ENHANZE® Drug Delivery Technology: Advancing Subcutaneous Drug Delivery using Recombinant Human Hyaluronidase PH20

By S. Karger

‘ENHANZE® drug delivery technology: Advancing subcutaneous drug delivery using recombinant human hyaluronidase PH20’ provides readers with in-depth information on the potential benefits and challenges of subcutaneous (SC) drug delivery, the biology of hyaluronan and hyaluronidases in the SC space, and a comprehensive overview on the history of hyaluronidases and the development of recombinant human hyaluronidase PH20 (rHuPH20). Current applications of rHuPH20 as well as approved biotherapeutics utilizing HuPH20-facilitated SC drug delivery are summarized, and the underlying non-clinical and clinical development approaches are introduced as a basis for future application to biologics in various disease areas. Table of Contents: • Introduction to subcutaneous drug delivery • Biology of hyaluronan and hyaluronidases in the subcutaneous space • History of hyaluronidases and development of rHuPH20 • The ENHANZE® platform: Clinical applications of a subcutaneous drug delivery technology • Application of ENHANZE® drug delivery technology: Development of currently marketed products

• Language: English
• Publisher: S. Karger
• Release date: Jun 14, 2022
• ISBN: 9783318070873

Book preview

1Introduction to subcutaneous drug delivery

Kenneth W. Locke and Daniel C. Maneval

Benefits and challenges of subcutaneous injection

Both enteral (gastrointestinal) and parenteral (non-gastrointestinal) delivery have been used for effective administration of therapeutic agents. Oral administration has historically been the choice for small-molecule drugs, but alternative administration routes have been developed to optimize delivery for biotherapeutics and drugs that have limited oral bioavailability. The most common parenteral routes include intravenous (IV), subcutaneous (SC), intramuscular (IM) and intradermal (ID) injection. SC injection involves inserting the needle into the fatty layer of the SC space (also known as the subcutis or hypodermis) just beneath the skin’s surface (Figure 1.1). The architecture of the SC space includes both capillary and lymphatic vessels (described in Chapter 2), and therapeutic agents injected into the SC space typically diffuse slowly with a sustained rate of absorption.¹ This makes SC delivery particularly effective for administering drugs that require continuous delivery at a low dose rate, such as insulin and pain medications.¹

Figure 1.1 Schematic of injection into the SC space. SC, subcutaneous.

The advantages of SC injection over IV administration include a simplified injection process, which removes the requirement for venous access, reducing the total administration time and enabling self-administration through more accessible injection sites. The SC route is, therefore, becoming a more common mode of delivery for monoclonal antibody therapeutics, including anti-cancer (e.g. rituximab and trastuzumab), anti-tumor necrosis factor (e.g. adalimumab and certolizumab pegol) and anti-immunoglobulin or anti-interleukin (e.g. omalizumab and mepolizumab) antibodies.²–⁴ IV administration has a relatively high healthcare burden for both patients and healthcare professionals (HCPs),⁵–⁹ and the specialized requirements for direct venous access may limit patient treatment with IV medications where there are insufficient administration centers or available trained operators.⁹,¹⁰ In addition, IV administration may be more complicated for certain populations. Patients undergoing repeated treatments may be at risk of complications such as phlebitis, infiltration, extravasation and infections,¹¹ and establishing and maintaining peripheral IV access may be particularly challenging in patients with small or collapsed veins.⁹ IV administration has also been identified as a source of medication errors such as incorrect doses and rates of administration, delays in administration, incorrect labeling procedures and patient identification errors.¹² These medication errors may be increased for some modes of IV administration, such as traditional gravity feed, compared with IV infusion devices.¹² In addition, IV administration of monoclonal antibodies has often been associated with a high incidence of infusion-related reactions.¹³

SC drug delivery regimens may enable patient self-administration and HCP administration outside of the hospital setting.⁵,¹⁴ Treating patients at home rather than in the hospital or infusion center setting has been shown to reduce costs, cause less disruption to activities of daily living and normal family life, and reduce stress to the patient.¹⁵–¹⁷ In addition, home-based treatment provides patients with more involvement in their own healthcare, leading to greater independence.¹⁶ Treatment at home can also increase scheduling flexibility, allowing administration at a time that does not impact on work or social life, and ultimately enabling improved adherence by avoiding missed doses.¹⁵–¹⁸ In cases where treatments need to be monitored and administered in a hospital setting, SC administration may reduce hospital resources associated with IV administration, including active HCP time, patient chair time and associated costs.⁶,¹⁹,²⁰ In addition, SC administration may reduce the incidence of systemic adverse events compared with IV infusion.⁷

