The success of the innovator drug market is critical not only for pharmaceutical companies, but also for their manufacturing partners and suppliers. Oncology, the largest therapeutic category in the global pharmaceutical market, offers great potential.

Riding a wave in cancer drug innovation, a recent analysis by the IMS Institute of Healthcare Informatics projects that global spending on oncology drug will reach about $100 billion in 2018, up from $65 billion in 2013. So what are the noteworthy developments in terms of recent new drug approvals and late-stage pipeline progress? What is the mix between small molecules and biologics, and what are the implications for contract API manufacturers? DCAT Value Chain Insights (VCI) examines the opportunities in the global oncology market.

Cancer NME approvals in 2014
Thus far in 2015, the US Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) has approved one drug for cancer. In February 2015, Pfizer received FDA approval for Ibrance (palbociclib), a small molecule to treat advanced (metastatic) breast cancer. Ibrance works by inhibiting molecules, known as cyclin-dependent kinases (CDKs) 4 and 6, involved in promoting the growth of cancer cells. Ibrance is intended for postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have not yet received an endocrine-based therapy. It is to be used in combination with letrozole, another FDA-approved product used to treat certain kinds of breast cancer in postmenopausal women. The FDA granted Ibrance breakthrough therapy designation, priority review, and accelerated review.

In 2014, FDA’s CDER approved 41 NMEs, 30 new drug applications (NDAs) (i.e., small molecules or diagnostic imaging agents) and 11 biologics license applications (BLAs).Of the 30 NDAs approved in 2014, five were small molecules for cancer indications or related to cancer (see Table I at end of article). These were AstraZeneca’s Lynparza (olaparib) for treating advanced ovarian cancer; Gilead Sciences’ Zydelig (idelalisib) for treating three forms of blood cancer; Helsinn’s Akynzeo (netupitant and palonosetron) for treating nausea and vomiting in patients undergoing cancer chemotherapy; Novartis’ Zykadia (ceritinib) for treating a certain type of metastatic non-small cell lung cancer; and Spectrum Pharmaceutical’s Beleodaq (belinostat) for treating peripheral T-cell lymphoma. Of the 11 NME BLA approvals in 2014, four were biologics for treating cancer and another biologic was approved for an orphan disease that acts similar to cancer (see Table I at end of article). These BLA approvals were: Amgen's Blincyto (blinatumonmab) for treating a rare form of leukemia; Bristol-Myers Squibb's Opdivo (nivolumab) for treating unresectable or advanced melanoma; Eli Lilly and Company’s Cyramza (ramucirumab), a drug to treat patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma; Johnson & Johnson’s Janssen Biotech's Sylvant (siltuximab), a drug to treat the rare disease, multicentric Castleman's disease, which although not a cancer, is a disease that acts like lymphoma; and Merck & Co's Keytruda (pembrolizumab) for treating advanced melanoma.

Reflecting the level of innovation among NME approvals, five of the NMEs approved by CDER in 2014 for a cancer indicated were granted breakthrough therapy designation, a relatively new classification by the FDA that is designed to encourage the development and approval of promising drugs. Authorized under the Food and Safety Administration Innovation Act of 2012, a breakthrough therapy is a drug intended alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition and for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. If a drug is designated as a breakthrough therapy, the FDA will expedite the development and review of such a drug. The NMEs with breakthrough therapy status approved by the FDA for a cancer indication were: Amgen's Blincyto (blinatumomab) for treating patients with Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia (B-cell ALL), an uncommon form of ALL; Bristol-Myers Squib's Opdivo (nivolumab) for treating unresectable or metastatic melanoma; Gilead Sciences' Zydelig (idelalisib), a drug to treat three types of blood cancer; Novartis' Zykadia (certinib), a drug to treat a certain type of metastatic non-small cell lung cancer; and Merck & Co,'s Keytruda (pembrolizumab) for treating metastatic melanoma. 

