Targeted protein degradation (TPD) represents a transformative approach within the field of therapeutic intervention, specifically for diseases where traditional small-molecule inhibitors have failed. This innovative strategy uses the cell’s own protein degradation mechanism to selectively remove disease-causing proteins. Unlike traditional drug treatments that might inhibit a protein’s function, TPD eliminates the target protein by recruiting the cell’s own ubiquitin-proteasome system.

Recent advancements in TPD include the use of bifunctional degraders, such as proteolysis-targeting chimeras (PROTACs), which simultaneously bind to both the target protein and a ligase, to bring the target protein and degradation enzyme into close proximity. Degradation is then induced by strengthening the interaction between the targeted protein and the ubiquitin ligase.

Another method involves using molecular glues that induce protein-protein interactions to trigger protein degradation. This method is already approved for treating certain oncology indications like multiple myeloma, with well-known examples including thalidomide, lenalidomide and pomalidomide.

The key benefit of TPD is that it completely eliminates the disease-causing proteins, rather than just inhibiting their function. With the drug remaining within the body, it can continuously target the protein molecules. As this technique features highly specific targeting, it has the potential to treat diseases in oncology, neurology and immunology where traditional approaches have had limited success.

According to recent statistics pulled from GlobalData鈥檚 Drugs database, there are currently 737 TPD drugs in active development 鈥� 75% of which are being explored in oncology indications, followed by 10% for central nervous system. The majority of these are in the discovery and preclinical stages of development, while 32 drugs have an IND/CTA filed and 145 are in clinical development, including 85 in Phase I, 45 in Phase II, and 15 in Phase III trials.  

However, while TPD is rapidly gaining momentum in the pharmaceutical industry, the larger molecular size and more complex structure of their active pharmaceutical ingredients (APIs) means they have reduced solubility compared to traditional small molecules. How do we address these challenges and provide treatments that can pass through the blood/brain barrier; while also ensuring they are easy to use for the patient?

Achieving good oral bioavailability for TPDs

Rebecca Coutts is Senior Director of 色界吧 Development at PCI Pharma Services, a world leading CDMO providing integrated end-to-end drug development. Coutts identifies several specific challenges associated with oral bioavailability in the context of TPD, including difficulty in crossing biological membranes, reduced absorption in the gastrointestinal tract, and potential for inconsistent drug delivery.

These challenges have significantly influenced TPD development, says Coutts, driving innovation in formulation technologies and necessitating more sophisticated approaches to achieve effective oral delivery.

鈥淎n additional factor is that, unlike conventional small molecules which align well with pharmacokinetic-pharmacodynamic principles, targeted protein degraders can sometimes have atypical properties that complicate formulation development and the delivery,鈥� says Coutts. “You need to look at the molecular weight and their solubility profile, and then evaluate their physiochemical characteristics and what they look like in terms of being able to then develop suitable orally available drugs that give the required bioavailability.鈥�

Several strategies can be employed to mitigate these challenges, says Coutts. 鈥淲e’re investigating a variety of formulation and processing methods that can improve solubility,鈥� she says. 鈥淭here are a number of approaches and enhancement techniques available that can improve solubility characteristics and provide the customer with optimum particle size or morphology [as well as] characteristics that will give you the solubility profile that you’re looking for.鈥�

Among others, these include micronisation and wet nanomilling 鈥� reducing the particle size of the drug substance, resulting in increased surface area for an improved solubility dissolution profile. Amorphous solid dispersions 鈥� where the drug substance is changed from a crystalline material to an amorphous material via spray drying or hot melt extrusion techniques 鈥� can also improve solubility.

Strategies and future developments

When it comes to the development approach for TPD drugs, Coutts explains that getting the best results is very molecule dependant. However, PCI Pharma鈥檚 strategy is to step in early with solubility screening assessments.

鈥淲e like to do that as early as possible, because we can provide feedback to our clients and the drug substance manufacturer to work with them at this early stage,鈥� says Coutts. 鈥淭his determines the best strategy to potentially employ in terms of improving formulation activities. We typically use what is called the developability classification system. Once we鈥檝e determined which class a drug falls under, techniques such as micronisation, for instance, can be employed. It’s very molecule dependent. As well as the solubility properties, we can look at other properties of the molecule, melting point, etc, and then determine which would be the best approach to take.鈥�

“As the field and enabling technology grows, then we are likely to see other particle engineering and solubility enabling approaches being developed,鈥� notes Coutts. For example, lipid-based formulation approaches are being explored to improve both solubility and permeability, especially for molecules with large molecular weights.

鈥淎s well as having solubility challenges, some molecules also have permeability challenges, and therefore you may need to involve some lipid-based formulation approaches to improve the solubility and permeability. That comes from some of the TPDs having a large molecular weight and being challenged in terms of their uptake,鈥� Coutts explains.

Advancing TPD development with a world leading CDMO

PCI Pharma Services offers a comprehensive, expert-driven approach to advancing targeted protein degrader development, making them an ideal CDMO partner for oral TPD projects. Leveraging over 35 years of experience with high-potent molecules, their core strengths include two specialised contained manufacturing facilities and a purpose-built high-containment packaging facility, ensuring the safe handling and processing of high-potency drugs. PCI鈥檚 approach of rapid solubility screening techniques and collaborative development are complemented by their technical capabilities, further strengthened by partnerships with specialised solubility technology experts.

PCI Pharma’s comprehensive understanding of TPD challenges and their ability to improve solubility and bioavailability profiles make them an ideal partner for advancing targeted protein degrader development. 鈥淎t PCI, we don’t just develop formulations 鈥� we solve complex molecular challenges. Our science-driven approach transforms promising targeted protein degraders from concept to clinic,” says Coutts.

To learn more about the latest trends and challenges in the wider market for targeted therapies, please download the whitepaper below.