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Top 10 Best-Selling Drugs of 2018 Fund US and EU Pharma R&D

2 / May 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)

Stephanie Yip Senior Analyst, Datamonitor Healthcare

May 2019 / 3© Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)

The top 10 drugs with the highest global sales in 2018 each generated revenues of at least $6.5bn (see Table 1). The total sales value of these drugs amounted to an astounding $87bn in 2018. To put this into context, this is comparable to the $90bn in pharmaceutical R&D expenditure across the US and EU in 2016.1 Humira (adalimumab; AbbVie/Eisai)

continued to dominate the pharmaceutical market; its global sales of $20.4bn were equivalent to approximately 23% of the top 10 drugs’ total sales. Easily head and shoulders above the rest, Humira’s substantial lead margin of $10.7bn was worth more than the worldwide sales ($9.7bn) of the second leading drug, Revlimid (lenalidomide; Celgene).2-5

The top 10 most lucrative drugs in 2018 were worth approximately $87bn

The top 10 commercially successful drugs each generated at least $6.5bn in 2018

1. EFPIA (2018) The Pharmaceutical Industry in Figures. Available from: https://www.efpia.eu/media/361960/efpia-pharmafigures2018_v07-hq.pdf [Accessed 4 March 2019].2. AbbVie (2019a) AbbVie Reports Full-Year and Fourth-Quarter 2018 Financial Results. Available from: https://investors.abbvie.com/news-releases/news-release-details/abbvie-reports-full-year-and-fourth-quarter-2018-financial [Accessed 27 February 2019].3. Celgene (2019a) Celgene Reports Fourth Quarter and Full Year 2018 Operating and Financial Results. Available from: https://ir.celgene.com/press-releases/press-release-details/2019/Celgene-Reports-Fourth-Quarter-and-Full-Year-2018-Operating-and-Financial-Results/default.aspx [Accessed 27 February 2019].4. Eisai (2018) FY2017 (Ended March 31, 2018) Full Year Financial Results Reference Data. Available from: https://www.eisai.com/ir/library/settlement/pdf/e2018Q4_52.pdf [Accessed 27 February 2019].5. Eisai (2019) Q3 FY2018 (Fiscal Year Ending March 31, 2019) Financial Results Presentation. Available from: https://www.eisai.com/ir/library/presentations/pdf/e4523_190204.pdf [Accessed 27 February 2019].6. Amgen (2019a) Amgen Reports Fourth Quarter And Full Year 2018 Financial Results. Available from: http://phx.corporate-ir.net/phoenix.zhtml?c=61656&p=irol-newsArticle&ID=2385241 [Accessed 27 February 2019].

Table 1. Highest-selling drugs in 2018

Rank Global sales, 2018 Brand (molecule) Companies (total sales by company)1 $20.4bn Humira (adalimumab) AbbVie ($19,936m), Eisai (¥46,300m*)

2 $9.7bn Revlimid (lenalidomide) Celgene ($9,685m)

3 $7.6bn Opdivo (nivolumab) Bristol-Myers Squibb ($6,735m), Ono Pharmaceutical (¥92,400m*)

4 $7.5bn Enbrel (etanercept) Amgen ($5,014m), Pfi zer ($2,112m), Takeda (¥35,900*)

5 $7.2bn Herceptin (trastuzumab) Roche (CHF6,982m)

5 $7.2bn Keytruda (pembrolizumab) Merck & Co ($7,171m)

7 $7.1bn Avastin (bevacizumab) Roche (CHF6,849m)

8 $7.0bn Rituxan (rituximab) Roche (CHF6,752m)

9 $6.7bn Eylea (afl ibercept) Regeneron ($6,746m)

10 $6.6bn Xarelto (rivaroxaban) Bayer (€3,631m), Johnson & Johnson ($2,477m)

*Sum of Q1–Q3 2018 sales and Q4 2017 sales.

Sources: Biomedtracker; Datamonitor Healthcare; Medtrack; Pharmaprojects; various 2-16


Key themes associated with the top 10 most profitable drugs in 2018, which are highlighted in

this report, are summarized in Table 2 below.

Source: Informa Pharma Intelligence

Table 2. Dynamics of the highest-selling drugs in 2018

Current dynamic Outlook• The highest-selling drugs were worth at least

$6.5bn each in 2018• US price infl ations contribute to lucrative global

revenues• Big Pharma companies co-market the top 10 drugs• Strategic partnerships in Asia are common to

support commercialization• Oncology supports more best-selling drugs than

other therapy areas

• Most products are growing but further sales growth is dependent on successful protection of market exclusivity

• Companies are adopting evergreening tactics to delay biosimilar/generic competition

Threats Drug cost issues• Patent expiry/loss of exclusivity• Patent litigation could result in earlier biosimilar/

generic entry than expected• Competition from newer brands in primary markets

• In the future, sales growth may be dampened by downward pricing pressures in the US, which is the largest pharmaceutical market. Other ex-US markets are more cost-conservative

• Potential removal of safe harbor protection for rebates involving prescription pharmaceuticals

7. Bayer (2019) Annual Report 2018. Available from: https://www.investor.bayer.de/securedl/16788 [Accessed 27 February 2019].8. Bristol-Myers Squibb (2019a) BMY-Q42018-Financial-Information. Available from: https://s21.q4cdn.com/104148044/files/doc_financials/quarterly_reports/2018/q4/BMY-Q42018-Financial-Information.xls [Accessed 27 February 2019].9. Johnson & Johnson (2019) Johnson & Johnson Reports 2018 Fourth-Quarter Results. Available from: https://www.jnj.com/johnson-johnson-reports-2018-fourth-quarter-results [Accessed 27 March 2019].10. Merck & Co (2019a) Merck & Co., Inc. Financial Highlights Package Fourth Quarter 2018. Available from: https://s21.q4cdn.com/488056881/files/doc_financials/2018/Q4/Financial-Highlights-Package-4Q18.pdf [Accessed 27 February 2019].11. Ono Pharmaceutical (2019) Consolidated Financial Results for the Third Quarter of the Fiscal Year Ending March 31, 2019 (IFRS). Available from: https://www.ono.co.jp/eng/investor/pdf/fr/2019/0201/fi0201.pdf [Accessed 27 February 2019].12. Pfizer (2019) Q4-2018-PFE-Product-Revenues-(Includes-Historicals). Available from: https://s21.q4cdn.com/317678438/files/doc_financials/Quarterly/2018/q4/Q4-2018-PFE-Product-Revenues-(Includes-Historicals).xlsx [Accessed 27 February 2019].13. Regeneron (2019) Regeneron Reports Fourth Quarter and Full Year 2018 Financial and Operating Results. Available from: https://investor.regeneron.com/news-releases/news-release-details/regeneron-reports-fourth-quarter-and-full-year-2018-financia [Accessed 27 February 2019].14. Roche (2019) Finance Report 2018. Available from: https://www.roche.com/dam/jcr:933329c4-4564-4b17-a29b-246ac7e617d5/en/fb18e.pdf [Accessed 27 February 2019].15. Takeda (2018) FY2017 DATA BOOK. Available from: https://www.takeda.com/siteassets/system/investors/report/quarterlyannouncements/fy2017/fy2017-full-year-results/qr2017_q4_d01_en.pdf [Accessed 27 February 2019].16. Takeda (2019) FY2018 3rd Quarter DATA BOOK. Available from: https://www.takeda.com/siteassets/system/investors/report/quarterlyannouncements/fy2018/fy2018-q3-announcements/qr2018_q3_d-en.pdf [Accessed 27 February 2019].