Pharma company activity
Among the large pharmaceutical companies, AstraZeneca had one NME approval for treating cancer, Lynparza (olaparib) for treating advanced ovarian cancer. AstraZeneca received US and EU approval of Lynparza in December 2014. Olaparib is a poly ADP-ribose polymerase (PARP) inhibitor that targets tumor DNA repair pathway deficiencies to preferentially kill cancer cells. It is the first PARP inhibitor to be approved for patients with germline BRCA-mutated advanced ovarian cancer as detected by an FDA approved companion diagnostic test, BRACAnalysis CDx, which detects the presence of mutations in the BRCA genes in blood samples from patients with ovarian cancer. The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumor growth. Women with mutations resulting in defective BRCA genes are more likely to get ovarian cancer, and it is estimated that 10% to 15% of all ovarian cancer is associated with these hereditary BRCA mutations. BRACAnalysis CDx is manufactured by and performed at Salt Lake City, Utah-based Myriad Genetic Laboratories, Inc. Olaparib was approved under the FDA's Accelerated Approval program based on existing objective response rate and duration of response data. Continued approval for this indication is contingent upon verification of clinical benefit in ongoing confirmatory Phase III trials.

Eli Lilly received approval for Cyramza (ramucirumab), a drug to treat patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma. It later received FDA approval for treating, in combination with docetaxel, metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy. Merck & Co. received FDA approval for Keytruda, the first FDA-approved drug that blocks a cellular pathway known as PD-1, which restricts the body's immune system from attacking melanoma cells. Keytruda is intended for use following treatment with ipilimumab, a type of immunotherapy. For melanoma patients whose tumors express a gene mutation called BRAF V600, Keytruda is intended for use after treatment with ipilimumab and a BRAF inhibitor, a therapy that blocks activity of BRAF gene mutations. 

Gilead Sciences had one NME approval for cancer in 2014: Zydelig (idelalisib) for treating three types of blood cancer. Zydelig was approved to treat patients whose chronic lymphocytic leukemia (CLL) has returned (relapsed) as well to two treat two other indications: relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma, another type of non-Hodgkin lymphoma. Other recent FDA approvals for treating CLL include Roche’s Gazyva (obinutuzumab) in November 2013, a new indication for Janssen Biotech/Pharmacyclics’ Imbruvica (ibrutinib) in February 2014, and a new use for GSK’s Arzerra (ofatumumab) in April 2014. Both Gazyva and Arzerra also received breakthrough therapy designation for this indication. 

Novartis received approval for its drug, Zykadia (ceritinib), for treating a certain type of metastatic non-small cell lung cancer. Zykadia is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that blocks proteins that promote the development of cancerous cells. It is intended for patients with metastatic ALK-positive non-small cell lung cancer who were previously treated with crizotinib, the only other approved ALK tyrosine kinase inhibitor. Bristol-Myers Squibb received FDA approval for its melanoma drug and PD-1 inhibitor, Opdivo (nivolumab), competing against Merck's PD-1 therapy, Keytruda, also approved in 2014.

Amgen received FDA approval for Blincyto (blinatumonmab), a drug that engages the body's T-cells, a type of white blood cell or lymphocyte, to destroy leukemia cells. The drug acts as a connector between a protein called CD19, which is found on the surface of most B-cell lymphoblasts, and CD3, a protein on T-cell lymphocytes. The FDA granted Blincyto breakthrough therapy designation, priority review, and orphan product designation.

Helsinn's Akynzeo is a fixed combination capsule comprised of two drugs involved indirectly in cancer treatment. Oral palonosetron, approved in 2008, prevents nausea and vomiting during the acute phase (within the first 24 hours) after the start of cancer chemotherapy. Netupitant, a new drug, prevents nausea and vomiting during both the acute phase and delayed phase (from 25 to 120 hours) after the start of cancer chemotherapy. Akynzeo is distributed and marketed by Eisai under license from Helsinn Healthcare S.A. 

As previously mentioned, Johnson & Johnson’s Janssen Biotech received approval for Sylvant (siltuximab), a drug to treat the rare disease, multicentric Castleman's disease. Multicentric Castleman’s disease is not a cancer but is a rare disease of lymph nodes and related tissues, but this form of the disease acts very much like lymphoma

Market opportunities and challenges
The global oncology market is a market of both opportunity and challenges. Oncology spending will reach $100 billion globally by 2018, an absolute growth of $30 billion to $40 billion, according to a recent analysis by the IMS Institute for Healthcare Informatics. Oncology continues to be the largest therapeutic category in developed countries, and the largest specialty area in pharmerging countries, a term used by IMS to denote emerging markets. Spending on medicines in oncology in developed markets is expected to increase at a compound annual growth rate (CAGR) of 7 to 10% in the forecast period of 2014─2018 and reach between $71 billion and $81 billion. In pharmerging countries, oncology will be the fourth largest therapeutic class behind pain, antibiotics, and hypertensive drugs, and the largest specialty therapeutic class. IMS projects that spending on oncology drugs in pharmerging markets will reach between $12 billion and $14 billion by 2018 and increase at a CAGR of 12% to 15% in the forecast period between 2014 and 2018.

