Emerging oncology treatments: A focus on targeted therapeutics, supergeneric reformulations and supportive care

Emerging oncology treatments: A focus on targeted therapeutics, supergeneric reformulations and supportive care (LeadDiscovery Special Feature - February, 2005)

The oncology market is the third largest pharmaceutical market, behind the cardiovascular and CNS therapy areas, and is currently experiencing strong growth. Worth an estimated $35 billion in 2003, analysts predict that the sector will grow to $60 billion by 2010, yielding a compound annual growth rate of 8% over this period. Major changes are however occurring in the oncology market. Cytotoxics, a cornerstone of oncology, are reaching patent expiry and the last cytotoxic genericization is expected in 2011 (Xeloda). To combat these patent expiries companies are developing supergenerics which differ from the original product in formulation or method of delivery. Supergeneric versions of Taxol, such as Cell Therapeutics' Xyotax (polyglutamate paclitaxel) and Abraxis Oncology's Abraxane (nanoparticle albumin-bound paclitaxel) have been developed and offer significant advantages over Taxol in terms of adverse effects and drug delivery. The frequency and debilitating nature of cytotoxic adverse effects will remain a considerable problem however, and the sale of supportive care treatments to limit anemia, neutropenia, nausea and oral mucositis therefore constitutes the majority of oncology sales. This will remain the case over the next decade and indeed supportive care therapeutics will be one of the only classes to maintain a positive compound annual growth rate over this period. The other class is that of the targeted therapeutics led by Biogen-Idec/Roche's MabThera, OSI/Genentech/ Roche's Herceptin and Novartis' Glivec. This special feature profiles the oncology market as well as emerging therapeutic classes and agents.

For up to date information on oncology therapeutics & markets see: Cancer Market Top 20 Drugs

The cancer therapeutics market will be worth $60 billion by 2010 despite some pharmacoeconomic constraints: Over the course of the next decade a number of global and country-specific factors will provide growth in the cancer market with the sector reaching a value of $60 billion by 2010. Opportunities for the pharma industry will come in the form of a predicted 50% rise in the global incidence of cancer between 2000 and 2020; a rise in prominence for treatment approaches employing molecular-targeted drugs; improved diagnostics and the emergence of personalized medicine; and the maintenance of cancer's high profile in shaping government healthcare policy. Conversely, pharmacoeconomic constraints such as increasing research and development costs, restrictive pricing and reimbursement policies and reduced periods of market exclusivity will mean that lifecycle management strategies will play an increasingly prominent role in maximizing product revenues and ensuring an adequate return for the financial risks incurred in developing new drugs.

The top 20 cancer drugs account for 77% of global oncology revenues however the market will dramatically change as many of these drugs come off patent: In 2004, the top 20 cancer drugs in each of the seven major pharmaceutical markets generated combined sales approaching $27 billion, with the US accounting for two-thirds (66%) of this total, Japan 13% and the five leading EU countries 21% (Midas, IMS Health, April 2004). Collective sales in these markets represent approximately 77% of global oncology revenues, clearly demonstrating the industry's strong reliance on these specific products and geographical markets for income generation. While the economic value of these brands is undisputed, the looming threats of therapeutic competition and, of even greater significance, patent expiry provide a considerable commercial and clinical challenge to the industry.

Patent expiries threaten anti-hormonal and cytotoxic sales: In breaking down the seven-market top 20 drugs by therapeutic class, the supportive care drugs including recombinant growth factors and antiemetic serotonin antagonists constitute the majority of sales (48%) exceeding those of the cytotoxics (24%), innovatives (15%) and antihormonals (13%). Over the course of the next decade, analysts predict that of the cancer drugs that currently have a top 20 position in the seven markets, only those in the innovative and supportive care classes will maintain a positive compound annual growth rate (5.1% and 3% respectively). Conversely, members in the cytotoxic and antihormonal categories will experience declining sales over the period 2004-14, with patent expiries having the greatest influence on reducing market share. In the US, for instance, patent expiration will affect six of the seven cytotoxic drugs in the current top 20, the latest date of genericization occurring in 2011 (Xeloda). Similarly, in the US market the patent on all drugs in the antihormonal class will be complete by 2009.