Rank

Glob

al s

ales

, 201

8

Bran

d (m

olec

ule)

Prop

ortio

n of

US

sale

s, 20

18

Initi

al F

DA

appr

oval

dat

e

US la

unch

dat

e

Form

ulat

ion

Rank

ing

of h

ighe

st-

selli

ng d

rugs

’ US

list p

rices

, 201

8

Chan

ge in

US

AWP

unit

list p

rice,

20

17–1

8

Num

ber o

f pric

e hi

kes,

2017

–18

1 $20.4bn Humira (adalimumab) 67.1% Dec-02 Jan-03 SC injection 3 9.7% 1

2 $9.7bn Revlimid (lenalidomide) 66.8% Dec-05 Dec-05 Oral capsule 6 16.5% 3

3 $7.6bn Opdivo (nivolumab) 55.4% Dec-14 Jan-15 IV 8 3.0% 24 $7.5bn Enbrel (etanercept) 64.3% Nov-98 Dec-98 SC injection 7 9.7% 1

5 $7.2bn Herceptin (trastuzumab) 41.6% Sep-98 Jan-99 IV 4 6.0% 2

5 $7.2bn Keytruda (pembrolizumab) 57.9% Sep-14 Jan-15 IV 2 3.0% 2

7 $7.1bn Avastin (bevacizumab) 42.4% Feb-04 Mar-04 IV 9 5.0% 28 $7.0bn Rituxan (rituximab) 63.5% Nov-97 Mar-98 IV/SC 5 8.0% 2

9 $6.7bn Eylea (afl ibercept) 60.4% Nov-11 Nov-11 Intravitreal injection 1 0.0% 0

10 $6.6bn Xarelto (rivaroxaban) 46.4% Jul-11 Nov-11 Oral tablets 10 8.0% 1Drugs were ranked by their AWP unit list price in Red Book, “1” being the most expensive.

Changes in list price were calculated using the prices that were listed for most of each year.

AWP = average wholesale price; FDA = US Food and Drug Administration; IV = intravenous; SC = subcutaneous

Sources: Biomedtracker; Datamonitor Healthcare; Medtrack; Pharmaprojects; various 2-16

Penetration of the dominant US market with inflated pricing is central to the success of lucrative drugs

Considering that the US represents the largest pharmaceutical market, it is unsurprising that, on average, the US sales of the highest-selling drugs constitute 56.6% of their total global sales (see Table 3) .1 Given the commercial opportunity, pharmaceutical companies tend to prioritize drug development in the US market first. The oldest of the top drugs – Rituxan (rituximab; Biogen/Roche/Zenyaku Kogyo), Enbrel (etanercept; Amgen/Pfizer/Takeda), and Herceptin (trastuzumab; Roche) – first

launched in the US in the late 1990s. Meanwhile, Opdivo (nivolumab; Bristol-Myers Squibb/Ono Pharmaceutical), Keytruda (pembrolizumab; Merck & Co/Taiho Pharmaceutical), Eylea (aflibercept; Bayer/Regeneron/Santen), and Xarelto (rivaroxaban; Bayer/Johnson & Johnson) were the latest of the top brands to penetrate the US market in the past decade (see Table 3) (Biomedtracker, 2019; Pharmaprojects, 2019).

Table 3. US perspective on the highest-selling drugs in 2018


The inflationary characteristic of the US market is a major contributor to the high value of drugs in the US.17 On average, there was a 6.9% rise in the US list prices of the most lucrative brands from 2017 to 2018. The greatest change from 2017 to 2018 was Revlimid’s 16.5% increase in list price, as the drug experienced three price hikes (Red Book, 2019) (see Table 3). It is recognized that ballooning drug prices are unsustainable, and mounting pressure for reform has led to finger pointing and disputes over responsibility by key players in the pharmaceutical industry and politicians alike. In January and February 2019, the US Senate Committee on Finance held hearings with top pharmaceutical executives to address the issue of rising prices. In particular, AbbVie’s performance incentive plan, whereby Humira sales are directly tied to senior executives’ bonuses, was under scrutiny, as these payouts drive incentives that are fueling continued price hikes .18-20 Pharmaceutical companies have challenged their admonishment, however, alluding to the patient assistance programs they offer that facilitate access, the costly decades of research and development invested, and the irrelevance of list prices due to the intricacies of the drug supply chain.19

While pharmaceutical companies represent one

component of the complex US pharmaceutical supply chain feeding into patients’ out-of-pocket costs, pharmacy benefit managers (PBMs) also hold an important role. The Trump administration has been vocal about changing the trajectory of drug prices, potentially by abolishing the rebates that drugmakers pay to PBM middlemen.21-25 If finalized, the proposed overhaul would be enforced from 2020, and would assert that PBM-negotiated discounts must be applied to list prices; as opposed to the current structure that causes patients downstream to pay high out-of-pocket costs, with cost reductions limited to insurance premiums.23 Senators Wyden and Grassley have called for an investigation into spread pricing to shed light on PBMs’ operations, which are guarded “with greater secrecy than HBO is guarding the ending of Game of Thrones,” according to Wyden.26 PBMs may profit by charging payers a higher price than the amount they reimburse pharmacies, and pocketing the difference; these transactions are shrouded in secrecy. Patients taking drugs with higher list prices pay more because they are charged based on list prices, rather than PBMs’ discounted prices, until they reach their deductibles. This can be detrimental to medication adherence and, subsequently, treatment outcomes.26

17. Kesselheim AS, Avorn J, Sarpatwari A (2016) The high cost of prescription drugs in the United States: origins and prospects for reform. Jama, 316(8), 858–871.18. US Senate Committee on Finance (2019a) Wyden Statement at Finance Committee Hearing on Drug Prices with Pharma CEOs. Available from: https://www.finance.senate.gov/ranking-members-news/wyden-statement-at-finance-committee-hearing-on-drug-prices-with-pharma-ceos [Accessed 17 April 2019].19. AbbVie (2018a) 2017 Annual Report on Form 10-K. Available from: https://investors.abbvie.com/static-files/8f8ea49f-4735-404c-be08-2f963441b74d [Addressed 6 March 2019].20. AbbVie (2019b) 10k. Available from: https://ir.celgene.com/press-releases/press-release-details/2019/Celgene-Reports-Fourth-Quarter-and-Full-Year-2018-Operating-and-Financial-Results/default.aspx [Accessed 4 April 2019].21. Department of Health and Human Services (2019) Fraud and Abuse; Removal of Safe Harbor Protection for Rebates Involving Prescription Pharmaceuticals and Creation of New Safe Harbor Protection for Certain Point-of-Sale Reductions in Price on Prescription Pharmaceuticals and Certain Pharmacy Benefit Manager Service Fees. Available from: https://s3.amazonaws.com/public-inspection.federalregister.gov/2019-01026.pdf [Accessed 5 March 2019].22. Federal Register (2019) Fraud and Abuse; Removal of Safe Harbor Protection for Rebates Involving Prescription Pharmaceuticals and Creation of New Safe Harbor Protection for Certain Point-of-Sale Reductions in Price on Prescription Pharmaceuticals and Certain Pharmacy Benefit Manager Service Fees. Available from: https://www.federalregister.gov/documents/2019/02/06/2019-01026/fraud-and-abuse-removal-of-safe-harbor-protection-for-rebates-involving-prescription-pharmaceuticals [Accessed 4 April 2019].23. HHS (2019) Trump Administration Proposes to Lower Drug Costs by Targeting Backdoor Rebates and Encouraging Direct Discounts to Patients. Available from: https://www.hhs.gov/about/news/2019/01/31/trump-administration-proposes-to-lower-drug-costs-by-targeting-backdoor-rebates-and-encouraging-direct-discounts-to-patients.html [Accessed 3 April 2019].24. United States Senate (2019a) Drug Pricing in America: A Prescription for Change, Part I. Available from: https://www.finance.senate.gov/hearings/drug-pricing-in-america-a-prescription-for-change-part-i [Accessed 5 March 2019].25. US Senate Committee on Finance (2019b) Wyden Statement at Finance Committee Hearing on Drug Prices and Pharmacy Benefit Managers. Available from: https://www.finance.senate.gov/ranking-members-news/wyden-statement-at-finance-committee-hearing-on-drug-prices-and_pharmacy-benefit-managers [Accessed 17 April 2019].26. Lyles, A (2017) Pharmacy benefit management companies: do they create value in the US healthcare system? Pharmacoeconomics, 35(5), 493–500.


