Spotlight February 2016

Niche Disease: Soft-Tissue Sarcoma (STS)

by Cheryl Scott

Cancer comes in two forms: the more common carcinoma form (of epithelial origin) and the less common sarcoma form. Sarcoma cells are mesenchymal in origin. Soft-tissue sarcomas are cancers of tissues such as fat, muscle, nerves, tendons, the lining of joints, blood vessels, or lymph vessels. Because there are at least 50 different types of STS, it is more accurately described as a family of related diseases rather than a single disease.

STS tumors are described in reference to the type of tissue that they most closely resemble (e.g., osteosarcoma resembles bone, chondrosarcoma resembles cartilage, and liposarcoma resembles fat). Some do not look like any type of normal tissue and are thought to come from stem cells.

Epidemiology: About 60% of the dozens of STSs begin in an arm or leg, 30% start in the torso or abdomen, and 10% occur in the head or neck. Children and adults both can develop these tumors. STS is more rare in adults (~1% of all adult cancers, most commonly liposarcomas) than children (~15% of all childhood cancers, most commonly striated muscle tumor). At any one time, about 50,000 patients are struggling with sarcoma worldwide. Some 15,000 new cases are diagnosed annually, and nearly 6,000 people die each year from STS.

Causes are unclear. Some studies have shown that people exposed to certain herbicides and wood preservatives have increased STS risk. Those exposed to high doses of radiation also are at greater risk. Researchers are also studying genetic abnormalities and chromosome mutations as possible causes. People with certain inherited diseases such as neurofibromatosis or familial syndromes associated with p53 mutations have higher risks of STS.

Treatment Options: STSs are diagnosed through surgical biopsy and treated with surgery, radiation therapy, and chemotherapy. Sometimes cured by surgery (~20% of the time) or surgery combined with chemotherapy and/or radiation (another 30%), STSs are totally resistant to all approaches about half the time — indicating an extreme need for new therapeutic approaches. Biological immunotherapies and genetargeting therapies present an alternative approach.

Targeted drugs specifically block molecules involved in cancer growth. Other targeted drugs may also be helpful against sarcomas. For example, Loxo Oncology, Inc. (Stamford, CT) was recently granted orphan-drug designation by the US Food and Drug Administration (FDA) for its LOXO-101 candidate. The drug is a selective inhibitor of tropomyosin receptor kinase (TRK) signaling molecules, which are involved in many tumor types. Cixutumumab is also being studied for STS indications.

Anti-angiogenesis drugs that block blood-vessel formation also may help kill sarcomas by denying them nourishment. Bevacizumab has shown a small benefit in sarcoma patients when given with doxorubicin.

Organizations: Although the American Cancer Society includes sarcomas in its purview, some organizations focus on them exclusively. The Sarcoma Alliance (www.sarcomaalliance.org) was founded in 1999 by a nurse and long-term sarcoma survivor. The Sarcoma Foundation of America (www.curesarcoma. org) is a fund-raising organization that provides grants to sarcoma researchers. Until 2014, the Liddy Shriver Sarcoma Initiative (www.sarcomahelp.org) increased public awareness, raised funds for research grants, and provided support and timely information to sarcoma patients, their families, and medical professionals. But the initiative is no longer active except for final-research funding and publishing research reports. Janssen Biotech (whose trabectedin STS treatment was approved in October 2015) operates a resource for patients and physicians online at www.challengesarcoma.com.

On 16–17 February 2016, the European Society for Medical Oncology presents its sixth annual ESMO Sarcoma and GIST Conference in Milan, Italy. The conference focuses on STS and gastrointestinal stromal tumors.

Introducing Editorial Advisor: Bryan Monroe

Bryan D. Monroe is a process development and manufacturing professional who has been employed in the biotechnology industry for over 25 years. He has worked on a broad range of successful drug candidates, including insulin, blood factors and fractionation products, fusion proteins, and cell therapies — as well as diagnostic kits for human immunodeficiency and T-cell lymphotropic viruses. His role in those programs included development, optimization, scale-up, and transfer of recombinant protein-expression processes based on yeast, Escherichia coli, insect cells, and mammalian cells. Monroe also has extensive experience in basal and feed media development and optimization, using analytical technologies to better understand cellular metabolism as it relates to protein expression processes in both fed-batch and perfusion modes.

Monroe holds a bachelor of science in virology and marine biology from the University of Puget Sound and a technology management certificate from the University of Washington. His past positions include manufacturing engineering development associate at Genetic Systems (three years), senior research scientist at Bristol-Myers Squibb (seven years), process development group leader at ZymoGenetics/Novo Nordisk (2.5 years), process development/clinical manufacturing manager at Dendreon (2.5 years), and senior process science fellow (customer consultation) at Life Technologies (nine years).