Innovative life cycle management to provide a driver for the market: Strategies to mitigate the challenge of patent expiry, generic incursion and therapeutic competition will rely on innovative approaches to lifecycle management and sustained research and development productivity to maintain a commercially attractive product pipeline. This is well exemplified by the vinca alkaloids, which include the taxanes, the largest class of cytotoxics in terms of sales. BMS’ Taxol (paclitaxel) once dominated not only the class but also the cytotoxic market as a whole. However, because of its patent expiry, it has lost its leading position to its rival drug, Aventis’ Taxotere (docetaxel). In order to maintain the dominance, Aventis will need to continue to market the drug aggressively in the light of generics. Generics are arriving on the market in two forms: commodity generics, which are clones of the original drug; and supergenerics which differ from the original product in formulation or method of delivery. Supergeneric versions of Taxol, such as Cell Therapeutics' Xyotax (polyglutamate paclitaxel) and Abraxis Oncology's Abraxane (nanoparticle albumin-bound paclitaxel) have been developed and offer significant advantages over Taxol.

Product focus - Abraxis Oncology's Abraxane (nanoparticle albumin-bound paclitaxel): Abraxane has significant advantages over paclitaxel and is set to become a key cytotoxic (see Breast Cancer - Complex Combinations of Old and New). Abraxane is an albumin-bound nanoparticle formulation of paclitaxel developed by American Pharmaceutical Partners. Paclitaxel is difficult to administer because it is formulated in Cremophor, a mixture of castor oil and ethanol, which is extremely irritating to blood vessels and requires surgical placement of a large catheter for administration. It also may cause allergic reactions, and typically requires a minimum of three hours of intravenous infusion. Abraxane is much more soluble than paclitaxel and does not require the use of toxic solvents allowing increased dosages to be administered over 30 minutes using standard IV tubing without premedication to prevent hypersensitivity reactions. A pivotal clinical trial has demonstrated that Abraxane had superior response rate when compared to Taxol in patients with metastatic breast cancer. (For an in depth insight into drug delivery technology in development for the treatment of cancer see Drug Delivery in Cancer - technologies, markets and companies). Abraxane is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. The Abraxane New Drug Application (NDA) was approved by the FDA on January 7, 2005 and was launched February 2005 by Abraxis Oncology, American Pharmaceutical Partners' proprietary sales and marketing division. Merrill Lynch analysts forecast Abraxane sales of $40 million in 2005 rising to $275 million by 2009.

Product focus - Cell Therapeutics' Xyotax (polyglutamate paclitaxel): Xyotax (paclitaxel poliglumex) is a biodegradable polyglutamate polymer developed to selectively deliver paclitaxel to tumors for the treatment of non-small cell lung cancer, ovarian cancer, and other cancers where taxanes are widely used. Xyotax is 80,000 times more water-soluble than paclitaxel, allowing it to be infused in the absence of Chremophor over ten minutes through standard IV tubing and at higher doses than can be achieved with paclitaxel. Also, because Xyotax is water-soluble, its administration does not require routine premedication with steroids and antihistamines to prevent severe allergic reactions. Furthermore studies have shown that Xyotax benefits from passive tumor targeting. This is because the size of the polymer ensures that Xyotax is preferentially taken up by the more permeable tumor vasculature. Once in the tumor milieu, Xyotax is taken up into cancer cells through endocytosis locking it into the cells prior to liberation of free paclitaxel. Cell Therapeutics initiated 3 pivotal phase III non-small cell lung cancer trials (STELLAR trials) of Xyotax in 2002. Enrollment for STELLAR 3 was completed in 2003 and data are expected imminently (mid-march, 2005) prior to an NDA filing with the FDA . A phase III trial in ovarian cancer patients is also in progress. Analysts expect peak annual sales for Xyotax to reach $500 million.

Significant sales to continue in the supportive care market: A Roper Starch survey of chemotherapy patients found that prior to starting treatment, 32% reported surviving cancer as their biggest concern versus 40% who said side effects were their biggest concern. The most serious adverse effects of chemotherapeutic agents include anemia and related fatigue; neutropenia and associated risks of infection; and nausea and vomiting. Anemia-related fatigue affects 76% of patients undergoing chemotherapy and a large proportion of these patients report that fatigue resulting from this anemia affects their lives more than any other side effect, including nausea, pain, and depression. Neutropenia is a serious clinical problem and affects half of cancer chemotherapy patients. Consequently the development of supportive care products to combat fatigue and neutropenia has played an important role in oncology research and development. This is well illustrated in the US, where in 2004 the epoetins and granulocyte colony-stimulating factors (G-CSFs) contributed $6.7 billion in sales. Epoetins including Johnson & Johnson's Erypo/Procrit and Amgen's Epogen are commonly employed for the treatment of fatigue and indeed the increasing use of epoetins to treat cancer-related anemia has resulted in these agents becoming the leading US oncology drugs, with sales estimated at $2.4 and $2.2 billion respectively. G-CSFs, which are used to treat neutropenia, include Amgen's two products Neupogen (filgrastim) and pegylated filgrastim, Neulasta (pegfilgrastim). Neulasta was launched in 2002 and its worldwide sales increased 40% to $426 million in the second quarter of 2004 (compared to 2003 figures). This mirrored a fall in Neupogen sales to $295 million in the second quarter of 2004 versus $331 million in the prior year and reflects the advantage of Neulasta in that only one administration is required per cycle of chemotherapy due to its increased half-life.

