Digital Transformation in Pharma Manufacturing

Patent Cliff Deals, Tariff Pressures, and the In Vivo Cell Therapy Bet

Behind the Headlines, Episode 23

ICH Q12 and Post-Approval Changes

Speed, Flexibility Top Large-Molecule Manufacturing Trends

Drug Digest July 2025

Key Insights from Industry Survey Results

Bio/Pharma's Tariff Response

Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

people in the shape of a target with an arrow, aim | Image Credit: © tai111 - Stock.Adobe.com

Compared with small-molecule therapies, which have been in use for more than a century, the field of biological therapies is reasonably nascent. Since the approval of the first recombinant protein in the 1980s, numerous biological therapies have been developed for a variety of indications (1).

“The field of biological therapies has indeed experienced a significant expansion and transformation, largely driven by advancements in molecular and cellular biology,” says Anupreet Kaur, post-doctoral associate in the Brinson Research Group, Institute for Bioscience and Biotechnology Research, National Institute for Standards and Technology, University of Maryland. “One of the key breakthroughs has been the widespread adoption of recombinant DNA technology, which has revolutionized the production of protein therapeutics.”

“[Going back to] the end of the last century, when there were mainly small-molecule drugs on the market, [patients were typically] suffering from major side effects,” notes Peter Timmerman, head of Peptide Science at Biosynth. “[These unwanted effects] paved the way for a new generation of drugs that were more specific and more biologically based.”

A major benefit of biological therapies is their ability to reach targets that have previously been thought of as ‘undruggable’ with more traditional small-molecule therapies (2). Despite being much larger than small-molecule drugs, biological therapies feature a greater affinity and selectivity to a specific target, making them more effective with less off-target toxicity, Timmerman explains.

Specificity to molecular targets is a key attribute of monoclonal antibodies (mAbs), remarks Kaur. “This specificity allows [mAbs] to distinguish between subtle differences, such as single amino acid variation and conformational changes, enabling precise targeting of disease-related molecules,” she says. “Additionally, the bivalency of each antibody molecule contributes to the higher binding strength, which enables mAbs to bind with exceptional affinities, typically ranging from picomolar to nanomolar levels.”

This high binding strength is important for differentiating between the binding partners and for enhancing the therapeutic efficacy of the mAbs, continues Kaur. “Moreover, the Fc [fragment, crystallizable] domains of mAbs play a crucial role in [biological] properties,” she adds. “This region can engage with various components of the immune system leading to functions such as antibody-dependent cellular cytotoxicity, or complete complement dependent cytotoxicity. These effector function-enhanced antibodies have the ability to eliminate the target cells and modulate the immune response, further improving therapeutic potential.”

®, Bill Whitford, Strategic Solutions leader at Arcadis, spoke to the 

progress being made by 3D printing in commercial biologics production

Having presented on the topic during one of the sessions at INTERPHEX 2024, Whitford highlighted the utility of 3D bioprinting for cell culture. “3D culture provides many unique capabilities; it’s more biomimetic,” he said in the interview. “Actually, there’s nothing natural about growing cells in monolayer on a styrene plate, so there are many 3D culture technologies that employ many different production methods that support many categories of application and individual products.”

Additionally, Whitford alluded to the potential use of 3D bioprinting for emerging therapies, such as cell and gene therapies. “The ability now—through site-directed CRISPR [clustered regularly interspaced short palindromic repeats]-type engineering—to drive the evolution of a cell towards exactly what phenotype is required is supporting the ability to … develop the bio ink … required to get the initial print job accomplished,” he said.

Bill Whitford of Arcadis Discusses 3D Printing for Biologics (INTERPHEX 2024)

“As targets for mAb therapies are identified, fewer are agonist targets and more are antagonistic targets,” remarks Scott Rudge, founder of SynerG Biopharma Group. “When an agonist target is found, the antibody can be designed to stimulate a cell or an organ to produce a certain outcome.For example, insulin is a protein agonist, because it causes cells to take up glucose and store it as glucagon.”

However, antagonists, such as check point inhibitors, actually block something from happening, Rudge emphasizes. “If every receptor in the body needs to be inhibited or down-regulated in some way, antagonists are going to require ever increasing doses, which means higher concentration, to be administered subcutaneously or some other way less invasive than intravenous administration,” he adds.

“Subcutaneous and intramuscular delivery, in particular, require highly concentrated formulations, as the maximum volume these routes of administration can accommodate is about 1 mL,” Rudge explains. “Alternatively, other means for delivering high doses of mAbs could be found that deliver more than 1 mL. Research in these two areas is very active.”

Additionally, the development of bispecific antibodies represents a significant milestone for the biopharma industry, Kaur adds. “This platform holds promise for enhancing the efficacy, increasing the half-life, and improving the stability and specificity of biologic therapies, while minimizing the side effects,” she says.

Looking beyond antibody therapeutics, Kaur highlights RNA vaccines as a promising platform that will enable the development of novel vaccines to tackle infectious and other diseases. “Ongoing research aims to further optimise RNA vaccine platforms and expand their application beyond infectious diseases,” she says.

“Also, there are short oligonucleotide therapies, which will present a versatile and promising approach for the treatment of orphan rare diseases by targeting specific genes and other regulatory elements,” Kaur specifies. “Continued research and development efforts are focused on improving the delivery strategies, enhancing the specificity and efficacy, and expanding the clinical application of oligonucleotide-based therapeutics.”

Focusing on potential future trends for the biologics field, Hans de Backer, head of the Peptide Division, Biosynth, emphasizes that there are several key trends that will be ongoing for a long period of time. Some are more industry generalized trends, such as accelerating time-to-market and moving towards more green solutions in manufacturing; however, a more specific trend for biologics will be the drive for increasingly patient-specific solutions instead of generic ‘one-size-fits-all’ type therapies.

A further trend that is shaping the biologics sector is the development of combination therapies, whereby companies are developing these products as combination options from the outset rather than considering a potential combination later on, De Backer specifies. “The expanded range of biological and small-molecule drugs already approved can be being used during development to act on multiple pathways or the same pathways through differing mechanisms. It is therefore increasingly important for researchers to be able to access reagents (as biosimilars or generics) early in development to understand modes and mechanism of action, and routes for improving efficacy,” he says.

