Oligonucleotide-based drugs continue to flow into developmental pipelines, and the relatively large numbers now being tested in humans and progressing through late-stage clinical studies have buoyed optimism that commercialization of oligo therapeutics may finally come sooner rather than later. In parallel to these advances is a high level of confidence in the industry’s ability to produce GMP oligos at large scale reliably, reproducibly, and cost effectively, and to meet the analytical and process-validation strategies needed to satisfy evolving regulatory requirements.
Stating that most of the challenges associated with scale-up of GMP oligos, particularly DNA sequences, have been managed, G. Susan Srivatsa, Ph.D., president of the independent consulting firm Elixin concludes, “I don’t believe our ability to manufacture is a factor in the industry’s success.”
The sole exception may be the chemistry, design, and engineering advances that will likely play an increasingly important role in oligo drug delivery strategies in development. Reproducible production, scale-up, and quality analysis of emerging delivery mechanisms—such as self-assembling nanoparticles or liposome-encapsulated oligos—and of complex dosage forms will present manufacturing challenges.
Large-scale oligonucleotide synthesizers and associated technologies to meet commercial needs are readily accessible. However, due to the relatively high cost of raw materials and to manage risk, companies continue to be prudent and manufacture at large enough scale to meet their commercial demands, while protecting their investment in raw materials and labor-intensive downstream processing in the event of a failed synthesis.
Dr. Srivatsa expresses some surprise at the buzz among CMOs at the recent “AsiaTIDES” conference in which they talked about building out additional capacity in anticipation of increased demand. Not so long ago, there appeared to be overcapacity for oligo manufacturing, and Dr. Srivatsa attributes the change in momentum and renewed energy to the critical mass of oligo drugs now in later stages of development.
“I think the CMOs realize that there are now enough balls in the air that even with a moderate success rate” enough drug candidates will make it through to regulatory approval and manufacturing demand will rise, she says.
Agilent Technologies’ Nucleic Acid Solutions Division has crunched the numbers on the current oligo therapeutic market—which has resurged following the 2009 economic downturn—and reports 2010 deals totaling $5.2 billion, with $529 million in direct investments. This investment drove up the number of oligo therapeutic development programs to a record 235 in 2011 (including both research and clinical stage).
Contributing to this increase has been a more than doubling of miRNA programs in 2011, making it the fastest-growing segment of the therapeutic oligos market. Furthermore, despite some upheaval in the RNAi sector and dire predictions regarding its future, Gary Carter, director of strategy and marketing at Agilent, reports that siRNA remains “the largest segment of the market with 81 programs in development, followed by antisense. We also saw record levels of deal activity in the siRNA segment, with $2.2 billion in total deal value in 2010.”