Cheryl Barton is director of PharmaVision, 

Cheryl Barton

cosmetic molecule and chromosome background | Image Credit: ©Thongden_studio - stock.adobe.com

Over the past century, life expectancy has dramatically increased in most parts of the world, but humans are spending more years in poor health than at any point in history (1). However, technological and scientific advances have increased our understanding of the ‘hallmarks of ageing’ resulting in molecular and cellular changes that lead to the modulation of mitochondrial dysfunction, inflammation, and cellular senescence (2).

This article was published in the October 2024 print issue of 

Ageing is emerging as a druggable condition with multiple pharmaceuticals able to alter the pace of ageing in model organisms. Anti-ageing activity has been demonstrated in some US Food and Drug Administration (FDA)-approved drugs such as the immunosuppressant rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, and the anti-diabetic agent, metformin, an AMP-activated protein kinase (AMPK) activator (3). US-based Aeovian Pharmaceuticals and Amplifier Therapeutics are looking to develop next-generation AMPK and mTOR inhibitors in age-related diseases (4,5).

Many biopharmaceutical companies are now prioritizing ageing research for early-stage discovery or therapeutic pipeline development. BioAge Labs, Fauna Bio, and Insilico Medicine are deploying artificial intelligence (AI)-enabled multi-omic platform technologies to identify novel anti-ageing targets. Several experimental drugs—dasatinib, fisetin, navitoclax, and quercetin—have demonstrated senolytic activity, and inhibitors targeting Bcl-2, HSP, tyrosine kinase or P53, are now being evaluated by biopharma as potential senolytics (6). One of the most advanced programmes is Unity Biotechnology’s UBX1325 (foselutoclax), a Bcl-2 inhibitor in Phase II development for the treatment of age-related macular degeneration (AMD) (7).

Several European start-ups are actively pursuing anti-ageing research including Swiss-based Vandria and UK-based clook.bio and Genflow Biosciences.

Vandria mitochondrial therapeutics look promising in neurodegenerative disease models

Vandria is developing novel mitophagy inducers that rejuvenate cells to treat age-related and chronic diseases. The decline in mitochondrial function has been implicated in many age-related diseases including mild cognitive impairment (MCI), neurodegenerative diseases, and muscular disorders. Vandria has demonstrated that removing damaged mitochondria via mitophagy can rejuvenate cells leading to an improvement in cellular functions and the generation of energy or ATP (adenosine triphosphate) (8).

 screening platform and generated a novel pipeline of small-molecule mitophagy inducers to target different tissues and address specific unmet medical conditions. Its lead programme, VNA-318, has completed investigational new drug (IND) studies for central nervous system (CNS) indications including MCI, Alzheimer’s, and Parkinson’s diseases, and other forms of dementia. Its other preclinical programmes include VNA-052 for sporadic inclusion body myositis, VNA-438 for Metabolic Dysfunction Associated Steatohepatitis (MASH), VNA-710 for idiopathic pulmonary fibrosis (IPF), and VNA-897 for an undisclosed target (9).

In February 2024, Vandria was awarded a CHF 2.5 million (US$2.8 million) research grant from the Swiss Innovation Agency Innosuisse to help advance the development of VNA-318 (10). The funds will be matched with CHF 4.6 million from the company initiative to progress VNA-318 into Phase I/IIb clinical trials in 2025. In preclinical animal models, VNA-318, has been shown to improve memory and learning. Additionally, VNA-318 has strong disease-modifying effects in Alzheimer’s and Parkinson’s disease models and has a wide safety window. The company has been issued a composition of matter patent by the US Patent Office covering VNA-318 and other compounds (10).

The company is also advancing the development of another mitophagy lead candidate, VNA-052, for muscle diseases. This clinical programme was awarded a research grant, totaling €1.1 million (US$1.2 million) from Eurostars, a programme co-funded by the European Union (10). In August 2024, Vandria announced the second closing of its Series A financing raising CHF 28.3 million (US$30.7 million). The funds will be used to support its clinical development programmes (11).

Pioneering gene therapies to decelerate the ageing process

Recent advances in gene editing and delivery have allowed scientists to partially reprogramme cells and reverse the effects of ageing (12). Two UK start-ups, clock.bio and Genflow Biosciences, are leveraging human inducible pluripotent stem cells (hiPSC) to prevent and treat age-related diseases:

 was founded in 2020, by Mark Kotter and has attracted more than US$4 million (€3.6 million) in funding (13). The company has developed an ageing model that force-ages hiPSCs to trigger self-rejuvenation. The company deploys unbiased clustered regularly interspaced short palindromic repeats (CRISPR) screens to identify gene candidates that are causally linked to cell rejuvenation. Clock.bio aims to decode the biology of human rejuvenation across the entire human genome and generate a comprehensive atlas of disease and rejuvenation targets for clinical translation (14).

