Monoclonal Antibody

Monoclonal Antibody “Gold Rush” Triggers Pharma R&D Paradigm Shift

Key Words: R&D shift, top ten, top companies, monoclonal antibodies, high cost, global sales.

Abstract

The overview of the monoclonal antibody R&D and analysis of the 2008 market and sales data is presented. During the past 5 years, the global mAbs market has grown from $7 billion in 2004 to $35 billion in 2008. Factors fueling the current Gold Rush and its implication for increased R&D funding are discussed. The commercial success has resulted in significant increase in R&D projects, late-stage clinical trials, new indications and filings for approval. There were over 200 antibodies out of 630 biologics in clinical trials testing for cancer, arthritis, infections, asthma, macular degeneration, osteoporosis, diabetes and other chronic diseases. Increased sales and profitability have attracted mainstream pharmaceutical companies. Traditional pharma has brought better focus, management and resources for regulatory approval and global marketing.

Introduction

When Remicade and Rituxan reached blockbuster status in 2004, the event was mostly ignored by the mainstream pharmaceutical industry and the media. A new generation of humanized and human mAbs targeting TNFα and cell surface receptors and growth factors has become the treatment of choice for immune inflammatory disease, cancer and infections. With the advance of technology and our understanding of the immune system, it is possible to generate mAbs against any type of biological target and then transform mice mAbs into humanized and fully human ones [1, 2]. The current paper discusses how the market success is driving the R&D and highlights some selected trends, opportunities, constraints and future risks. Data Collection and Analysis Company annual and quarterly reports and presentations provide easy access to real data for their top selling products. The listing of their top selling drugs, sales and R&D portfolio and new drug filings and approval are available at company web sites. The annual sales forecast for top selling medicinal brands is based on company annual guidance, 3Q sales data and growth rates. To validate the projection method once again, both actual and projected brand sales for 2008 are provided. Data about approved drugs is available from FDA, FDA advisory committee material, Med Watch, Prescribing Information and Black Box Warning if any and EMEA scientific evaluation as well as safety alerts. Drug specific sites established by companies and other sites list drug-related information, list of ongoing clinical trials, list of publications and abstracts at scientific meetings and reported adverse events.

Results and Discussion

Introduction of new generation of commercially successful brands and protection from patent expiry and lack of biosimilar has revived industry interest in research and development of safe and more effective human mAbs.

