January 15, 2017 (Vol. 37, No. 2)

Improving Manufacturing of Advanced Therapies Is One of Several Initiatives Being Put in Place

“The U.K. has ambitions to become the third largest global life science cluster by 2025,” stated Nick Gardiner, COO of the BioIndustry Association (BIA) at the recent bioProcessUK Conference in Newcastle. This goal could be achieved, attendees suggested, by various means. For example, many attendees agreed that the U.K. could attract and retain manufacturers of advanced therapy medicinal products (ATMPs). However, producing ATMPs such as cell and gene therapies is not an easy business. It requires investments in infrastructure, skilled people, and processes for efficient and profitable manufacturing.

To guide ATMP investments, the U.K. set up the Advanced Therapies Manufacturing Taskforce, which brings together academic institutions and industrial partners, as well as regulators and government organization. This taskforce is chaired by Ian McCubbin, a senior vice president at GlaxoSmithKline, and Jo Johnson, a minister for science from the U.K. government, and it reports that there are three issues that must be addressed if the U.K. is to become a global hub for ATMP manufacturing.

The first issue is the need to strengthen and secure an internationally competitive fiscal landscape. Speakers at the conference agreed that the U.K. government is supportive of building an ATMP industry. They pointed out that the government is maintaining the Patent Box, which enables U.K. biotech and pharma companies with IP to apply a lower rate of Corporation Tax on profits. At present, the lower rate is fixed at 10%.

Speakers added, however, that the U.K. needs to keep up a competitive position relative to countries such as Singapore and Ireland in order to succeed. Additionally, the U.K. government should put in place capital allowances for research involving manufacturing scale-up.

“The U.K. is great at research in cell therapies,” commented Jim Faulkner, Ph.D., head of manufacturing at Autolus, a biopharmaceutical company developing next-generation engineered T-cell therapies to treat cancers. “But it has a time-limited window of maybe two years to ensure that we anchor commercial manufacturing expertise in the U.K.

“The rules on what can and can’t be claimed under the current R&D tax credit scheme are a bit ambiguous. It is important that advanced therapy manufacturing development activities are included, as this will really help fund commercialization here.”

Lack of Manufacturing Know-How

The second issue cited by the taskforce and discussed at the conference is the need to maintain science and innovation funding. Without adequate funding, the U.K. would struggle to support cutting-edge technologies and overcome any number of practical problems, such as insufficient production capacity for viral vectors, critical components in producing engineered cell and gene therapies. Some speakers at the conference stated that insufficient amounts of consistently manufactured viral vectors could prove to be a barrier to manufacturing in the U.K.

“We can make sufficient amounts of good quality adeno-associated virus (AAV) for Phase I studies without a problem,” stated Julian Hanak, vice president of manufacturing and CMC at NightstaRx, a clinical-stage company developing novel gene therapies to maintain and restore sight in patients with inherited retinal dystrophies. “But we find that getting enough good quality vector from an industrialized process is more challenging.

“There are very few CMOs that can handle the tech transfer, the right skills, and the technology platforms to ensure that viral vectors are the same quality from batch to batch. This is a problem. Most U.K.-based cell and gene therapy companies are solving this by doing their vector manufacturing in the United States or are building in-house capabilities, but this costs too much for many small biotechs to do, without loans or grants.”

Commentary on this issue was also provided by James Miskin, Ph.D., CTO at Oxford BioMedica, a University of Oxford biopharma spin-out that develops lentiviral vectors. Dr. Miskin said that his company would not have been able to develop its vector manufacturing capacity to its current scale without £7.7 million in catalytic funding, which was provided partly as a grant and partly as a loan by the U.K. government’s Advanced Manufacturing Supply Chain Initiative (AMSCI).

“Initially, we made our vectors with external CMOs in mainland Europe, always using our own in-house developed process,” Dr. Miskin detailed. “In 2010, the company made the strategic decision to bring manufacturing in-house, to supplement our existing GMP licence for analytics and batch release, which manifested in the purchase of our first manufacturing site in Oxford in 2011.

“Having the development funding helped us to both expand GMP capacity, as well as to further and more rapidly explore different scale-up platforms, such as development of a custom robotic system selecting and screening packaging and producer cell lines, as well as developing a serum-free lentiviral vector production process that has now been scaled up to 200 L single-use bioreactors in GMP to facilitate platform commercialization.”