“All of the aforementioned trends will be mainly boosted by the introduction of artificial intelligence (AI), which is being seen in all areas playing a key role” De Backer says. In particular, he points out that AI is helping to accelerate time-to-market for drug development, all the way from discovery to production. AI is helping companies to deliver results that in turn are fitting in with funding cycles and ultimately helping them commercialize their drug products.

In terms of personalized medicine, AI will enable further personalized drug manufacture options—but also personalized prescription. AI can be used by clinicians to assess the sort of response they can expect from a therapy, which is allowing them to choose the best therapeutic option for their patients (3). “AI will definitely bring new opportunities and allow for better forecasts [of therapy outcomes], driving personalized medicine to the next level,” De Backer asserts.

Additionally, Timmerman states that he has high expectations of AI as it has the potential to provide information that hasn’t been seen before, particularly for drug discovery. Currently, when trying to look at the drug space, industry is limited to only a fraction of what is available, he emphasizes, whereas AI has the potential to be used to map out the complete drug space, enabling the identification of a greater number of novel chemical entities (4).

There are other areas where AI can provide new information, Timmerman notes. “For example, there is a new modeling program called AlphaFold that basically can predict the structure of all proteins from their primary amino acid sequences,” he says. “[So, now it is not necessary to have] any crystal structure or any other type of 3D structure to know how the protein looks and how to develop a drug against it.”

Recent research has also demonstrated the ability for AI and machine learning to speed up protein engineering (5,6). “Advancements in protein engineering have facilitated the development of novel molecular scaffolds, optimized molecular functions, and improved drug properties,” Kaur adds. “These molecule-level innovations have opened up new possibilities for creating biologics with enhanced therapeutic effects.”

“Gaining an in depth understanding of accepted and multiple antibody interactions will undoubtedly revolutionize the future of biological formulation, as this knowledge can lead to the design of excipients that have beneficial impacts on the protein structure, thereby improving quality and efficacy [of antibody therapeutics] in the future,” summarizes Kaur. “Moreover, understanding the dynamics of antibody and antigen binding properties at the molecule level will help in designing the effective next-level antibodies. Manipulating these binding properties can optimize antibody performance and specificity and affinity for specific application.”

1. Andrews, L; Ralston, S; Blomme, E.; Barnhart, K. A Snapshot of Biologic Drug Development: Challenges and Opportunities. 

, 34 (12), 1279–1285.
2. Leach, M.W.; Rottman, J.B.; Hock, B.; et al. Immunogenicity/Hypersensitivity of Biologics. 

, 42 (1), 293–300.
3. Johnson, K.B.; Wei, W.-Q.; Weeraratne, D.; et al. Precision Medicin, AI, and the Future of Personalized Health Care. 

, 14 (1), 86–93.
4. Duncan, K.K.; Rudnicki, D.D.; Austin, C.P.; Tagle, D.A. Exploring Novel Biologically-Relevant Chemical Space Through Artificial Intelligence: The NCATS ASPIRE Program. 

, 6, 1–6. DOI: 10.3389/frobt.2019.00143
5. Wait, S.J.; Expòsit, M.; Lin, S. Machine Learning-Guided Engineering of Genetically Encoded Fluorescent Calcium Indicators. 

, 4, 224–236.
6. Case, M.; Smith, M.; Vinh, J.; Thurber, G. Machine Learning to Predict Continuous Protein Properties from Binary Cell Sorting Data and Map Unseen Sequence Space. 

Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.

When referring to this article, please cite it as Thomas, F. Biologics on Target for the Future. 

Articles

A greater understanding of molecular and cellular biology and technological advancements are revolutionizing the field of biologics. 

Biologics on Target for the Future

Feliza Mirasol is the science editor for 

Text sign showing Industry News. Business photo text delivering news to the general public or a target public | Image Credit: © Artur - © Artur - stock.adobe.com

Certain additives or a combination of additives in downstream bioprocessing have demonstrated an improvement in the separation and clearance of empty and partially full capsids during the manufacturing of viral vectors, noted Ohnmar Khanal, PhD, Downstream Technology Lead, Spark Therapeutics, at the 

American Society of Gene and Cell Therapy’s (ASGCT’s) 27th Annual Meeting

, which is being held from May 7–11, 2024 in Baltimore, Md.

 on the work her team has been doing to test the removal of empty and partially filled adeno-associated virus (AAV) capsids in the downstream processing stage of AAV vector production. Khanal stated that she and her team have been looking at additives and the role they play in AAV purification. In particular, her team focused on copper ions and conducted oversaturated loading experiments using multicolumn anion exchange (AEC) chromatography.

“A current challenge in the downstream purification of recombinant [AAV] is the separation of transgene-containing capsids from empty [capsids] and undesired capsid variants,” Khanal stated. “AEX resin is often used below its saturated binding capacity to separate empty and full AAV particles on a single column. However, the outcome of the traditional single-column operation can be impacted by variability in load composition, sensitivity to buffer composition, and fractionation strategies,” she explained.

Khanal noted that, in reviewing past studies, her team found that the removal of empty and partial capsids with a high yield was rarely demonstrated in the literature. In her talk, Khanal presented three-stage separation strategies for two recombinant AAV constructs (rAAV) and demonstrated a way to overcome the trade-off between yield and purity.

In the first strategy, a resin chemistry (Poros XQ, Poros HS, Poros I) is selected and used with a concoction of kosmotropic agents (e.g., ammonium sulfate or sodium sulfate). These agents (i.e., additives) were used to promote capsid stability at low ionic strength. Meanwhile, metal ions (e.g., copper, magnesium, calcium) were used to promote selectivity of the desired capsid. “Using copper ions improved the resolution between empty and full capsid separation and helped remove other product-related impurities,” Khanal pointed out in her presentation.

In the second strategy, the team used an appropriate resin/media structure and geometry to exclude AAV from smaller resin pores (e.g., Poros XQ). Doing so minimized particle dispersion and improved resolution. “Monolith and membrane chromatography showed better peak resolution than traditional resin-based on favorable transport behavior,” Khanal said.