Most of the top drugs benefit from the marketing experience and resources of multiple companies, including Big Pharma

The top 10 drugs are marketed by at least one Big Pharma (companies with annual revenues in excess of $15bn) player (see Table 4). Celgene broke into the Big Pharma category in 2018, with total revenues of $15.3bn.3 Two Big Pharma companies appear multiple times in the top 10 list. Roche

markets the most top drugs: Avastin (bevacizumab), Herceptin, and Rituxan (with its affiliate Chugai). Meanwhile, Bayer co-markets Eylea and Xarelto in partnership with Regeneron/Santen and Johnson & Johnson, respectively (Pharmaprojects, 2019).

Most of the top brands are marketed by multiple companies and harness their substantial pooled marketing experience and commercial resources (see Table 4). Success in the Asian market is supported through strategic partnerships with pharmaceutical companies headquartered in the Asia-Pacific region, such as Eisai, Takeda, and Ono

Pharmaceutical, which have an established presence and experience in the targeted market. While Roche has not entered into a strategic partnership for the marketing of two of its most lucrative drugs, it utilizes the expertise of its Japanese subsidiary, Chugai (Pharmaprojects, 2019).

Sources: Biomedtracker; Datamonitor Healthcare; Pharmaprojects

Table 4. Companies associated with the top drugs in 2018

Rank Brand (molecule) Originator Marketing companies1 Humira (adalimumab) AstraZeneca AbbVie (US/RoW); Eisai (Japan)

2 Revlimid (lenalidomide) Celgene Celgene; BeiGene (China); GENESIS Pharma (Greece)

3 Opdivo (nivolumab) Ono Pharmaceutical Bristol-Myers Squibb (US/RoW); Ono Pharmaceutical (Japan)

4 Enbrel (etanercept) Amgen Amgen (US/RoW); Pfi zer (EU); Takeda (Japan)5 Herceptin (trastuzumab) Roche Roche; Chugai (subsidiary of Roche) (Japan)

5 Keytruda (pembrolizumab) Merck & Co Merck & Co; Taiho Pharmaceutical (subsidiary of Otsuka) (Japan)

7 Avastin (bevacizumab) Roche Roche; Chugai (subsidiary of Roche) (Japan)

8 Rituxan (rituximab) Biogen Roche; Biogen (US); Chugai (subsidiary of Roche) (Japan); Zenyaku Kogyo (Japan)

9 Eylea (afl ibercept) Regeneron Regeneron (US/RoW); Bayer; Santen (Japan)10 Xarelto (rivaroxaban) Bayer Bayer; Johnson & Johnson (US)

RoW = rest of world


Oncology is the chief therapeutic area targeted by the most lucrative drugs

Six of the 10 most commercially successful drugs are oncologic therapies (see Table 5). Revlimid and Rituxan are used to treat hematologic cancers, while Herceptin and Avastin are used to treat solid tumors. Opdivo and Keytruda are indicated for both types of cancer. The primary indications for these drugs are: breast cancer, chronic lymphocytic leukemia,

non-small cell lung cancer (NSCLC), diffuse large B-cell lymphoma, non-Hodgkin’s lymphoma, brain cancer, B-cell lymphoma, and follicular lymphoma (see Figure 1). Immunology and inflammation is the next most common therapy area and is occupied by Humira, Enbrel, and Rituxan (Pharmaprojects, 2019).

Source: Datamonitor Healthcare

Table 5. Therapy areas targeted by the highest-selling drugs in 2018

Rank Brand (molecule) Therapy areas1 Humira (adalimumab) Immunology and infl ammation2 Revlimid (lenalidomide) Oncology3 Opdivo (nivolumab) Oncology4 Enbrel (etanercept) Immunology and infl ammation5 Herceptin (trastuzumab) Oncology5 Keytruda (pembrolizumab) Oncology7 Avastin (bevacizumab) Oncology8 Rituxan (rituximab) Oncology, immunology and infl ammation9 Eylea (afl ibercept) Ophthalmology

10 Xarelto (rivaroxaban) Cardiovascular


Oncology is an attractive market to develop drugs for as there is high unmet need, translating to considerable opportunity for market penetration and generating substantial product revenues. Cancer is the second leading cause of death globally, responsible for 9.6 million deaths in 2018.27, 28 The serious, aggressive nature of cancer and the lack of curative treatments contribute to poor patient prognosis and low overall survival. Therefore, immediate treatment is crucial. This has led to the traditional use of potent, standard-of-care treatments, such as chemotherapy and radiotherapy, which are associated with toxic side effects. The prospect of extending overall survival in cancer patients has driven interest in the burgeoning

field of immuno-oncology (see Datamonitor Healthcare’s Immuno-Oncology Overview).29 Checkpoint inhibitors Opdivo and Keytruda are programmed death-1 (PD-1)-targeted monoclonal antibodies, and are the most recently launched drugs to enter the ranks of the top 10 highest-selling drugs globally. Furthermore, the growing field of personalized medicine has paved the way for the stratification of cancer patients by pharmacogenetic biomarkers in targeted clinical trials, which appears to have a positive effect on a drug’s overall clinical program and likelihood of approval (see Pharma Intelligence's One Size No Longer Fits All: The Personalized Medicine Trial Landscape).30 The high prices that can be charged for oncologic drugs,

Source: Pharmaprojects, 2019

Figure 1. Top diseases targeted by the highest-selling drugs in 2018

27. IHME (2017) GBD Results Tool. Available from: http://ghdx.healthdata.org/gbd-results-tool [Accessed 6 March 2019].28. Our World in Data (2017) Share of deaths by cause, World, 2016. Available from: https://ourworldindata.org/grapher/share-of-deaths-by-cause-2016 [Accessed 6 March 2019].29. Datamonitor Healthcare (2017) Immuno-Oncology Overview. Available from: https://service.datamonitorhealthcare.com/hkc/disease/oncology/oncology-overview/immunooncology/pipeline/article139839.ece [Accessed 17 April 2019].30. Shin D (2017) One Size No Longer Fits All: The Personalized Medicine Trial Landscape. Available from: https://pharmaintelligence.informa.com/resources/product-content/personalized-medicine-whitepaper [Accessed 17 April 2019].

