Issue:May 2021
GLOBAL REPORT - 2020 Global Drug Delivery & Formulation Report: Part 3, Notable Drug Delivery & Formulation Transactions & Technologies of 2020
Part 3 of a Four-Part Series
Part 1: A Review of 2020 Product Approvals
Part 2: Notable Drug Delivery and Formulation Product Approvals of 2020
Part 3: Notable Drug Delivery & Formulation Transactions and Technologies of 2020
Part 4: The Drug Delivery and Formulation Pipeline
By: Kurt Sedo, Vice President Operations, PharmaCircle LLC
Introduction
There are only a limited number of plots or scales when it comes to movies and music. That is of course until something new is discovered and everyone quickly follows. It is much the same with drug delivery and formulation. Everyone was all in on oral sustained-release delivery and transdermals until the opportunities dried up. This was followed by injectables, notably longer-acting injectables. More recently, the drug delivery and formulation technologies that have captured the interest of pharmaceutical companies revolve around the use of injectables in the outpatient market. These technology shifts have largely arisen in response to the changing product opportunities presented with new molecular motifs and commercial realities. Transdermal and oral sustained release provided clinical and business opportunities for the large inventory of small molecule actives that could benefit from dose modification. Long-acting injectable technologies were a response to the emerging macromolecule and biologics sector. The development of more convenient injection technologies for outpatient use was less a response to a therapeutic challenge than a commercial opportunity. Office or hospital cased injections were not only more costly, but also inconvenient to providers and patients.
It seems that the latest evolution in pharmaceutical products is on par with the transition from small molecule oral therapeutics to macromolecules, proteins, and antibodies. The recognition that RNA represents a significant therapeutic motif has required the development of technologies that can effectively deliver these molecules to very particular cellular targets. At the same time, there is a growing confidence that gene and cell therapies can provide similar benefits with longer horizons. These new products also require effective and efficient drug delivery and formulation technologies to ensure efficacy, safety, and stability.
In terms of transactions, while the numbers jumped in 2020, the deals largely used the same commercial templates as in previous decades. An exception might be the increasing number of deals announced that involve companies selling future milestone and royalty revenues in exchange for upfront cash. Drug delivery and formulation technologies in 2020 were a mix of the old and new, and their importance was reinforced. As we saw in 2020, even something as seemingly trivial as relaxing storage and transportation temperatures or larger vial sizes can make a big difference in terms of impacting a global pandemic.
2010s Technologies of the Decade – Subcutaneous Injectables
If the 1980s through 1990s were the decades of transdermal and extended- release oral technologies, and the 1990s through 2000s were the decades of PEGylation and injectable depot technologies, we can with some confidence declare the 2010s the decade of subcutaneous injectable technologies.
With the development and approval of a wide range of biologics possessing intrinsic long-acting properties, the therapeutic and commercial opportunity that quickly became apparent was making these therapeutics more convenient for patients and the healthcare system. Biologics can generally be readily administered without much complexity using an intravenous route of delivery. Too often, this requires in-patient administration that can demand hours-long infusions with complex dose ramping. Moving these often chronically administered biologics to out-patient use requires rerigging the products, preferably with limited formulation adjustments to simplify regulatory requirements and to reduce any chance of a clinical surprise.
The solution began to appear in the 2000s with the development of subcutaneous injection devices that not only simplified out-patient dosing with single-dose injectors, but also removed the intimidation of a typical needle. The opportunity that largely pushed this development was the increasing use of insulin for the treatment of Type 2 diabetes. While patients with Type 1 diabetes had long resigned themselves to drawing up a dose and injecting subcutaneously for the rest of their lives, Type 2 patients were intimidated by the process of doing dose calculations and going through the injection process.
These single and multidose injectors were soon adopted for low-volume biologicals that required injection as often as daily or as infrequently as monthly. These injectors not only met a pressing therapeutic need, but also accelerated the adoption of these biological products in the out-patient setting. Products like AbbVie’s Humira and Amgen’s Enbrel have managed to achieve multibillion dollar annual sales even though they require patient self-injection.
Despite the acceptance of these devices, there remained a significant therapeutic gap and commercial opportunity. These pen devices were generally limited to the injection of relatively small volumes, on the order of 1 ml or less. This limited the opportunities for products that required larger volumes for a variety of reasons, including stability and viscosity. The prospect of multiple individual doses was not an appealing option.
The solution to this challenge was provided by Halozyme and their Enhanze technology, a drug delivery system that uses high-dose recombinant human hyaluronidase PH20 enzyme (rHuPH20) co-administered subcutaneously along with the therapeutic, either sequentially or with co-formulation. The enzyme degrades hyaluronan [sodium hyaluronate or hyaluronic acid (HA)], a polysaccharide found within the extracellular matrix. Degradation of hyaluronan at the local injection area allows dispersion and absorption of the therapeutic agent more easily and rapidly and is restored via normal processes within 24-48 hours. The Enhanze technology permits large- volume administration, 2-20-ml subcutaneous injections, and up to 600-ml subcutaneous infusion.
Notable approved products utilizing Enhanze include:
- Genentech (Roche) – Herceptin SC/Herceptin Hylecta
- Biogen/Roche – Rituxan Hycela/MAbThera
- Baxalta (Takeda Pharmaceutical) – HyQvia
- Genentech (Roche) – Phesgo FDC
- Janssen/Genmab – Darzalex FASPRO
Surprisingly, for the better part of a decade, Halozyme has been the sole provider of high-volume subcutaneous formulation technology. Year after year, Halozyme has been signing deals with new and existing partners to extend the use of the Enhanze technology, but there may be some competition in the wings with Arecor’s Arestat technology.
If the 1980s and 1990s were defined by transdermal and long-acting oral technologies, the 1990s and 2000s by PEGylation and long-acting injectable depot technologies, and the past decade by subcutaneous injection devices and technologies, what comes next? The early favorites are gene and cell technologies along with RNA delivery technologies.
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