of any cancer.¹⁷

“The approval of Ogivri represents a monumental achievement for Mylan to increase patient access to biosimilars and deliver significant savings to the US healthcare system. It will allow us to bring this important biosimilar — the first of its kind—to market in the [United States], expanding cancer patient access to more affordable treatment,” Mylan chief executive officer Heather Bresch said in a statement. “As one of the nation’s leading suppliers of cancer medicines, Mylan is excited to add to our portfolio a product representing a new generation of targeted therapies that have radically changed the way the disease is treated.”¹⁷

While biosimilars offer promise for cost savings, results have been slow to materialize. “Many of us have been disappointed by the economic savings

we’ve seen from biosimilars so far,” said FDA Commissioner Scott Gottlieb, MD, during his confirmation hearing before the Senate Health, Education, Labor, and Pensions Committee. “But I do think there’s a lot of opportunity for [biosimilars] to have meaningful impact on consumers and spending going forward.”¹⁸⁺

Although biosimilars usually provide patients with up to 15% cost savings for these life-saving treatments, the US price for Ogivri has not yet been announced. When Biocon launched the trastuzumab biosimilar in India in 2014, the reported savings compared with the reference product was 25%.¹⁹

FDA approval of Ogivri followed Mylan’s settlement with Genentech and Roche to bring the biosimilar to the market, but those terms have not been made public.¹⁶ While a precise arrival date of Ogivri is not known, a Barclays analyst projected it to be in 2019.20

Response From Payers, Patients

Herceptin has no competitor in the United States, but that did not stop Humana from reclassifying Herceptin from a preferred drug to a nonpreferred drug in some Florida markets for 2018.

Becker’s Hospital Review said some policyholders report the change has left them with 20% copays, translating to out-of-pocket (OOP) costs of more than $900 per monthly dose until they reach their yearly OOP limit, for a treatment that was previously on a preferred formulary tier.⁸

In a statement to Becker’s, Humana said, “We recognize the importance of medications like Herceptin. Herceptin remains covered in Humana’s plans, as it has been since FDA approval. Humana’s 2018 Medicare cost-sharing structure for Herceptin changed under select Medicare Advantage plans in 4 markets and is now the same as [under] most other Medicare Advantage plans and original Medicare.”⁸

Asked if she’d heard about Humana’s action happening in other markets, Rugo said, “I haven’t heard of a reclassification to a non-preferred drug. I think that they’re doing that ahead of time in preparation for the biosimilar availability in the next year. I’m guessing that that will happen wholesale, that every regulatory group and mass insurer will change to say trastuzumab is what is preferred, and the type of trastuzumab doesn’t matter.”

Humana did not respond to several requests for comment from EBO^TM, including a question regarding whether Herceptin’s move to a nonpreferred formulary tier occurred in anticipation of Ogivri’s availability. There has been considerable outcry over Humana’s move, since cancer patients do not yet have a substitute for Herceptin.

But once Ogivri arrives, making the biosimilar the preferred therapy would not be without precedent. Rugo said she has already seen this happen at the institution level with tbo-filgrastim (Granix), the treatment for neutropenia that has a biosimilar competitor, filgrastim-sndz (Zarxio). In August 2016, CVS Health, the nation’s second-largest pharmacy benefit manager, announced it was dropping the mainstay insulin Lantus, a top seller for Sanofi, from its formulary in favor of Eli Lilly’s biosimilar, Basaglar.²¹

Having more approved biosimilars in the US market could be a game-changer in the marketplace, as it could be the best way to drive down the cost of biologic medications that have been on the market for years. The cost savings of treating people on far less costly biosimilars, even counting just newly diagnosed patients, were estimated to be an anticipated $250 billion by 2024 by Express Scripts in a 2013 report.²²

The question remains: Will patients take advantage of these cost savings?

“The FDA continues to grow the number of biosimilar approvals, helping to promote competition that can lower healthcare costs. This is especially important when it comes to diseases like cancer, that have a high cost burden for patients,” Gottlieb said. “We’re committed to taking new policy steps to advance our biosimilar pathway and promote more competition for biological drugs.”²

As the FDA continues to approve more biosimilars, physicians’ reported attitudes towards them change. InCrowd surveyed physicians across 5 subspecialties in which biologics prescribing is significant: dermatology, endocrinology, gastroenterology, oncology, and rheumatology. In November 2016, 84% of those surveyed said that they expect to prescribe, assume they will prescribe, or look forward to prescribing more biosimilars in the coming 3 years, up from 70% in February 2016.23 However, only 17% in November 2016 said they would allow pharmacy- level substitution of these drugs for their patients, versus 28% in February 2016.²³ They continue to weigh more factors into their choice of potentially prescribing biosimilars at all.

“I think once the drugs are available, there’s going to be a big need for education and understanding of where these drugs should be and how comfortable people feel with them,” Rugo said, discussing biosimilars beyond cancer care. “But right now, I think in the United States because we can’t use them yet, the main interest has been in supportive care and in rheumatologic disease.”

Good Timing for Mylan

Ogivri was approved by the FDA based on a review of evidence including structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrate the molecule’s biosimilarity to Herceptin.