Finally, in the third strategy, the transition from single column to multiple columns in series was tested. This was done by loading 1.5x the resin saturation capacity. Khanal noted that this allowed for over 40% reduction of partial capsids and over 95% removal of empty capsids. “Using these strategies, we provide the best modality to achieve maximum empty and partial capsid removal with a yield of over 80%,” she concluded.

Experiments conducted by the downstream technology team at Spark Therapeutics involving metal ion-containing additives showed improved capsid clearance in AAV production.

ASGCT 2024: Additives Play a Role in Removal of Empty and Partial AAV Capsids

Science laboratory test tubes, laboratory equipment | Image Credit: © BillionPhotos.com - © BillionPhotos.com - stock.adobe.com

Capsida Biotherapeutics presented new preclinical evidence for its first-in-class IV administered gene therapy, CAP-002, on May 7, 2024 at the American Society of Gene & Cell Therapy (ASGCT) annual meeting in Baltimore. The presented data support the potential of CAP-002 to achieve levels of gene supplementation that corrects neurological phenotypes associated with genetic epilepsy due to syntaxin-binding protein 1 (STXBP1) mutations. CAP-002 is a “first-in-class next-generation intravenous (IV)-administered gene therapy that achieves brain-wide neuronal expression while simultaneously detargeting the liver” (1). The program is in investigational new drug-enabling studies and the company expects the therapy to enter the clinic in the first half of 2025.

Mutations in the syntaxin-binding protein 1 (STXBP1) gene cause genetic epilepsy, which impacts an estimated one in 30,000 children born each year globally. Severe developmental delay and intellectual disability, treatment-resistant seizures, and sudden unexpected death in epilepsy (SUDEP). The STXBP1 protein is present in every neuron in the brain and is essential for normal neurotransmission. There are no disease-modifying therapies for this disorder.

According to the company, earlier-generation adeno-associated viruses (AAVs) or wild-type AAVs could not achieve the level of widespread neuronal transduction that would be needed to modify the disease. Gene therapy for genetic epilepsy due to STXBP1 mutations, therefore, has not been previously possible.

The first presentation at the ASGCT event, “AAV Gene Therapy Corrects Neurological Phenotypes with Clinically Relevant Doses in a Mouse Model of STXBP1-Related Developmental and Epileptic Encephalopathy,” is co-authored with Mingshan Xue, PhD, associate professor, Department of Neuroscience, Department of Molecular and Human Genetics at Baylor College of Medicine and the Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

The study showed that “IV administration of the gene encoding STXBP1 in adult mice lacking one functional copy of the STXBP1 gene rescues key phenotypic defects in a dose-dependent manner and does so with long-lasting effects” (1). The dose-dependent rescue of neurological phenotypes (i.e., epileptic seizures, motor deficits, and cognitive impairments) was observed to be dependent on “supplementation of STXBP1 in neurons throughout the brain and at levels not achievable by wild-type serotypes, such as AAV9.”

“This study built upon our previous proof-of-concept study and represents a significant advancement in our understanding of the therapeutic potential of engineered AAV gene supplementation therapy in the treatment of genetic epilepsy and developmental disorders due to STXBP1 mutations. These data are encouraging and emphasize the potential for CAP-002 to meaningfully improve outcomes in patients with this disease,” said Xue.

On May 8, 2024, Capsida will present additional data in a poster presentation that show “a single IV infusion of CAP-002 results in brain-wide STXBP1 gene expression and is capable of transducing up to 70% of neurons at therapeutically relevant doses in non-human primates (NHPs). This level of gene expression raises neuronal STXBP1 protein to levels comparable to those that reversed disease phenotype in the mouse model. CAP-002 had no clinical pathology, histopathology, or immunogenicity findings” (1).

“These data demonstrate that our STXBP1 program effectively crosses the blood-brain barrier in NHPs following IV delivery and achieves breakthrough levels of widespread brain transduction and STXBP1 protein expression needed to achieve disease-modifying impact as demonstrated in the mouse model data,” said Capsida’s Chief Scientific Officer, Susan Catalano, PhD. “Coupled with significant detargeting of the liver compared to AAV9, CAP-002 holds the promise of effectively reversing disease and does so via less-invasive IV administration. We look forward to advancing our STXBP1 program into clinical development in the first half of 2025, so that we can bring this disease-modifying treatment option to people suffering from this devastating disease.”

1. Capsida. Capsida Biotherapeutics Presents New Preclinical Evidence Indicating Novel First-in-Class IV-Administered Gene Therapy Effectively Treats Genetic Epilepsy Due to STXBP1 Mutations. Press Release. May 7, 2024.



The company is presenting preclinical data at the American Society of Gene & Cell Therapy annual meeting that supports the potential of the company’s CAP-002 gene therapy for correcting neurological phenotypes associated with genetic epilepsy due to syntaxin-binding protein 1 (STXBP1) mutations.

Data for First-in-Class IV-Administered Gene Therapy to Treat Epilepsy Presented at ASGCT 2024

is quality unit lead and technical director, Bristol Myers Squibb, São Paulo, Brazil.

is director CMC Technical Advocacy and Policy, Merck Sharp and Dohme, LLC, Horsham, PA, USA.

is chief pharmaceutical officer, Sanofi Vaccines, Lyon, France.

is quality assurance director, Merck & Co. Inc., Rahway, NJ, USA.

is scientific director, Johnson & Johnson Innovative Medicine, Leiden, The Netherlands.

is head of External Affairs Europe, Amgen (Europe) GmbH, Rotkreuz, Switzerland.

is global SME Quality Advocacy, Vaccines Global Quality, GSK, Wavre, Belgium.

Erledigte Aufgaben werden auf einer To-Do-Liste abgehakt | Image Credit: © Ralf Geithe - Stock.Adobe.com

Submitted: January 9, 2024.
Accepted: February 6, 2024.

This study reviews changes in in-country testing (registration testing, import testing) requirements and analyzes current trends. In the context of international harmonization of good practices and standards as well as the improved information exchange between national regulatory authorities, in-country testing is considered outdated and redundant in many cases. More and more countries acknowledge the limited value of in-country testing compared to the benefit of full or partial testing waivers. Analyzing the changing testing requirements, the authors find that a predominant trend is waiver schemes based on unilateral reliance on reference countries with a mature regulatory system.