The following factors have played a major role in the revival of mAbs R&D [3-5]. 1. Technology for humanized and human mAbs. 2. Commercial success of Remicade, Rituxan, Avastin, Herceptin and Humira. The first 3 are in the top ten and all five are in the top twenty list of best selling global medicinal brands in 2008. 3. Strong demand from patients with unmet medical needs: cancer, arthritis, psoriasis, Crohn’s disease, ulcerative colitis and RSV. 4. Efficacy of new mAbs with improved affinity and specificity in target binding and higher success rate for approval. 5. High cost in the $5000-30000 range leading to faster commercial success like Avastin and Humira. 6. Considered highly innovative, life saving and improving quality of life. 7. Approval in chronic indications, multiple sclerosis, diabetes, asthma, osteoporosis and macular degeneration to expand market. 8. Absence of biosimilar products. Global Market, Top Ten Drugs Monoclonal antibodies are one of the current success stories of the modern biotechnology R&D. The global sales of monoclonal antibodies were $33 billion in 2008 as compared to $27 billion in 2007 (Fig 1). No other drug class can match the double digit growth of the past 5 years [6]. The main market for mAbs in 2008 was for treatment of cancer 51% and immuno-inflammatory diseases 39% (Fig.2). Several new commercial monoclonal antibodies research reports issued in 2008 (Datamonitor, Frost and Sullivan), predicted that the total monoclonal antibody market would reach $30 billion only in 2011. These reports once again underestimated the total market and high growth rate due to unmet medical need of the cancer and autoimmune and inflammatory disease patients. Remicade has been the best selling antibody since 2004 and was the market leader with sales of $6.5 billion in 2008, followed by Rituxan, Avastin, Herceptin and Humira. The first 3 made the top ten and all 5 made the top twenty global best selling human medicinal brands [6, 7]. There were 8 monoclonal antibodies with sales of $1 billion or more in 2008 (Table 1). The time taken by each of these top brands to reach blockbuster sales has been described previously [5]. Roche was the market leader in this segment with five blockbuster drugs followed by J&J and Abbott. Only two biotechnology companies (Amgen and Biogen Idec) are listed in Table 1. Most of the other biotechnology companies were acquired by pharmaceutical majors. Sales data for all other approved and marketed monoclonal antibodies with sales <$100 million are not included. Sales data for low selling brands is not available in public domain. These include 3 brands used in transplant Zenapex, OKT3 and Simulect, Amevive for Psoriasis, anticancer like Campath, Mylotarg, Zevalin, Bexxar, 3 diagnostic products, two new Chinese brands, one new Indian brand and a Cuban product Arzerra (BIOMab) were excluded (Table 1). Commercial reports are suitable for sales data for these minor brands and for sales in China and India. It is estimated that these other mAbs generated sales of $1 billion which will swell the global sales to $34 billion [8]. The recently approved and launched monoclonal antibodies, Lucentis has already crossed $1 billion annual sales, Tysabri and Xolair will reach the milestone in 2009. Cimzia will reach blockbuster sales within the next 2-3 years depending on approvals in new indications. The pathway for biosimilar monoclonal antibodies has not been defined so far either by EMEA in Europe or by FDA in USA. Thus monoclonal antibodies are immune to patent expiry or entry of biosimilar generics. Failed/Discontinued/Delayed Projects Poor results in advanced Phase III clinical trials and lack of efficacy resulted in termination or delays of 6 leading monoclonal antibodies in 2008. These included Certolizumab, Aurograb, Ovarex, Ticilimumab, Nuvion and Ipilimumab. Novartis terminated one of NeuTec project AuroGrab vs. drug resistant MRSA and its second MycoGrab vs. Candida approval was blocked by EMEA due to quality issues. Eisai discontinued its filing for approval in Japan for a TNF mAbs without providing any details. At least 6 mAbs in Phase III trials failed to meet efficacy criteria. Lack of clear results for Ipilimumab for melanoma with variable and low response rates (<10%) has delayed the regulatory filing for approval by three years [5, 6]. FDA asked for progression free survival data which will be available in early 2010. Phase II data shows 34-38% of treated patients survived for 24 months or more compared to historic controls at 6 months. FDA Approval Only one new monoclonal antibody was approved by FDA in 2007 and 2008. Cimzia from UCB and Tysabri from Biogen Idec for additional indication for Crohn’s disease were approved in 2008. Soliris (Eculizumab) a complement C5 inhibitor from Alexion was approved for paroxysmal nocturnal hemoglobinuria in 2007. In early 2009, there were 25 monoclonal antibodies in Phase III trials, 30 in Phase II and 6 filed for approval with FDA/EMEA. Roche Actemra (Tocilizumab) an IL6R monoclonal antibody was approved to treat RA patients in Japan and is awaiting approval in USA/Europe. Stelara (Ustekinumab, CNTO 1275) from J&J to treat psoriasis was approved by Canada in 2008 and by EMEA for Europe in Jan 2009. A Cuban-discovered EGFR targeting monoclonal antibody BIOMab (Nimotuzumab) has been marketed in a number of countries to treat squamous cell carcinoma and glioma. Similarly China and India have approved 2 and 1 cancer mAbs. Golimumab (CNTO 148) a TNF inhibitor from J&J was filed for regulatory approval in US and Europe for treating rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Denosumab which targets RANK pathway from Amgen is likely to be approved for osteoporosis and breast and prostate cancer in 2009? GSK and Genmab have submitted Ofatumumab an anti CD20 mAb for FDA approval to treat refractory chronic lymphocytic leukemia [6].

Several promising monoclonal antibodies are in Phase III trials like Pfizer/ImClone human Ramcirumab for breast cancer, Pfizer IgG2 mAbs for non small cell lung cancer, GSK anti CD3 Otelexizumab for diabetes, Roche Pertuzumab for metastatic breast cancer, Lilly mAb to decrease the amount of soluble amalyoid and Wyeth/Elan Bapineuzumab for Alzheimer's disease. 