 was founded in 2020 and has R&D facilities in Belgium. Its lead compound, GF-1002, a suspension of an adeno-associated virus vector-based (AAV-based) gene therapy that delivers the centenarian variant of the sirtuin 6 (SIRT6) gene, a gene intricately linked to cellular stress responses that can promote longevity in mice. GF-1002 has demonstrated promising preclinical results and is due to enter clinical development in 2025 for the treatment of MASH (15). In January 2024, Genflow established two technological innovation partnerships with Revatis SA and with EXO Biologics to develop advanced therapy medicinal products (ATMPs) in sarcopenia and Werner Syndrome, respectively (16). In April 2024, Genflow raised £715,000 (US$959,000) through the placing and subscription for new stock organized by Capital Plus Partners (17). Genflow has been awarded a European Patent with the University of Rochester, New York, for SIRT6 in the prevention and treatment of age-related diseases (18).

In the United States, numerous companies are also pursuing cellular reprogramming strategies including Altos Labs, Longeveron, Retro Biosciences, Rejuvenate Bio, and Turn Biotechnologies (19–23).

Great strides have been made in anti-ageing longevity research, numerous drug targets have been identified, and several agents are progressing steadily through the clinic. In 2021, venture capitalists invested $9.26 billion (€8.3 billion) in this area, with cellular reprogramming and rejuvenation attracting the most attention (24). Pharma has announced several partnerships in this space including Eli Lilly/Fauna Bio, Sanofi/Insilico Medicine, and Pfizer/VitaDAO. While US biotechs dominate the scene, European and UK start-ups are gaining traction, and there are significant opportunities for pharma to expand their foothold and take a more proactive approach in the treatment of chronic age-related diseases.

We’re Spending More Years in Poor Health than at Any Point in History. How Can We Change This?

Hallmarks of Aging: An Expanding Universe

Faragher, R. Anti-ageing Treatments: These Two Drug Types are Being Investigated. 

Aeovian Pharmaceutical doses first participants in Phase 1 Clinical Trial, Strengthens Leadership Team, and Raises Additional $50 million Financial

Amplifier Therapeutics. Amplifier Therapeutics, a Cambrian Bio Pipeline Company, Doses the First Patients in the Phase 1B Clinical Trial and Closes New Financing fromFuture Ventures and RA Capital Management. New Release, 17 Oct. 2023.

Senolytics: from Pharmacological Inhibitors to Immunotherapies, a Promising Future for Patients’ Treatment

Lobo, A. Parkinson’s Grant will Advance VNA-318 for Parkinson’s, Age-related Diseases. 

Hevolution Foundation and Dolby Family Ventures join Vandria’s 2nd Series A closing, bringing the total round to $30.7M (CHF 28.3M) to Progress the Mitophagy Inducer VNA-318 into CNS Clinical Development

Cellular Rejuvenation: Molecular Mechanisms and Potential Therapeutic Interventions for Diseases

Clock. bio Launches to Decode Rejuvenation Biology Across the Human Genome

A White Paper for Rejuvenation Therapies and Blueprint for Clock.bio

Secures Two Research Grants from Belgium’s New Technological Innovation Partnership

Genflow Biosciences Plc Successful Placing and Subscription To Raise £715,000, Grant of Warrants and PDMR Notifications

Genflow Biosciences Plc Announced the Publication of a Key European Patent in Partnership with the University of Rochester, New York

Altos Labs Launches with the Goal to Transform Medicine through Cellular Rejuvenation Programming

Longeveron Announces Second Quarter 2024 Financial Results and Provides Business Update

Rejuvenate Bio Announces New Preclinical Research Evaluating Cellular Reprogramming for Age Reversal

Turn Biotechnologies Reports Historic Skin Cell Rejuvenation Breakthroughs at ESDR this Week

Longevity Investment Hits 3.01 Billion in Full Year 2023

Cheryl Barton, PhD,is director of PharmaVision.


Vol. 36, No. 9
October 2024
Pages: 14–15, 18

When referring to this article, please cite it as Barton, C. European Biotech Targeting Anti-ageing. 

Articles

Novel mitophagy inducers and gene therapies that restore cellular function and decelerate the ageing process.

European Biotech Targeting Anti-ageing

Landkarte *** Europa | Image credit: ©beugdesign - Stock.adobe.com

On 5 Sept. 2024, the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) published high-level principles and recommendations for staff across the European Medicines Regulatory Network (EMRN) regarding the use of generative artificial intelligence (AI), namely large language models (LLMs) (1).

This article was published in the October 2024 issue of

LLMs are widely used by regulatory staff in various daily tasks including education and tutoring, language translation, search and summarizing information, writing assistance, and providing coding language support (2). However, the deployment of LLMs may result in variable results and inaccurate responses, and they can present potential data security risks in terms of confidential information, data protection, and privacy (2). Thus, the guidelines and principles lay the foundation for the safe and responsible use of LLMs so users “avoid pitfalls and risks” (1).