In 2015, an overview of in-country quality control (QC) testing requirements for pharmaceutical products—the term “pharmaceutical product”, or simply “product”, will be used in this article to refer to small molecules, biologicals, and/or vaccines—and data on the efficiency of this practice were published by Garbe 

 (1). Findings from this study on import testing, based on data collected from multinational pharmaceutical companies, suggested that import testing does not add significant benefits to the quality or safety of drugs, provided that the products are uninterruptedly controlled according to the globally harmonized manufacturing and distribution standards. The authors, therefore, recommended establishing more exemptions from import testing, subject to well-defined conditions, and that waiver procedures are applied where a company has demonstrated appropriate controls of manufacturing and distribution processes.

This article reviews changes in in-country testing requirements since this key publication in 2015, summarizes the evolution in the field of in-country testing, and analyzes current trends.

Two categories of in-country testing form part of the considerations of the review:

 which is performed in conjunction with the product registration.

 which is the repeated QC testing of pharmaceutical products entering a country, including lot release testing of vaccines and blood products.

The different categories of in-country testing and their impact are further described by Garbe 

Both categories of re-testing raise comparable challenges with regards to technical/supply/environmental issues, efficiency, and costs. One of the main impacts of in-country testing is delayed supply of products to patients. Import testing can cause drug shortage situations (1–5) while registration testing (initial market application) can cause long delays in patient access to new medicines (6), which can damage public health.

Several articles on in-country testing were published since 2015 (1–6). Therein, import testing was analyzed regarding its efficiency, the associated risks, challenges, issues, and costs. Supported by real data (1), a limited value of the procedure was concluded.

, is global quality manager and policy lead, F. Hoffmann‑La Roche Ltd., Pharma Global Technical Operations, Basel, Switzerland; 

is quality unit lead and technical director, Bristol Myers Squibb, São Paulo, Brazil; 

is director CMC Technical Advocacy and Policy, Merck Sharp and Dohme, LLC, Horsham, PA, USA;

 is director, Regulatory Intelligence, Pfizer Global Supply, New York, US; 

is chief pharmaceutical officer, Sanofi Vaccines, Lyon, France; 

is quality assurance director, Merck & Co. Inc., Rahway, NJ, USA; 

is scientific director, Johnson & Johnson Innovative Medicine, Leiden, The Netherlands; 

is head of External Affairs Europe, Amgen (Europe) GmbH, Rotkreuz, Switzerland; 

*To whom all correspondence should be addressed

When referring to this article, please cite it as Garbe, J.H.O.; Conti, T.; McGoldrick, M.; et al. Reliance-Based Waivers Become the Predominant Trend in In-Country Testing of Pharmaceutical Products. 

This study reviews changes in in-country testing (registration testing, import testing) requirements and analyzes current trends. In the context of international harmonization of good practices and standards as well as the improved information exchange between national regulatory authorities, in-country testing is considered outdated and redundant in many cases.

Reliance-Based Waivers Become the Predominant Trend in In-Country Testing of Pharmaceutical Products

Cheryl Barton is director of PharmaVision, 

Creative background, the human brain on a blue background, the hemisphere is responsible for logic, and responsible for creativity. different hemispheres of the brain, 3D illustration, 3D render | Image Credit: © Aliaksandr Marko - Stock.adobe.com

The global central nervous system (CNS) therapeutics market is forecast to increase from US$80.25 (€74.7 billion) in 2023 to US$106.19 billion (€98.78 billion) by 2031, growing at a compound annual rate of 4.8%. This market growth can be attributed to a few drivers, including the fact that biopharma companies, such as AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Co, Eisai, Lundbeck, Merck & Co., Novartis, Pfizer, Roche, and Takeda, are all targeting hard-to-treat neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) (1).

Numerous disease-modifying biologics are in late clinical development for treating neurodegenerative diseases (

 [2]), and several brain-penetrant monoclonal antibodies (mAbs) have recently been approved for treating AD. In 2021, the US Food and Drug Administration (FDA) approved Biogen and Eisai’s aducanumab (Aduhelm), the first amyloid beta-directed antibody to reach the market for the treatment of AD (3). However, the clinical results were mixed, and the developers withdrew the European Medicine Agency (EMA) marketing application in April 2022. Aducanumab has also been withdrawn from the US market as a result of low uptake and payor challenges. Aducanumab appears to disrupt the blood–brain barrier (BBB) to have a marginal impact on amyloid plaque formation (4).

Disease modifying biologics under clinical development for Alzheimer’s disease (AD) and Parkinson’s disease (PD).

In the meantime, Biogen/Eisai received FDA approval for lecanemab (Leqembi), in the US in January 2023, and EMA is expected to review the marketing authorization application shortly (5). Leqembi is making steady inroads within the US Alzheimer’s community, and the partners are now working on a subcutaneous formulation to ease use and drive uptake. Now the race is on to see who can develop the next biologic to treat AD or the elusive PD; to do this they will need to use the latest CNS delivery technology to ensure targeted delivery and durable responses.

CNS drug development remains challenging and is associated with high costs and high failure rates, largely due to the difficulties associated with getting drugs across the BBB (6). A host of biomaterials have been designed to bypass or facilitate the passage of small molecules across the BBB including passive transcytosis, conjugate ligands, membrane coating (e.g., erythrocytes, macrophages, neutrophils), liposomal and polymeric nanoparticles, micelles and nanogels, and stimuli-triggered BBB disruption (e.g., electroacupuncture, light, ultrasound) (

). However, the systemic delivery of biopharmaceuticals such as gene therapies, mAbs, and enzyme replacement therapies has remained off-limits as they cannot cross the BBB, so companies have relied on intrathecal or intracranial injections to deliver these therapeutics to the site of action (7). But things are about to change.

Novel approaches to central nervous system drug delivery.

Biopharma companies have begun to develop novel approaches using neurotropic viruses and receptor-mediated transcytosis or “peptide shuttles” to deliver biologics into the brain (8,9). For example, Spain-based Gate2Brain (G2B) has developed peptide shuttles that co-opt receptor mediated transcytosis pathways to transport therapeutic cargo into the brain (10). Conversely, VectorY Therapeutics has taken a novel approach combining antibodies with adeno-associated virus (AAV) capsids to form vectorized antibodies to selectively target the CNS and treat neurodegenerative diseases (11).