Serious Infections Tysabri (Natalizumab, Biogen Idec, and Elan) for multiple sclerosis was approved in Nov. 2004 but withdrawn in Feb. 2005 due to a rare fatal brain lesion (progressive multifocal leukoencephalopathy PML) in some patients and was approved in June 2006 under a risk minimization plan and black box warning. Regular monitoring of patients at 3 and 6 months is required after starting the treatment. PML deaths and infections have been reported in patients and linked to treatment with Raptiva and Rituxan. Black box warnings have been added by FDA and EMEA was considering market withdrawal of Raptiva. Prolonged and wider use of monoclonal antibodies may results in increased risk of serious infections like tuberculosis, invasive fungal infections and bacterial sepsis (Humira, Cimzia) [9]. As the therapeutic use of existing and newer mAbs extends to millions of patients over longer periods, the incidence of serious adverse events including deaths are going to increase. All companies should follow the lead of Biogen Idec and implement similar risk identification and minimization plan for regular monitoring and follow up of patients treated with mAbs. Clinical trials of monoclonal antibodies targeting chronic diseases in patients should be closely monitored for signs of serious brain and other infections.

High Cost = Rolls Royce Status

Monoclonal antibodies are more expensive to produce in comparison with other biologics like proteins. As a result mAbs are marketed at higher prices. Bexxar (Tositumomab, GSK) and Zevalin (Ibritumomab, Biogen Idec) to treat Non Hodgkin’s Lymphoma are considered the “Rolls Royce” of medicinal brands. As the most expensive medicinal brands, these two have a price tag of $28000-30000 per month of treatment. The overall sales of these two drugs are low as high cost restricts the therapeutic use. The high price of Amgen Vectibix for at $8500 per month and absence of any additional benefits when given together with standard chemotherapy has prevented its incorporation into a standard treatment regimen for colon cancer [10].

Treatment of arthritis patients has increased to $30000 and cancers like leukemia and lymphoma to $100000 per year. If all new drugs were used for colon cancer, the cost would go up to $250000. No healthcare system in the world can cope with such cost increases for all the new indications/chronic diseases for which new mAbs are marketed. The majority of patients in developing world and poor countries are waiting for access to affordable new biologic treatments.

PhRMA’s Partnership for Prescription Assistance (https://www.pparx.org/Intro.php) provides access to over 475 public-private patient assistance programs in USA. Low income and poor patients without healthcare insurance can enroll in a matching program and obtain free prescription drugs or drugs at a nominal cost. Patients can request samples from their healthcare providers or enroll in clinical trials to obtain free medication.

Pharmaceutical Grab

The explosive growth in the antibody market over the past 5 years, with increasing profits, attracted corporate raiders ahead of the mainstream pharmaceutical industry. Traditional pharma now dominates the market and has displaced the original and innovative biotechnology players. It is now difficult to find a pharmaceutical company without mAbs in advanced clinical trials or regulatory filings. All pharma CEOs highlighted the value of mAbs in annual presentations of results and R&D updates in early 2009. Pharmaceutical companies’ outright acquisition of biotechnology companies and licensing of technology/late stage monoclonal antibody projects in development increased in spite of the market downturn in 2008. This was evident by MerckAG acquiring Serono, Astra Zeneca absorbing MedImmune and Cambridge Antibody Technology, Takeda taking over Millennium and Roche taking over the remaining shares of Genentech for $47 billion. These deals provided late stage mAbs projects to the pharma company and added value, balanced the portfolio and increased chances for technical success. MedImmune provided Astra Zeneca with 2 regulatory filings, 2 Phase III, 4 Phase II and 8 Phase I projects. Commercial success of just 1 or 2 projects will pay back the investment.

There were five billion dollar licensing deals in mAbs.33 GSK valued a Phase III mAbs from Genmab for over $2 billion, application for marketing approval from FDA was filed in early 2009. Sanofi Aventis and Novartis raised the stakes by paying $1 billion each for pre IND candidates from Regeneron and MorphoSys [11].

The market and sales data for monoclonal antibodies in 2008 provide once again strong support for the continued Gold Rush and R&D paradigm shift to biologic and within biologic towards human mAbs.

Acknowledgements

I thank my wife Dr. Sunita Maggon for literature search, review and critical comments on the draft and to Mr. Jean-Antoine de Mandato (PDP, Geneva) for providing office facilities and administrative support.

Conflict of interest

The author has not declared any conflict of interest except as an industry professional and consultant to the industry. The direct and indirect cost of this article has not been funded by any sponsor, public or private agency.