The EMA/HMA’s guiding principles aim to ensure users to do the following:

take appropriate measures to ensure safe input of data, apply critical thinking, and cross-check outputs continuously learn how to use LLMs effectively know who to consult when facing concerns and report issues (2). In addition, the organizational principles:

define governance that helps users have a safe and responsible use, specifying permitted use cases, providing training, and monitoring risks

Overall, the guiding principles provide a working framework to ensure LLMs are used safely and ethically and are effectively implemented in regulatory science and for medicines regulatory activities.

HMA-EMA multiannual AI workplan 2023-2028

The guiding principles represent one of the deliverables from the HMA/EMA 

 published in December 2023 (3). This workplan guides EMA and EMRN in their use of AI, maximizing the benefits while managing the risks and facilitating information sharing. The first version of the Multi-annual AI Workplan focuses on four critical dimensions—guidance, policy and product support; tools and technologies; collaboration and change management; and experimentation—and will be regularly updated under the oversight of the HMA-EMA Big Data Steering Group (BDSG) (3).

Over the coming months and years, EMA’s Committee for Medicinal Products for Human Use (CHMP) Methodology Working Party (MWP) will help to develop the 

document, which will include domain-specific guidance on pharmacovigilance and other areas. From mid-2024 work was initiated on preparations for the European Artificial Intelligence Act (AI Act), which came into force in August 2024, and an observatory will be created to monitor the impact of AI and the emergence of novel systems and approaches (3,4).

The EMRN will survey its capabilities to analyse data including the use of AI, and this survey will be used to inform collaborative efforts to enhance the analytics capability of the ERMN to ensure all parties are compliant with data protection legislation. In addition, a Network Tools policy will be published to help foster collaboration, integration, and reusability of tools and models within the EMRN (3).

The EMRN will continue to work with partners on AI on an international scale including the International Coalition of Medicines Regulatory Authorities and other agencies in the European Union, as well as with academia and the devices sector. Furthermore, the European Specialised Expert Community of the EMA MWP, will establish a Special Interest Area on AI to provide a forum for collaboration and knowledge sharing, and the EU-Network Training Centre will provide a framework and platform to upskill staff on AI and Data Analytics and support the development and delivery of BDSG Data Science Curriculum (3).

EMA and HRA recognize that AI is a rapidly moving field, and it is essential for regulatory personnel to be provided with a structured approach to integrate these tools in their daily tasks while safeguarding information and maintaining trust. EMA is leading by example and has promptly responded to the implementation of the AI Act, which aims to ensure that AI developed and used in the EU is trustworthy and that there are sufficient safeguards in place to protect people’s fundamental rights. Pharma should take heed as the AI ACT will impact all industries, and it will be essential that companies work closely with the AI Office and other relevant authorities to ensure the safe deployment of AI solutions that will be beneficial to society and drive future innovation in the European pharmaceutical industry (5).

Harnessing AI in Medicines Regulation: Use of Large Language Models (LLMs)

Guiding Principles on the Use of Large Language Models in Regulatory Science and for Medicines Regulatory Activities

Multi-Annual Artificial Intelligence Workplan 2023-2028: HMA-EMA Joint Big Data Steering Group

European Artificial Intelligence Act Comes into Force

Barton, C. European Artificial Intelligence Act Comes into Force. 

Cheryl Barton, PhD, is founder and director of PharmaVision, Pharmavision.co.uk.

When referring to this article, please cite it as Barton, C. Responding to the Increased Use of Generative AI. 

Regulators, EMA and HMA, have published principles and recommendations 
on the use of LLMs, which are being increasingly used for daily tasks.


Responding to the Increased Use of Generative AI

On 1 Aug. 2024, the European Artificial Intelligence Act (AI Act) came into force (1). The AI Act is designed to ensure that artificial intelligence (AI) developed and used in the European Union (EU) is trustworthy, and that there are safeguards in place to protect people’s fundamental rights. In January 2024, the European Commission (EC) launched a package of measures to support European small and medium enterprises (SMEs) and start-ups in the development of trustworthy AI, and in May, the EC established an AI Office (2,3). In July 2024, the amended European High Performance Computing Joint Undertaking (EuroHPC JU) Regulation came into force to further develop, deploy, extend, and maintain the EU supercomputing and data infrastructure (4). This paved the way for the establishment of AI Factories, dedicated AI supercomputers, that can be used for training General Purpose AI (GPAI) models (5).

This article was published in the September 2024 issue of 

The AI Act aims to harmonize AI across the EU to encourage the uptake of this technology and support innovation and investment. The AI Act also prohibits certain AI practices and sets out regulations on “high-risk” AI systems and those that pose transparency risks (

Figure 1. Definition of artificial intelligence (AI)-based product safety and risk-based approach. (Figure courtesy of the author)

The AI Act also introduces rules to reduce the systemic risk of systemic GPAI models that are capable of performing a wide range of distinct tasks such as the generation of human-like text (6). The new legislation imposes stricter regulation and fines on tech companies operating generative AI models (i.e., DeepMind and OpenAI will fall under the general-use AI category and would be classed as minimal risk). However, developers of high-risk models would be asked to evaluate models, assess and mitigate systemic risks, conduct adversarial testing, report serious incidents to the EC, ensure cybersecurity, and report on their energy efficiency (6).