G2B novel peptide shuttles to treat glioblastomas

G2B was established in 2020 by CEO, Meritxell Teixidó to exploit delivery technology that was developed at IRB Barcelona. The biotech company focuses on developing innovative non-antigenic, protease-resistant, peptide shuttle conjugates that can penetrate the BBB to deliver antibodies, DNA/RNA, proteins, and small molecules through receptor-mediated transcytosis. It is currently developing G2B-002, with its lead drugs, and is planning to conduct studies with G2B-002 in the treatment of a rare paediatric cancer, diffuse intrinsic pontine glioma (DIPG) (10).

In 2021, G2B was granted financial support from DTI, the Center for Industrial Technological Development, Ministry of Science and Innovation, within the framework of the Neotec projects (12). In December 2022, G2B received €2.5 million in funding to develop its drug delivery technology to target brain cancers. These funds will enable the company to drive the clinical development of G2B-002 over the next few years (13).

But competition in this field is increasing. US-based Denali Therapeutics has also developed transferrin-mediated peptide shuttles to efficiently transport small molecules and biologics drugs to the brain to restore lysosomal function, glial biology, and cellular homeostasis in a variety of rare diseases (14). Denali will begin a Phase I/II clinical trial testing DNL310 (ETV:IDS) in children with Hunter syndrome and plans to expand this technology beyond enzymes and therapeutic antibodies to transport anti-sense oligonucleotides.

Meanwhile, Roche has developed its own transferrin-mediated peptide shuttle delivery technology which it has deployed in its Aβ-immunotherapy gantenerumab. Unfortunately, this antibody failed to show a decline in AD in Phase II clinical trials despite being brain penetrant (15,16).

VectorY Therapeutics next-generation gene therapies

VectorY Therapeutics was established in October 2020 at the Amsterdam Science Park in The Netherlands. The biotech company focuses on the development of innovative gene therapy approaches for the treatment of muscular and neurodegenerative disorders through vectorized antibodies. These non-immunogenic viral vectors enhance the properties of cell type specificity, to improve the delivery, durability, and accessibility of targeted tissues and cells. The company has developed three proprietary delivery technologies:

—an AAV vector that delivers the VecTab transgene (a pathogenic protein) to the neuron where the therapeutic antibody (VecTab) is subsequently produced. The therapeutic antibody binds to disease-associated lipids and proteins to modify the disease.

—a vectorized antibody fused with a degron sequence that directs the target toward pathway-specific degradation. The AAV delivers the VecTron transgene to the neuron where the therapeutic antibody-degron fusion protein (VecTron) is produced and leads to pathway-specific protein degradation.

—tissue-specific recombinant AAV capsids which are optimized for efficient delivery of antibodies intracellularly in the CNS.

—VecTab vectorized antibody programme targeting TDP-43 for the treatment of amyotrophic lateral sclerosis (ALS)

—VecTab/VecTron vectorized antibody targeting misfolded and aggregated huntingtin (HTT) proteins for the treatment of Huntington’s disease (HD)

—VecTab/VecTron vectorized antibody targeting alpha-synuclein for the treatment of PD (17).

On 15 June 2021, VectorY completed a €31 million seed financing round. The oversubscribed round was co-led by founding investors Forbion, BGV, and Eli Lilly & Company (18). In October 2023, VectorY raised €119 million (US $138 million) in a Series A financing round to advance its vectorized antibody programmes in neurodegenerative diseases. The round was co-led by EQT Life Sciences and the Forbion Growth Opportunities Fund and included existing investors MRL Ventures Fund (a corporate venture arm of Merck & Co.) Insight Partners, ALS Investment Fund, Forbion Ventures, BioGeneration Ventures (BGV), and others (19).

Several other companies are looking to use AVV to vectorize antibodies, including US-based Voyager Therapeutics which teamed up with AbbVie on the development of tau and alpha-synuclein vectorized antibodies to treat AD and PD, respectively. AbbVie later terminated the agreement due to a change in pipeline strategies (20). Voyager recently partnered with Neurocrine Biosciences to develop a candidate for the GBA1 gene programme to treat PD utilizing its intravenously administered, BBB penetrant, novel capsid derived from Voyager’s TRACER capsid discovery platform (21).

Challenges and future opportunities in CNS drug delivery

Introducing disease-modifying biologics into the brain poses a unique set of challenges compared to other body tissues due to the protective mechanisms of the BBB. However, new delivery technologies such as G2B’s peptide shuttles and VectorY’s vectorized antibodies demonstrate that these challenges can be overcome, and now it is down to pharma to identify the most appropriate therapeutic targets to pursue. Whether that’s anti-amyloid or anti-tau mAbs for the treatment of AD or alpha-synuclein-targeting gene therapies for PD, a new era of CNS biopharmaceuticals awaits.

1. Precision Reports. CNS Therapeutics Market Size in 2024: Increasing Technological Advancements by Top Key Players to 2031. 6 March 2024.
2. ALZFORUM, Therapeutics. Accessed 1 April 2024.
3. Glymour, M.M.; Weuve, J.; Dufouil, C.; Mayeda, E.R. Aduhelm, the Newly Approved Medication for Alzheimer Disease: What Epidemiologists Can Learn and What Epidemiology Can Offer. 

, 191 (8), 1347-1351.
4. Haddad, H.W.; Malone, G.W.; Comardelle, N.J.; et al. Aduhelm, a novel anti-amyloid monoclonal antibody, for the treatment of Alzheimer’s Disease: A comprehensive review. 

, 10 (3), 37023.
5. Biogen. FDA Approves LEQEMBI™ (lecanemab-irmb) Under the Accelerated Approval Pathway for the Treatment of Alzheimer’s Disease. News release, 6 Jan. 2023.
6. Nance, E.; Pun, S.H.; Saigal, R.; et al.Drug Delivery to the Central Nervous System. 