However, the news of Ogivri’s approval could not have come at a better time for manufacturer Mylan, which had been criticized over pricing strategy for its emergency allergy product, the EpiPen, and more recently, alleged drug-price fixing.

Mylan President Rajiv Malik, the company’s second-ranked executive, was accused of taking part in a “vast and sinister price-fixing conspiracy among global makers of generic pills that kept prices of the medications artificially high,” nearly every US state claimed in a new lawsuit.²⁴

This 243-page complaint states that Mylan, along with 17 other generic drug makers, conspired to fix prices of certain critical treatments for patients suffering from conditions such as diabetes, hypertension, high blood pressure, and rheumatoid arthritis, according to new allegations by the top law enforcement officials in 46 states.²⁵

The complaint comes less than a year after Mylan was at the center of a firestorm over the soaring prices of the EpiPen, which is used as a rescue product for those with severe allergies who experience anaphylaxis. The price of the product, which costs Mylan about $30 to produce,²⁴ increased more than 500% when it rose from $103.50 in 2009 to more than $608.61 in 2016.²⁶

Rugo, for her part, said the price points will matter, because if payers and institutions see the potential for large savings, “then they will want us to switch over to the biosimilars, which I am very happy to do. I think these are agents which are biosimilar, so I don’t have a problem switching over. And I don’t have a problem a switching a patient, either.

“It’s going to be an interesting time to see what happens,” she said.

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8. Haefner M. Humana faces backlash for raising breast cancer drug copays. Becker’s Hospital Review website. beckershospitalreview.com/payer-issues/ humana-faces-backlash-for-raising-breast-cancer-drug-copays.html. Published January 18, 2018. Accessed January 22, 2018.

9. FDA approves Herceptin for the adjuvant treatment of HER2-positive node-positive breast cancer [news release]. South San Francisco,

CA: Genentech; November 16, 2006. gene.com/media/press-releas- es/10207/2006-11-16/fda-approves-herceptin-for-the-adjuvant-. Accessed January 24, 2018.

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11. NCCN includes Herceptin in guidelines as therapy in HER2-positive early breast cancer. CancerConnect.com website. news.cancerconnect.com/ nccn-includes-herceptin-in-guidelines-as-therapy-in-her2-positive-early- breast-cancer/. Published December 21, 2005. Accessed January 5, 2018.

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16. Davio K. First trastuzumab biosimilar, Ogivri, approved by FDA. The Center for Biosimilars® website. centerforbiosimilars.com/news/first-trastu- zumab-biosimilar-ogivri-approved-by-fda. Published December 1, 2017. Accessed January 5, 2018.

17. U.S. FDA approves Mylan and Biocon’s Ogivri, the first biosimilar for trastu- zumab, for the treatment of HER2-positive breast and gastric cancers [news release]. Hertfordshire, England: Mylan; December 1, 2017. newsroom. mylan.com/2017-12-01-U-S-FDA-Approves-Mylan-and-Biocons-Ogivri- TM-the-First-Biosimilar-for-Trastuzumab-for-the-Treatment-of-HER2-Posi- tive-Breast-and-Gastric-Cancers. Accessed January 5, 2018.

18. Ramsey L. New drugs could save the US billions of dollars—but there’s something holding them back. BusinessInsider website. businessinsider. com/how-well-biosimilars-are-saving-money-2017-4. Published April 6, 2017. Accessed January 5, 2018.

19. Biocon launches cheaper breast cancer drug. The Hindu website. thehindu. com/business/Industry/biocon-launches-cheaper-breast-cancer-drug/ article5590132.ece. Published January 18, 2014. Updated May 13, 2016. Accessed January 23, 2018.

20. Mishra M. FDA OKs Mylan’s biosimilar of Roche cancer drug Herceptin. Reuters website. reuters.com/article/us-mylan-nl-fda/fda-oks-mylans-bi- osimilar-of-roche-cancer-drug-herceptin-idUSKBN1DV5BI. Published December 1, 2017. Accessed January 23, 2018.

21. Caffrey M. Diabetes drugs take hits on formulary updates. The American Journal of Managed Care® website. ajmc.com/newsroom/ diabetes-drugs-take-hits-in-formulary-updates. Published August 3, 2016. Accessed January 23, 2018.

22. $250 billion potential of biosimilars. Express Scripts website. lab. express-scripts.com/lab/insights/industry-updates/the-%24250-billion-po- tential-of-biosimilars. Published April 23, 2013. Accessed January 23, 2018.

23. More doctors say yes to biosimilars than 6 months ago, but with increased caution [news release]. Boston, MA: InCrowd; November 16, 2016. incrowdnow.com/press-release/more doctors-say-yes-to-biosimilars-but- with-increased-caution-than-6-months-ago-says-new-data-from-incrowd/. Accessed January 5, 2018.

24. Plaintiff states v. Defendant Actavis Holdco U.S. Inc, 16-AG-27240, U.S. District Court Eastern District of Pennsylvania.

25. Sagonowsky E. Mylan president Rajiv Malik targeted as states expand price-fixing suits against top drugmakers. FiercePharma website. fiercepharma.com/legal/states-target-mylan-president-rajiv-malik-oth- er-top-drugmakers-expanded-price-fixing-suit. October 31, 2017. Accessed January 29, 2018.

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