The European Federation of Pharmaceutical Industries and Associations (EFPIA) welcomes the AI Act and “believes in the potential of applying AI to deliver benefit for patients, life-science companies, and society” (7). However, it stresses that “the regulatory frameworks governing the use of AI in research, development, and manufacture must be fit-for-purpose, risk-based, non-duplicative, globally aligned, and adequately tailored” (7). When AI-enabled tools are used in pharma R&D, they are exempt from the requirements of the EU AI Act; however, developers and deployers of AI-enabled digital health tools (DHTs) and AI-enabled digital medicine would be impacted by the AI Act, but they would not be considered high risk (8).

Enforcement of the AI rules will be phased in

EU Member States have a year to designate national competent authorities to oversee the application of the AI rules. The Commission’s AI Office will oversee the implementation of the AI Act at the EU level, and be responsible for enforcing the rules for GPAI models (1).

The EC will establish the following three advisory bodies to support the implementation of the rules:

European Artificial Intelligence Board—

to ensure the uniform application of the AI Act across EU Member States and to cooperate between the EC and the Member States.

A scientific panel of independent experts—

to offer technical advice and input on enforcement. The panel can issue alerts to the AI Office about risks associated with GPAI models.

a diverse set of stakeholders to offer guidance to the AI Office (1).

The AI Office has the power to enforce these policies. Companies that do not comply with the rules will be fined 1.5–7% of their global annual turnover depending on the violation (e.g., companies can be fined up to 1.5% for supplying incorrect information) (1).

The AI Act’s regulations will take effect in phases. Rules regarding prohibited practices will apply as of 2 Feb. 2025; obligations on GPAI models will apply as of 2 Aug. 2025; and both transparency obligations and obligations on high-risk AI systems will apply as of 2 Aug. 2026 (9).

In the interim, the EC launched the AI Pact to encourage and support organizations before implementing the AI Act (10). The EC has urged the industry to voluntarily commit to the AI Act requirements before the legal deadline. In November 2023, it obtained responses from more than 550 organizations, and the AI Office initiated the development of the AI Pact, based upon two pillars:

establish a gateway to engage the AI Pact network, encourage the exchange of best practices, and provide practical information on the AI Act implementation process

encourage AI system providers and deployers to prepare early and take actions towards compliance with requirements and obligations set out in the legislation.

The AI Pact has enabled the EC to work with stakeholders to support them in understanding the objectives of the AI Act, to adapt and prepare for the implementation of the AI Act, and to share knowledge and build trust in AI technologies (10).

Meanwhile, the Joint Research Centre continues to undertake independent, evidence-based research to support EU policies and determine the societal impact of the AI Act across Europe.

The EU AI Act sends a clear message to the rest of the world that Europe is taking AI very seriously and emphasises the importance of trust, transparency, and accountability. The EC is the first governmental body to create a legal infrastructure on AI and has paved the way for others to emulate and replicate.During the coming months, rules will be phased in and European standards will be refined. Therefore, companies need to work closely with the AI Office and other relevant authorities to ensure the safe deployment of AI solutions that will be beneficial to society and drive future innovation in Europe.

Commission Launches AI Innovation Package to Support Artificial Intelligence Startups and SMEs

Commission Establishes AI Office to Strengthen EU Leadership in Safe and Trustworthy Artificial Intelligence

Setting Up of AI Factories is Now Possible after EuroHPC Regulation Amendment

The EU Passes the AI Act and its Implications for Digital Medicine Are Unclear

International Bar Association. The Regulation of Foundation Models in the EU AI Act. 

EFPIA Statement on the Use of AI in the Medicinal Product Lifecycle in the Context of the AI Act

Cheryl Barton, PhD,is founder and director of PharmaVision, Pharmavision.co.uk.


Vol. 36, No. 8
September 2024
Pages: 9-10

When referring to this article, please cite it as Barton, C. European Artificial Intelligence Act Comes into Force. 

What impact will the AI Act have on pharma and digital medicine?

On 3 July 2024, the Health Committee of the Bundestag amended and approved the Federal Government’s Medical Research Act (Medizinforschungsgesetz or MFG) (1). The new legislation will impact national laws to simplify clinical trials and approval processes for drugs and medical devices. MFG will also amend rules on advanced therapy medical products (ATMPs) and drug pricing and reimbursement laws (Arzneimittelmarktneuordnungsgesetz [AMNOG]). In addition, the new legislation will result in a reorganization of the regulatory agencies (The Federal Institute for Drugs and Medical Devices [BfArM] and Paul Ehrlich Institute [PEI]) and ethics committees (2).

