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Building a biologics boom
BOSTON—Advances in formulation and delivery will help pharmaceutical firms modify proven drugs by targeting molecules now off patent, besides developing fifth-generation drugs designed to activate stem cells to fight diseases such as cancer.
Fourth-generation biologics, with improved delivery and pharmacokinetics, will continue to drive the overall biologics industry, which is already worth more than $120 billion, according to a recent Lux Research report, "Of Biologics and Cells: Are Formulation and Delivery Technologies Keeping Up with the Progression?"
"With advances in cloning and assay development, the therapeutics industry has managed to artificially engineer these molecules to address therapeutically important targets," says Yan Xiang Yang, a Lux Research analyst and the lead author of the report. "Fifth-generation biologics delivery will focus on manipulating molecular switches that turn on specific cellular differentiation and metabolic pathways. Initial switch regulators will be monoclonal antibodies designed to up-regulate, as opposed to down-regulate, pathways and cellular interactions. To that extent, the ability to mask immunogenicity and extend circulating half-life, either through direct protein engineering or via encapsulation or coating, will be important for chronic, on-demand administration."
Looking longer term, the movement towards patient convenience and at-home healthcare delivery via self-injectable devices will necessitate improvements in cold-chain processing, protein stabilization, emulsion and penetrants, as well as encapsulation and coatings. As more physiobiological information is gained about targets, it may be possible to engineer shorter proteins for greater bioactivity and loading, Yan states.
"The possibility also exists for positive up-regulation of cellular activity by fifth-generation biomolecular drugs that may be used to activate stem cells or boost immune system functions for diseases such as cancer," Yan adds.
Underscoring both Yan's analysis and the buzz about cancer immunotherapy heard at this summer's American Society of Clinical Oncology conference, Immunovaccine Inc., a clinical-stage vaccine company, is advancing its ovarian cancer vaccine into Phase II clinical trials with its new collaborator, NCIC Clinical Trials Group, a Canadian academic clinical trials cooperative. The study will enroll approximately 250 patients in order to evaluate response to Immunovaccine's DPS-Survivac in combination with low-dose oral cyclophosphamide. In a second Phase II study based in Rome, DPX-Survivac will be tested in newly diagnosed glioblastoma patients.
And in a third recently announced development, a project supported by an $8-million European Union Framework 7 program grant will aim at developing a novel class of therapeutic cancer vaccines. The Glioma Actively Personalized VAccine Consortium (GAPVAC) is the first EU-funded initiative aimed at clinically developing biomarker-guided actively personalized vaccines (APVACs) to treat cancer. The consortium consists of 14 organizations from the biotech industry and academia led by immatics biotechnologies GmbH (coordinator) and BioNTech AG (vice coordinator). Both companies are located in Germany and are dedicated to a biomarker-guided approach to fight cancer. A Phase I clinical trial that will enroll 30 newly diagnosed glioblastoma patients is expected to start in 2014.
Putting numbers to the current market, Lux Research reports that autoimmune and inflammatory biologics lead, followed by hematologic disorders, metabolic disorders (which is dominated by insulin analogs) and cancer, which together account for more than $100 billion in sales. The most lucrative indication is autoimmune diseases; the top-four drugs sharing more than $25 billion in sales and the next seven adding another $14 billion. The hematologic disorders market, worth $21.5 billion, is slightly larger than the $20.5-billion cancer drug market.
Roche/Genentech, Novo Nordisk, Amgen and Sanofi/ Genzyme are clear leaders in this game, Yan states, with Abbvie holding onto blockbuster Humira. The top-10 best-selling biologics in 2012 were Humira, Enbrel, Rituxan, Lantus, Herceptin, Avastin, Remicade, Neulasta/ Neupogen, Copaxone and Lucentis.
Several factors place antibodies at the forefront of the biologicals wave, including the depth and breadth of knowledge supporting their use, as well as innate properties such as stability and targeting ability. Blockbuster successes such as Herceptin and Lucentis have also driven others in the industry to follow suit with a likely glut of such therapies on the horizon.
Challenges remain for other biologics. Physical instability, chemical degradability, enzymatic digestibility and the inability to penetrate barriers are some key hurdles facing developers of nucleic acid technologies. Also, with only one active cellular therapy trial in the United States, progress in cell-based therapeutics will remain slow, leaving protein therapeutics the dominant biologic therapy.
"Based on what we are observing, there is exciting ongoing work enabling the delivery of these biologics via more convenient routes, such as subcutaneous delivery or even oral," Yan notes. "Achieving this would be a breakthrough in the biologics sector, enhancing patient compliance and ease of use. Some ongoing examples include subcutaneous delivery of Herceptin in a Halozyme/Roche linkup, and the long-awaited progress in oral insulin."