This manufacturing expertise helped Oxford BioMedica secure a strategic partnership with Novartis that includes a licence to OXB lentiviral technology, as well as OXB in-house manufacture of the lentiviral vector that is used in Novartis’ CAR-T cell therapy, CTL019.

“Being able to build and demonstrate robust GMP manufacturing processes helped us with negotiating a major partnership deal with Novartis because they could see we would manufacture to the high-quality standards they expect,” Dr. Miskin explained. “Now we provide them with the vector to generate their CTL019 therapy, which is showing excellent results for treating relapsed/refractory paediatric acute lymphoblastic leukemia (ALL). Novartis is expected to file for a Biologics License Application (BLA) in 2017 for this product.”

Viral vector capacity also concerned professor Michael Linden, vice president of gene therapy at Pfizer. “CMO capacity for producing viral vectors is limited and every company that knows what it’s doing is developing its own disease portfolio,” he noted. “Therefore, Pfizer has recently acquired companies like Bamboo and is partnering with firms such as Spark to build our in-house know-how and anchor some manufacturing capacity for producing viral vectors.”

Undaunted, the U.K. is working to address the capacity issue. In September 2015, the U.K. opened the Centre for Process Innovation (CPI), a technology center at Darlington. The CPI is working with Cobra Biologics, a contract development and manufacturing organization (CDMO), on a project to develop an industrial manufacturing platform for AAV production.

The CPI’s director of biologics, Fergal O’Brien, offered this statement: “We have a great team and a powerful capability to be part of U.K. strategy to become world leaders in manufacturing advanced therapies, and funding for industrial partnerships like the one we have with Cobra will help achieve this goal.”

Professor Robert MacLaren of the University of Oxford performs an eye examination in support of the NightstaRx gene therapy trials, which are evaluating whether AAV delivery of the REP-1 gene to eye cells can help resolve choroideremia.

Regulatory Landscape and Access

Another key issue discussed was ensuring that the U.K. had the right regulatory landscape to attract ATMP developers. At the bioProcessUK event, speakers agreed that the U.K.’s Medicines & Healthcare products Regulatory Agency (MHRA) and the National Institute for Biological Standards and Control (NIBSC) represent unique selling points for U.K. bioprocessing. These institutions are respected globally for their scientifically rigorous approach their commitment to accelerating the development of innovative medicines.

“Post-Brexit, we have a real opportunity in the U.K. to have the MHRA and NIBSC help achieve and set global standards that  advance regulatory pathways for a speedy approval of advanced medicines,” insisted McCubbin.

One thorny issue identified is ensuring that there is a pathway for adopting ATMPs more readily so that patients can rapidly access them. According to McCubbin, the U.K. has published the Accelerated Access Review on how to produce innovative new medicines, but this is not complete as there needs to be a strategy for getting these advanced medicines to be taken up more rapidly by the U.K.’s National Health Service (NHS). He suggests that regional cell and gene therapy treatment centers could be set up for this purpose.

A “Penicillin” Moment?

To ensure that the U.K. is concentrating its efforts on improving manufacturing of advanced therapies, several initiatives are being put in place. Besides providing part of the funding the CPI, the U.K. government is also investing £55 million to build a new manufacturing hotel for advanced therapies at Stevenage, located on the same site as GSK’s medicines research center in the U.K. This new center is due to open in 2017.

“Advanced therapies are reaching their ‘penicillin’ moment, where there will be a paradigm shift in how patients are treated,” said McCubbin, who added this warning: “If history repeats itself with monoclonal antibody manufacturing, the U.K. will do all the innovation but precious little of the commercialization.” He asserted that the U.K. could avoid this outcome only if it acted now to secure capacity and skills.

“The ‘penicillin’ moment may seem fanciful,” McCubbin continued, “but in the 1940s, when penicillin was first made at Glaxo’s Barnard Castle site, it set the roots for manufacturing a whole range of medicines there. I’m certain if we anchor commercial production of ATMPs in the U.K., it will set roots for another 50 years of pharmaceutical manufacturing here, too.”

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