Pharma may choose confidential pricing … but at a cost

The MFG allows pharmaceutical companies confidential pricing, providing they have drug research departments in Germany that can demonstrate “relevant own projects and cooperation with public institutions in preclinical or clinical drug research in Germany” (3). For instance, if at least 5% of approved study subjects participate in clinical trials in Germany, then manufacturers could be exempt from the AMNOG guardrails that were introduced with the Statutory Health Insurance Finance Stabilization Act in November 2022 (4).

Once a pharma company has completed price negotiations with the National Association of Statutory Health Insurance Funds (GSK-SV), they will have five days to decide whether to keep the pricing of new patent-protected drugs confidential or transparent. Within seven days of receipt, the GSK-SV will decide whether ‘sufficient’ proof has been provided. If a pharmaceutical company requests confidential pricing, an additional discount of 9% will be imposed on the agreed sales price (not the pharmacy sales price) (3).

Companies that opt for confidentiality will also be obligated to reimburse the health insurance funds and other payors the overpaid difference between the ‘public’ and the ‘real’ price and will also have to reimburse the health insurance funds the overpaid portions of the mandatory surcharges for pharmacies and wholesalers and value-added tax (VAT) (3). Therefore, the final price negotiated by companies to keep drug prices secret could result in more than the 9% discount. The new rules for confidential reimbursement prices shall apply as of 1 Jan. 2025 and will be enforced until 28 June 2028 and reviewed in late 2026 (3).

Confidential pricing has proved a contentious issue among stakeholders in Europe. On one hand, the pharma industry in Europe has been keen to move towards confidential pricing because German reimbursement prices are regularly used as reference prices in other European countries, and an unfavourable price in Germany can have a significant impact on the price achieved in other European countries and abroad. In the past, this has led manufacturers to withdraw drugs from the German market; for instance, Bristol Myers Squibb decided not to launch the cancer drug Opdualag (nivolumab/relatlimab combination) in Germany, due to pricing pressures (5). If a company chooses to keep the reimbursement price confidential, it would not be listed in public sources or disclosed to pharmacies and could lead to differential pricing, the ‘public’ price, and the ‘real’ or agreed (discounted) price (3).

In 2022, the ‘AMNOG guardrails’ regulations were introduced to protect against excessive prices for patent-protected drugs with no or only a small or non-quantifiable benefit (6). These regulations will be deleted and replaced by the economic development goals laid out by the German Government in its new Pharma Strategy (6,7). However, the GSK-SV fears the lack of transparency could lead to increases in pharmaceutical expenditure (8,9). This is a major concern given that more than 73 million German citizens with statutory health insurance have already witnessed a significant increase in health insurance contributions earlier this year, and there is pressure on the Federal Ministry of Health to raise contributions further (6).

The new Pharma Strategy aims to make Germany more attractive to the pharma industry

The MFG is part of the German government’s National Pharma Strategy to strengthen Germany’s position as a business and pharmaceutical location (10). The Strategy Paper 4.0–Improving the General Conditions for the Pharmaceutical Sector in Germany lists several specific reform ideas all of which will have a significant impact on the pharmaceutical industry and aim to improve market access and pricing environment in Germany (Figure 1).

Figure 1: Strategy Paper 4.0 points of reform. Source: modified from (10). Figure courtesy of the author.

Germany is the fourth largest pharmaceutical market in the world and the largest European market generating €56.5 billion in 2022 and growing by 5.4% per annum (11). According to Marcus Schmidt, Germany Trade & Invest Director of Chemicals and Health, “The pharmaceutical strategy underlines the great importance of this sector for the federal government. Together with the laws that have already been introduced, Germany will expand its leading role in Europe in the areas of research and development as well as production” (10). Several pharma companies—Daiichi-Sankyo, Eil Lilly, and Sanofi—have all increased their investment in Germany in the past nine months (12).

The latest reform could have a significant impact on drug pricing and will link it more closely to local investment in clinical trials and R&D in Germany. However, the MFG will not come into force until it has received the seal of approval from the German Federal Council (Bundesrat), and this is unlikely to occur until the fourth quarter of 2024 (3).

 Entwurf eines Medizinforschungsgesetze Drucksache 20/11561. 29 May 2024.

Germany Amends Drug Pricing and Reimbursement Laws with the “Medical Research Act”–Drug Pricing Becomes Intertwined with Local Clinical Research Expectations.

 Blog. Insideeulifesciences.com. 12 July 2024.

Health Committee Approves Medical Research Act.

Simon-Kucher. Germany: How the GKV-FinStG Law is Transforming the Pharma P&R Landscape. Simon-kucher.com. 24 Feb. 2023.

Are German Drug Pricing Regulations Chasing Some Drug Makers Away, Causing Them To Not Launch Products In The Market?

Health Insurance Companies Should Support the Pharmaceutical Industry

German Government Pursues New Pharma Strategy with Significant Reform Ideas

. Blog. Covington. Insideeulifesciences.com. 21 Nov. 2024.

Secret Prices Make Care More Expensive Without Improving It

. GKV. GKV-spitzenverband.de. 6 June 2024.

