Navigating the Complexities of Emerging Therapy Development

The global population is aging, and the prevalence of chronic illnesses is on the rise, meaning that bio/pharmaceutical companies are seeking out new therapeutic approaches that may not only provide relief from disease symptoms but may also offer a real cure. Emerging therapies, such as genetic medicines, cell therapies, multispecific antibodies, and other novel modalities, are providing viable therapeutic options to a whole host of disease areas. However, these therapeutic modalities are highly complex and present numerous challenges to their development across formulation, manufacturing, analysis, regulatory compliance, and other activities. While significant advances have been made in the past decade, new hurdles continue to emerge as drug companies seek to bring promising candidates through the clinic and to the market more rapidly and at lower cost.

A wide range of hurdles to overcome

Both small and large biopharmaceutical companies developing emerging therapies must overcome a wide range of hurdles as they seek to bring their candidates forward, regardless of the modality. One of the major challenges heavily emphasized by Kate Broderick, chief innovation officer at Maravai Life Sciences, is limited access to funding. “In the current environment, finding the funding essential for supporting projects from initial discovery to first-in-human trials is extremely difficult,” she states.

A big issue for Yochi Slonim, CEO and cofounder of Anima Biotech, is the current limited understanding of disease biology, which combined with traditional drug-discovery methods and existing datasets, leads to reinforcement of pre-existing hypotheses rather than mechanistic insights.

“Genes and proteins play a critical role in the onset and progression of disease, but the conventional drug-development approach still fails to account for the complex interplay at the molecular and cellular levels, which leads to poor translatability for emerging therapies,” agrees Asim Siddiqui, senior vice president and scientific fellow at Seer.

Slonim also highlights the fact that many key disease-driving proteins, including transcription factors, scaffolding proteins, and intrinsically disordered proteins, are well established in disease pathology but remain undruggable using conventional small-molecule or biologic approaches. Furthermore, he notes that while powerful, phenotypic screening is often unable to elucidate the mechanism of action (MoA) of promising compounds.

“For these reasons,” says Slonim, “researchers often lack a clear understanding of how compounds function within disease biology, and as a result many promising molecules fail to progress, even when they demonstrate strong initial effects.”

The complexity of development due to the involvement of cutting-edge technologies such as gene editing and cell engineering that require deep scientific expertise, precise control, and extensive validation—and, therefore, longer development timelines and increased costs—is another general challenge, according to Jeng Her, founder and CEO of AP Biosciences. The lack of translationally relevant preclinical models that accurately predict treatment response in humans is an additional important issue.

Material sourcing is also often a hurdle in the development of emerging therapies. Access to plasmid DNA is often cited as a limiting factor for many genetic medicines. Ensuring the necessary supply of excipients crucial for the stability and efficacy of novel formulations that meet stringent purity, regulatory compliance, and functional requirements remains a persistent bottleneck as well, according to Marie-Sophie Quittet, head of customer relationships for Adragos Pharma.

Development of cost-effective, robust, scalable processes that afford high yields of high-quality drug substances and drug products is a key challenge for most new modalities. “Many novel therapies require intricate processes that must be efficiently scaled while ensuring batch-to-batch consistency, particularly bispecific antibodies,” observes Her. Cell therapies and viral vector-based gene therapies are also complex and difficult to manufacture, causing very high manufacturing costs and patient access issues, according to Jens Vogel, president and COO at Mirai Bio.

Difficulties with integration of automation technologies and rapid analytics is an important contributor to this issue, says Mike Paglia, chief technology officer with ElevateBio BaseCamp. He also notes that the shift to platform processes can help address some manufacturing issues, but maintaining flexibility and adaptability is also essential in optimal processes developed to produce novel therapies.

Regulatory challenges. Many regulatory hurdles exist as well. Navigating regulatory landscapes is particularly challenging, as existing guidelines were primarily designed for small molecules and biologics rather than these newer, more complex modalities, according to Her.

“Pioneering new science requires forging a new regulatory path, which for both regulatory authorities and developers can be complex and time-consuming,” Broderick comments.