, 7, 314–331.
7. Wu, D.; Chen, Q.; Chen, X.; et al. The Blood-Brain Barrier: Structure, Regulation, and Drug Delivery. 

, 8, 217.
8. Terstappen, G.C.; Meyer, A.H.; Bell, R.D.; et al. Strategies for Delivering Therapeutics Across the Blood-Brain Barrier. 

, 20, 362–383.
9. Sheridan, C. Drugs Catch a Ride Through the Blood-Brain Barrier. 

, 41, 1182–1184.
10. Gate2Brain. Pipeline & Therapeutic Proof of Concept. Accessed 1 May 2024.
11. VectorY Therapeutics. Efficient Intracellular Therapeutic Antibodies. VectorY Platform. Accessed 1 May 2024.
12. Gate2brain, Gate2Brain has been granted financial support by the CDTI. News release, 22 Dec. 2021.
13. Gate2brain. Gate2brain Receives €2.5m Funding to Develop a Technology that Enhances Drug Delivery to the Brain. News release, 21 Dec. 2022.
14. Denali Therapeutics. Pipeline. Accessed 1 May 2024.
15. ALZFORUM. Molecular Transport Vehicle Shuttles Therapies into Brain. 29 May 2020.
16. Alzheimer Research, UK. Alzheimer’s Drug Gantenerumab Fails to Slow Decline in Phase III Clinical Trials. 14 Nov. 2022.
17. Konstantinova, P. Precision Targeted Therapies for Neurodegenerative Diseases. DHDRN Presentation. 23 Jan. 2023.
18. VectorY Therapeutics. VectorY Raises €31 million in Seed Financing to Develop Next-Generation Gene Therapies Aimed at Muscular and CNS Disorders. News release. 15 June 2021.
19. VectorY. VectorY Raises €129 Million ($138 Million) Series A Financing to Advance Vectorized Antibody Programs in Neurodegenerative Diseases. News release, 13 Nov. 2023.
20. Voyager Therapeutics. Voyager Therapeutics Provides Update on AbbVie Vectorized Antibody Collaborations. News release, 3 Aug. 2020.
21. Voyager Therapeutics. Voyager Therapeutics Announces Selection of Development Candidate for GBA1 Program in Collaboration with Neurocrine Biosciences, Triggering Milestone Payment. News release, 16 April 2024.

Cheryl Barton is director of Pharmavision, info@pharmavision.co.uk.

When referring to this article, please cite it as Barton, C. Frontrunners in CNS Drug Delivery. 

Novel delivery technologies enhance brain penetration to target neurodegenerative diseases and glioblastomas.

Frontrunners in CNS Drug Delivery

US-headquartered ProPharma, a US-headquartered provider of regulatory, clinical, and compliance services for the life sciences industry and a portfolio company of Odyssey Investment Partners, and Italy-based PBL, a custom solutions provider to the pharmaceutical, chemical, and diagnostics industries have launched the Cell Factory Box (CF Box), an enclosed, fully automated cell factory device. The companies launched the device under a partnership. 

The CF Box enables the decentralized manufacturing of all types of cell and gene therapies (CGTs) in Class D (ISO8) or controlled not classified surrounding areas, according to a May 2, 2024 press release.

“Regarding treatment options, many are adopting a decentralized approach to manufacturing [CGTs],” said Eleonora Casucci, vice-president of Quality & Compliance EU, ProPharma, in the press release. “The CF Box provides key advantages compared to the devices currently available. Our collaboration with PBL positions us to serve those in the [CGT] segment fully.”

According to the release, the CF Box uses already-approved artificial intelligence (AI) technology and is extensively automated, allowing it to significantly reduce manual operation. The nature of the device also reduces the need for high-class clean rooms. Using approved AI technology, the CF Box employs batch detection recognition, which is set to a frozen state during validation, and batch manufacturing. Users can select modules based on individual needs and select the type of products/technologies desired. Additional modules can also be added at later stages.

“Robotic arms, cameras, liquid transfer systems, conveyor belts, components, and tools are available in the market, enabling full automation, including but not limited to alerting the operator once the culture has reached the desired values,” the press release states. The design allows for flexibility in automating manual processes and supports diverse manufacturing tasks. The CF Box is also programmable for various processes, including optimized cell culture expansion, and streamlining manufacturing timelines effectively, according to the release.

“We are honored to work with ProPharma on such a monumental effort,” said Filippo Begarani, Research and Innovation manager, PBL, in the press release. “Our first goal is always to conceive, design, and implement technologically advanced solutions with the highest standards of quality and innovation, and the CF Box device will not only change but elevate how [CGTs] are manufactured since it supports high reproducibility of the process at various locations.”

The CF Box will be demonstrated in Frankfurt, Germany, during ACHEMA, which will be held June 10–14, 2024. PBL is also offering demonstrations after the event and upon request at its facility in Parma, Italy.

The global CGT market size is projected to grow to $82.24 billion by 2032 from $15.46 billion in 2022, with a compound annual growth rate of 18.3% (1). Key market drivers are the exponential increase in the CGT clinical pipeline and an increase in the number of regulatory approvals for innovative medicines.

Cell and Gene Therapy Market (By Therapy Type: Cell Therapy and Gene Therapy; By Indication: Cardiovascular Disease, Cancer, Genetic Disorders, Infectious Diseases, Neurological Disorders; By Delivery Method: In-Vivo and Ex-Vivo; By End-Users: Hospitals, Cancer Care Centers, Wound Care Centers, Others)—Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2023-2032

ProPharm and PBL have introduced a fully automated, enclosed cell factory manufacturing device.

New Cell Factory Box Launched by ProPharma and PBL for Automated CGT Manufacturing 

In a new research collaboration and license agreement, Poseida Therapeutics and Astellas Pharma’s wholly owned subsidiary, Xyphos Biosciences,will develop novel 

CAR programs to target solid-tumor cancers.

Under the agreement, the companies plan to combine Poseida’s proprietary allogeneic chimeric antigen receptor T cell (CAR-T) platform with Xyphos’ ACCEL technology to create one Poseida-developed CAR-T construct. This construct is intended to serve as the basis of two 

CAR product candidates targeting solid tumors.

