By Peter G. Traber, M.D. on October 15, 2015
When thinking about the development of a drug, one naturally tends to think of performing animal and human studies to demonstrate the safety and effectiveness of the drug in the intended disease indication. However, a drug development program not only includes these safety and efficacy studies, but importantly it also must provide the chemistry, manufacturing and controls (CMC) information to demonstrate the quality and stability of the drug product. This CMC information includes the physical and chemical properties of the drug, the processes by which the drug is made, the formulations for administration of the drug to patients, quality control specifications and stability data to ensure the quality of the drug product over time.
The CMC information is a critical part of regulatory submissions for approval. In 2008, Booz Allen Hamilton, an independent consulting firm hired by the U.S. Food and Drug Administration (FDA) found that approximately 20% of all deficiencies delaying first cycle reviews of drug applications were related to CMC issues1. A more recent study by the FDA, published in 2014 by the Journal of the American Medical Association, confirmed that CMC information remains critical to the FDA’s review and approval of new drugs, indicating that CMC deficiencies were the cause of 12.6% of first cycle review failures and 21.1% of delays following application resubmissions2.
The CMC development program for GR-MD-02
What follows is a general overview of the CMC development program for GR-MD-02, Galectin Therapeutics’ leading drug under development, which targets and inhibits the expression of galectin-3 protein. Galectin-3 is important in the promotion of multiple types of diseases, including inflammation, fibrosis, and cancer. We have focused the use of this drug in a development program for potential treatment of patients with liver fibrosis, and specifically in those patients with NASH (non-alcoholic steatohepatitis) with advanced fibrosis or the most severe form of fibrosis, cirrhosis, and in moderate-to-severe plaque psoriasis. Currently, Phase 2 clinical trials are being conducted with GR-MD-02 in patients with advanced liver fibrosis due to NASH, which at present has no available therapies approved, and an exploratory Phase 2a study has commenced for the psoriasis indication.
Please be patient with me through this discussion, because the technical details really matter here. It is important to note that GR-MD-02 is a polysaccharide (polymeric carbohydrate) with defined chemical and physical characteristics. Several polysaccharide drugs have been approved by the FDA. One example is heparin, an anticoagulant which is a composite of poly-sulfated glycosaminoglycan. (For those who want to get very technical, GR-MD-02 is a patented galactoarabino-rhamnogalacturonate polysaccharide derived through proprietary chemical processing and modification from pharmaceutical grade apple pectin.)
Understanding the physical properties of GR-MD-02
From the beginning of the program, we performed studies to characterize the physical, chemical and biological properties of GR-MD-02 utilizing state-of-the-art analytical techniques and methodologies, some of which were developed in collaboration with leading scientists in the academic field of carbohydrate research.
As a composite polysaccharide, characterization of GR-MD-02 required the development of some very sophisticated new analytical techniques and technologies to adequately assess GR-MD-02’s building blocks and integrity. A variety of high pressure liquid chromatography (HPLC) methods and detection systems were optimized to measure the polymeric molecular weight and molecular weight distribution, carbohydrate composition, degradation products and impurities. In addition, two-dimensional nuclear magnetic resonance (NMR) were successfully validated to detect the infrastructure of GR-MD-02. Advanced mass spectrometry methods and technologies developed in cooperation with the University of Georgia were implemented to characterize the internal linkages of the carbohydrates within the polymeric structure, creating a “fingerprint” mapping of GR-MD-02.
Determining the most effective formulation
Initially, several formulations of GR-MD-02 were evaluated to determine the best method of delivering an intended dose to patients, including oral, subcutaneous (SC) and intravenous (IV) routes of administration. The proof of concept and efficacy of GR-MD-02 formulations were verified in multiple animal models of liver inflammation and fibrosis3, 4. The IV formulation of GR-MD-02 was determined to be optimal for further development based on the intended patient population and the bioavailability of the drug. Considering the dosages established in the animal fibrosis NASH models and preclinical safety studies, a sterile IV solution of 30 mg/mL of GR-MD-02 in 10 mL vials was then designed for the current drug product formulation being used in our clinical trials.
Ensuring consistency, stability, and shelf life
Specifications for GR-MD-02 were established to ensure the safety, identity, strength, quality and purity of the active drug substance and final drug product. These specifications include analytical methods to control all stages of manufacturing from raw material to drug substance to final drug product formulations. Each GR-MD-02 batch produced is tested for conformance to the specifications to ensure the consistency and quality of batches used throughout the development program. The batches are also tested periodically to ensure that GR-MD-02 is stable and will meet product specifications over time. The data from these stability studies provide the basis for the established shelf life of the product.
Optimizing the production process
Current production processes for GR-MD-02 were designed considering the physical and chemical properties of the drug, yield, cost, quality raw material availability, safety and environmental factors, among other quality considerations. Experiments were performed to define the optimal process for the synthesis and production of the bulk drug substance (the API, or active pharmaceutical ingredient) and the final drug product (30mg/mL sterile solution).
Procedures and tests were implemented throughout the production process to control the quality of the starting materials, intermediates and final drug product. Initially, the synthesis of the drug was developed and optimized in the laboratory and then transferred to scaled-up manufacturing facilities for production of batches for preclinical and clinical studies. Eventually, the processes will be further optimized and scaled-up for larger batch sizes to meet commercial and market needs.
Commitment to the Highest Quality and Regulatory Standards
The FDA requires that all production and testing of human drug products meet a high standard for quality of pharmaceuticals, referred to as the good manufacturing practices (GMPs). Galectin maintains a continued communication with the FDA to make sure that GR-MD-02 and all aspects of its production meet regulatory-established GMP standards and requirements. Further, all contracted laboratories and manufacturing sites used in the production of GR-MD-02 are certified GMP facilities, audited by both Galectin and the FDA to meet these standards.
Galectin Therapeutics continues to seek out new and innovative technologies and strategies to improve our products, and we are committed to maintaining the highest quality standards and principles in the development of anti-galectin drugs for fibrotic disease and cancer.
These “CEO Perspectives” will be a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events and use words such as “may”, “could”, “expect” and others. These statements include those regarding the hope that Galectin’s development program for GR-MD-02 will lead to the first therapy for the treatment of fatty liver disease with advanced fibrosis and cirrhosis. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2014, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements
Please look for future editions in which multiple aspects of our development programs for unmet medical needs will be addressed.
Reference List
- Booz Allen Hamilton, “Independent Evaluation of FDA’s First Cycle Review Performance – Final Report”, July 16, 2008, http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm127117.htm
- Leonard V. Sacks, Hala H. Shamsuddin, Yuliya I. Yasinskaya, Khaled Bouri, Michael L. Lanthier, Rachel E. Sherman. Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012. JAMA, 2014; 311 (4): 378 DOI: 10.1001/jama.2013.282542
- Traber PG, Chou H, Zomer E, Hong F, Klyosov A, Fiel MI, et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS One 2013;8(10):e75361.
- Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS One 2013;8(12):e83481.