References

1. Gombotz W, Bechtold-Peters K, Andva J. eds. Pharmaceutical Aspects of Monoclonal Antibodies. Springer, 2009. ISBN 0387766421, 9780387766423 2. Grewal I. S. Therapeutic Targets of the TNF Superfamily. Springer. 2009 ISBN: 978-0-387-89519-2 3. Tabrizi M. A, et al. (2009) Translational strategies for development of monoclonal antibodies from discovery to the clinic. Drug Discov Today. 14(5-6): 298-305. Epub 2009 Jan 17. PMID: 19152840 [PubMed - in process] 4. Reichert J. M. (2008) Monoclonal antibodies as innovative therapeutics. Curr. Pharmaceut. Biotechnol. 9: 423-430. 5. Maggon K. (2007) Monoclonal Antibody “Gold Rush”. Current Med. Chem. 14: 1978-1987. http://dx.doi.org. 10.2174/092986707781368504. 6. Maggon K. (2009) Global Monoclonal Antibodies Market Review 2008 (World Top Ten mAbs). http://knol.google.com/k/krishan-maggon/global-monoclonal-antibodies-market/3fy5eowy8suq3/11# 7. Maggon K.(2009) Global Pharmaceutical Market Review & World Top Ten/Twenty Drugs 2008. http://knol.google.com/k/krishan-maggon/global-pharmaceutical-market-review/3fy5eowy8suq3/6# 8. Scolnik P.A. (2009) mAbs: A business perspective. mAbs. 1:2: 179-184. 9. Salliot C, Dougados M, Gossec, L. (2009) Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomized placebo-controlled trials. Annals Rheumat. Dis. 68: 25-32. 10. Yan L, Ehrich P.J, Gibson R, Beckman R.A. (2009) How can we improve antibody based cancer chemotherapy? mAbs, 2009; 1:1: 67-70. 11. Villiger R. Bogdan B. (2009) Dissecting monoclonal antibody mega-deals. mAbs. 1 :2: 172-178.

Table 1. Best Selling Monoclonal Antibodies 2006-2008 Sales $ billion Generic Name Target Brand FDA Approval web site Company Monthly mAb Cost $ Indications 2006 2007 2008 Actual (Projected) Infliximab TNFα Remicade 1998 www.remicade.com J&J 2000-2500 CD, UC,AS,RA, Ps, PsA 4.2 5.04 6.2 (6.5) Rituximab CD20 Rituxan 1997 www.rituxan.com Roche 4000-13000 Leukemia, Lymphoma, RA 4.7 5.01 5.48 (5.6) Bevacizumab VEGF Avastin 2004 www.avastin.com Roche 4500 Colon, Lung BreastCancer 2.4 3.93 4.82 (4.7) Trastuzumab HER2 Herceptin 1998 www.herceptin.com Roche 3000 Breast Cancer 3.14 4.4 4.72 (4.8) Adalimumab TNFα Humira 2002 www.humira.com Abbott 2500 RA, JIA, PsA, Ps, AS, CD 2.04 3.06 4.5 (4.4) Ranibizumab VEGF Lucentis 2006 www.lucentis.com Novartis, Roche 2000 Macular Degeneration 0.38 1.2 1.77 (1.5) Cetuximab EGFR Erbitux 2004 www.erbitux.com Bristol Myers Squibb Merck Serono 10000 Colon, Head & Neck Cancer 1.1 1.35 1.57 (2.0) Palivizumab RSV Synagis 1998 www.synagis.com Astra Zeneca 5600 RSV 1.1 1.1 1.23 (1.2) Natalizumab, α4 Integrin Tysabri 2004/2006 www.tysabri.com Biogen Idec, Elan 2200 Multiple Sclerosis, CD 0.06 0.46 0.85 (0.6) Omalizumab IgE Xolair 2003 www.xolair.com Roche, Novartis 600-2700 Allergic Asthma 0.52 0.64 0.73 (0.85) Abciximab CD3 ReoPro 1994 www.reopro.com/ J&J, Lilly 1400 Thrombosis Inhibitor 0.28 0.29 0.35 Efalizumab CD11a Raptiva 2003 www.raptiva.com/ Genentech MerckSerono 1100 Psoriasis 0.16 0.21 0.25 (0.28) Panitumumab EGFR Vectibix 2006 www.vectibix.com Amgen 8500 Colon Cancer 0.04 0.21 0.15 (0.3) Certolizumab TNFα Cimzia 2008 www.cimzia.com/ UCB 2500 CD, RA 0.015 Tocilizumab IL6 Actemra Japan 2008 EMEA 2009 Roche RA Ustenkinumab Il12, IL23 Stelara EMEA 2009 J&J Psoriasis Golimumab Simponi FDA 2009 J&J RA, PsA, AS