“We are excited to expand our relationship with Astellas, where we share a vision that cutting edge, off-the-shelf cell therapies can address significant unmet needs of patients with solid tumor malignancies. Today’s agreement further reinforces the economic value of Poseida’s highly differentiated non-viral technologies and enables development in areas beyond our core pipeline focus,” said Kristin Yarema, PhD, president and CEO of Poseida, in a May 1, 2024 company press release.

Under the transaction, Xyphos will reimburse Poseida for costs incurred as part of the research agreement. Xyphos will be responsible for the development and future commercialization of products generated from the collaboration. Poseida will receive a $50 million upfront payment as well as potential development and sales milestones and contingency payments that could total up to $550 million. Poseida is also eligible for up to low double digit tiered royalties as a percentage of net sales.

“At Astellas, we have a strong commitment to developing novel treatments for patients with cancer and have positioned immuno-oncology as a [p]rimary [f]ocus of our R&D strategy [1] … we are focused on reinvigorating the immune system’s ability to discover, disarm, and destroy cancers in more patients. By combining the ACCEL platform with Poseida’s elegant and cutting-edge genetic editing platforms, we believe the collaboration will bring synergies between the two companies’ breakthrough research and will ultimately lead to expansion of Astellas’ portfolio and to delivery of innovative CAR-T cell therapies to cancer patients,” said Adam Pearson, chief strategy officer of Astellas, in the press release.

Astellas is making a strategic investment in Poseida, which it announced in August 2023 (2). Under this transaction, Astellas is investing a total of $50 million, comprising $25 million to acquire 8,333,333 shares of Poseida common stock, a one-time $25 million payment for a right of exclusive negotiation and first refusal to license P-MUC1C-ALLO1, one of Poseida's clinical-stage programs. The candidate is an allogeneic CAR-T cell therapy being developed to treat multiple solid tumor indications. Also under this transaction, Astellas has been granted a board observer seat on Poseida’s board. The position includes the ability to attend Poseida’s scientific advisory board meetings as well as certain notice rights related to any potential change of control of Poseida.

 (accessed May 6, 2024).
2. Astellas Pharma. Astellas and Poseida Therapeutics Announce Strategic Investment to Support Poseida’s Commitment to Redefining Cancer Cell Therapy. Press Release, Aug. 8, 2023.

The two companies will combine their cell therapy platforms to develop convertibleCAR programs targeting solid tumors.

Poseida Therapeutics and Astellas to Develop Novel Allogeneic Cell Therapies

The United States Federal Trade Commission (FTC) is seeking more information on Novo Nordisk parent’s $16.5 billion proposed acquisition of Catalent, a US-based contract development manufacturing organization (CDMO). Catalent stated on May 3, 2024 that both companies were gathering information in order to respond to the FTC’s request (1), which was received on May 2. This request was submitted weeks after an application to the FTC was refiled to approve the deal.

Novo Nordisk announced its decision to acquire Catalent in early February 2024 (2). Under a planned merger of Novo Holdings, the parent company of Novo Nordisk, and Catalent, Novo Nordisk would receive three of Catalent’s fill/finish sites and related assets. Those three sites, located in Anagni, Italy; Bloomington, Indiana (US); and Brussels, Belgium, would be advantageous for Novo Nordisk, which has been steadily increasing production of Wegovy as demand for the drug explodes.

Novo Nordisk emphasized its goals of expanding Wegovy production in its own press release on the acquisition (3). The deal would enable the company to expand manufacturing capacity while allowing flexibility for its existing supply network. “We are very pleased with the agreement to acquire the three Catalent manufacturing sites which will enable us to serve significantly more people living with diabetes and obesity in the future,” said Lars Fruergaard Jørgensen, president and chief executive officer, Novo Nordisk (2). “The acquisition complements the significant investments we are already doing in active pharmaceutical ingredients facilities, and the sites will provide strategic flexibility to our existing supply network.”

Demand for Wegovy, Novo Nordisk’s obesity and cardiovascular disease treatment, has skyrocketed over the last year, alongside its sister diabetes therapy, Ozempic. Wegovy was approved in the US in early March of 2024 to reduce risk of major adverse cardiovascular events (MACE) including cardiovascular death, non-fatal heart attack (myocardial infarction), or non-fatal stroke in either overweight or obese adults with established cardiovascular disease (CVD) (4). Novo Nordisk also filed for a label expansion in the European Union.

Both Novo Nordisk and Catalent still expect to close the deal by the end of 2024, but doubts were raised when Novo Nordisk refiled the application in April. According to a Reuters press release, David Ricks, CEO of Eli Lily, a major competitor to Novo Nordisk and Wegovy, raised potential antitrust concerns, calling Novo Nordisk’s proposal to buy the plants “unusual” (4). Novo Nordisk did not disclose details about why the application was refiled.

US SEC. Form 8-K. Current Report Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934, Catalent, Inc. May 3, 2024. https://www.sec.gov/Archives/edgar/data/1596783/000119312524129990/d797118ddefa14a.htm

Novo Holdings to Acquire Catalent in Deal Valued at $16.5 billion

Novo Nordisk to Acquire Three fill-finish Sites from Novo Holdings A/S in Connection with the Catalent, Inc. Transaction

Wegovy Approved in the US for Cardiovascular Risk Reduction in People with Overweight or Obesity and Established Cardiovascular Disease

US FTC Seeks More Information on Novo Nordisk Parent-Catalent Deal

The request for more information was received weeks after an application to the FTC was refiled to approve the deal.

US Federal Trade Commission Seeks Additional Information on Novo Nordisk Parent-Catalent Deal

Data are the biopharma industry’s most valuable asset today, which is prompting the industry to step up its measures to not only gather these data, but to protect them as well. In a conversation with Nathalie Batoux, product manager, Research Innovation, IDBS, 

 delved into the approaches the biopharma industry has taken to shore up data integrity protection. 

Editor's note: this article was published in the Pharmaceutical Technology Europe May 2024 issue.

 Explain why data are the biopharma industry’s most valuable asset. The analogy is that there’s a gold rush for data (1); what does that mean?