Cancer, breastCancer, leukaemia, chronic lymphocytic

Cancer, lung, non-small cellCancer, lymphoma, B-cell, diffuse large

Cancer, lymphoma, non-Hodgkin’sCancer, brain

Cancer, lymphoma, B-cellCancer, lymphoma, follicular

Cancer, prostateCancer, colorectal

Cancer, renalArthritis, rheumatoid

Cancer, gastrointestinal, stomachCancer, melanoma

Cancer, myelomaCancer, ovarian

Cancer, peritonealCancer, cervical

Cancer, fallopian tubeCancer, gastro-oesophageal junction

Cancer, liverCancer, lung, small cell

Cancer, lymphoma, Hodgkin’sCancer, oesophageal

Cancer, solid, unspecified

0 2 41 3 5

Dise

ase

indi

catio

n

Number of top drugs

Oncology

Immunology and inflammation


Sources: Biomedtracker; Datamonitor Healthcare; Pharmaprojects; various 2-16

With biosimilar erosion carving out sales, intellectual property is vital to continued success

While total sales of the top 10 drugs grew during 2017–18, Enbrel, Herceptin, and Rituxan declined (meanwhile, sales of growing brands increased by 23.4% on average) (see Table 6). These products face biosimilar erosion across the major markets (see Table 7). As more biosimilars enter the market,

competition will intensify, and these brands are expected to continue declining as their market share is increasingly eroded. At the height of their success, Enbrel ($9.2bn in 2016), Herceptin ($7.2bn in 2017), and Rituxan ($7.6bn in 2017) accumulated total sales of $24.1bn.15, 31-34

Table 6. 2017–18 global revenues of the highest-selling drugs in 2018

Brand (molecule) Companies Rank Global sales, 2018

Global sales, 2017

Change in global sales, 2017–18

Humira (adalimumab) AbbVie, Eisai 1 $20.4bn $18.8bn 8.2%Revlimid (lenalidomide) Celgene 2 $9.7bn $8.2bn 18.3%

Opdivo (nivolumab) Bristol-Myers Squibb, Ono Pharmaceutical 3 $7.6bn $5.8bn 31.0%

Enbrel (etanercept) Amgen, Pfi zer, Takeda 4 $7.5bn $8.3bn -9.6%Herceptin (trastuzumab) Roche 5 $7.2bn $7.2bn -0.5%

Keytruda (pembrolizumab) Merck & Co 5 $7.2bn $3.8bn 88.3%Avastin (bevacizumab) Roche 7 $7.1bn $6.9bn 2.4%

Rituxan (rituximab) Roche 8 $7.0bn $7.6bn -8.6%Eylea (afl ibercept) Regeneron 9 $6.7bn $5.9bn 14.2%

Xarelto (rivaroxaban) Bayer, Johnson & Johnson 10 $6.6bn $6.2bn 5.7%

31. Amgen (2017) Annual Report 2016. Available from: http://phx.corporate-ir.net/External.File?item=UGFyZW50SUQ9NjY1NTQ1fENoaWxkSUQ9MzczMzk1fFR5cGU9MQ==&t=1 [Accessed 12 March 2019].32. Chugai (2018) Financial and Non-Financial Highlights. Available from: https://www.chugai-pharm.co.jp/english/ir/reports_downloads/annual_reports/files/eAR2017_12_04.pdf [Accessed 12 March 2019].33. Roche (2018b) Finance Report 2017. Available from: https://www.roche.com/dam/jcr:b70415c0-954f-4a2a-a0e2-47f94bd280e0/en/fb17e.pdf [Accessed 6 March 2019].34. Pfizer (2017) Financial report. Available from: https://s21.q4cdn.com/317678438/files/doc_financials/Annual/2016/2016-financial-report.pdf [Accessed 12 March 2019].

especially with various rare cancer indications, also accounts for their lucrative product revenues. Biologic therapies are more complicated to develop and manufacture, therefore they are priced more dearly. Only two of the most profitable brands are oral small molecules, while the rest are injectable biologics. Revlimid and Xarelto boast convenient oral

treatment modalities and have lower list prices than many of the other best-selling drugs (see Table 3) (Biomedtracker, 2019; Pharmaprojects, 2019; Red Book, 2019).


Sources: Biomedtracker; Datamonitor Healthcare; Pharmaprojects; various 35-47

As the most recently launched products, which are earlier in their product lifecycles, Opdivo and Keytruda experienced the greatest growth in their global sales, garnering ≥30% more sales from 2017 to 2018 (see Table 6).8,11,53 Avastin’s sales momentum has trundled down as it approaches its US patent cliff, and its global brand sales only

increased by 2.4% during 2017–1814 (see Tables 6 and 8). In mid-2019, Avastin’s primary US patent is expected to expire, and thereafter bevacizumab biosimilars will be able to enter the market.34 Amgen and Allergan’s bevacizumab biosimilar, Mvasi, was the first FDA-approved biosimilar indicated for cancer.48

Table 7. First approvals and launches in the US, Japan, and EU for etanercept, trastuzumab, and rituximab biosimilars

Brand (molecule) Companies

US EU Japan

First biosimilar approval

First biosimilar

launch


First biosimilar

launch


First biosimilar

launch

Enbrel (etanercept)

Amgen, Pfi zer, Takeda Aug-16

Ongoing patent

litigationJan-16 Feb-16 Jan-18 May-18

Herceptin (trastuzumab)

Roche, Chugai (subsidiary of

Roche)Dec-17 Expected

in H2 2019 Nov-17 Mar-18 Mar-18 Aug-18

Rituxan (rituximab)