Striking a balance between the technical expectations of customers and regulatory constraints is a significant obstacle, Quittet adds. “Each innovation brings unique requirements and specifications that must be harmonized with the evolving regulatory guidelines to ensure safety and efficacy,” she says.

An example highlighted by Brian Pepin, CEO of Rune Labs, is the reliance of regulators on existing clinical assessment tools for clinical endpoint validation that were developed before digital technologies and artificial intelligence (AI)/machine learning (ML), which he believes do not offer the scalability or precision required to demonstrate the effectiveness of emerging therapies.

For novel modalities, summarizes Chris Learn, senior vice-president and head of Parexel International’s Cell and Gene Center of Excellence, regulatory guidance can be limiting, constantly evolving, and differ from one agency to another. He does emphasize, though, that while the uncertainty is challenging, it also presents opportunities for developers if they take the right approach.

New technologies. Many people today are also wary about the new technologies upon which emerging therapies are based. As an example, Rajiv Gangurde, vice-president, technical at Parexel points out that patients may hesitate to enroll in clinical trials that require an invasive, investigative procedure—particularly with irreversible, single-dose administrations. He adds that emerging therapies also face the challenges common to all new medicines associated with misinformation, its influence on public opinion, and its downstream effects.

Unique development challenges

Given the diversity of novel modalities advancing in the clinic today, it should not be surprising that some development challenges are uniquely associated with specific classes of compounds. For bispecific antibodies and bispecific antibody-drug conjugates (ADCs), target selection, engineering, and safety profile management present hurdles due to the fact these molecules engage two different targets simultaneously, according to Her. “Some of the difficulties lie in identifying target pairs that work synergistically without triggering unwanted immune activation or systemic toxicity, maintaining structural integrity and ensuring proper antigen engagement, and fine-tuning protein engineering to prevent mispairing and aggregation while optimizing batch consistency,” he says.

For nucleic acid-based candidates, the biggest challenge according to Broderick is finding manufacturers that can produce products in the desired form at the appropriate quality and yield in a specified timeframe. “A lot of companies claim they can do all of these things, but in actual practice producing these drugs is much more complex than most people think,” she observes.

Small molecules that modulate messenger RNA (mRNA) biology regulators without introducing synthetic mRNA are a new approach in the RNA field. They enable disease-specific control of mRNA expression and have the potential to treat conditions that previously have been considered undruggable, according to Slonim, but present a new set of challenges, such as identifying the precise regulatory mechanisms that control mRNA function in disease, ensuring target specificity, developing new screening methods for mRNA regulation, and understanding the complex functional impact of modulating mRNA pathways.

In the field of radiopharmaceuticals, Kathy Spencer-Pike, chief commercial officer for Nucleus RadioPharma, notes that one of the biggest challenges is talent acquisition and retention, because trained nuclear pharmacists, radio and analytical chemists, microbiologists, and radiation safety experts are often not easy to find in the exact locations and in the proper timelines. She also notes that due to the short half-lives of radiopharmaceuticals, they must be administered to patients within days or sometimes hours of production. “In addition to the special equipment and knowledge needed to handle radiopharmaceuticals, developers must have a foolproof plan leveraging a complex combination of production, quality control, proper handling, and transportation capabilities to bring these therapeutics and patients together,” Spencer-Pike contends.

Problematic formulation

Stability, solubility, and pharmacokinetic (PK) optimization are three important formulation challenges for emerging therapies, according to Her. Solubility and viscosity problems can be problematic in high-concentration formulations intended for subcutaneous administration, Her adds. “Innovative strategies for use of novel excipients, predictive modeling for sequence optimization, and advanced drug-delivery systems are needed to address many of these formulation issues,” he comments.

While lipid nanoparticles (LNPs) have proved useful for the delivery of the COVID-19 mRNA vaccines, they do suffer from several limitations with respect to unwanted side effects and delivery, largely to the liver. “The challenge,” says Broderick, “is to develop delivery systems that can, for instance, target the right muscles, the brain, or nerves to treat Huntington’s, Alzheimer’s, and multiple sclerosis, respectively. However, pioneering new opportunities requires proving new technologies are safe and effective and garnering regulatory acceptance, both of which can be challenging, arduous, and time-consuming,” she says.