Despite the promise of the oncology market, a recent analysis, “Researching Cancer Medicines: Setbacks and Stepping Stones” by the Pharmaceutical Research and Manufacturers of America (PhRMA) shows the potential and difficulty in bring new cancer drugs to market. The report focuses on three cancers that are particularly difficult to treat: melanoma, lung cancer and brain cancer. The report shows that between 1998 and 2014, 96 potential treatments for melanoma did not make it through clinical trials, but paved the way for seven FDA-approved medicines, a nearly 14:1 ratio of “failures” to “successes.” In the same period, 10 medicines were approved by the FDA to treat lung cancer, whereas 167 other potential treatments did not make it through clinical trials. And only three new medicines were approved to treat brain cancer, while another 75 investigational medicines were unsuccessful in the development process. Despite the difficulty in advancing clinical candidates, drugs for cancer continue to be an active area in the industry's pipeline. According to the PhRMA report, published in October 2014, there were 771 cancer medicines and vaccines either in clinical trials or awaiting review by the FDA. Of these medicines, more than 50 are for the treatment of melanoma, 98 for lung cancer, and 47 for brain cancer. Up to 80% have the potential to be first-in-class medicines, meaning they would represent novel approaches to combating cancer.

Personalized medicine is becoming central to cancer care and many of the innovative types of medicines reflect this approach. This approach to treatment uses diagnostic tools to identify specific biologicalmarkers, often genetic, and help assess which medical treatments and procedures will be best for each patient. The PhRMA report cites information from the Personalized Medicine Coalition to show the growing importance of personalized medicines. In 2006, 13 prominent examples of personalized medicines, treatments, and diagnostics were available, and that had grown to 113 products by 2014. The report also cited a 2010 survey by the Tufts Center for the Study of Drug Development, which found that 94% of biopharmaceutical companies surveyed are investing in personalized medicine research, and 12% to 50% of the products in their pipelines are personalized medicines. Personalized medicines is also gaining public policy support, with President Barack Obama requesting $215 million as part of the US government's fiscal year 2016 budget to fund the Precision Medicine Initiative. The funding will go to the National Institutes of Health (NIH), together with the Food and Drug Administration (FDA), and the Office of the National Coordinator for Health Information Technology (ONC) to support the initiative

Reflecting that trend, immunotherapy or other targeted therapies are important targets in pharmaceutical development. A key strategy in oncology overall and for immunotherapies is to advance the drug for multiple cancer indications. In early September 2014, Merck & Co. received FDA approval for Keytruda (pembrolizumab) for treating advanced or unresectable melanoma, making it, the first anti-PD-1 therapy approved in the United States. The drug is also being developed to treat bladder cancer and gastric cancer. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, Keytruda releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

Bristol-Myers Squibb's Opdivo (nivolumab), the company's PD-1 immune checkpoint for treating advanced melanoma, is also being developed for other cancer indications. Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types, which consists of more than 35 trials, as monotherapy or in combination with other therapies, in which more than 7,000 patients have been enrolled worldwide. Among these are several potentially registrational trials for non-small-cell lung cancer, melanoma, renal cell carcinoma, head and neck cancer, glioblastoma, and non-Hodgkin lymphoma.