Roche, Chugai (subsidiary of

Roche)Nov-18 Expected

in H1 2019 Feb-17 Apr-17 Sep-17 Jan-18

35. Celltrion (2017) Celltrion, Truxima™ Europe official launching in Europe … Start the first prescription in England. Available from: http://www.celltrion.com/en/pr/reportDetail.do?seq=425 [Accessed 11 March 2019].36. Celltrion (2018) FDA Approves Celltrion’s Rituximab Biosimilar, Truxima. Available from: https://www.centerforbiosimilars.com/news/fda-approves-celltrions-rituximab-biosimilar-truxima [Accessed 11 March 2019].37. EMA (2018a) Ontruzant. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ontruzant [Accessed 11 March 2019].38. EMA (2018b) Benepali. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/benepali [Accessed 6 March 2019].39. Mochida (2018) Mochida obtains marketing approval for etanercept biosimilar in Japan. Available from: http://www.mochida.co.jp/english/news/docs/2018/180119_etanerceptBS.pdf [Accessed 12 March 2019].40. The Center for Biosimilars (2018) First Trastuzumab Biosimilar Launches in Europe. Available from: https://www.centerforbiosimilars.com/news/first-trastuzumab-biosimilar-launches-in-europe [Accessed 11 March 2019].41. Nippon Kayaku (2018a) Nippon Kayaku Receives Manufacture and Marketing Approval in Japan for Biosimilar of Trastuzumab Monoclonal Antibody. Available from: https://www.nipponkayaku.co.jp/english/news/detail.php?n=20180323_E2HVSD66 [Accessed 11 March 2019].42. Nippon Kayaku (2018b) Nippon Kayaku launches Trastuzumab BS for I.V. Infusion 60mg “NK”-150mg “NK”, a humanized anti-human HER2 monoclonal Antibody. Available from: https://www.nipponkayaku.co.jp/english/news/detail.php?n=20180820_AM1VH3MS [Accessed 11 March 2019].43. Novartis (2018) Novartis delivered good operational performance and landmark innovation in 2017, entering our next growth phase. Available from: https://www.novartis.com/sites/www.novartis.com/files/q4-2017-media-release-en.pdf [Accessed 11 March 2019].44. Pharma Japan (2018a) Japan’s 1st Enbrel Biosimilar Makes Its Debut. Available from: https://pj.jiho.jp/article/p-1226592440169 [Accessed 12 March 2019].45. Pharma Japan (2018b) Kyowa Kirin Officially Announces Launch of Japan’s 1st Rituxan Biosimilar on Jan. 18. Available from: https://pj.jiho.jp/article/p-1226591337771 [Accessed 12 March 2019].46. Pharma Japan (2018c) Japan Approves 1st Rituxan Biosimilar from Sandoz. Available from: https://pj.jiho.jp/article/p-1226590448055 [Accessed 12 March 2019].47. Roche (2018a) 9 Months Sales 2018 Webcast Replay. Available from: https://www.roche.com/investors/agenda/q3-2018.htm [Accessed 11 March 2019].48. FDA (2017) FDA approves first biosimilar for the treatment of cancer. Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm576112.htm [Accessed 12 March 2019].


Rank Brand (molecule) CompaniesUS primary patent expiry year

Comment

1 Humira (adalimumab) AbbVie, Eisai 2022

AbbVie has entered into settlement agreements with several companies, including Amgen, Samsung Bioepis, and Mylan, for the entry of adalimumab biosimilars in 2023.

2 Revlimid (lenalidomide) Celgene 2027

As part of Celgene’s settlement agreement with Natco Pharma, generic lenalidomide will be permitted to enter the US market in March 2022 via Natco Pharma’s volume-limited license.

3 Opdivo (nivolumab)Bristol-Myers Squibb, Ono Pharmaceutical

2027

A patent term extension of Bristol-Myers Squibb and Ono Pharmaceutical’s composition of matter patent has extended expiry to 2028.

4 Enbrel (etanercept) Amgen, Pfi zer, Takeda 2029

There is ongoing patent litigation with Sandoz, which has an FDA-approved etanercept biosimilar, Erelzi.

5 Herceptin (trastuzumab)

Roche, Chugai (subsidiary of Roche)

2019

Roche and Mylan entered into a global settlement agreement regarding Mylan’s trastuzumab biosimilar (Ogivri); however, potential launch dates were undisclosed. Ogivri is expected to be the fi rst trastuzumab biosimilar to reach the US market.

5 Keytruda (pembrolizumab) Merck & Co 2028

7 Avastin (bevacizumab)

Roche, Chugai (subsidiary of Roche)

2019

8 Rituxan (rituximab)Roche, Chugai (subsidiary of Roche)

2018

9 Eylea (afl ibercept) Regeneron, Bayer, Santen 2023

Regeneron’s original composition of matter patent term was extended from May 2020 to June 2023 by the US Patent and Trademark Offi ce.

10 Xarelto (rivaroxaban)

Bayer, Johnson & Johnson 2024

FDA = US Food and Drug Administration

Table 8. US patent expiries of the highest-selling drugs in 2018

Sources: Biomedtracker; Datamonitor Healthcare; Medtrack; Pharmaprojects; various 7, 19, 33, 49-54, 63, 64


Patent litigation is a prevailing theme, and pharmaceutical companies are constantly defending their intellectual property in a fierce manner. During the US Senate Committee on Finance hearing in February 2019, Democratic Senator Ron Wyden likened AbbVie’s protection of Humira’s exclusivity to “Gollum with his ring.”19 This is unsurprising considering that Humira alone accounted for ~61% of AbbVie’s total net revenues in 2018.21 Although biosimilar erosion is less intense than generic erosion, due to numerous barriers to development including the complexity of manufacturing biosimilars, their lower equivalence to the originator product, and the clinical trial requirements for approval, biosimilars are nevertheless a significant threat.55 The EU biosimilar market is more mature than its US counterpart, and there are fewer historical examples of biosimilar launches in the US.56 However, Zarxio (filgrastim; Sandoz/Novartis) gained a 20% share of short-acting filgrastim sales in one year in the US.57 Peak biosimilar penetration rates in the US are expected to vary between 10–35% over four years.58 Given the greater risk and costs associated with developing biosimilars, these offer smaller price discounts compared to generics. Historically, generic erosion in the US has been very strong, with cheap generics claiming 85–90% of the originator’s market within two years of their launch.59-61

Considering that biosimilars and generics can capture substantial market share from pharmaceutical companies’ principal revenue generators, originators respond competitively to biosimilars. Evergreening tactics to prolong exclusivity and retain market share may be adopted, such as seeking patent extensions, development of second-generation drugs, and developing novel drug delivery systems.62 In 2017, Amgen launched its AutoTouch reusable auto-injector for use with Enbrel Mini – a new drug formulation of its blockbuster Enbrel that is associated with less injection site pain .63 Additionally, Roche developed Gazyva (obinutuzumab; Roche/Biogen/Chugai/Nippon Shinyaku) as its third-generation cluster of differentiation (CD)20-targeted monoclonal antibody (MAb), as a follow-on from the success of its anti-CD20 MAb, Rituxan. Gazyva is designed as a stronger inducer of direct cell death and antibody-dependent cell-mediated cytotoxicity versus Rituxan. It is also less dependent on complement-dependent cytotoxicity, which is associated with infusion-related side effects (Datamonitor Healthcare, 2019). Furthermore, a patent term review of Bristol-Myers Squibb and Ono Pharmaceutical’s composition of matter patent has extended Opdivo’s exclusivity by a year (see Table 8) .64

