How a device could kill your revolutionary mAb or C>, and what to do about it
The world of pharma is now, largely, a world of biologics. Whether a monoclonal or bispecific antibody, advanced cell or gene therapy, or recombinant protein; biologics are opening up revolutionary new therapeutic pathways, creating more specific treatments whilst reducing off-target effects, and pushing forward the boundaries of what is possible in healthcare.
In with all of the potential and promise though, we should lose sight of the fact that biologics also have some specific challenges and limitations, which need to be considered and responded to to make any particular treatment a success. These challenges and limitations include:
High cost: Compared to small molecule drugs, biologics are orders of magnitude more expensive to develop and manufacture, typically needing complex and difficult processes to manufacture the large structured proteins at the core of the therapeutic benefits
High complexity: These large structured proteins also come with a high degree of complexity, meaning a high potential for the drug substances to interact with environmental compounds and materials, in ways that are difficult to predict
Increased sensitivity: This complexity also goes hand-in-hand with a higher sensitivity, where interactions are more likely to result in damage to the drug substance itself, harming safety and efficacy. This is particularly true where interactions cause conformation changes in complex quaternary structures
Complex Administration and Pharmacokinetics: Unlike small molecule drugs most biologics cannot be delivered orally due to their sensitivity to damage. Moreover, while parenteral delivery is common, the large molecule weights involved mean they cannot cross capillary cell walls and so follow more complex routes to their site of therapeutic action
Specific site targeting: Most biologics target a tightly specific site of therapeutic action in the body. This is of course fantastic for targeting the therapeutic effect of the drug, but ties bioavailability and therapeutic efficacy tightly to the precision of site targeting during delivery
Drug-Device Integration
The result of these challenges is that, much more so than for small molecule drugs, the safety and efficacy of a biologic drug product is tightly influenced by the characteristics and mode of action of the device used to deliver it, as well as the process of delivery itself. Drug and device form a single, unified, therapeutic system, with the qualities of the drug, device, and drug-device combination determining the safety, efficacy, and cost effectiveness of any treatment.
This creates a challenge for drug developers used to a small molecule drug world, where the device used to deliver the drug product can be treated as a relatively late stage afterthought.
This is not the case for biologics; where the wrong delivery device surface coating an create adsorption of the drug substance on the wall greatly reducing bioavailability. Where leaching of a material into the drug formulation can create drug agglomoration reduced efficacy and an increased prevalence of unwanted immunogenicity. Where the rapid flow of the drug product through the system can lead to conformational changes in the drug substance, and a loss of therapeutic power.
At every stage of delivery, compared to a small molecule drug, biologics are more susceptible to sorption, agglomoration, and denaturation. Their more complex journey through the body also increases the proportion of drug product which never makes it to a site of therapeutic action, and so produces no therapeutic benefits. All of this in the context of drug products that are hugely more costly to produce, and have an affordability that is greatly affected by what proportion can be made to be therapeutically effective
And these challenges have effects that can make or break a drug product. We all know of a drug product or two which have looked hugely promising in pre-clinical and Phase 1 testing, but failed to have a strong enough therapeutic impact in Phase II or Phase III for there to be a viable business case - costing manufacturers, costing patients, and costing society.
But what if some of those drug products could have been viable if closer attention had been paid to optimising their delivery? This is part of the question that was asked by Pfizer several years ago in their transition to a more effective R&D process, an effort that increased Phase II success rates from 19% to 53%, and lifted Phase III approval rates above 80%.
Part of this approach was their 3 pillar/POM paradigm that declared that a strong potential development candidate needed to demonstrate three fundamental elements:
Exposure at the site of action
Binding to the pharmacological target
Expression of pharmacological activity from the site of action
All three of these elements are enhanced by avoiding the delivery related sorption, agglomeration and denaturation that biologics are particularly susceptible to, as well as providing better targeted and more direct delivery. The negative is also true - poor delivery could be what turns your promising drug candidate into a commercial failure.
Addressing the challenge
Addressing the challenge means more dilligently understanding and designing for the type of drug, device and delivery interactions that can negatively impact the safety and efficacy of a specific biologic.
Some examples of the types of interaction we have encountered with our clients include:
Interactions driven by the material of the delivery device flowpath – with adsorption possible in the absence of suitable surfactants in the formulation
A fluid flow path geometry, fluid flow rate and injection force that interacted with the characteristics of the drug product formulation to induce conformation changes in the drug substance through excessive shear stresses
Certain silicone oils in the device driving protein aggregation
Tungsten microparticles and residues contributing to protein fragmentation and aggregation
These represent only a subset of the general type of susceptibilities which can come about from drug/device interaction.
Crucial is that the drug and device are co-developed together from the earliest stages of development, and treated as a single therapeutic system. The enables early and diligent actions to identify any susceptibilities that emerge from the interaction, and design the combinant drug product-device system to ensure the consistency, safety, and efficacy of treatment.
In addition, biologics need precise and targeted delivery to the target tissues themselves to avoid excessive loss of bioavailability at the target sites of therapeutic action. This is particularly true with an increasing number of such molecules being delivered subcutaneously, or intramuscularly, rather than intravenously.
For example, depending on the desired exposure profile, different characteristics are required of subcutaneous or intramuscular depot. In addition the site of injection (e.g. abdomen vs arm) will produce a more or less beneficial effect due to the natural variation in biology between sites. Where a slower drug release is required, delivery to the less extensively vascularised subcutaneous layer is beneficial. However, depot size and shape also has an impact – with a depot that has more horizontal spread minimising the transfer of the drug molecule to the more highly vascularised dermis, or intramuscular layers.
Summary
Biologics have a range of susceptibilities limiting their therapeutic benefits that aren't present to the same extent in small molecule drugs. These extent of the effect that these susceptibilities have can be enhanced or mitigated by the way in which the drug product is delivered, as well as the feature and mode of action of the delivery device.
This means that biologics and devices operate much more as a single therapeutic system with both drug and devices elements having an influence over safety and efficacy. The effects here can be large enough such that the overall success of a biologic drug product can be determined by how well the drug and device elements are integrated to optimise delivery.
These factors also drive a need for co-development of the drug and device, to achieve precise accurate, and consistent dosing, and in turn safe and effective outcomes for patients. This need is tightly coupled to the unique nature of biologic molecules – both in terms of their specific susceptibilities to Adsorption, Aggregation, and Degradation, as well as achieving consistency and quality in their transfer to the target sites of therapeutic action.
Are you wanting to increase the safety and efficacy of your biologic drug product? Feel free to contact us directly here for a no obligation 1-on-1 chat