What are the Implications of Confidential Rebates in Germany?

Big Changes Coming in German Health, Pharma, Pharmaceuticals

. Germany Trade and Invest, GTAI. gtai.de 14 Dec. 2023.

. Germany Trade and Invest, GTAI. gtai.de (accessed 12 July 2024).

Germany’s New Medical Research Act Will Allow Pharma Companies Confidentiality on Price

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

®
Vol. 36, No. 7
July/August 2024
Pages: 9–10

When referring to this article, please cite it as Barton, C. Germany Amends and Approves the New Medical Research Act. 

Germany’s Medical Research Act allows pharmaceutical companies to keep drug prices confidential.

Germany Amends and Approves the New Medical Research Act

European union DNA | Image Credit: ©Kestutis - stock.adobe.com

Over the past two decades, 32 cell and gene therapies (CGTs) have been approved by the regulatory authorities worldwide, and more than 2000 novel products are under clinical investigation (1). However, many patients do not have access to these life-saving therapies, partly due to the complexity and high cost of manufacture (2). But how can CGTs be made more cost-efficient given the high labour and facility costs?

According to Miguel Forte, CEO, of Kiji Therapeutics, France, and president of the International Society for Cell & Gene Therapy, “It is clear that CGTs have the opportunity to deliver enormous value to patients; nonetheless, manufacturing is complex, and it has been challenging to deliver the product. Innovative technologies and services have enabled the industry to move towards an automated, closed-system approach that is easier and safer to operate and is less costly and closer to the patient.”

Cell therapies can be derived ex vivo from autologous cell therapies (patient to patient), allogenic cell therapies (donor to patient), or in vivo cell therapies (cell line to patient). Each approach requires manufacturers to tailor the biomanufacturing process to generate specific cell types (and/or vectors), safely, efficiently, and cost-effectively. Manufacturing tools have tended to lag behind scientific advances in CGTs leading to bottlenecks in cell production. Currently, most CGT manufacturers use disconnected single-step/modular or semi-automated solutions; however, the industry is migrating towards fully automated cell therapy manufacturing processes (3). And this approach could significantly reduce manual intervention, risk of contamination, and human error; improve product quality and speed of delivery; and reduce production costs (4).

According to David Smith, vice president of Development, BioCentriq, “Labour costs, and facility costs are sky high, which have led to high price points, particularly in autologous cell therapies where production is 1:1. Automation is a key part of improving costs, reducing labour both in and outside the clean room, and implementing release by exception can help to reduce bottlenecks. Companies are trying to integrate unit operations whether it’s an ‘all-in-one-box’ approach or a ‘unit-operator’ approach where units can be plugged in or out and are integrated within robotic systems to offer greater flexibility.”

For instance, Lonza’s Cocoon Platform and Miltenyi Biotec CliniMACS Prodigy offer an ‘all-in-one-box’ approach providing a closed, automated system for patient-scale cell therapy manufacturing from cell isolation, activation, transduction/transfection, expansion, and harvest within a validated cell manufacturing system (5,6). CliniMACS Prodigy modular Instruments can also be run in parallel to provide large-scale batch production.

UK-based Ori Biotech launched its IRO platform developed in 2024 in collaboration with CTMC (a joint venture between Resilience and MD Anderson Cancer Center). This platform automates the activation, transduction, expansion, and harvest of a wide range of cell types to rapidly scale up manufacturing from the clinic to the commercial setting (7).

Paris-based Astraveus SAS has developed the Lakhesys Benchtop Cell Factory, an end-to-end solution for the manufacture of adherent, non-adherent, and inducible pluripotent stem cells (iPSCs) (8). The company has raised €16.5 million in seed financing and received a €10.4 million grant from the French government as part of its “Innovation in Biotherapies and Bioproduction” initiative, to advance the development of its technology (9).

Several companies are developing integrated bioreactors, robotic systems, and smart monitoring technologies that can support a ‘unit operator’ approach.

UK-based Cellular Origins, launched Constellation, a closed fully automated, and configurable robotic platform for CGT manufacture in 2023 (10). In May 2023, it forged a partnership with ScaleReddy (a joint venture between Bio-Techne, Fresenius Kabi, and Wilson Wolf) to automate its CGT manufacturing workflow using Cellular Origin’s robotic system (11). According to Jason Jones, Global Business Development lead, Cellular Origins, “Our company integrates existing, proven technologies with mobile robotics to provide fully automated factories that can be scaled up to manufacturers’ requirements, minimize risks, and are GMP [good manufacturing compliance] compliant. We can achieve a 30-fold increase in space efficiency and manufacture and a 16-fold labour reduction, equating to a 51% reduction in cost-of-goods and enabling manufacture 24/7, 365 days a year.”

Swiss-based Limula has taken a different approach and developed a modular solution that combines a bioreactor and centrifuge into one device for on-demand and at-scale manufacturing of cell therapies (12). In May 2024, the company raised CHF 6.2 million (US$6.8 million, €6.24 million) in seed funding to develop its automated CGT manufacturing platform, the funding round was over-subscribed highlighting the interest that venture capitalists have in this field (13).

