Steven Hager, Ph.D. Director of Science and Technology, Catalent Biologics
Lisa Caralli Director of Science and Technology, Pharmaceutics, Catalent
Carla Vozone VP Inhalation Strategy, Innovation and Partnerships, Catalent
Over the past year, have there been any “game-changing” drug delivery technologies released?
Steven Hager, Ph.D., Director of Science and Technology, Catalent Biologics: Antibody-drug conjugates (ADCs) are one of the fastest-growing drug classes in oncology. They are an effective drug delivery system that can target tumor cells by employing the specificity of an antibody, combined with the cell-killing potential of a small molecule toxin, while minimizing any off-target side effects of traditional chemotherapy treatments. First-generation ADC technologies showed the potential efficacy of ADCs, though some were tarnished by issues related to in vivo instability, resulting in off-target toxicity and a narrowing of the therapeutic window. Additionally, these initial drugs had complicated manufacturing processes with variable drug-to-antibody ratio (DAR) and involved overly complex analytics that resulted in extended development timelines.
Newer-generation ADC technologies have been developed to address these issues, including having greater manufacturability of the antibody at both clinical and commercial scale, without altering the antibody’s native properties, and utilizing advanced conjugation chemistries to enable optimization of the payload. Additionally, there is greater understanding of how to engineer the number and precise location of conjugation sites in order to simplify analytics while increasing DAR, as well as identifying new toxins with improved efficacy and developing linkers that incorporate stable chemistries to broaden the therapeutic window and allow selective, cleavage to target membrane and intracellular targets.
These advances in ADC engineering and chemistry are leading to greater efficacy and improved patient outcomes, and have the potential to be transformative in cancer therapy.
What medical indications seem to be getting a lot of attention from a drug delivery perspective? Why?
Lisa Caralli, Director of Science and Technology, Pharmaceutics, Catalent: The pandemic has shone a spotlight on mental health, and we have seen an increase in medications targeting addiction and psychiatric indications. Interest in psychedelic drugs such as psilocybin, 3,4-methylenedioxymethamphetamine (MDMA), and lysergic acid diethylamide (LSD) for treatment of psychiatric disorders is gaining momentum, possibly fueled by the deregulation of marijuana by some U.S. states. Controlling the pharmacokinetics of these drugs, such as their Cmax and duration of action through dose design is critical. For example, sublingual psilocybin can provide faster onset and shorter duration for treatment of depression. Companies are also looking at modifications to existing molecules to reduce any psychedelic effects while maintaining their therapeutic properties.
As the need for vaccines grows, will there be a concerted effort to deliver vaccines in other forms than the traditional syringe?
Caralli: Studies of pregastric and nasal delivery of vaccines are growing. Since most pathogens enter the body via the respiratory, reproductive or gastrointestinal mucosae, delivering drugs to mucosal membranes has clear advantages. Conventionally, systemic delivery via syringe does not induce a strong mucosal immune response, so orally disintegrating tablets could provide benefits of ease of use, including the ability to self-administer, that they are fast dissolving, and are also suitable for pediatrics. This non-invasive route of delivery is also important for tolerogenic vaccination for allergenic indications, where treatment can last for years.
Carla Vozone, VP Inhalation Strategy, Innovation and Partnerships, Catalent: Immunization via intranasal vaccine administration has gained considerable attention during the COVID-19 pandemic, with the expectation of an easier and needle-free alternative to delivery of vaccines to large population groups. Nasal delivery of vaccines induces a rapid mucosal immune response, which creates a shield to block the pathogens at its point of entry in the upper airways, potentially providing better protection against infectious agents. Intranasal vaccination induces a strong systemic immune response because of the fast absorption to the blood circulatory system, and may also induce protection at other mucosal sites. In particular, the development of nasal powders has grown extensively, because powders are highly stable compared with liquid formulations, and extend the residence time on the nasal mucosa, potentially increasing the local and systemic immune response.
As biologics and vaccines get most of the attention – how will oral solid dosage products remain competitive? What drug delivery technologies can help these products remain relevant?
Caralli: The success of biologics and vaccines has not meant any slowdown in the development of oral solid dosage forms, where we have seen successful innovation in oral drug delivery technologies. The success of RYBELSUS® (oral semaglutide) has shown that large molecule products can be viable when launched using the oral route of administration for the correct indications.
Degradation and permeation are two key areas of focus for new dosage forms. Effective delivery to the intestine is the critical first step, where enteric coatings or shells may be employed to bypass the harsh gastric environment. A multiparticulate versus monolithic approach can also be effective to ensure passage through the pylorus. To improve systemic uptake, permeation enhancement remains an area of investigation. The most common approach is with the addition of tight junction openers such as C10 or salcaprozate sodium (SNAC) as excipients. However, in situ formation of gap junction openers through lipid digestion using technology is also possible to ensure close interaction of the drug and the open tight junctions. The recent success of solid lipid nanoparticles for vaccines could also provide strategies to both protect the drug payload, and modify how the body will uptake the molecule. Both oral and nasal delivery of nanoparticle constructs have seen increased interest too.
In the next few years how will drug delivery technologies adapt to a world where a fear of pandemics becomes the norm? Do you see drug delivery technology providers playing a big role in bringing new treatments to market as quickly and safely as possible?
Caralli: Our fear of pandemics should be greater than any fear or distrust of science, and helping people to understand that “new” does not mean “unsafe” is clearly a challenge, especially for new drug modalities. In the current environment, novel delivery of existing drugs may be a more universally accepted approach by physicians and patients and yet provide significant benefits. To that end, physiologically-based pharmacokinetic modeling will play an increasingly prominent role in quickly identifying the target product profile for a newly emerged indication. For example, modeling the impact of altering local versus systemic exposure, or changing the route to inhalation or nasal delivery, can assist developers in their strategy to repurpose drugs.
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