Vogel agrees. “Delivering nucleic acid medicines involves multiple steps once the drugs are injected, each of which is impacted by the design of the delivery vehicle, the chemistry of the various components, the size and polydispersity of the particles, the placement of any shielding and targeting moieties, and the specific formulation in terms of the ratio of the different components used. Formulation optimization therefore needs to holistically take all parameters into account,” he notes.

Formulation challenges also arise for many emerging therapies due to the need for careful control of storage conditions, according to Quittet. Storage at ultra-low temperatures requires not only specialized equipment, but formulations designed to mitigate risks. That necessitates at the least, she says, selection of materials that align with the sensitivity of these therapies and the development of sensitive, robust, and sophisticated material testing protocols to ensure the compatibility and stability of products.

Many manufacturing hurdles

The complexity of novel modalities and their manufacturing processes create hurdles for all emerging therapies, particularly those with compositions that differ greatly from traditional small-molecule and biologic drugs. A key challenge in emerging therapies, contends Mercedes Segura, vice-president of process development with ElevateBio, is the need to develop robust and scalable manufacturing processes from the start, ensuring a smooth transition into GMP manufacturing while supporting commercial readiness in the future.

The issue, adds Paglia, is not only to develop processes that are rapid, robust, and potent, but that can be consistently reproduced and scaled in multiple locations/regions to ensure global commercial success. He emphasizes the value of advanced digital quality and control systems and the need to have an overarching quality and control system that allows for standardization across many manufacturing locations.

That issue ties into the question of whether to conduct process development work in-house or outsource. If the latter is selected, one challenge then becomes choosing the right contract service provider, which, according to Christiane Niederlaender, vice-president, technical with Parexel, “depends on the scope, complexity, and timeline for manufacturing an advanced therapy asset as well as the financial, geographical, and scaling considerations that a sponsor must reconcile often without the benefit of certainty or assurances.” She does agree that moving to a decentralized manufacturing model involving distributed production across multiple, geographically dispersed locations may result in reduced transportation costs and lead times, increased flexibility and responsiveness, and enhanced opportunities for customization, but does require robust and reproducible processes.

Manufacture of nanoparticles, says Quittet, requires meticulous processes to ensure sterilization while avoiding sedimentation during filling, which can be particularly difficult for gene-modified particles and ADCs. Similarly, the need to achieve extremely high purities for gene-editing therapies and the challenges associated with developing processes that can meet these expectations while also affording high yields in a cost-effective manner are highlighted by Broderick. Quittet also notes that development of efficient and industrially feasible scalable lyophilization cycles complicates manufacturing for many emerging therapies.

When it comes to adoptive cell therapies, Segura believes that “investing early in process development (PD) with experienced PD teams and leveraging their extensive processing and testing capabilities, optimized workflows, and manufacturing platforms for both cell products and gene-modifying components not only mitigates chemistry, manufacturing, and control (CMC) risks—such as process failures, costly comparability exercises, and scale-up challenges—but also paves the way for long-term success.”

The advent of personalized mRNA-based cancer vaccines, meanwhile, poses challenges related to downscaling rather than upscaling, according to Broderick. The same is true for autologous cell therapies, for which the biggest challenge is that one batch equals one patient, and manufacturing can only be scaled out, not up, observes Vogel.

These therapies, says John Tomtishen, Cellares’ senior vice-president and Integrated Development and Manufacturing Organization general manager, require highly skilled professionals to operate in large cleanroom facilities leveraging manual benchtop equipment to produce one therapy for a patient at a time. “Automation and integrated manufacturing approaches that can lower costs, accelerate timelines, and enable commercial-scale manufacturing are pivotal to transforming the cell therapy manufacturing paradigm,” he states.

While Vogel recognizes that allogenic cell therapies enable some scale-up, he also expects the continued need for partial human leukocyte antigen (HLA) matching to present supply-chain challenges. The solution, he believes, is to replace complex ex vivo engineering and manufacturing of cells with targeted engineering of cells in vivo.