UK-based MicrofluidX has developed a space-saving stackable multi-bioreactor instrument—the Cyto Engine Stack. Each bioreactor can be controlled and monitored independently, to allow cell therapy manufacturers to expand their manufacturing capacity without increasing the facility footprint. The first Cyto Engine product is scheduled for launch in early 2025 (14).

Other companies have focused on leveraging digital tools and advanced analytics to streamline the manufacturing process. For instance, UK-based Autolomous has launched AutoloMATE Launchpad, a cloud-based CGT platform that allows for the scalability and adaptability of different CGT modalities (15). According to Alexander Seyf, the CEO of Autolomous, “Addressing manufacturing challenges effectively demands a shift towards more integrated and automated systems. By leveraging digital tools and advanced analytics, we can enhance process control, increase reproducibility, and reduce labour-intensive procedures which, in turn, decrease costs significantly. Moreover, digitization can streamline data flow across the manufacturing process, ensuring that critical information is accessible and actionable. This integration leads to improved decision-making, faster turnaround times, and ultimately, more standardized production of therapies.”

In 2024, US-based Cellares, became the first Integrated Development and Manufacturing Organization (IDMO) to offer a high-throughput fully, automated smart manufacturing platform Cell Shuttle. In April 2024, the company signed a US$380 million (€349 million) supply agreement for the manufacture of chimeric antigen receptor-T cell therapies with Bristol-Myers Squibb, and it announced a similar agreement with Kite in June (16,17).

Over the next decade, the demand for CGTs is expected to grow as they move further up the treatment cascade and target more common diseases. It will be essential for companies to address the challenges associated with scaling up the manufacturing process to provide high-quality, consistent autologous and allogenic cell products while adhering to stringent regulatory standards. Fully automated space-saving modular technologies will allow manufacturers to steadily scale up capacity and adapt to demands (18).

Smith notes, “CDMOs [contract development and manufacturing organizations] are looking at the trajectory of pipeline products and questioning where and when they need to invest in new facilities and technologies. Manufacturing is one of the biggest areas of risk in CGT developments, but if we can de-risk the process by deploying robust engineered manufacturing processes and automation, we can reduce the cost of autologous cell manufacture and increase the speed and flexibility to meet individual needs. On the allogenic side, the processes tend to be on a larger scale, and the drug product cost is shared amongst many patients. Although automation can assist in cost reduction, the burden is less steep than for autologous, that said, many of the same automation tools can be used across processes, and the industry is looking to standardize manufacturing.”

In the longer term, the industry could move towards a more decentralized manufacturing model that utilizes automated point-of-care technologies to enable on-sitepreparation of CGTs in or near hospitals, helping to bring therapies closer to the patient.

“The current acute unmet need is on scaling centralized systems, but we’ve had some interesting conversations around decentralization negating operator variability/increasing process comparability and digitalization of information of the product and opening up facilities at the national, regional, and near-hospital levels depending on the therapy and medical need,” observes Jones.

Gene, Cell, and RNA Therapy Landscape Report.

 Q1 2024 Quarterly Data Report. 11 Apr 2024.

Harrison, P.T., Friedmann, T. Correction: Cost of Gene Therapy. Gene Therapy, 2024, 31, 195-196.

Closed, Automated Cell Therapy Manufacturing–Is Your Facility Ready?

Harris, R. Cell Therapy Manufacturing Shifts to Automatic. Genetic Engineering & Biotechnology News. 4 Oct 2021.

The Cocoon® Cell Therapy Manufacturing Platform.

 miltenyibiotec.com (accessed July 2024).

Ori Biotech Unveils IRO Platform at Annual International Society for Cell & Gene Therapy Conference

Lakhesys™ Benchtop Cell Factory - Astraveus - Enable a Healthier Tomorrow

PRNewswire. Astraveus Raises €16.5 Million Series Seed Round to Advance the Development of its Automated, Microfluidic Cell and Gene Therapy Manufacturing Platform. News Release. 27 Jun 2023.

Cellular Origins Launches Constellation™, Its Configurable Robotic Platform to Enable Scalable Manufacture of Advanced Therapies

Cellular Origins Partners with ScaleReady to Simplify, Standardize, and Automate Cell Therapy Manufacturing

The Future of Cell and Gene Therapy is Automated

Limula Raises CHF 6.2 Million in an Oversubscribed Seed Round to Develop an Automated Cell and Gene Therapy Manufacturing Platform

MicrofluidX Secures Innovate UK Award to Advance High Throughput

Autolomous Releases the CGT industry’s First Free eBR Builder, autoloMATE Launchpad, to Empower Digital Planning

Bristol Myers Squibb, and Cellares Announce a $380M Worldwide Capacity Reservation and Supply Agreement for the Manufacture of CAR T Cell Therapies to Bring the Promise of Cell Therapy to More Patients, Faster.

