No aspect of biopharma better epitomizes the goals and promise of delivering personalized medicine to treat and perhaps even cure intractable and disabling diseases than the emerging fields of cell and gene therapy.
Adding to the excitement surrounding these technology-driven treatment approaches are their recent advance to the marketplace and increasing examples of progress in meeting clinical-scale production and regulatory challenges and achieving commercial success.
The progress and opportunities, obstacles and solutions, and optimistic projections and cautionary portents were all part of the science, technology, economic analysis, and insights presented, debated, and discussed at the recent “Phacilitate Cell & Gene Therapy Forum”.
Mahendra Rao, Ph.D., director of the NIH Center for Regenerative Medicine and head of the Laboratory of Stem Cell Biology at the NIH, led off the meeting and highlighted a key distinction from previous years: the growing number of commercial products now available for regenerative medicine.
Success begets new challenges, however, and Dr. Rao identified some of the issues this new reality is creating for young biotechnology companies. These may include how they ship their product, how to make a profit, how to deal with reimbursement and insurance issues, and how to manage competition.
The unique characteristics of cell therapies present new hurdles for this fledgling industry sector: individualized products prepared in small and even single doses; entirely or largely manual processes that need to be automated; and the challenges associated with reducing the cost of goods and leveraging economies of scale.
Other critical factors related to the actual products include storage, transport, time- and temperature-sensitivity, and time-out-of temperature specifications; chain of custody, overall quality control issues; and logistics considerations across the supply chain.
The main take-home message was to start thinking about factors related to commercialization of a cell therapy product early in its development, and at every step along the way—including, for example, the potential impact of a change in a process, protocol, raw material, or analytical method.
Also emphasized by several presenters was the inevitable move toward automation, in the short-term at least aimed primarily at allogeneic cell therapies. Automated processing of cells and cell-based products will be essential for achieving optimal quality control and standardization, designing closed, disposable process streams, eliminating the risks associated with manual intervention and open systems, and reducing costs.
Moving to the Market
A roundtable discussion among a group of industry executives who have navigated the process of cell therapy commercialization focused on the question, “what does a commercially successful cell or gene therapy look like?”
One example was CartiStem®, developed by Medipost, and approved in 2011 in Korea for cartilage regeneration in the treatment of traumatic and degenerative osteoarthritis. The product has been used in about 250 patients but is not yet reimbursable. CartiStem is in Phase II trials in the U.S.
John Maslowski, vp scientific affairs at Fibrocell Science, which markets the aesthetic autologous human dermal fibroblast product azficel-T (LAVIV®) to improve the appearance of wrinkles, spoke about the labor-intensive nature of current autologous cell manufacturing processes.
Geoff MacKay, president and CEO of Organogenesis, described the company’s semi-automatic manufacturing process in place to produce its recently approved Gentuit™ product, composed of allogeneic human keratinocytes and fibroblasts, for oral tissue regeneration around teeth and implants.
For TiGenix, key hurdles in bringing to market its ChondroCelect® autologous cartilage product for the repair of single symptomatic defects have included lack of regulatory harmonization, and the need to reduce the cost and increase the effectiveness of therapy. Access drives uptake, the company has found, and its commercialization strategy has included offering regulatory authorities cost controls and volume caps, identifying and targeting patient subgroups likely to have the best outcomes, and pursuing a stepwise, managed market introduction. TiGenix presents the product to physicians and regulators as a value proposition, with evidence-based results and support services.
Driving Market Uptake
Reed Tuckson, M.D., evp and chief of medical affairs, UnitedHealth Group, one of the largest healthcare insurers in the U.S., told the attendees, “We believe you need to succeed and we believe deeply in innovation.” It is important to facilitate access to these new products and technologies, he added, but at the same time, he expressed real concern about the dire implications of escalating healthcare costs in the U.S., for which consumers will bear the burden going forward.
There is too much waste in the system now, noted Dr. Tuckson, and too many aspects of healthcare are poorly managed. The prospect of adding increasingly complex and costly therapies into the mix, such as cell therapies, is extremely worrisome from a payer’s perspective. It would not be acceptable to waste or misuse these potentially life-saving innovations.
Dr. Tuckson described three emerging strategies essential for the future of the healthcare industry: value-based designs that emphasize individual accountability; value-based reimbursement design that will replace the fee-for-service paradigm; and value-based technology assessment, in light of optimizing outcomes and looking at the total cost of care—for example, a treatment that can provide a lifelong cure vs. a lifetime of medication, and options that allow for oral vs. parenteral therapy or outpatient vs. inpatient treatment.
He encouraged companies developing cell therapies to begin talking to insurers early. “We need to know how it will work and how it will be used in the real world,” he said, urging companies to provide data, identify an optimal patient population, and develop unit cost projections.
Automation Is Critical
From the perspective of efficiency and economy, the consensus among presenters was that manufacturing of cell-based therapies will have to move toward more automated processes. Automation and closed process streams are becoming more commonplace in the allogeneic cell therapy setting, and autologous product development strategies will have to follow suit. Even with autologous cell therapy, companies need to think in terms of volume, scale, and platform technologies, urged the speakers. Scale, however, need not necessarily imply scale-up, as in the traditional pharmaceutical manufacturing model, but instead scale-out, producing multiple individualized products in parallel.
Overall, the presenters were optimistic that cost would not be an obstacle to successful commercialization of cell therapies in the future, and attractive cost/benefit ratios will be achievable. They offered insights and suggestions for minimizing cost of goods, maximizing efficiency of operations, developing best practices, and optimizing manufacturing and business models.
Knut Niss, Ph.D., senior R&D manager, Stem Cell Initiative, EMD Millipore, distinguished between the needs in producing an autologous cell therapy—low cell numbers, a fast process, and one manufacturing run/patient—and an allogeneic product, in which the aim is to generate as many doses as possible in a single batch, with the goal of moving toward bioreactors for large-scale manufacturing.
Kim Warren, head of development services for cell therapy at Lonza, commented on one of the challenges in moving the production of adherent cells to bioreactors and the use of microcarriers to increase cell yields. Ideally it would be better to move away from microcarriers and go to cell clusters, but that is “easier said than done,” Warren said. Another challenge is how to isolate the cells from the large volumes used in bioreactors. “I don’t think we have the downstream technology yet,” added Warren.
An important target for reducing the cost of goods in allogeneic cell therapy is the media in which the cells are grown, and decreasing or eliminating serum and other animal-based components. Warren noted, however, that these would have to be replaced with recombinant growth factors and supplements, and the cost of those remains relatively high due to limited demand. We are caught “between the problem of supply and demand,” Warren said. Another concern when bovine serum and animal proteins are removed is whether the cells change in any fundamental way.
Frederick Miesowicz, COO and vp of manufacturing at Argos Therapeutics, presented a case study summarizing the do’s and don’ts of an automated approach for scale-up of personalized immunotherapies. Argos is automating its Arcelis personalized immunotherapeutic platform technology. The method involves capturing all of the unique antigens from a patient’s tumor and developing an immunotherapeutic agent that targets the patient’s mutated tumor antigens without provoking an autoimmune reaction, thereby sparing the healthy tissue. The company has a product in a Phase III trial in renal cancer.