At Phacilitate’s recent “Cell & Gene Therapy Forum”, enthusiasm greeted reported advances in the research laboratory and successes in the commercial arena for technologies that represent high-risk ventures for the companies developing them. Excitement also accompanied the introduction of pioneering therapeutic strategies that epitomize the promise of personalized medicine.
Sharing the spotlight with the research and clinical news, however, was an omnipresent reminder of scaleup and manufacturing challenges, regulatory and reimbursement hurdles, cautious acceptance by the healthcare community, and skepticism and skittishness among investors—particularly in the current economic climate.
The push-and-pull between optimism for the future and the reality of overcoming current challenges was evident—one presentation was entitled, “So you’ve got a C> product that works—now, how are you going to make money from it?”
The focus of many of the talks was Dendreon’s autologous cellular immunotherapy, sipuleucel-T (Provenge®), which received FDA approval nearly a year ago for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. In January, Dendreon reported $48 million in 2010 revenues for Provenge and announced plans to seek marketing authorization in Europe. The company plans to increase production capacity by about 10-fold in 2011, with concomitant increases in its sales force and its marketing and physician/patient education efforts.
A key topic of discussion was how cell and gene therapies will be assessed by insurers for reimbursement. Robyn Karnauskas, Ph.D., director and research analyst at Deutsche Bank Securities, gave a sobering appraisal of the current investment picture as she summarized the lessons learned from the Dendreon experience. Increasingly cautious investors want to see positive healthcare outcomes to assess the potential of a company’s new drug or therapeutic intervention.
Demonstrating a promising response rate is no longer enough; companies need to show survival data and “superclean trial results,” said Dr. Karnauskas. This will entail longer, more expensive trials and increased risk. She described an underlying fear among investors of drugs with novel mechanisms as well as growing concern around biosimilars.
The news from the investment arena is not all disheartening, though, as Dr. Karnauskas noted a rising trend in IPOs and the availability of funding for companies that prove worthy.
She emphasized the uncertainty surrounding regulatory and reimbursement factors as well. The FDA “has set the bar higher for approval” since about 2009, she said, and companies need to demonstrate a clear clinical strategy for development. She described the recent FDA decision to withdraw its approval of Avastin in breast cancer due to the drug’s side effects as “not expected.”
Additionally, “reimbursement has become more challenging,” said Dr. Karnauskas, as evidenced by Medicare’s restrictions on Epogen to treat anemia associated with dialysis and the Alzheimer disease drug Aricept. The Centers for Medicare and Medicaid Services has initiated a National Coverage Analysis of Provenge to determine reimbursement.
Clifford Goodman, Ph.D., vp at The Lewin Group and chair of the Medicare Evidence Development & Coverage Advisory Committee, emphasized the importance of comparative effectiveness research (CER) and its role in advancing personalized medicine. CER requires a direct comparison of alternative interventions—head-to-head comparisons of new treatments against standards of care, not placebo—and reporting of health outcomes. It is not sufficient to rely on response rates or increased/decreased levels of surrogate biomarkers as indicators of efficacy.
“Personalized medicines must show that an intervention has some direct, or at least demonstrably indirect, favorable impact on health outcomes in real-world practice settings,” said Dr. Goodman.
Furthermore, “for CER to contribute to personalized medicine, it will have to emphasize priorities and study designs that account for individuals’ genetic, behavioral, environmental, and other personal traits,” he added. “CER needs to incorporate subgroup analyses,” as mean effects derived from an entire trial population are not necessarily indicative of a treatment’s effect in an individual or subpopulation (a concept known as heterogeneity of treatment effects).
Representatives of Dendreon shared the company’s experiences and strategies in the development and ongoing commercial roll-out of Provenge. The therapy is derived from peripheral blood mononuclear cells obtained by leukapheresis and activated with a combination of recombinant prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor to yield CD54+ T cells that are expanded ex vivo and returned to the patient.
Michael Covington, Dendreon’s CMC director, regulatory affairs, spoke about the need to demonstrate that a product made at multiple manufacturing sites is the same. To limit the need for repeated batch-to-batch testing, Covington suggested instead that product comparability can be demonstrated by documenting comparability of the GMP systems in place at different facilities and by thorough product characterization.
Robert Preti, Ph.D., is president and CSO at Progenitor Cell Therapy, a CMO that produced Provenge for use in Dendreon’s Phase II and III trials. He stressed the value of having a well-characterized product and of building in desirable traits, such as longer shelf-life, earlier in development. He said there’s no need to recreate the wheel when facing the challenges of commercial development of autologous cell therapies. There is much to be learned from the blood industry and from the experiences of antibody and biopharmaceutical manufacturers, he noted.
David Smith, head of global therapeutic cell solutions at Lonza, described the company’s work on allogeneic cell therapy beginning in 2008 and the strategies devised to reduce the cost of goods and bring down the initial $500 per dose cost of an allogeneic cell therapy. By optimizing scaleup, facility design and utilization, and downstream processing, Lonza is now able to manufacture the product for less than $250/dose.
Lonza is now applying a similar strategy to the production of autologous cell therapy products. The company recently constructed cGMP high-throughput manufacturing facilities in Walkersville, MD, and in Singapore. As manufacturing processes are scaled to commercial levels, the main cost driver is product testing, Smith explained. To help bring down manufacturing costs, companies need better informatics, more automated and high-throughput testing methods, and improved regulatory strategies, cost-of-goods logistics, and extended product shelf-life.