May 1, 2014 (Vol. 34, No. 9)
Reformulations Significantly Improve Stability of Proteins and Peptides
When biologics took center stage in the pharmaceutical development pipeline, Thomas Reese Saylor, president and CEO of Arecor, realized that developers needed new approaches to drug formulation. As he tells GEN, “When pharmaceutical pipelines were dominated by small molecules, formulation was considered only when drugs were in the later stages of development. But with biologics, formulation must be considered at the beginning. If there’s no stable formulation, there’s no product.”
After investigating ways to meet the stability challenges posed by biologics, Saylor identified a novel formulation strategy advanced by a Unilever spinoff and acquired the rights. Arecor was formed in 2007, attracting many of the original scientists.
“We’re addressing the physical and chemical properties of proteins and peptides to minimize degradation. We focus on the degradation pathways, rather than the molecule,” Saylor emphasizes. “We have worked with more than 60 proteins and peptides and built a dataset for computation systems that enable scientists to narrow the formulation options with pinpoint precision.”
Arecor’s drug formulation approach uses hypotheses that are based on structural, chemical, and mechanistic insights regarding the effects of various excipient combinations upon degradation pathways. Then, it tests the hypotheses by making deliberate combinations of excipients that would not normally be screened. According to Saylor, when the company designs formulations for a client company, it conducts “a feasibility study to develop a formulation that meets the client’s criteria over several months,” builds patentable intellectual property, and then licenses that formulation to the client.
Arecor was formed around broad intellectual property developed by Jan Jezek, Ph.D., now CSO, to improve protein stability. The initial challenge was to develop a novel, sterile wound dressing containing a protein with a three-year shelf life at room temperature.
“We developed insights around proteins in equilibrium with their environment,” Saylor recalls. “We found that very subtle changes could have a dramatic impact on protein stability. Equilibrium-based reactions, such as the exchange of protons, can lead to protein aggregation or conformational changes.”
Arecor hit upon a solution that involves replacing the conventional buffer with a displaced buffer. This measure, the company found, reduces the rate of proton exchange.
Since then, Arecor’s tools, collectively known as Arestat™, have grown to include a wide range of technologies that address most of the major degradation pathways. They are being applied to biopharmaceuticals, vaccines, medical devices, and diagnostics. These tools enable lyophilized compounds to be stored in liquid form to enhance ease of use. They also can improve thermal stability to eliminate the need for refrigeration.
Saylor reports a pressing need—and extreme interest—in formulations that improve heat and shelf-life stability, particularly in emerging markets where the “cold chain” is unreliable. Arecor’s tools also allow antibodies to be produced and delivered at higher concentrations, potentially enabling simple injections to replace slow infusions.
A Simple, Smart Approach
“Our philosophy is not to modify the drug itself, but to use approved, ‘generally regarded as safe’ excipients that can be incorporated into standard manufacturing procedures so new formulations are as easy as possible to implement,” Saylor explains. Therapeutics that are easier to deliver and use can provide a very significant competitive advantage, particularly for products that are self-administered, he points out. “I don’t see us developing new molecules.”
“We started with proteins, then moved to peptides and vaccines, and now we even reformulate and stabilize live, attenuated viruses.” Saylor admits that he was skeptical at first, but Arecor’s capabilities grew after its scientists found that stabilizing surface proteins maintained the immunogenic responses of the live vaccines.
Arecor’s approach to formulating live, attenuated vaccines produced a liquid format of measles vaccine that appears stable for two years at 2 to 8°C, rather than the –80°C normally required, and retains activity even after being stored at 37°C for 30 days. This formulation virtually ensures the vaccine will be potent when administered, thereby improving patient safety and reducing costs to the manufacturer.
Likewise, the Arestat formulation of the hepatitis B vaccine remains immunogenic for at least 12 months at 37°C. This breakthrough makes it possible to eliminate the need for cold chain handling entirely for this important vaccine, thus making it increasingly relevant in developing nations where refrigeration is sporadic or nonexistent.
Arecor’s Arestat technology also enables high concentrations of antibodies in aqueous formulations. With such formulations, the rate of aggregation and the viscosity are reduced.
To accelerate the effects of time, it is common in the industry to use elevated temperatures during formulation development. For example, Arecor has developed a high-concentration formulation for Rituximab that is virtually aggregate-free following storage at 40°C for more than 20 weeks. In contrast, the antibody kept in the original formulation shows an unacceptable increase in aggregates over the same period, manifested by precipitation of the protein and conversion of more than 10% of the native antibody to soluble aggregated species.
Another project concerns Arecor’s aqueous formulation of erythropoietin. It remains stable for more than six months at the high temperature of 40°C.
Big Pharma Buy-In
Arecor’s scientific expertise is robust. Many of the technology’s original scientists remain on the staff, moving from Bedford to Cambridge as the company has grown. It now holds 14 families of patents, Saylor says, and has projects under way with half the top 20 major pharmaceutical companies. They include umbrella agreements with Eli Lilly and Genzyme, as well as licenses with GlaxoSmithKline Biologicals. The company also has been approached to design formulations for biosimilars.
Saylor’s own goals include shaping Arecor into a center of excellence in biologic formulation. To that end, the company is devoting approximately half its revenue to R&D, which includes continuously advancing its computational systems.
Saylor anticipates expanding existing relationships and forming strategic relationships with additional companies. “We can solve a specific problem for a company, but the most productive relationships are strategic,” Saylor comments. “What could you accomplish, and what new products could you create from existing products with new formulation technologies?”
Location: 2 Cambridge Science Park, Cambridge, CB4 0FE, U.K.
Phone: +44 1223-426 060
Principal: Thomas Reese Saylor, President and CEO
Number of Employees: 20
Focus: Arecor’s approach to formulation leverages the company’s insights into the way proteins and vaccines degrade during storage, at high concentration, or in the presence of ionizing radiation. Arecor’s formulations present advantages during manufacturing, storage, and use.