The patent expiry of Zofran is set to change the antiemetics market: According to the National Cancer Institute, over 500,000 Americans received chemotherapy in 2004. Patients receiving chemotherapy for cancer reported a greater degree of treatment-induced nausea and vomiting than generally recognized. An estimated 75% suffer from nausea or vomiting within 24 hours of treatment, and about 90% of all patients suffer from chemotherapy-induced nausea or vomiting 2-5 days after treatment (delayed onset chemotherapy-induced nausea and vomiting). If left untreated, chemotherapy-induced nausea and vomiting can result in a delay or discontinuation of chemotherapy and the majority of patients thus receive an antiemetic. The 5-HT3 receptor antagonists revolutionized the treatment of chemotherapy-induced nausea and vomiting. All major antiemetic treatments currently on the market (Roche's Kytril,GlaxoSmithKline's Zofran, and Aventis' Anzemet) are 5-HT3 antagonists and the market is dominated by Zofran (Ondansetron), generating annual US sales worth approximately $1.0 billion in 2003. The product patent expires in June 2006. While this opens the way for generic competition, novel formulation with improved efficacy may also compete for this market. Hana Biosciences is developing one such agent, a lingual spray formulation of ondansetron. The company has recently announced a clinical study that will compare the pharmacokinetic profile of this formulation with that of Zofran. Based on successful results of this pilot bioequivalence trial in healthy volunteers, Hana intends to file an Investigational New Drug (IND) Application with the aim of making the oral spray version available in 2007. Such a formulation is expected to increase the speed of therapeutic onset; avoid the need to swallow a tablet is also of obvious benefit in patients suffering emesis. Alternative 5HT3 antagonists with improved profiles may also capture the ondansetron market. For example MGI Pharma's Aloxi (palonosetron), which was approved in 2003, has an improved pharmacokinetic profile and may therefore provide an extended duration of action. Aloxi is currently approved for the prevention of acute nausea and vomiting associated with moderately and highly emetogenic cancer chemotherapy, and the prevention of delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy. Recent data suggest however that approval of higher doses of palonosetron could offer a new treatment for delayed emesis produced by highly emetogenic chemotherapy.

First treatments entering the market for oral mucositis: Severe mucositis resulting from destruction of the mucosa can affect up to 100% of patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation as well as 80% of patients with head and neck malignancies receiving radiotherapy, plus many other cancer patients on standard chemotherapy. In total this translates to approximately 400,000 patients per year who may develop acute or chronic oral complications during chemotherapy. Up until recently there were no approved treatments of oral mucositis, however in 2004 the FDA approved Amgen's Kepivance (palifermin) for the treatment of severe oral mucositis in patients with hematologic cancers undergoing high-dose chemotherapy, with or without radiation, followed by a bone marrow transplant. Kepivance is a human recombinant keratinocyte growth factor (KGF), a protein in the fibroblast growth factor family. Binding of KGF to its receptor result in proliferation, differentiation, and migration of epithelial cells. At present approval of Kepivance is limited to patients being treated for hematologic cancers and its initial sales potential has been approximated to $200 million, however the potential could be increased to $1billion if Kepivance is effective in treating mucositis in patients with solid tumors.

While immediate efforts are falling on supportive care and improved delivery of cytotoxics, the longer term focus will be on the development on molecular-targeted treatments with improved efficacy and fewer adverse effects: Cytotoxics have been a cornerstone of cancer therapeutics and will remain to do so. Patent expiries have driven companies to prolong the life cycle of cytotoxics through the development of supergenerics with improved drug delivery and pharmacokinetic properties. This in turn promises a reduction in the adverse effects of this class. Although these supergenerics will provide competiton for commodity generics, the latter will remain extensively employed driving the development of supportive care therapeutics. Long term goals are however to develop innovative therapeutics that are targeted towards molecular mechanisms selectively affected in cancer. While in most of the markets, the presence of innovative class members in the top 20 was limited to Biogen-Idec/Roche's MabThera, OSI/Genentech/ Roche's Herceptin and Novartis' Glivec, analysts predict that the continued research and development focus on molecular-targeted treatments will see their emergence as the key players in the delivery of cancer pharmacotherapy. Analysts believe that the future use of molecular-targeted treatments in combinatorial treatment approaches with traditional cytotoxic chemotherapy, together with their use in the setting of chronic disease management, will see them constitute an increasing proportion of the top 20 cancer drugs by 2014. Already angiogenesis inhibitors and growth factor inhibitors have enjoyed significant success.

