Bryostatin-1 is derived from a marine bryozoan, Bugula neritina, and is a potent modulator of the protein kinase C (PKC) enzyme system, a family of proteins involved in cellular signaling, cell proliferation and cell death. As such bryostatin-1 has application across several therapeutic indications. To date, 20 different bryostatins have been isolated. Bryostatin-1, is the best characterized, and the only member of the bryostatin family to have been evaluated in human clinical trials. At low concentrations, it is a potent PKC activator, and results in induction of transcription, and the cell membrane expression of tumor and/or HIV antigens. Bryostatin-1 thus makes these cells more visible to the host immune system, and exogenously administered immunotherapeutic agents that target these antigens.
The National Cancer Institute (NCI) studied bryostatin-1 extensively in the 1990-2010 period. More than 1100 individuals were treated with the compound as part of the then current chemotherapeutic, and cell toxicity approach to malignancy. Efficacy was modest in these studies, safety was acceptable, and toxicity, including maximum tolerated dose, as well as clinical pharmacology were characterized. The bryostatin-1 programs were however terminated, due in part to the modest efficacy, significant environmental impact and damage, as well as the prohibitive cost of goods using the natural marine source, roughly $1,000,000 per gram. The breakthrough synthesis by the Wender laboratory allows the use of bryostatin-1’s in the clinic and commercially due to a new reliable, scalable and affordable source.
The use of bryostatin-1, until now, has been limited by its natural scarcity, variable production by its natural marine source, and costly extraction techniques. The NCI funded the creation of the existing supply of bryostatin-1 approximately 25 years ago for pre-clinical and clinical research use. In that campaign, 18 grams of GMP bryostatin-1 were purified from 14 tons of the source organism. This source was the basis for the nearly forty clinical trials that have evaluated bryostatin in the clinic. This original supply of bryostatin-1 is nearly exhausted, but remarkably the compound remains stable, and available for clinical use. Further extraction from marine sources is no longer being considered, nor necessary.
Bryostatin-1 Synthesis for Availability, Scalability, and Affordability
Professor Paul Wender and his group at Stanford University have succeeded in pioneering a proprietary, scalable approach for the synthetic production of bryostatin-1. In addition to the scalable production of the parent agent, more than 200 analog compounds, bryologs, have been produced. The bryologs can be selected for attributes relating to efficacy, safety, and PKC isoform specificity, and thus provide a means to optimize the bryostatin-1 effect on PKC.
BryoLogyx is evaluating internationally regarded manufacturing organizations, and has assembled GMP synthesis professionals, and plans to commence production of bryostatin-1, and selected bryologs, in 2018. The synthetic process is the central portion of the intellectual property covered under the exclusive license agreement with Stanford University, and covers all indications within cancer and HIV globally.
While bryostatin-1 is a pan-PKC modulator, different analog compounds have ‘tuned’ isoform selectivity, and optimized pharmacological properties. BryoLogyx is evaluating this portfolio of compounds to improve upon the native properties of bryostatin-1. These, and subsequently developed analog compounds, have composition of matter patent protection. Characterization and preclinical screening of bryologs will commence in 2018.