Matthew N. O’Brien Laramy’s scientific contributions

Nucleic acid drug delivery with lipid nanoparticle (LNP) formulations has enabled the development of novel therapeutics and vaccines. LNP formulations are composed of both naturally occurring and synthetic lipid excipients. This perspective shares current practices in the nonclinical safety assessment of novel lipid excipients contained in LNP formulations and identifies gaps in current regulatory guidance on this topic. There is no globally harmonized regulatory guidance for the nonclinical safety assessment of novel excipients or guidance specific to safety testing of novel excipients in LNPs. Given the complexity of these LNP formulations, most nonclinical safety studies to support development are conducted with the drug product or with a LNP that contains non-active cargo. Three case studies (Onpattro ® , Comirnaty ® , and SpikeVax ® ) highlight that specific assessments may differ depending on the encapsulated modality, the intended use (e.g., therapeutic versus preventative vaccine), dose, and frequency of dosing. These case studies also suggest that regulatory agencies are open to scientific rationale to justify why certain tests should or should not be performed. As more products are approved, it will be important to understand how precedents set for approved products can be leveraged and what additional unique strategies may be applied to ensure nonclinical safety assessments are predictive, relevant, and meaningful for human safety. Proactive alignment with regulatory authorities will be critical in this context, especially as new approaches are proposed. Guidance documents may need to be revised or created as more experience is acquired to reflect the unique considerations for these novel excipients.

Lipid nanoparticles (LNPs) for nucleic acid delivery often use novel lipids as functional excipients to modulate the biodistribution, pharmacokinetics, pharmacodynamics and efficacy of the nucleic acid. Novel excipients used in pharmaceutical products are subject to heightened regulatory scrutiny and often require data packages comparable to an active pharmaceutical ingredient. Although these regulatory requirements may help to ensure patient safety they also create economic and procedural barriers that can disincentivize innovation and delay clinical investigation. Despite the unique structural and functional role of lipid excipients in LNPs, there is limited specific global regulatory guidance, which adds uncertainty and risk to the development of LNPs. In this Perspective we provide an industry view on the chemistry, manufacturing and controls challenges that pharmaceutical companies face in the use of novel lipid excipients at each stage of development, and propose consensus recommendations on how to streamline and clarify development and regulatory expectations.

The addition of a novel therapeutic agent to an organ preservation solution has the potential to address unmet needs in organ transplantation and enhance outcomes for transplant recipients. However, the development expectations for novel therapeutic agents in this context are unclear because of limited precedence and published regulatory guidance documents. To address these gaps, we have articulated a drug development strategy that leverages expectations for parenteral drug products administered via more conventional routes (eg, intravenous) and provided considerations for when deviations may be justified. We have supplemented this strategy with a comparison to available regulatory guidance from the US Food and Drug Administration to highlight potential areas for further clarification. The strategy articulated here is based on Genentech’s internal experience for a program intended for use in kidney transplantation.

PF-07304814 is a water-soluble phosphate ester prodrug of a small molecule inhibitor for the SARS CoV-2 3CL protease designed for the treatment of COVID-19. The amphiphilicity and self-assembly behavior of the prodrug was investigated computationally and experimentally via multiple orthogonal techniques to better design formulations for intravenous infusion. The self-assembly of PF-07304814 into micellar structures enabled an increase in the solubility of lipophilic impurities by up to 1900x in clinically relevant formulations. The observed solubilization could help extend the drug product shelf-life and in use stability through inhibition of precipitation, without the need for solubilizing excipients. The work presented in this manuscript provides a roadmap for the characterization of prodrug self-assembly and highlights the potential for prodrug modifications to enhance solubility of both active ingredients and impurities and to extend drug product shelf-life.

The recent clinical and commercial success of lipid nanoparticles (LNPs) for nucleic acid delivery has incentivized the development of new technologies to manufacture LNPs. As new technologies emerge, researchers must determine which technologies to assess and how to perform comparative evaluations. In this article, we use a quality-by-design approach to systematically investigate how the mixer technology used to form LNPs influences LNPstructure. Specifically, a coaxial turbulent jet mixer and a staggered herringbone microfluidic mixer were systematically compared via matched formulation and process conditions. A full-factorial design-of-experiments study with three factors and three levels was executed for each mixer to compare process robustness in the production of antisense oligonucleotide (ASO) LNPs. ASO-LNPs generated with the coaxial turbulent jet mixer were consistently smaller, had a narrower particle size distribution, and had a higher ASO encapsulation as compared to the microfluidic mixer, but had a greater variation in internal structure with less ordered cores. A subset of the study was replicated for mRNA-LNPs with comparable trends in particle size and encapsulation, but more frequent bleb features for LNPs produced by the coaxial turbulent jet mixer. The study design used here provides a road map for how researchers may compare different mixer technologies (or process changes more broadly) and how such studies can inform process robustness and manufacturing control strategies.

Over the past 3 years, the first bivalent protein degraders intentionally designed for targeted protein degradation (TPD) have advanced to clinical trials, with an initial focus on established targets. Most of these clinical candidates are designed for oral administration, and many discovery efforts appear to be similarly focused. As we look towards the future, we propose that an oral-centric discovery paradigm will overly constrain the chemical designs that are considered and limit the potential to drug novel targets. In this Perspective, we summarize the current state of the bivalent degrader modality and propose three categories of degrader designs, based on their likely route of administration and requirement for drug delivery technologies. We then describe a vision for how parenteral drug delivery, implemented early in research and supported by pharmacokinetic–pharmacodynamic modelling, can enable exploration of a broader drug design space, expand the scope of accessible targets and deliver on the promise of protein degraders as a therapeutic modality. Bivalent protein degraders such as proteolysis targeting chimeras (PROTACs) are entering clinical trials, with a current focus on oral administration. O’Brien Laramy et al. propose that implementing non-oral drug delivery technologies guided by pharmacokinetic–pharmacodynamic modelling could expand the chemical design space for degraders as well as the number of druggable targets.

Introduction: Ocular long-acting injectables and implants (LAIIs) deliver drug at a controlled release rate over weeks to years. A reduced dose frequency eases the treatment burden on patients, minimizes the potential for treatment-related adverse effects, and improves treatment adherence and persistence. Areas covered: This review provides a comprehensive landscape of ocular LAII drug delivery technologies with clinical precedent, including eight commercial products and 27 clinical programs. Analysis of this landscape, and the specific technologies with the greatest precedent, provides instructive lessons for researchers interested in this space and insights into the direction of the field. Expert opinion: Further technological advancement is required to create biodegradable LAIIs with extended release durations and LAIIs that are compatible with a broader array of therapeutic modalities. In the future, ocular LAII innovations can be applied to diseases with limited treatment options, prophylactic treatment at earlier stages of disease, and cost-effective treatment of ocular diseases in global health settings.