Key targeted therapies for cancer in the pipeline include Roche's investigational cancer immunotherapy, MPDL3280A (anti-PDL1 or anti programmed death ligand-1) targets patients with advanced bladder cancer. The drug has received Breakthrough Therapy Designation by the FDA. Roche is also developing the drug with its cancer drug Avastin (bevacizumab) for treating metastatic renal cell carcinoma (RCC). Roche is also developing an investigational candidate in use with an immunotherapy. Roche also reported positive Phase III results for people with previously untreated BRAF V600 mutation-positive, advanced melanoma who received the MEK inhibitor cobimetinib plus Zelboraf (vemurafenib). Cobimetinib was discovered by Exelixis Inc. and is being developed by Roche in collaboration with Exelixis. Cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumor types such as non-small cell lung cancer and colorectal cancer. Cobimetinib is designed to selectively block the activity of MEK, one of a series of proteins inside cells that make up a signalling pathway that helps regulate cell division and survival. Cobimetinib binds to MEK while Zelboraf binds to mutant BRAF, another protein on the pathway, to interrupt abnormal signaling that can cause tumors to grow. Zelboraf was co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, now a member of the Daiichi Sankyo Group. It is approved now in 80 countries to treat unresectable or metastatic melanoma with BRAF V600 mutation as detected by a validated test, such as Roche's cobas 4800 BRAF Mutation Test. Zelboraf posted 2013 revenues of CHF 354 million ($372 million).

AstraZeneca is advancing its anti-PD-L1 immune checkpoint inhibitor, MEDI-4736, and tremelimumab, the company's investigational anti-CTLA4 monoclonal antibody. MedImmune has initiated additional Phase I immunotherapy combination trials, including MEDI4736 and MEDI0680, an anti-PD-1 monoclonal antibody from AstraZeneca as well as a study for MEDI4736 and MEDI6469 (OX40), an in-licensed asset from Agonox. AgonOx is a spin-off company from the Providence Cancer Center in Portland, Oregon. It licensed the rights to use OX40 agonists in cancer from Providence Health & Services-Oregon. AgonOx is developing OX40 agonists and other immune system activators for use in cancer therapy. X40 is a protein transiently expressed on the surface of effector T-cells, but only after activation of the T-cells by immune-stimulating antigens, including tumor antigens. Binding OX40 with either anti-OX40 antibodies or OX40 ligand compositions has been shown to inhibit apoptosis in such T-cells, causing T-cell proliferation, immune attack on tumors, and sometimes very distinct tumor-specific therapeutic responses. AgonOx is focused on the development of immune system modulators in combination with other therapies, such as cytotoxic agents, other immunologic modifiers, and tumor-ablation techniques and devices.

GlaxoSmithKline is advancing Tafinlar (dabrafenib) in patients with BRAF V600E mutant metastatic melanoma. Dabrafenib is a licensed monotherapy in the EU for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation as detected by a validated test. Dabrafenib is also approved in the US, Canada, and Australia.

Pfizer announced in November 2014 that it entered into an agreement with Merck KGaA to jointly develop and commercialize MSB0010718C (proposed international non-proprietary name is avelumab), an investigational anti-PD-L1 antibody currently in development as a potential treatment for multiple types of cancer. Pfizer and Merck KGaA will explore the therapeutic potential of this anti-PD-L1 antibody as a single agent as well as in various combinations with Pfizer's and Merck KGaA's broad portfolio of approved and investigational oncology therapies. Both companies will collaborate on up to 20 high priority immuno-oncology clinical development programs expected to commence in 2015. These clinical development programs include up to six trials (Phase II or III) that In addition, separate from the PD-L1 programs, Pfizer and Merck KGaA will also combine resources and expertise to advance Pfizer's anti-PD-1 antibody into Phase I trials. The parties have also agreed to co-promote Pfizer's Xalkori (crizotinib), a drug to treat non-small-cell lung cancer, in the U.S. and several other key markets. Under the terms of the agreement, Merck KGaA received an upfront payment of $850 million and is eligible to receive regulatory and commercial milestone payments of up to approximately $2 billion. Both companies will jointly fund all development and commercialization costs, and split equally any profits generated from selling any anti- PD-L1 or anti-PD-1 products from this collaboration.

The growth in the oncology market is important for contract manufacturers of active pharmaceutical ingredients (APIs) for both small molecules and biologics. On the small-molecule side, this is seen in opportunities in high-potency manufacturing and on biologics for overall recombinant protein or monoclonal antibody development. For high-potency manufacturing, whether for an API or finished drug product, high-containment manufacturing requires specialized approaches in facility design, equipment selection, and manufacturing processes to achieve the desired levels of containment and minimize operator exposure. High-potency manufacturing has been and is likely continue to be an area has been an area of recent investment among contract manufacturers.