Updated and Modified Table 1 from references 4-5. mAbs Identification -omab Mouse, -ximab Chimeric, -zumab Humanized, -umab Human, Abbreviations Used IgE Immunoglobulin E, IL 2,6,23 Interleukins, CD11a, 20, 3 cell surface receptor, HER 2 human epidermal growth factor receptor 2, VEGF Vascular endothelial growth factor, EGFR Epidermal growth factor receptor, RSV Respiratory Syncytial Virus TNFα Tumor Necrosis Factor Alpha

AS Ankylosing spondylitis, CD Crohn’s Disease; Ps Psoriasis, PsA Psoriatic arthritis, RA Rheumatoid Arthritis UC Ulcerative Colitis, JRA Juvenile Rheumatoid Arthritis

The Antibody Resource Page. http://www.antibodyresource.com/educational.htmlMonoclonal Antibody Journal mAbs. http://www.landesbioscience.com/journals/mabs/ FDA http://www.fda.gov EMEA http://www.emea.eu.int PhRMA’s Partnership for Prescription Assistance https://www.pparx.org/Intro.php IMS http://www.ims-global.com/ DataMonitor http://www.datamonitor.com/ ASCO 2009 Abstracts dealing with mAbs http://www.abstract.asco.org/CatAbstView_65_10_AA.html

Updated and modified Figure 1 from references 4-5.

Cimzia was approved by FDA with black box warning and under stringent new safety plan to detect, identify and minimize risk Risk Management and Minimization Plan. It the only TNF blocker with such conditional approval and carries higher risk of cardiovascular, drug induced cancer and serious infections.

In early 2009, two new mAbs were approved. FDA approved a self injecting TNF blocker Simponi (golimumab, J&J) to treat rheumatoid arthritis, rheumatic psoriasis and ankylosing spondylitis and EMAE approved Stelara (Ustenkinumab, J&J) an interleukin blocker for psoriasis.

Tocilizumab (Actemra) has been hailed and touted as the new blockbuster mAbs from Chugai/Roche to treat arthritis and two recent reviews were published in latest editions of Nature Review Drug Discovery (with IMS sales projections) and in mAbs (ex IMS Health staff is Chief editor). These reviews were timed by Roche to its market launch in Europe. It was approved in Japan last year and by EMEA in January 2009. So relying on primary sources, it is a great new potential blockbuster.

In March 19, 2009, a Chugai press release stated that Actemra has been linked to 15 suspected deaths in Japan in within 10th month of marketing (Reuters news alert). In addition the drug was linked with 221 cases of serious adverse reactions. These are very high numbers as only 5000 patients were treated with the drug in Japan. Roche web site and Roche Actemra site (checked yesterday) does not mention this important fact. IMHO, Actemra is unlikely to get FDA approval and may face regulatory problems in Europe and is a R&D failure in my view.

It confirms my general statement that wider use of biologics need careful monitoring and regular follow up.

In Actemra case, the primary sources of information has been overtaken by the secondary source. In my view both the primary and secondary sources can be manipulated and timed by the industry.

References

Oldfield V, Dhillon S, Plosker GL. (2009) Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs. 69(5): 609-32. doi: 10.2165/00003495-200969050-00007.

C Scheinecker, J Smolen, U Yasothan, J Stoll, P Kirkpatrick. (2009). Nature Reviews Drug Discovery 8, 273-274 (April 2009) |doi :10.1038/nrd2863.

. M Hirao, J Hashimoto, H Tsuboi, A Nampei, H Nakahara, N Yoshio, T Mima, H Yoshikawa and N Nishimoto. (2009). Laboratory and febrile features after joint surgery in patients with rheumatoid arthritis treated with tocilizumab. Published Online First: 2 June 2008. doi:10.1136/ard.2008.090068. Annals of the Rheumatic Diseases 2009; 68:654-657[[Category:|Category:]]