Cellares Announces Agreement with Kite to Evaluate Its Cell Shuttle Automated Manufacturing Platform.

Small Footprint Automated Closed Production Platforms for CAR-T and Other Advanced Therapies

Cheryl Barton, PhD, is director of PharmaVision, 


Vol. 36, No. 7
July/August 2024
Pages: 14–16

When referring to this article, please cite it as Barton, C. Frontrunners in Automated Cell and Gene Therapy Manufacturing. 

Innovative solutions are making personalized cell and gene therapies accessible to all.

Frontrunners in Automated Cell and Gene Therapy Manufacturing

On 3 May 2024, the European Medicines Agency (EMA) initiated a public consultation to review draft recommendations published in its reflection paper on “the use of real-world data (RWD) in non-interventional studies (NIS) to generate real-world evidence (RWE)” (1). The paper discusses methodological aspects of NIS using RWD, such as claims databases, hospital data, electronic health records (EHR), registries, and medical health data, to generate RWE for regulatory decision-making. The paper is part of the Methodology Working Party Workplan 2022–2024 and the joint Heads of Medicines Agency (HMA)-EMA Big Data Steering Group plan 2023–2025 (2,3).

According to EMA, a clinical trial is defined as a clinical study where:

the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within the normal clinical practice of the member state concerned

the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study

diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects. RWD are data that describe patient characteristics (including treatment utilization and outcomes) in routine clinical practice (1).

A NIS is a clinical study that does not fulfil any of the above conditions, based on Article 48 of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use (4).

Key topics discussed in the reflection paper

The reflection paper discusses feasibility assessment, bias, confounding, and data quality and provides guidance on four key areas:

The paper also recognizes the importance of using protocol formats when designing NIS for RWD generation. For example, applying the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Checklist for Study Protocols and The HARmonized Protocol Template to Enhance Reproducibility (HARPER) protocol template (5,6).

In March 2024, the US Food and Drug Administration (FDA) published its draft guidance on 

Real-World Evidence: Considerations Regarding Non-Interventional Studies for Drug and Biological Products

, which is open for consultation until 18 June 2024 (7). EMA’s guidance closely aligns with FDA’s; however, the regulatory agencies’ definition of NIS differs and further clarification and standardization will help drive the utilization of RWD moving forward (8).

EMA promotes the use of RWD in decision-making

EMA’s Regulatory Science Strategy to 2025 promotes using high-quality RWD in decision-making (9). To this end, EMA aims to create a flexible framework to deliver rapid access to and analysis of RWD throughout a product’s lifecycle; to develop computing capacity and skills in the agency to analyze large amounts of healthcare data, and to implement processes to feed data into regulatory assessments.

In March 2024, EMA launched its RWD catalogues to help regulators, pharmaceutical companies, and researchers identify and use RWD to investigate the safety and effectiveness of medicines (10). The catalogue of RWD sources replaces the ENCePP Resources Database. The data are searchable and can be exported by registered entities.

In April 2024, EMA’s Real-World Evidence Team (TDA-RWE) of the Data Analytics and Methods Task Force released new guidance detailing the types of studies that can be performed for RWE generation and how it can be used to support regulatory decision-making (11). The regulators recognize that RWD provides additional benefits compared to traditional randomized control trials. For instance, it can be generated quickly and reduce the risk of data duplication, RWD can be used to fill in knowledge gaps and provide tailored analyses to the committee’s questions (11).

The draft reflection paper highlights the importance that EMA places on RWD and its potential impact on decision-making. It also establishes a framework for scientific and methodological rigour, helps to improve the transparency of data collection and analysis, and ultimately should increase the reliability of RWD generated by the industry.

The reflection paper will be presented at the multi-stakeholder joint HMA-EMA workshop on RWE methods on 14 June 2024 (12). Stakeholders are invited to provide feedback on the draft reflection paper by 31 Aug. 2024.

1. EMA. Reflection Paper on the Use of Real-World Data in Non-Interventional Studies to Generate Real-World Evidence. Draft Reflection Paper. 

. 15 April 2024.
2. EMA. Revised Consolidated 3-Year Work Plan for the Methodology Working Party (MWP). Work Programme. 

. 15 Jan. 2024
3. HMA/EMA Joint Big Data Steering Group. Big Data Workplan 2023–2025. Work Programme. 

Regulation (EU) No 536/2014 on Clinical Trials on Medicinal Products for Human Use

. 16 April 2014.
5. ENCePP. ENCePP Checklist for Study Protocols. 

, 15 Oct. 2018.
6. Wang, S.V.; Pottegård, A.; Crown, P.; et al. HARmonized Protocol Template to Enhance Reproducibility of Hypothesis Evaluating Real-World Evidence Studies on Treatment Effects: A Good Practices Report of a Joint ISPE/ISPOR Task Force. 

EMA is promoting the use of RWD in decision-making and has started a public consultation to review its draft recommendations.