Complicated analytics

Developing fit-for-purpose analytical assays for novel therapies is complicated by many factors ranging from regulatory uncertainty to material availability and assay performance issues. “The timeline for regulatory agencies to publish analytical development guidelines can be quite lengthy, and for many emerging therapies, including those for which preliminary guidance has been published, clarity is often lacking regarding many issues, including which assays are acceptable,” Broderick comments.

One example highlighted by Quittet is the lack of validated methods for nanoparticle suspensions intended for injectable use. For instance, endotoxin testing is challenging for solutions that are already turbid; although, alternative methods are being explored when the turbidity is manageable. “Establishing reliable analytical methods involves leveraging prior knowledge and adapting to product-specific and regulatory requirements, while developing novel approaches validated over time,” she says.

Material (i.e., drug substance, drug product) availability can be problematic as well. “Material must be produced to develop an assay, but material production in turn relies heavily on analysis, (e.g., methods to assess purity and yield). So, process and analytical development need to be coupled and appropriately balanced,” Niederlaender explains. He also notes that development activities require heavy investments in terms of time and resources, which can be difficult, particularly at the onset of a project.

Of particular concern for Tomtishen is the development of potency assays for novel therapeutic modalities. He points to assays for cell therapies as being particularly challenging due to the inherent variability of cell-based products, including patient-to-patient variability and complex MoAs.

Regulatory uncertainty

Lack of comprehensive analytical guidance is just one challenge derived from regulatory uncertainty. A more overarching issue, according to Barbara Abissi, manager of regulatory affairs for Parexel, is the lack of regulatory frameworks in many countries, which makes it difficult to properly categorize and evaluate emerging therapies. “Different regulatory authorities often operate independently without effective communication, and the resultant lack of coordination can lead to inconsistent evaluations, requirements, and timelines without predictability. These regulatory challenges underscore the need for harmonized approaches and clear guidelines to ensure the safe and efficient development of emerging therapies while maintaining rigorous oversight,” she contends.

No one single strategy for success

With so many different challenges to overcome, there is no one single strategy that developers can pursue to ensure successful advance of their promising drug candidates. In fact, while some strategies apply across different challenges, in many cases different approaches are needed to address each individual challenge.

The first step is to enhance understanding of biology and human health. Siddiqui points to the promise of integrating deep proteomic insights with genomic research, known as proteogenomics, for revealing the relationships between proteins and genetic information and pinpointing the underlying drivers of disease. “Integrated proteomic workflow technologies coupled with mass spectrometry offer enhanced protein coverage beyond the limitations of affinity-based methods for known proteins on a panel. With this approach, it is possible to conduct unbiased proteomic analyses to study the effects of emerging therapies, such as profiling xenotransplantation and immune dynamics or targeting cancer vulnerabilities with RNA-based treatments,” he says. Ultimately, Siddiqui believes that by better identifying how drug interactions affect the proteome, therapies can be designed that will dramatically improve patient outcomes.

The next step is collaborating with experienced service providers, both contract research and contract manufacturing and development organizations. “Engaging with such partners as early as possible in development allows process development and regulatory expectations to be aligned,” Quittet states. She adds that proactive collaboration ensures that manufacturing processes are robust and compliant and support the complex, often bespoke, needs of novel therapeutic modalities and can streamline the transition from development to commercialization.

Due to the unique manufacturing challenges posed by radiopharmaceuticals, in fact, Spencer-Pike believes that outsourcing to established service providers with expertise in handling radioactive materials and a comprehensive distribution network can be a viable option for developers of all sizes. “Smaller biotechs can find the flexibility helpful, while Big Pharma companies can use outside partners to mitigate the uncertainty and wasted capacity that can come with building too much of their own manufacturing infrastructure,” she comments.

Another general strategy being pursed to overcome manufacturing challenges is the development and implementation of platform processes. This approach has been highly effective for increasing the efficiency and productivity and reducing the cost of recombinant protein and monoclonal antibody production, and many emerging therapy developers are seeking to establish platform solutions for novel modalities with the same goals in mind.

