Spotlight for February 2017

Introducing New Editorial Advisor

Jason Condon is a senior CMC project manager at Vaccinex, Inc., in Rochester, NY as well as an assistant adjunct professor in biomedical engineering at the University of Rochester. He has held roles in biopharmaceutical manufacturing and process development at Bristol Myers Squibb and Janssen R&D. His expertise in cell culture and current good manufacturing practice (CGMP) manufacturing has contributed to developing manufacturing processes for monoclonal antibody (MAb), cell therapy, and vaccine production throughout his 13-year career in the industry. A significant portion of that work involved continuous (perfusion) bioreactors and hollow-fiber filter cell-retention devices.

Condon is responsible for the clinical supply chain at Vaccinex, where he oversees drug-substance and drug-product manufacturing and testing along with packaging, labeling, and distribution of finished products. He has written or contributed to the CMC section of numerous investigational new drug (IND) applications for MAbs and cell therapies. Condon is a past contributor to the BPI Conference, where he presented work on fluidized-bed and disk-stack centrifugation of a biopharmaceutical in two separate conferences.

In his role at the University of Rochester, Condon developed a course on bioprocess engineering and has been teaching both undergraduate and graduate students for the past two years. It is the first class of its kind at the university.

Condon holds a bachelor’s degree in biomedical engineering from the University of Rochester and a master’s degree in biotechnology from the University of Pennsylvania. He enjoys playing guitar and basketball, practicing yoga, and spending time with his wife and two children at their home outside of Rochester, NY.

Niche Disease: Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a progressive genetic disease in which bone forms in muscles, ligaments, tendons, and other connective tissues. Extra bone grows across joints, restricting movement. The condition generally starts in a patient’s neck and shoulders before progressing down the body. FOP is severely disabling, and patients usually do not live past 40 years old. The disease affects one in two million people, with 800 confirmed cases in the world (285 in the United States). It is often misdiagnosed as cancer, but surgery worsens the condition. Flare-ups can occur spontaneously or result from traumas such as falls, childhood immunizations, or viral illnesses. Currently, there are no effective treatments yet approved by regulatory authorities.

Treatments in Development: Two companies — Regeneron and Clementia — have promising potential FOP treatments in clinical trials.

In 2015, Regeneron found that the FOP mutation acts in a different way than was previously believed. Instead of becoming more active, the mutant receptor appears to be activated by a specific molecule in the immune system: the injury- and inflammation-related ligand, activin A. Normally, it inhibits the ADVR1 receptor to prevent excess bone growth. But in FOP patients with mutant receptors, activin A seems to have the opposite effect and promotes bone growth in muscles and connective tissues. Regeneron’s research shows the link between inflammation and heterotopic ossification in FOP patients. The team found a MAb that blocks activin A and prevented heterotopic bone formation in a mouse model.

Regeneron recently announced that its anti–activin-A antibody (REGN2477) is now in a clinical trial with healthy volunteers to ensure its safety, tolerability, and pharmacological activity in humans. The company hopes to begin clinical studies in patients with FOP soon.

Meanwhile, Clementia is working with an investigational retinoic acid receptor gamma (RARγ) agonist called palovarotene, which has the potential to prevent abnormal growth of bone in people with FOP. The company is investigating palovarotene as an oral therapy in phase 2 clinical trials by evaluating the effects of different doses during and after a flare-up in FOP patients. This drug inhibits secondary messenger systems in the bone morphogenetic protein (BMP) pathway for bone formation. Preclinical studies in animal models demonstrated that it did block abnormal bone formation.

Clementia licensed palovarotene from Roche Pharmaceuticals, which considered it as a treatment for chronic obstructive pulmonary disease (COPD) and had completed patient safety evaluations with more than 800 healthy volunteers and patients. In 2014, the product received orphan-drug designation from both the US Food and Drug Admininstration (FDA) and the European Medicines Agency (EMA) because it was the first potential compound to treat FOP. Palovarotene also received fast-track designation from the FDA.

Organizations: The International Fibrodysplasia Ossificans Progressiva Association (IFOPA, www.ifopa.org) is a nonprofit organization seeking to cure FOP by funding research and supporting medical research. It also supports affected individuals and their families through public awareness, education, and patient advocacy.