49. AbbVie (2018b) AbbVie Reports Third-Quarter 2018 Financial Results. Available from: https://investors.abbvie.com/news-releases/news-release-details/abbvie-reports-third-quarter-2018-financial-results [Accessed 6 March 2019].50. Celgene (2018) Annual Report 2017. Available from: https://s22.q4cdn.com/728481125/files/doc_financials/annual/Celgene_AR_complete_PDF_041718.pdf [Accessed 6 March 2019].51. Mylan (2017) Mylan Announces Global Settlement and License Agreements with Genentech and Roche on Herceptin®. Available from: http://newsroom.mylan.com/2017-03-13-Mylan-Announces-Global-Settlement-and-License-Agreements-with-Genentech-and-Roche-on-Herceptin-R [Accessed 11 March 2019].52. Merck & Co (2019b) Form 10K. Available from: https://s21.q4cdn.com/488056881/files/doc_financials/2018/Q4/2018-Form-10-K-(without-Exhibits)_FINAL_022719.pdf [Accessed 6 March 2019].53. Regeneron (2018) Form 10K. Available from: https://newsroom.regeneron.com/static-files/9bb09f38-74f7-414a-99a2-6ec085781d42 [Accessed 6 March 2019].54. USPTO (2018) Patent Terms Extended Under 35 USC §156. Available from: https://www.uspto.gov/patent/laws-and-regulations/patent-term-extension/patent-terms-extended-under-35-usc-156 [Accessed 18 April 2019].55. Fuhr JP, Chandra A, Romley J, Shih T, May SG, Vanderpuye-Orgle J (2015) Product naming, pricing, and market uptake of biosimilars. Generics Biosimilars Initiat J, 4, 64–71.56. Rovira J, Lindner L, Giménez E, Espín J, de Labry AO, García L (2013) Biosimilars in the European market. GaBI J, 2(1), 30–35.57. Sarshad M (2017) Major lessons learned from Zarxio’s US launch: the start of a biosimilar revolution. GABI JOURNAL-GENERICS AND BIOSIMILARS INITIATIVE JOURNAL, 6(4), 165–173.58. Mattison et al. (2010) Biosimilars: How Much Entry and Price Competition Will Result? Available from: https://www.ohe.org/publications/biosimilars-how-much-entry-and-price-competition-will-result# [Accessed 3 April 2019].59. Danzon PM, Furukawa MF (2011) Cross-national evidence on generic pharmaceuticals: pharmacy vs. physician-driven markets (No. w17226). National Bureau of Economic Research.60. Grabowski H, Long G, Mortimer R, Boyo A (2016) Updated trends in US brand-name and generic drug competition. Journal of Medical Economics, 19(9), 836–844.61.MUFG (2016) Global Generic Pharmaceutical Industry Review. Available from: https://www.krungsri.com/bank/getmedia/a5599675-701b-49d8-a857-33d247c773a0/BTMU-Research-201602-29.aspx [Accessed 3 April 2019].62. Kumar A, Nanda A (2017) Ever-greening in pharmaceuticals: Strategies, consequences and provisions for prevention in USA, EU, India and other countries. Pharm Regul Aff, 6, 1–6.63. Amgen (2019b) 10-K. Available from: http://investors.amgen.com/phoenix.zhtml?c=61656&p=irol-SECText&TEXT=aHR0cDovL2FwaS50ZW5rd2l6YXJkLmNvbS9maWxpbmcueG1sP2lwYWdlPTEyNzA0NTgyJkRTRVE9MCZTRVE9MCZTUURFU0M9U0VDVElPTl9FTlRJUkUmc3Vic2lkPTU3 [Accessed 6 March 2019].64. Bristol-Myers Squibb (2018) Form 10K. Available from: https://s21.q4cdn.com/104148044/files/doc_financials/annual_reports/2017/Bristol-Myers-Squibb-2017-10-K-FINAL.pdf [Accessed 6 March 2019].


Humira’s strong sales are consolidated by its gold-standard clinical attractiveness, with a broad label and physician familiarity

Humira continues to epitomize commercial drug success as the most lucrative drug in the history of the pharmaceutical market. Prominently, it initially entered the rheumatoid arthritis market as the

first fully humanized MAb therapy.66 Thereafter, its clinical evidence base expanded extensively with global investigations spanning a range of diseases in the immunology and inflammation space, which has earnt it broad coverage with 10 different indications in Humira’s US label (see Table 9).67 Thus, Humira has secured its reputation as the product of choice for rheumatologists.

A deeper dive into the top three drugs in 2018: Humira, Revlimid, and Opdivo

65. Celgene (2019b) Celgene Settles U.S. REVLIMID® Patent Litigation with Alvogen. Available from: https://ir.celgene.com/press-releases/press-release-details/2019/Celgene-Settles-US-REVLIMID-Patent-Litigation-with-Alvogen/default.aspx [Accessed 3 April 2019].66. Abbott (2003) ABBOTT LABORATORIES’ HUMIRA(R) (ADALIMUMAB) MARKS SUCCESSFUL FIRST YEAR TREATING PATIENTS WITH RHEUMATOID ARTHRITIS. Available from: https://www.abbottinvestor.com/news-releases/news-release-details/abbott-laboratories-humirar-adalimumab-marks-successful-first [Accessed 14 March 2019].67. Humira prescribing information (2018) Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125057s410lbl.pdf [Accessed 14 March 2019].

Humira stands firm as the epitome of commercial drug success

The onslaught of patent challenges that companies face places their prized drugs at indefinite risk, and many enter into settlement agreements with biosimilar and generic manufacturers. For example, Celgene entered into a settlement agreement with generics companies whereby the companies hold volume-limited licenses to produce and sell

generic lenalidomide in the future. The permitted percentage volumes of generic lenalidomide are confidential; however, Celgene will provide the companies with a license to allow unlimited sales from January 2026.65 Table 8 highlights key events that affect the exclusivity of the top brands in 2018.


Table 9. Humira’s approved indications

Sources: Biomedtracker; Datamonitor Healthcare; Pharmaprojects; various 67,68

Approved indication US EU

Rheumatoid arthritis (RA) x x

Juvenile idiopathic arthritis (JIA) x x

Polyarticular juvenile idiopathic arthritis x

Enthesitis-related arthritis x

Axial spondyloarthritis x

Ankylosing spondylitis (AS) x x

Axial spondyloarthritis without radiographic evidence of AS x

Psoriatic arthritis (PsA) x x

Psoriasis x

Plaque psoriasis x

Pediatric plaque psoriasis x

Hidradenitis suppurativa (HS) x x

Crohn’s disease (CD) x x

Pediatric Crohn’s disease (CD) x x

Ulcerative colitis (UC) x x

Uveitis (UV) x x

68. Humira SmPC (2018) Available from: https://www.medicines.org.uk/emc/product/2150/smpc [Accessed 14 March 2019].


Humira is forecast to reach peak sales of $7bn in the rheumatoid arthritis market

Humira’s primary indication is rheumatoid arthritis, and Datamonitor Healthcare forecasts Humira to reach peak sales of $7.0bn in 2022 in this market across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) (see Datamonitor Healthcare’s Rheumatoid Arthritis Forecast: Humira,69 Figure 2, and Table 10). Humira

is one of rheumatologists’ and insurers’ first-line choices in the rheumatoid arthritis treatment landscape, alongside competitor Enbrel. Despite having tough competition from first-in-class anti-tumor necrosis factor (anti-TNF) MAb, Enbrel, Humira’s sales in rheumatoid arthritis ($6.2bn in 2018) have exceeded Enbrel’s ($5.3bn in 2018).2,

4-6, 12, 15, 16 Humira offers a longer fortnightly dosing schedule, which is more convenient than Enbrel’s weekly schedule.68, 70

69. Datamonitor Healthcare (2017c) Rheumatoid Arthritis Forecast: Humira. Available from: https://service.datamonitorhealthcare.com/disease/immunology-and-inflammation/rheumatology/rheumatoid-arthritis/forecast/article133632.ece [Accessed 17 April 2019].70. Enbrel prescribing information (2018) Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103795s5569lbl.pdf [Accessed 17 April 2019].

