Althea’s protein crystal technology supports the switch from intravenous to highly concentrated subcutaneous therapeutic protein delivery, and with it self-administration, long-acting formulation, and lifecycle extension. Protein crystals are related to but should not be confused with CLECs (crosslinked enzyme crystals), which Althea inherited through its acquisition of Altus Biologics.
Protein crystal formulations are delivered as suspensions of 5–10 micron particles, not solutions. When formulated as suspended solids, proteins are far less prone to stability and aggregation issues. Since the drug is significantly less viscous than highly concentrated protein solutions, it may be delivered through a fine-gauge needle.
For example, it takes less than one minute to load a 1 mL syringe with crystalline infliximab (Remicade) at a nominal concentration of 200 mg/mL. By comparison, a 1 mL syringe of soluble infliximab at only 150 mg/mL takes 20 minutes to load. Similarly, injection of the crystalline product takes 20 seconds compared with 100 seconds for the solubilized protein.
John Hicks, director of corporate development at Althea, is quick to note that alternative subcutaneous injection formulations exist, “although there aren’t many, and few achieve high drug concentrations.” Most notable is Halozyme’s partnership with Roche to develop subcutaneous Rituxan and Herceptin using a recombinant hyaluronidase technology.
“It appears that they can deliver subcutaneously,” Hicks says. “However with Herceptin, Roche had to invest $185 million on a proprietary delivery device to target 5–10 minute administration of injections as high as 12 mL. Pain becomes a serious issue with injections significantly larger than 1.5 mL.”
The switch to subcutaneous administration involves an IP or lifecycle component—companies hurrying to switch before their IV patents expire. But healthcare economics is undoubtedly the true driving force. “Why bring a patient into a hospital or an infusion center when the treatment can be administered in an office or even self-administered?”
Crystalline suspensions don’t necessarily require longer development times than conventional platforms, but they do require a somewhat different skill set. Chemists may use any reagent they like to produce crystals, whereas bioprocessors are restrained to pharmaceutically acceptable buffers under conditions that promote rapid crystallization at high yield. Althea claims yields of greater than 90% in 24 hours.
Protein crystallization does not change the state of the native protein, yet Althea has met with resistance to the technology.
“There’s a knee-jerk reaction against injecting crystals, most likely based on the potential for immunogenicity. We haven’t seen any in the weekly hGH trials so far,” says Hicks. “Besides, insulin crystals have been used for years on a daily basis, for example Lilly’s Humalog, which is a mix of soluble and crystalline insulin.”