Such efforts are being encouraged by FDA, which published draft guidance on its Platform Technology Designation Program for Drug Development in May 2024 (1). “Reviewing and adjudicating safety and efficacy profiles across dozens of new therapy submissions each year that are each produced with custom processes and technologies is extraordinarily challenging for regulators. By moving to platform approaches, both development and approval times are reduced,” Learn observes.

Indeed, such platform technologies can allow for standardized and modular approaches to manufacturing, formulation, and delivery, according to Her. Once a product has been approved that is developed and manufactured using such platform technologies, some requirements can be reduced and review can be achieved more quickly for future products developed and produced using the same technologies, Broderick says.

In the end, Tomtishen believes that use of platform technologies within drug development, particularly for complex and diverse emerging therapies, will have a profound impact on reducing time-to-market while also ensuring patient access to safe, efficacious, and high-quality drug products.

Leveraging AI and predictive modeling tools

Underlying many strategies for overcoming development challenges posed by novel modalities is the application of AI and other digital technologies, which today are being leveraged to improve drug discovery, lead selection and optimization, process development, and manufacturing in many different respects.

“Automation, modeling, and AI when combined are impacting various stages of advanced therapy development, from initial research to patient care,” says Gangurde. He points to advances in target identification/drug design, manufacturing optimization, quality control, patient stratification, and treatment optimization algorithms.

The power of AI, ML, and other predictive modeling tools, believes Vogel, is manifested in their capacity to analyze very large and complex datasets and find patterns amidst the noise. “This new ability to leverage high-throughput platforms to generate high-quantity and high-quality data sets, particularly of in vivo data, is accelerating and derisking the development of emerging therapies. By leveraging data lakes and advanced machine intelligence, we are enabling the rapid implementation of learnings into drug and cargo design. This is creating an immense opportunity to crack the code of delivery and pioneer cures for patients in need,” he concludes.

One key example for Slonim is the analysis with AI of proprietary deep data (large-scale experimental datasets generated directly from both healthy and diseased cells), which he notes is providing unique insights into disease mechanisms and thus supporting more effective drug discovery. He highlights visual biology as an important advance that integrates experimental biology with large-scale pathway visualization. “This approach generates millions of high-content images for a given disease, capturing hundreds of cellular pathways and uncovering mechanistic insights that traditional methods cannot access and allows for building of evolving AI models that further enhance disease understanding and target discovery,” he explains.

AI and predictive modeling tools are also being used to enhance process design, augment training, and allow for rapid reporting of key performance indicators and process data, which in turn support automation of routine activities, reduction of costs, and increased consistency, according to Paglia. “The ability to have data collection, analysis, and reporting fully automated allows for reduced operating expenses, which has a direct impact on product cost of goods and allows for more rapid release of a product for treatment,” he says.

Broderick is also excited about the potential for real-time data analysis in clinical trials, which she believes will “completely change the dynamics of drug discovery and development.”

Leveraging AI and moving from subjective and episodic assessments to objective, continuous real-world monitoring with digital biomarkers could accelerate regulatory approval and improve clinical decision-making, Pepin agrees. AI models are also being used to match patients with the right therapies to optimize patient recruitment for clinical studies. The use of predictive algorithms to anticipate symptoms, such as off-times in Parkinson’s, can, furthermore, enable proactive care adjustments, he says.

Caution around the application of AI and other advanced technologies is warranted, though. “For these efforts to be meaningful, notable acceleration and efficiencies gained will have to be demonstrably shown in terms of research advancements, personalized treatment, and improved clinical outcomes,” Learn cautions.

Reference

1. FDA. Draft Guidance for Industry: Platform Technology Designation Program for Drug Development (Rockville, MD, May 2024).

About the author

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 49, No. 3
April 2025
Pages: 10–15

Citation

When referring to this article, please cite it as Challener, C.A. Navigating the Complexities of Emerging Therapy Development. Pharmaceutical Technology 2025 49 (3).