Figure 2. Humira sales in rheumatoid arthritis across the US, Japan, and five major EU markets, by country, 2016–25

7000

6000

5000

4000

3000

2000

1000

02016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US Japan France Germany Italy Spain UK

Sale

s ($

m)

Source: Datamonitor Healthcare, 201769

Sales 2016-25: Min: 2016: $5,174mMax: 2022: $6.954m CAGR 2016-25: 1.08% Sales Change 2016-25: $527m


Humira has reached its overall peak revenue, and will experience increasing biosimilar erosion

Biosimilar adalimumab first entered the EU market in October 2018, following Humira’s EU patent expiry.20,71 Consequently, Humira’s international sales figures will contract from 2019 onwards. In 2023, biosimilar entry is expected in the US, and biosimilar adalimumab may launch with a 20% discount compared to Humira (see Datamonitor Healthcare’s Rheumatoid Arthritis Forecast:

Humira).69 Rheumatologists’ initial caution with biosimilars will likely translate into relatively slow preliminary uptake of biosimilar adalimumab, with use primarily limited to new patients. Increased biosimilar erosion will progress in the long term as physicians’ confidence is bolstered through familiarity and post-marketing data. Anticipated reductions in biosimilar pricing, as additional cheaper biosimilar adalimumab entrants launch, will also contribute to their growing uptake.

71. Center for Biosimilars (2018) Europe Sees Its First Adalimumab Biosimilar Launches. Available from: https://www.centerforbiosimilars.com/news/europe-sees-its-first-adalimumab-biosimilar-launch [Accessed 4 April 2019].

Table 10. Humira sales in rheumatoid arthritis across the US, Japan, and five major EU markets, by country ($m), 2016–25


Note: totals may not sum due to rounding.

Country 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

US 4,028 4,765 5,067 5,348 5,620 5,870 6,164 6,189 5,771 5,233

Japan 283 284 277 265 247 223 194 163 134 112

France 94 76 75 72 67 61 54 45 37 31

Germany 298 296 291 277 259 234 206 174 145 121

Italy 183 180 173 166 157 144 128 110 92 77

Spain 104 103 102 99 94 86 77 66 55 46

UK 184 184 181 174 163 149 132 113 95 80

Total 5,174 5,888 6,164 6,401 6,607 6,768 6,954 6,859 6,327 5,701


Revlimid’s blockbuster sales reflect its integral importance in the multiple myeloma treatment algorithm

Revlimid’s strong commercial performance may be attributed to its use in treating hematological cancers including multiple myeloma, where the drug generates the most revenue (see Table 11). Revlimid has become well established, with expansive use across all lines of therapy, and it is a staple for multiple myeloma treatment regimens as a backbone therapy for combinations

featuring recently approved drugs. It also offers the advantage of greater convenience as an oral formulation, which adds to its clinical attractiveness. Revlimid is Celgene’s oral lenalidomide, which is an analog of thalidomide that is designed to be more potent than its parent compound. The company is experienced in the multiple myeloma market with its portfolio of related drugs – Thalomid (thalidomide), Revlimid, and Pomalyst (pomalidomide) – and Celgene has leveraged its presence in the market to bring Revlimid success (Pharmaprojects, 2019).

Datamonitor Healthcare forecasts severe generic erosion of Revlimid’s multiple myeloma sales after peaking at $10.9bn in 2021

Datamonitor Healthcare forecasts Revlimid to reach peak sales of $10.9bn in 2021 for multiple myeloma across the US, Japan, and five major EU markets (see Datamonitor Healthcare’s Multiple Myeloma Forecast: Revlimid).74 Its sales are anticipated to remain healthy until 2022, when Accord Healthcare is permitted by a settlement agreement to market generic lenalidomide in the EU and US – Revlimid’s US patent cliff is expected in March 2022 .75 Thereafter, severe erosion of Revlimid’s sales is expected, especially since there are fewer barriers to generic development and uptake than with biosimilars, as previously

discussed. Generic lenalidomide will likely be a prime target for many generics manufacturers, considering that Revlimid is the second highest-selling drug. Johnson & Johnson’s CD38-targeted MAb, Darzalex (daratumumab), and Takeda’s oral proteasome inhibitor, Ninlaro (ixazomib), pose further threats to Revlimid’s share of the multiple myeloma market as they are being positioned to compete in the newly diagnosed multiple myeloma and maintenance settings, respectively. In order to maximize commercial opportunities prior to its patent cliff, Revlimid’s potential is being investigated for a number of additional patient segments: first-line diffuse large B-cell lymphoma (ABC subtype), relapsed refractory indolent lymphoma, and first-line follicular lymphoma.76

Revlimid

72. Revlimid prescribing information (2019) Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021880s056lbl.pdf [Accessed 14 March 2019].73. Revlimid SmPC (2018) Available from: https://www.medicines.org.uk/emc/product/347 [Accessed 14 March 2019].74. Datamonitor Healthcare (2018a) Multiple Myeloma Forecast: Revlimid. Available from: https://service.datamonitorhealthcare.com/disease/oncology/other-hematological-cancers/multiple-myeloma/marketed-drugs/?articleId=99181 [Accessed 17 April 2019].75. Celgene (2019c) 10k. Available from: https://www.federalregister.gov/documents/2019/02/06/2019-01026/fraud-and-abuse-removal-of-safe-harbor-protection-for-rebates-involving-prescription-pharmaceuticals [Accessed 4 April 2019].76. Celgene pipeline (2019) Available from: https://www.celgene.com/research-development/pipeline-pdf/ [Accessed 1 April 2019].

Table 11. Revlimid’s approved indications


Approved indication US EU

Multiple myeloma x x

Myelodysplastic syndromes x x

Mantle cell lymphoma x x


Figure 3. Revlimid sales for multiple myeloma across the US, Japan, and five major EU markets, by country, 2017–26

Table 12. Revlimid sales for multiple myeloma across the US, Japan, and five major EU markets, by country ($m), 2017–26



Country 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026

US 4,642 5,125 6,094 7,535 9,357 9,406 5,620 2,892 1,621 1,287

Japan 413 428 442 282 139 114 102 98 97 97

France 118 121 129 144 162 122 67 46 36 32

Germany 256 276 303 347 401 346 212 146 112 100

Italy 312 317 334 369 410 310 168 115 89 79

Spain 137 140 150 174 202 157 86 60 46 42

UK 132 136 149 177 210 180 115 81 65 59

Total 6,011 6,543 7,600 9,027 10,880 10,634 6,369 3,439 2,066 1,695


10000

8000

6000

4000

2000

02017 2018 2019 2020 2021 2022 2023 2024 2025 2026


Sale

s ($

m)

Sales 2017-26: Min: 2021: $10,901mMax: 2026: $1,695m CAGR 2017-26: -13.12% Sales Change 2017-26: -$4,316m


Opdivo is a first-in-class PD-1 immune checkpoint inhibitor used to treat solid tumors

Opdivo is a fully human immunoglobulin G4 PD-1 immune checkpoint inhibitor that is used to treat solid tumors. It has garnered impressive sales as part of the innovative immuno-oncology wave, and

notably boasts the advantage of a broad label and first-in-class status in multiple settings, including NSCLC and renal cell carcinoma. Opdivo has a wide label, with approvals for nine types of cancer, and NSCLC is its most lucrative indication 79 (see Table 13).