 With the current digital transformation happening in the biopharma industry, the industry has also seen the explosion of [tools such as] artificial intelligence (AI) and machine learning (ML). There is also a significant amount of data that exists now based on the products already on the market. With the explosion of AI and ML, people want to reuse the data that they have. So, instead of running new experiments, already existing data are being used; these historical data are very important. There are some new initiatives underway to review and repurpose existing drugs for other applications, thus, AI and ML are being used to review these already existing data. Not only is the biopharma industry producing a vast amount of new data, it also has its hands on a significant amount of historical data.

 Describe the impact of this perception—this ‘gold rush’ for data—on data integrity. Has it led to a flurry of activity?

Yes, there is a flurry of activity. There are many startups that are proposing AI and ML to the biopharma industry, amongst other industries. There are initiatives, as I mentioned, around the repurposing of existing drugs using historical data at hand.

 Can you discuss where data integrity practices in the biopharma industry are the strongest and where they are the weakest?

 My perspective is to look at the evolution within the industry, and where we are now with digitalization, data integrity is getting much stronger. Looking at the practice of manually recording, or manually transcribing, data from one system to another, this is very much error prone. Whether intentionally or accidentally, errors are highly likely. If there is an error in the data, then any analysis conducted later on will be incorrect, and the decision-making using that data will not be good and will thus be counterproductive. This will cost money at the end of the day.

Good data integrity involves the use of more automated systems, using digital transformation where the system records the context around the results. For example, in an experiment, scientists—even though they are very well trained—are still human. There’s only a finite number of parameters that they can deal with. While a computer, or a series of computers, can record all sorts of things around the context. It’s as simple as the date and time of an experiment that might change the outcome, whether [the experiment] is done in the summer or winter. That is important as temperature and humidity conditions may affect the outcome.

The other advantage is that, with data digitally recorded, there is traceability, and most of the modern systems now have audit capabilities. [This makes it easier] to understand what has happened to generate that data, but also what has happened after the data has been generated—such as, has the data been transferred from one system to another? Having all that context, having this history, ensures that, in the first place, the data—that is, the data that will be used to train the models for ML or analysis, or for use by AI—will be of quality. [And that assurance comes from] all that context, all that history behind the data.

Data that are digitally recorded [are] easier to find. [In the laboratory], finding an experiment on paper or in a notebook is not easy. [Digitally recorded data] offer interoperability and [better] accessibility. If [the data are] on paper, for example, [the lab tech] needs to have that piece of paper in front of [them] to be able to see it. This hinders interoperability [because] that piece of paper, if the handwriting is, as they say, like a doctor’s handwriting, not many people will be able to understand it. Being ‘reusable’ as a whole is very, very important for data, so having FAIR [findable, accessible, interoperable, and reusable] data is one of the principles of data integrity. This will enable the digital transformation and all those initiatives that are happening with ML and AI.

 Let’s talk about the data itself. Good data versus bad data; how is that determined?

 As mentioned earlier, having all the context around the data recorded is one of the attributes of good data. The other attributes, as I mentioned, are the FAIR principles; however, one needs to make sure that they are recording everything. It’s human nature to try to record things that are happening and [what is] working, but from a learning perspective—and for ML, in particular—one needs to also record what didn’t work because [there is] much more to learn from things that didn’t work. So, the ‘how to’ recognize good data versus bad data requires having rigour, using well documented SOPs [standard operating procedures], and having controls in place, all of which are quite important because these help with the reproducibility of that data.

In addition, if using a digital system with controls in place, then [the technician] will receive an alert, and [this allows] them to record an exception. It is very important to record all those things, not only for good data in general, but also for the data that regulatory bodies require. [Keep in mind], all the compliance requirements are very important. Another point [to highlight] is that for accessibility and interoperability, more than one system will need to be used; likely, it will require several systems. And, data needs to be connected easily, so having silos that are not talking to each other, that don’t represent each other, that is not good data. Having the ability to connect the data—to connect to the structure of that data in order to understand them—that is a symptom of good data.

 How is the biopharma industry handling this flow of data; how is it preparing for this gold rush that was mentioned earlier?

 [With the] digitalization that is happening, less companies are using paper, and [it seems that] more and more companies have been investing in data scientists to be able to mine the data. However, there is a difference between having all that data mined by specialists and the people who are actually using the data at the bench, so having democratization of data is extremely important. Empowering [bench] scientists with decision-making based on large data sets, including past data, at the click of a button is very valuable. Rather than having to wait for a few weeks for data scientists’ analyses—although the data scientists’ skills are still important for more complex analyses—a more diverse set of scientists or end users can have accessibility to data with [the goal] of helping to put algorithms in place for the analyses, and so on.

1. Batoux, N.; Rayner, D. In a Digital Gold Rush, Data Integrity is Priceless. 

®
Vol. 36, No. 5
May 2024
Pages: 33–34

When referring to this article, please cite it as Mirasol, F. Shoring Up Data Integrity Practices. 

Digital transformation is allowing for better handling, analysis, and protection of vast data collection.

Shoring Up Data Integrity Practices

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Taking patient needs and expectations into consideration when designing and developing new drugs has become increasingly important as evidence mounts that more convenient and easier-to-take products increase medication compliance. To be effective, drug therapies require patient adherence. For oral dosage drugs, particularly liquids, dispersible powders (granules), orally disintegrating tablets or films, chewable tablets, and minitablets, taste-masking can be critical for increasing patient compliance, as these dosage forms result in exposure of taste buds to the APIs, which can be an unpleasant experience, according to Liliana Miinea, technology manager, Pharmaceutical Excipients, at Lubrizol Life Science.

Leveraging taste-masking technologies and solutions that impart an attractive appearance help overcome such issues. It is a complex task, however, that requires consideration of numerous variables including patient profiles, drug product characteristics, and regulatory rules, among others, observes Nasrin Mahmoudi, Sr., lead applications scientist at IFF Pharma Solutions. As such, expertise in these formulation technologies is essential to implementing a patient-centered approach to drug development and ultimately improved therapy outcomes.

The use of appropriate taste-masking and appearance technologies can facilitate patient compliance.

Featured Content

Digital Transformation in Pharma Manufacturing

Behind the Headlines, Episode 23

ICH Q12 and Post-Approval Changes

Drug Digest July 2025

Bio/Pharma's Tariff Response