The therapeutic importance of angiogenesis inhibitors took a leap forward in 2004 with the US approval of Genentech/Roche's Avastin (bevacizumab), followed closely by European approval. Fourth-quarter financial results reported sales of Avastin to be approximately $200 million, a figure expected to swell to peak sales of between $845.3 million and $1.7 billion now that European approval has been granted. Despite renewed confidence in the angiogenesis inhibitors there is a lack of late-stage development and the only competitive threat to Avastin is likely to come from Novartis' PTK787 in the short to medium term (see Colorectal Cancer - Avastin and Erbitux Pave The Way For Pipeline Targeted Therapies). A more distant threat to Avastin is AstraZeneca's orally active VEGF-2 receptor antagonist, ZD6474. ZD6474 blocks VEGF pathways but in contrast to Avastin which bind to VEGF, ZD6474 selectively inhibits VEGF-2 tyrosine kinase activity producing inhibition of VEGF-stimulated endothelial cell proliferation. ZD6474 has additional activity against the epidermal growth factor receptor in parallel with Iressa. ZD6474 successfully emerged from Phase I clinical development and interim results are expected in the next few weeks on a phase II study combining ZD6474 with chemotherapy in the treatment of non-small cell lung cancer patients.

Another class of innovative and targeted therapeutics that has attracted considerable attention is the growth factor inhibitor class and in particular Glivec, Iressa and Tarceva. Glivec was one of the first targeted anti-cancer agents to be be approved. Targeting the kinase activity of Bcr-Abl (an oncogene responsible for chronic myeloid leukaemia) as well as c-kit, Glivec was approved for the treatment of CML and gastrointestinal stromal cell tumors in 2001-2002. The approval of Glivec was followed by that of AstraZeneca's Iressa (Gefitinib, ZD1839), a small molecule that specifically inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate (ATP) binding site. The side effect profile of gefitinib is good with the most common side effects being are low-grade rash or diarrhea. Based on data from pivotal phase II trials, IDEAL 1 and 2, which showed Iressa to shrink tumors and to improve symptoms, gefitinib received accelerated approval on May 5, 2003 by the FDA as a monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Disappointingly however, in a press release on December 17th, 2004, AstraZeneca announced that the initial analysis of the IRESSA Survival Evaluation in Lung cancer (ISEL) showed that IRESSA failed to significantly prolong survival in comparison to placebo in the overall population or in patients with adenocarcinoma. This dissapointing news contrasts with the progress of Tarceva which has recently been approved for the treatment of non-small cell lung cancer. This EGFR-1 tyrosine kinase inhibitor, which is being developed by Roche in collaboration with OSI Pharmaceuticals, differs significantly from Iressa in that it can extend survival time by up to 40%. According to OSI, a strong post-approval development plan is in place seeking to expand the label and use of Tarceva to other forms of cancer where EGFR is implicated and where indications of activity have been seen. Current forecasts for US Tarceva sales in 2006 range from $300 million to $600 million and between 0.5 and $1 billion in by 2008.

For up to date information on cancer therapeutics & markets see: Cancer Market Top 20 Drugs

This PharmaReport alert features the following related reports.

See also

• Innovative therapies
  • Cancer Vaccines
  • Developments in oncolytic viruses
  • Colorectal Cancer - Avastin and Erbitux Pave The Way For Pipeline Targeted Therapies
  • Breast Cancer - Complex Combinations of Old and New
  • Molecular-Targeted Pharmacotherapy in Myeloma
  • Innovative Agents in Lung and Colorectal Cancer
  • Drug Delivery in Cancer
• Market Evaluation
  • The Cancer Market Outlook to 2009
  • Cancer Therapeutics Markets
• Supportive Care
  • Growth Factors: Indications, Products, and Markets
  • Cancer Pain
• Other Selected New reports
  • Pancreatic Cancer
  • Hepatocellular Carcinoma
  • Brain Metastasis