Opdivo

In the coming years, Revlimid will fall under Bristol-Myers Squibb’s remit

In April 2019, Bristol-Myers Squibb announced that its shareholders approved its acquisition of Celgene, after investors had previously pushed back against the deal77 (see also Scrip: Will Shareholders Support the Bristol/Celgene Merger? – an Informa Pharma Intelligence Podcast78). The deal, worth $74bn, is set to close in Q3 2019. In particular, Revlimid was a sticking point for Bristol-Myers

Squibb’s institutional investors. Considering that Revlimid is Celgene’s chief revenue generator, worth 63% of the company’s total revenue in 2018, the potential for generic lenalidomide to carve out a substantial portion of sales after the next few years was considered risky.75 Nevertheless, this merger means that Bristol-Myers Squibb will own two of the most profitable drugs in the pharmaceutical market (Revlimid and Opdivo), in addition to Celgene’s prized immuno-oncology portfolio.

77. Bristol-Myers Squibb (2019b) Bristol-Myers Squibb Shareholders Approve Celgene Acquisition. Available from: https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-shareholders-approve-celgene-acquisition [Accessed 17 April 2019].78. Scrip (2019) Will Shareholders Support the Bristol/Celgene Merger? – an Informa Pharma Intelligence Podcast. Available from: https://scrip.pharmaintelligence.informa.com/SC124973/Will-Shareholders-Support-The-BristolCelgene-Merger--An-Informa-Pharma-Intelligence-Podcast [Accessed 17 April 2019].79. Opdivo prescribing information (2019) Available from: https://packageinserts.bms.com/pi/pi_opdivo.pdf [Accessed 18 March 2019].80. Opdivo SmPC (2019) Available from: https://www.medicines.org.uk/emc/product/6888 [Accessed 18 April 2019].

Table 13. Opdivo’s approved indications


Approved indication US EUMelanoma x xNon-small cell lung cancer (NSCLC) x xSmall cell lung cancer x* Renal cell carcinoma (RCC) x xClassical Hodgkin lymphoma (cHL) x* xSquamous cell cancer of the head and neck (SCCHN) x xUrothelial carcinoma x* xColorectal cancer (CRC) x* Hepatocellular carcinoma x *This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.


Opdivo has established a strong position in the NSCLC market, and Datamonitor Healthcare forecasts peak sales of $4.9bn in 2024

For Opdivo’s primary market, NSCLC, Datamonitor Healthcare forecasts the drug to achieve peak sales of $4.9bn in 2024 (see Datamonitor Healthcare’s NSCLC Forecast: Opdivo).81 The PD-1 inhibitor demonstrated potent overall survival (OS) improvements over chemotherapy in pivotal Phase III trials investigating patients with squamous and non-squamous metastatic NSCLC who

experienced disease progression during or after a prior platinum doublet-based chemotherapy regimen. In the CheckMate 057 trial testing Opdivo in non-squamous NSCLC (ClinicalTrials.gov identifier: NCT01678367), patients treated with Opdivo experienced a median survival extension of 2.8 months over docetaxel chemotherapy (12.2 months versus 9.4 months). In the CheckMate 017 trial (ClinicalTrials.gov identifier: NCT01642004), OS was 3.2 months longer in the Opdivo arm compared to docetaxel chemotherapy (9.2 months versus 6.0 months) (Biomedtracker, 2019).

81. Datamonitor Healthcare (2018b) Non-Small Cell Lung Cancer Forecast: Opdivo. Available from: https://service.datamonitorhealthcare.com/disease/oncology/lung-cancer/non-small-cell-lung-cancer/marketed-drugs/?articleId=118908 [Accessed 17 April 2019].

Figure 4. Opdivo sales for NSCLC across the US, Japan, and five major EU markets, by country, 2017–26


5000

4000

3000

2000

1000

02017 2018 2019 2020 2021 2022 2023 2024 2025 2026


Sale

s ($

m)

Sales 2017-26: Min: 2019: $1,788mMax: 2024: $4,906m CAGR 2017-26: 10.87% Sales Change 2017-26: -$2,786m


Opdivo’s market share is under threat from competitors in its class, including Merck & Co’s Keytruda, and sales are expected to decline prior to patent expiry

Opdivo sales are forecast to decline prior to patent expiry as a result of competitor dynamics within the PD-1 inhibitor class. Bristol-Myers Squibb and Ono Pharmaceutical missed a key opportunity to demonstrate robust data to support Opdivo’s first-line use in NSCLC, and therefore Merck & Co’s Keytruda may represent a more attractive option. Bristol-Myers Squibb’s decision to adopt the less well-established tumor mutational burden (TMB) biomarker in its Phase III CheckMate 227 trial (ClinicalTrials.gov identifier: NCT02477826) at the first-line setting, after the failure of the first-line CheckMate 026 trial (ClinicalTrials.gov identifier: NCT02041533) that used accepted PD-L1 expression

levels, did not inspire confidence from physicians (Biomedtracker, 2019). Adopting the TMB biomarker puts Opdivo at a disadvantage compared to other PD-1 inhibitors. Notably, Keytruda (another top brand in 2018) may be favored in light of its positive KEYNOTE-189 trial (ClinicalTrials.gov identifier: NCT02578680), which allowed it to become the first PD-1/PD-L1 inhibitor to secure approval in the first-line setting.82 Nonetheless, Bristol-Myers Squibb and Ono Pharmaceutical are testing Opdivo at the first-line setting in combination with their anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) MAb, Yervoy (ipilimumab), and platinum-based doublet chemotherapy, in the Phase III CheckMate 9LA trial (ClinicalTrials.gov identifier: NCT03215706), which is due to complete towards to end of 2019 (Biomedtracker, 2019). This could facilitate greater penetration of the largest possible target patient population for Opdivo.

82. Eli Lilly (2019) FDA Expands Lilly's ALIMTA® (pemetrexed) Label with Combination of KEYTRUDA® (pembrolizumab) and Platinum Chemotherapy for the First-Line Treatment of Metastatic Nonsquamous Non-Small Cell Lung Cancer. Available from: https://investor.lilly.com/news-releases/news-release-details/fda-expands-lillys-alimtar-pemetrexed-label-combination [Accessed 25 April 2019].

Table 14. Opdivo sales for NSCLC across the US, Japan, and five major EU markets, by country ($m), 2017–26



Country 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026US 801 816 854 1,112 1,508 1,917 2,207 2,338 2,401 2,467 Japan 510 503 499 630 903 1,206 1,385 1,422 1,372 1,293 France 90 85 78 94 136 185 216 221 214 160 Germany 135 126 115 133 184 245 281 286 275 218 Italy 134 126 116 135 187 247 283 289 279 223 Spain 81 76 70 87 134 189 223 230 222 152 UK 68 63 57 62 80 103 116 119 116 93 Total 1,819 1,794 1,788 2,254 3,132 4,092 4,711 4,906 4,881 4,605


About the Author

Stephanie YipSenior Analyst

As a Senior Analyst at Datamonitor Healthcare, Stephanie Yip provides in-depth insights as part of the central nervous system and immunology & inflammation team. Her work involves liaising with key opinion leaders, analyzing treatment landscapes, and tracking market-moving events to build robust forecasts. Since joining Datamonitor Healthcare in 2017, Stephanie has produced disease content on epilepsy, bipolar disorder, schizophrenia, pulmonary hypertension, and depression. She will further expand her primary coverage to include rheumatoid arthritis as well as other immunology & inflammation disorders. Stephanie also writes comments for Biomedtracker on a wide range of diseases, and produces thought leadership pieces. Prior to working at Datamonitor Healthcare, Stephanie gained experience as an editorial assistant in scientific publishing. She graduated from Imperial College London with a Biomedical Science degree.

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