Monroe founded Primus Consulting, LLC nearly four years ago to share his knowledge and experience with companies large and small. As a consultant, he has contributed to successful scale-up/ transfer of more than 75 unique therapeutic programs throughout the global market, targeting more efficient processes, reduced time to clinical investigation, cost-of-goods improvements, and development of robust expression platforms.

2015: A Record Year for Outsourcing M&A

A drastic increase in mergers and acquisitions (M&A) activity propelled the value of pharmaceutical outsourcing deals from US$9.9 billion in 2014 to nearly $17.6 billion through October 2015, according to GlobalData senior healthcare industry analyst, Adam Dion. In an article for Arena International Event Group’s Clinical Trial Year Book 2016, he writes that after a sharp rise in M&A activity over recent years, the value of deals in this sector more than doubled to record levels in 2015.

“This year has seen a number of high-valued transactions,” Dion says, “including LabCorp’s $6.1 billion purchase of Covance, and WuXi being sold for $3.3 billion to a Chinese private equity group. Contract manufacturers have also been busy in 2015.” Siegfried Holding AG, an active pharmaceutical ingredient (API) company based in Switzerland, bought BASF’s pharmaceutical supply business. “And Lannett acquired Kremers Urban Pharmaceuticals, a specialty generic drug maker and subsidiary of UCB, for $1.2 billion.”

The combined LabCorp–Covance business is valued at ~$6.1 billion, with pro forma revenue near $8.4 billion. That vaults it ahead of its closest rival, Quest Diagnostics, and establishes a new leader in medical testing. “LabCorp’s intentions seem pretty clear,” says Dion. “It wants a larger piece of the contract research organization (CRO) market.”

That sector has enjoyed impressive growth over recent years. Plummeting sales from the loss of exclusivity for branded drugs, high costs of pharmaceutical research and development (R&D), and globalization of clinical trials have increased demand for outsourced clinical-trial work.

Industry Needs to Improve R&D Returns

The R&D divisions of 12 leading pharmaceutical companies have pushed 306 projects into latestage pipelines since 2010, with projected lifetime returns >$1.41 trillion. But according to a study by Deloitte and GlobalData, those returns are declining in percentage terms. Measured by 2008–2009 R&D spending, the top 12 public research-based life-science companies studied are Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck & Co., Novartis, Pfizer, Roche, Sanofi, and Takeda.

Published by the Deloitte Centre for Health Solutions, the report states that collective R&D returns for those 12 have declined markedly from 10.1% in 2010 to just 4.2% in 2015, while the average cost of product development has risen by a third. The study takes a long-term view of R&D returns to reduce the volatility of static measures, which can be skewed by particularly high or low revenue expectations. Drugs can take ~15 years to get from discovery to launch, and revenue forecasts can change substantially through late-stage development, so a longer-term view provides for more robust analysis.

Jim Coutcher, GlobalData’s global head of healthcare, points out an increasing focus on specialized therapeutics in the industry. “The R&D focus has been shifting toward specialty therapy areas, given the high levels of patient unmet need and the identification of discrete patient populations. However, this study shows an increased degree of specialization within primary-care therapy areas.” Companies are looking to new types of therapies, mechanisms of action, and patient segments as untapped opportunities.

Making Deals Count: A concurrent study by GBI Research has found collaboration to be crucial to offsetting the costs of developing novel drugs. Claiming the average cost of doing so at almost $2.5 billion (and with few products now achieving blockbuster status), GBI says that deal-making is becoming increasingly vital for pharmaceutical companies to offset rising R&D costs. The company’s latest CBR Pharma Insights report — Pharmaceutical Deal Trends (2010–2015) and In-Depth Analysis of Recent Deal Activity — states that those challenges are complicated by shifts in patent laws and the struggling global economy.

GBI analyst Priyatham Salimadugu says deal-making can help drug companies enhance their research and regulatory approaches and help them expand and diversify product portfolios and enter niche markets. And it can aid in product commercialization and sales. “Small companies that primarily carry out research, development, and production activities want to enter into agreements with key industry leaders — to use their strengths in commercialization expertise and global presence to boost their revenues. Meanwhile, big-pharma corporations keen to secure novel and promising molecules will cooperate with small players to expand their portfolios and reduce R&D risks.”

A general industry shift from small to large molecules has created opportunities and increased the numbers of deals being made. The report states that overall pharmaceutical deal values remain $110–160 billion from 2010 to 2014 but will rise markedly for 2016, with a total value of $261 billion already amassed by the end of July. “This creates a pyramid whereby more companies are developing drug molecules at the bottom of the pyramid and than commercializing them at the top,” Salimadugu explains, “as typified by Pfizer’s recent $160 billion takeover of Allergan.

Partnerships were the most common type of deal January 2014 to July 2015, followed by licensing deals and acquisitions. Although acquisitions were fewer, their disclosed values were highest.