There are, however, some drawbacks to SC injection. SC injections are typically limited to small volumes to avoid induration and potential pain at the injection site. The maximum volume that is generally accepted is approximately 2 mL.¹⁰,²¹,²² Administration of overall larger SC volumes has historically been accomplished by implementing more frequent dosing compared with IV administration, multiple injection sites or very slow infusion rates.⁵,²²,²³ These modifications to enable administration of larger SC volumes may increase the treatment burden for patients.⁵,²²–²⁴

Given that SC injection offers a potentially more cost-effective and patient-friendly mode of drug delivery compared with IV administration, a number of technological developments have been undertaken to optimize this approach. These include drug delivery devices (e.g. self-injection systems and auto-injectors) and changes in product formulations (e.g. increased concentrations, lipid formulations and dispersion-enhancing agents). In the next section, we provide an overview of some of the existing SC drug delivery techniques and highlight advances in the optimization of SC administration for biotherapeutics.

Overview of existing drug delivery approaches

Devices

Self-injection systems can allow patients to self-administer SC injections at home, thereby reducing the burden on the healthcare system and making treatment more convenient for patients.²⁵ These systems may simplify and overcome some of the limitations associated with traditional SC self-injection (e.g. administration of an incorrect dosage, potential sterility and safety issues, or difficulties injecting due to impaired dexterity). Three main types of self-injection system are available: pre-filled syringes, pre-filled injection pens and electronic injection devices (e-devices).²⁶

Pre-filled syringes are devices that are visually similar to ‘conventional’ syringes used to withdraw liquids from a glass vial, but the syringes are pre-filled with a fixed drug dose (e.g. aflibercept and omalizumab).²⁷,²⁸ Pre-filled syringes are provided by the product manufacturer and minimize waste, limit dosing errors and decrease the risk of microbiological contamination compared with vial-based formulations.²⁹ The physical features of the syringe (e.g. finger flange and plunger rod) can be ergonomically designed to help patients with impaired dexterity handle the device.³⁰ Pre-filled syringes provide many benefits to optimize patient dosing, but product development can be affected by additional considerations required to ensure patient safety, such as the need to assess for chemical species derived from pharmaceutical packaging or delivery systems, which may pass into the product over time (i.e. extractables and leachables).³¹,³²

Pre-filled injection pens (also known as auto-injectors) are designed as automated injection systems to deliver a fixed drug dose.²⁶,³³,³⁴ Features can be added to make these mechanical devices easier to use and increase patient confidence, including automated activation by a push button, audible clicks to confirm administration of the dose, a hidden needle and a viewing window for observing injection progress.³⁵–³⁷ Perhaps the most well-recognized applications of this technology are the EpiPen® (for allergic reactions) and insulin delivery (for diabetes). This technology is also US Food and Drug Administration (FDA) approved for delivering therapeutic proteins, which are bioengineered molecules such as the monoclonal antibodies adalimumab, golimumab and evolocumab, and the cytokine modulator etanercept.²⁶,³⁸–⁴¹

E-devices are based on the pre-filled pen or auto-injector design but with enhanced technical features (e.g. SureClick® and Pushtronex®).⁴² They are reusable and have advanced electronic functions to support disease management, such as on-screen instructions, injection logs, a skin sensor and injection speed control.²⁶ With further development, e-devices have the potential to optimize drug therapy by real-time monitoring and feedback control (e.g. bionic pancreas).⁴³ Additionally, e-devices may include features to optimize injection safety. For example, an injection may be automatically stopped when skin contact is lost, or a medication information chip reader may be included to authenticate medication and to ensure it is within its use-by date.²⁶,³⁷

Patient preference for pen injection versus a pre-filled syringe has been found across a number of therapy areas, including anemia associated with chronic kidney disease,⁴⁴ rheumatoid arthritis,⁴⁵ diabetes⁴⁶,⁴⁷ and ulcerative colitis.⁴⁸ Specific benefits reported by patients for pen injection versus a pre-filled syringe include increased convenience and ease of use,⁴⁴ reduced redness at the injection site,⁴⁵ preference for long-term use⁴⁶ and increased dosing accuracy.⁴⁷ Furthermore, adherence benefits and