DUBLIN – Every technology shift has its winners and losers. Ireland, long a key location for small-molecule and biologics manufacturing, is now gearing up to ensure it is on the right side of the divide as the rollout of cell and gene therapies (CAGT) gathers momentum. There are no guarantees that the same technological and economic factors that contributed to its success during earlier eras of pharmaceutical and biopharmaceutical manufacturing will apply to the coming era of regenerative medicine. But the country's inward investment agency, IDA Ireland, is betting that its long-established relationships with the top tier of biopharma companies and its longstanding expertise in meeting FDA manufacturing requirements will help in the battle to win new investment projects.

"It's a very interesting challenge," Tommy Fanning, head of biopharmaceuticals at IDA Ireland, told BioWorld. The country has ridden the transition from small-molecule production to biologics production over the past two decades. "We got over $10 billion in biologics investment, capital investment, in the sites," he said. But the pipeline of new projects is getting thinner. "There's not a lot of new biologics capacity to be built globally."

Existing facilities continue to expand capacity, a trend that is "working very well for Ireland," he said. Merck & Co. Inc., of Kenilworth, N.J., is building only its second in-house facility for its blockbuster programmed cell death 1 (PD-1) inhibitor Keytruda (pembrolizumab) at Swords, north of Dublin, to complement an existing manufacturing site in the Netherlands. The company, which this week posted $2.6 billion in Q2 sales of the drug, also relies on CMOs in the U.S. and Germany. The 325,000 square-foot Swords site is due to go live early in the next decade. Earlier this year, antibody developer Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y., announced plans to invest €200 million (US$223 million) to add another 240,000 square feet to its existing 400,000 square-foot facility in Limerick. Shanghai-based CMO Wuxi Biologics is currently building a €325 million single-use biologics manufacturing facility in Dundalk, the company's first production plant outside China.

But a smaller-scale initiative underway at a Takeda Pharmaceutical Co. Ltd. facility at Grange Castle, on the outskirts of Dublin, points the way to Ireland's possible future in the production of CAGT. The Osaka-based company is investing €30 million in the development of a cell therapy facility to produce Alofisel (darvadstrocel), an allogeneic mesenchymal stem cell therapy, which received European approval in March 2018 to treat complex perianal fistulas in patients with Crohn's disease. (See BioWorld, Jan. 8, 2018.)

The therapy originated at Takeda's erstwhile partner Tigenix NV, of Leuven, Belgium, which the Japanese pharma acquired for €520 million on foot of the approval. Although Belgium is a globally competitive region both for cell therapy development and manufacturing, Takeda's Irish subsidiary was chosen to take charge of the production of Alofisel. The same unit was the first Takeda active pharmaceutical ingredient (API) facility to be located outside Japan.

The process is the product

Of course, one swallow does not a summer make. CAGT therapy manufacturing differs from both small-molecule and biologics production in several key respects. The scale requirements of CAGT production are radically different. Autologous cell therapies, in particular, involve small-scale production runs and do not require large manufacturing facilities. Moreover, because the process is literally the product in regenerative medicine, companies tend to locate manufacturing adjacent to the R&D function.

Because of its low corporation tax rates and small-scale clinical infrastructure, Ireland has never been a major center for basic research or therapeutic development. But IDA Ireland is betting that industry consolidation will aid its strategy of positioning Ireland for some of the action in CAGT manufacturing. It has well established relationships with top-tier firms such as Bristol-Myers Squibb Co., which is soon to acquire Celgene Corp., along with its big-ticket CAR T acquisition Juno Therapeutics, and Gilead Sciences Inc., which entered the CAR T arena through its acquisition of Kite. Such U.S. companies will serve the U.S. market from their home locations. "Then they have to build out in Europe," Fanning said.

Whether Ireland will be the location of choice for these any of build-outs is an open question for now. In addition to Belgium, the UK and France are two further examples of European countries that have invested in CAGT manufacturing long before Ireland has even considered its potential. The London-based Cell and Gene Therapy Catapult, which is supported by Innovate UK, houses about 170 cell and gene therapy specialists and has a £55 million (US$69 million) large-scale GMP manufacturing facility. It disclosed Cambridge, Mass.-based TCR2 Therapeutics as the first U.S. collaborator to establish process development at the facility, and it is helping a further five indigenous firms to develop their production processes. It has also established an apprenticeship scheme to address the skills shortage in the area.

In France, the not-for-profit gene therapy research organization Généthon has spun out a commercial gene therapy CMO, Yposkesi SAS, of Corbeil-Essonnes, which recently entered a strategic development and manufacturing alliance with Basel, Switzerland-based Axovant Gene Therapies Ltd., under which it will gain preferred access and reserved capacity in cGMP grade viral vector production. It is located within the Genopole cluster, just south of Paris, which is home to 96 biotech companies and 16 academic research labs.

"We're looking very closely at where Ireland plays," Fanning said. IDA Ireland is charging the National Institute of Bioprocessing Research and Training (NIBRT) with the responsibility of mapping the country's needs in and extending its mission to CAGT production. There is no cGMP-grade viral vector manufacturing in the country at present, while the National University of Ireland, Galway (NUIG), is home to one small cGMP cell therapy manufacturing unit. As yet, however, there is no obvious alignment in Ireland's innovation and industrial policies for CAGT. Several years ago, Science Foundation Ireland, the country's leading science agency, downgraded the Remedi cell therapy research center with which the NUIG unit is associated, while placing a large bet on small molecule manufacturing by funding the Synthesis and Solid State Pharmaceutical Centre at the University of Limerick, which is focused on small-molecule process development.

IDA Ireland originally seeded NIBRT, a €72 million initiative to building the country's capabilities in biologics production. It is now exporting its training model to the U.S., through a partnership with Thomas Jefferson University, in Philadelphia. But it is entering a whole new arena in CAGT, an area that has, after a long lag time, started to mature quite rapidly. Investment is now flowing steadily into the area – the Alliance for Regenerative Medicine recently reported that CAGT firms raised $2.2 billion in investment in Q1 this year. On top of that, large pharma firms, such as Novartis AG, Pfizer Inc. and others are also making big bets. IDA Ireland hopes it can succeed in diverting some of that capital to Ireland. But the country's past performance is no guarantee of future success.

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