Reference: Hatsell SJ, et. al. ACVR1R206H Receptor Mutation Causes Fibrodysplasia Ossificans Progressiva By Imparting Responsiveness to Activin A. Sci. Transl. Med. 7(303) 2015: 303ra137; doi:10.1126/scitranslmed.aac4358.

GE Healthcare Commits to Training and Regional Development

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GE Healthcare’s Life Sciences business announced in September the opening of a Fast Trak Center in South Korea’s Incheon Metropolitan City. This US$7.4 million center will support the growth of South Korea’s rapidly expanding biopharmaceutical industry by providing hands-on practical training, technology evaluation, manufacturing support, and consultancy services in the latest strategies and technologies for upstream and downstream bioprocessing.

Demand for services from GE’s newest Fast Trak center is expected to be high. Songdo is already home to a number of leading South Korean biopharmaceutical companies. According to Dan Stanton of Biopharma Reporter, the domestic production of biopharmaceuticals in South Korea grew 9% over the past five years (www.biopharma-reporter.com/Markets-Regulations/Korea-positioned-to-be-a-global-biopharma-powerhouse-says-CPhI). Exports grew nearly 34% between 2014 and 2015, from $589 million to $809 million. Excellent national and international transport links should provide GE customers from the country and other parts of southeast Asia with easy access to services at the center.

Kieran Murphy (president and CEO of GE Healthcare Life Sciences) said that this “brings us closer to our customers in one of the world’s key bioprocessing hubs, enabling us to share our global knowledge and expertise at a local level. South Korea has some of the world’s most innovative biopharma companies, and we look forward to further supporting the growth of the industry here.”

This 2,200-m² Asia–Pacific Fast Trak Center in Songdo, South Korea, adds to GE’s existing global network of Fast Trak centers in the United States, Sweden, India, and China. The company also has smaller “satellite” Fast Trak Centers in Turkey, Japan, and Singapore. Besides standard courses, they all offer customized training on request. These training centers are designed to help biomanufacturers increase process productivity, reduce cost, and bring products to market quickly. The facilities are equipped with the latest bioprocess technologies in an environment and at a scale that closely replicates a real-life industrial setting. For over 30 years, thousands of customers worldwide have been trained by Fast Trak leadership teams (working in local languages) on process and analytical development, process scale-up, and manufacture of drug substances for use toxicology studies and phase 1–2 clinical testing.

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And in Ireland: Also in September, Mary Mitchell O’Connor (the Republic of Ireland’s minister for jobs, enterprise, and innovation) announced that GE will invest €150 million in a new biomanufacturing campus on Industrial Development Agency (IDA) Ireland’s strategic site at Loughbeg in Ringaskiddy, County Cork. GE BioPark Cork will feature Europe’s first KUBio prefabricated, off-the-shelf biomanufacturing facilities. It will serve as a focal point for further investment in next-generation biomanufacturing in Ireland.

“The biopharma industry makes a huge contribution to the Irish economy in terms of jobs and manufacturing exports,” said O’Connor, “and is one of the fastest growing sectors. I am delighted that GE is making a significant investment in Cork. This is a further testament to our talented workforce.”

This GE-managed campus will include four fully equipped KUBio factories owned by independent biopharma companies manufacturing proprietary medicines, with GE running centralized shared utilities, process development, and site services. GE BioPark Cork is expected to bring more than 500 new jobs when fully operational (400 with biopharma companies and a further 100 employed directly by GE). Subject to planning approvals, construction should begin by mid-2017, employing 800. The project is supported by the Irish government through IDA Ireland.

Martin Shanahan (IDA Ireland’s CEO) says the campus will help Ireland bring in additional biomanufacturing investment by acting as a catalyst to attract new innovator companies and grow existing operations. The country has won over €10 billion in such investments through the past 10 years, making it now a top global location for biopharmaceutical development. “This creates significant secondary employment in construction and other services.”

Patient demand for innovative medicines is driving rapid global growth of the biopharmaceutical industry, increasing demands for manufacturing capacity. KUBio technology speeds up facility construction and commissioning and increases manufacturing flexibility at a lower cost than comparable traditional facilities. GE says that carbon dioxide emissions can be reduced by 75% and water and energy use by ~80% while build times are cut in half.

To further develop biopharmaceutical manufacturing skills and expertise in Ireland, GE and the National Institute for Bioprocessing Research and Training (NIBRT) also announced a plan to create a single-use center of excellence at NIBRT’s Dublin facility. The organization expects to train up to 1,500 bioprocessing professionals annually there. The same next-generation biomanufacturing technologies will be used in GE BioPark Cork’s facilities.

