BioPharm International - March 2021

BioPharm International - Regulatory Sourcebook - March 2021

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8 BioPharm International eBook March 2021 a stark absence of treatment options to correct the underlying cause. An ASO provides a potential means to treat these patients and has revealed a development pathway for a long- sought goal—individualized medi- cine," he emphasizes. Templin notes that, while not specific to ASOs, in general prod- uct quality, nonclinical assessment, and clinical development of an ASO are addressed by various guidance documents from regulatory bod- ies. What's more, the traditional pathway—from IND to new drug application (NDA) to commercial product—has been successf ully completed for several oligonucle- otide-based therapies. Nevertheless, programs were focused on diseases common among a multitude of patients and intended for broad use, he adds; and the development path- way to treat many patients does not simply scale down to a single patient, he points out. " T h e n e w d r a f t g u i d a n c e , I N D S u b m i s s i o n s f o r I n d ivi d u a l ize d A n t i s e n s e O l i g o n u c l e o t i d e D r u g Products: Administrative and Procedural Recommendations Guidance for Sponsor- Investigators, is a major step in estab- lishing the procedures and processes for communication between FDA and a sponsor-investigator with the intent to treat a single patient with a genetic-based disease for which the genetic variant is unique to that patient. In this situation, a research IND is the means of establishing the plan to initiate treatment," Templin says. The treatment plan is highly focused to the specific patient and the disease state, he adds, and, as the draft guidance points out, early communication with FDA is para- mount because it allows for more focused efforts and progress—a critical aspect because patients are often in rapid decline. Furthermore, early communication assures that fundamental product quality and clinical safety parameters are pre- served, Templin says. Jen n i fer Pa nagou l ias, sen ior v i c e - p r e s i d e n t , R e g u l a t o r y, Compliance & Policy, at Wave Life Sciences, a biotechnolog y com- pany specializing in nucleic acid therapeutics, adds that, while FDA has not issued an ASO -specific guidance up until this point, the industry has sought to have such guidelines developed to help estab- lish the regulatory considerations relevant for these compounds. "ASOs are large molecules with molecular weights that fall between a traditional small-molecule and bio- logics, but, due to their complexity, development and regulatory consid- erations often straddle the fence, so to speak, in terms of application of concepts from the ICH [International Cou nc il for Ha r moni zat ion of Te c h n i c a l R e q u i r e m e n t s f o r Registration of Pharmaceuticals for Human Use] Quality and Safety guide- lines (2)," Panagoulias says. Although ASOs are reg ulated as drugs, some ICH-Q guidelines exclude them from their scope, Panagoulias adds. She explains that feedback from European regulators suggests that the application of tradi- tional nonclinical safety concepts, as outlined under the ICH M3 (3) guideline, are not always appropriate for ASOs given their make-up and pharma- cological characteristics. "For exam- ple, while genotoxicity studies are generally performed for oligonucle- otides, they are unlikely to interact with DNA as would small-molecule chemicals. Few ASOs, if any, have been demonstrated as genotoxic in such studies (4), thus the consider- ations for biologics where an evalu- ation would be performed based on a product-specific concern in lieu of traditional studies may be more appropriate," she says. Panagoulias also states that regulatory guidance specific to nonclinical, chemistry, manufacturing, and controls (CMC), and pharmacology considerations for oligonucleotides would be of great use to sponsors developing these compounds. CHALLENGES IN ASO DEVELOPMENT One particular challenge in devel- oping ASO therapeutics has been the ability to improve their phar- macologic properties, which would enhance delivery and uptake, notes Panagoulias. There have been chem- ical modifications that have helped improve distribution and tolerabil- ity, and these improvements have been critical in advancing this class of drugs. Some companies have spent years developing and enhanc- ing their platform chemistry to opti- mize the pharmacologic properties of these types of drugs, Panagoulias points out. Cost of manufacture, demonstrat- ing sufficient safety in nonclinical and clinical studies, and validation of clinical efficacy, to name a few, have been and continue to be chal- lenges in development of ASOs, says Templin. However, he points out, there has been extensive research into the manufacture of oligonu- cleotide-based therapeutics (oligos) and improved chemical modifica- tions for greater drug-like properties. Furthermore, data from nonclini- cal and clinical studies have signifi- cantly expanded and increased the underlying knowledge base for these compounds. "All have been crucial steps in the transition for oligos from research to commercialization," Templin says. Wave Life Sciences, for instance, was founded on the principle of applying novel optimization strate- gies to oligonucleotide design, start- ing with a unique ability to control chirality in oligonucleotides, which the company defines as "stereopure oligonucleotide," says Panagoulias. Through a focus on stereochemical Regulatory Sourcebook Quality

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