Producing Cannabinoids with Yeast

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Florida-based biotechnology company BioTork LLC has doubled the rate and production of a cannabinoid precursor by using an engineered yeast strain. The company is using its proprietary technology to produce safe, pure, and reasonably priced cannabinoids. Even as the therapeutic benefits of marijuana have made headlines, the psychoactive nature of the drug remains controversial. This technology is meant to provide one without the other.

Marijuana plants produce multiple cannabinoids, the most well-known of which is the psychoactive tetrahydrocannabinol (THC). The plants also produce many other related substances, some of which are solely therapeutic (e.g., cannabidiol, CBD). It has anticonvulsive effects and may be useful in treating intractable forms of epilepsy. In states with legalized marijuana, CBD is sold in nutritional supplements, including the preparation “Charlotte’s Web.” Meanwhile, the global epilepsy drug market is forecast to reach over US$5.4 billion by 2024, with CBD in particular boasting a market value of $40,000–100,000/kg.

Some companies have begun genetically engineering yeast to produce cannabinoids by inserting genes from the marijuana plant into yeast strains. But BioTork says that such approaches cannot make enough cannabinoids to be profitable because the yeast grows slowly and produces only small amounts. But yeast can be engineered to produce just the therapeutic cannabinoids (such as CBD) but not those that are psychedelic or psychotropic (e.g., THC). Yeast could be used to make pure products for nutraceutical or pharmaceutical purposes, which is not the case for plants making more than 100 different types of cannabinoids. Currently, the FDA does not allow CBD to be marketed as a supplement, partially because that made by plants always contains some traces of THC. Even with future legalization of cannabis cultivation, producing CBD would involve the extra cost of purification and chemical separation.

BioTork addressed the challenge of poor yield by using a “natural evolution” process to improve its engineered yeast strain’s growth rate and product expression of a cannabinoid precursor. This improves the economic viability of cannabinoid production in cell culture, giving the market hope for low-cost production of pure, nonpsychoactive, therapeutic cannabinoids.

Reuters Ranks Most Innovative Universities

Last fall, Reuters ranked California’s Stanford University as #1 on its second annual list of the 100 most innovative universities in the world. [Editor’s Note: See the last page of this issue for more on Stanford’s approach to innovation.] This ranking identifies those institutions that advance science and invent new technologies to help drive the global economy. Rather than relying on subjective surveys, Reuters bases its list on empirical data such as patent filings and research-related metrics. Big breakthroughs and highly influential papers/patents can drive a university up the list for a year, and its ranking will drop without continued advances. Consistency is key, and truly innovative institutions put out groundbreaking work year after year.

Some universities saw significant movement up the list since the first ranking: the University of Chicago (from #71 in 2015 to #47 in 2016); the Netherlands’ Delft University of Technology (#73 to #44), and South Korea’s Sungkyunkwan University (#66 to #46). Others dropped out of the top 100, most notably Carnegie Mellon.

The top 10 for 2016 are Stanford, the Massachusetts Institute of Technology (MIT), Harvard University, the University of Texas system, the University of Washington, the Korea Advanced Institute of Science & Technology (KAIST) in South Korea, the University of Michigan system, the University of Pennsylvania, KU Leuven in Belgium, and Northwestern University in Illinois.

Stanford’s students and faculty have consistently innovated for decades. Alumni have founded companies such as Hewlett Packard and Google. MIT and Harvard share Stanford’s record of consistent innovation. Researchers from the former were behind important innovations such as the development of digital computers and completion of the Human Genome Project; the latter has produced 47 Nobel laureates over its 380-year history.

The United States dominates the list, with 46 universities in the top 100. Japan comes in second, with nine ranked universities. France and South Korea have eight each, Germany has seven, and the United Kingdom has five. Switzerland, Belgium, and Israel each have three; Denmark, China, and Canada have two, and the Netherlands and Singapore each have one. KAIST (#6) was founded by the South Korean government and modeled after engineering schools in the United States.

To compile its ranking, Thomson Reuters identified more than 600 global organizations that publish the most academic research. Each candidate was evaluated on 10 different metrics and ranked based on performance. See the entire report online at www.reuters.com/article/amers-reuters-ranking-innovative-univers-idUSL2N1C406D#listing.