Cheryl Barton is director of PharmaVision, 

Cheryl Barton

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 Aducanumab has also been withdrawn from the US market as a result of low uptake and payor challenges.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. 

Articles

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

Frontrunners in CNS Drug Delivery

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

In December 2021, the European Parliament (EP) passed new legislation, European Union regulation 2021/2282, which amended directive 2011/24/EU and substituted the parallel evaluations of clinical data conducted by multiple country-specific health technology assessment (HTA) bodies with a single harmonized relative effectiveness assessment to reduce fragmentation and duplication (1).

The joint clinical assessment (JCA) is currently a voluntary collaboration, participation by member states is not mandatory, and non-EU countries can participate as observers or in specific collaborations (2). However, the process will be phased in for eligible health technologies starting with oncology products and advanced therapy medicinal products (ATMPs) in January 2025 (

, [3]). Once it is fully implemented in 2030, all drugs registered by the European Medicines Agency (EMA) via the centralized procedure will be subject to a JCA, and therefore, sponsors will need to prepare their new molecular entities (NMEs) for this process.

European Union joint clinical assessment (JCA) regulation will apply from 2025 onwards. 

The JCA enables EMA to run consultations in parallel with the European Network for Health Technology Assessment (EUnetHTA) 21 consortium. It aims to streamline the clinical assessment and cost-effectiveness of medicines to provide recommendations on pricing and reimbursement (P&R) decisions at the national level and improve patient access (4). Although the results of the JCA are currently non-binding, member states must give “due consideration” to the JCA report and can leverage the data to inform P&R decisions that remain under the jurisdiction of each member state (5).

Importantly, the JCA is designed to take into account the different member states’ requirements, for instance, regarding the standard of care (SoC) and patient preferences regarding clinical outcomes (2).

The main aspects covered by regulation (EU) 2021/2282 include:

cooperation and exchange of information with EMA during JCAs

deadlines and procedures for various stages, such as finalizing the assessment scope, submitting dossiers, preparing draft reports, and considering updates

interaction and timing with the Coordination Group, its subgroups, health technology developers (HTDs), patients, clinical experts, and other relevant experts

procedural rules for selecting and consulting stakeholders, patients, clinical experts, and other relevant experts

provisions for confidentiality requests and processing of personal data

requirements for correspondence and use of the HTA IT platform

rules for handling changes to therapeutic indications, re-initiating assessments, and updating assessments

templates and formats for dossiers, JCA reports, and summary reports (6).

Since the framework has been put in place, 68 JCA committees have occurred, but the use of JCA results remains limited by the member states (2). However, the JCA has established numerous guidance documents on procedures, methodology, the Scoping Process, direct and indirect comparisons, and report and dossier templates to help streamline the process (7).

According to OPEN Health analysis, pilot JCAs have considered a wider scope of clinical trials and product comparators compared with national HTAs. In addition, JCAs used a variety of safety endpoints and there was a good level of agreement in the use of efficacy endpoints by the JCA and national HTAs. The analysts concluded: “The new process will likely guarantee fairness in determining the true value and pricing of new technologies, but reimbursement decisions will ultimately rest at the national level” (8).

The JCA process is composed of four main steps:

the scoping phase, encompassing the development and validation of population, intervention, comparator, and outcomes (PICOs)

the publishing of the final JCA report (6).

The JCA directive aims to minimize the number of PICO elements; historically, at least five PICOs have been required. The assessment scope phase is around 90 days, which provides sponsors with limited time for evidence generation; therefore, sponsors must engage early with local affiliates and external stakeholders (9). Timelines for JCA dossier development are around six months, so, dossiers should be started at the time of EMA marketing authorization (MA) submission, to allow for sufficient preparation. The JCA dossier is required 45 days before the EMA’s Committee for Medicinal Products for Human Use (CHMP) opinion and will be published at the latest 30 days after approval of the medicine by EMA. The JCA report may influence country-specific HTA processes and procedures to start pricing negotiations (

Timeline for EMA and joint clinical assessment (JCA) dossier submission.

As of September 2023, the EUnetHTA 21 consortium was disbanded and all HTDs can now seek scientific advice from the national HTA body (HTAb) and EMA in parallel, via the Gemeinsamer Bundesausschuss/Federal Joint Committee, Germany (G-BA) (10).

The JCA is viewed by many in the industry as a good “starting point” to harmonize EU regulation and to accelerate and broaden equitable access to medicines across all member states. However, some patient organizations have raised concerns regarding the involvement of patient representatives in the JCA process. At a webinar held by Cencora Pharma, Antonella Cardone, CEO, of Cancer Patient Europe Cancer, noted it is unclear when, where, and how the patient voice will be incorporated into this process, and further work is needed to increase transparency and establish best practices, standards, and the selection of comparators and outcomes to maximize market access (11).

Future considerations for pharma before JCAs are compulsory

The future success of the JCA relies on significant coordination and cooperation between different stakeholders, including regulatory agencies, healthcare providers, and patient groups. To date, the JCA has reviewed a limited number of products due to restricted resources; therefore, additional funding and resources may be required to meet future demands. In the meantime, the JCA needs to continue to monitor and accommodate the needs and preferences of different regions and countries and to work closely with manufacturers and local stakeholders to ensure that drugs are accessible and affordable to patients in different regions and countries (12).

Moving forward, JCAs will have a considerable impact on market access and how pharma interacts with the EMA and HTA bodies. As the joint EU HTA process evolves, stakeholders will need to monitor how EU countries implement the EU HTA into their legislation and processes particularly given that each EU member state will vary in treatment patterns, patient populations, and equitable access to medicines. Pharma should seek early engagement with EU HTA assessors, to gather information and gain insights on pivotal trial designs, and any additional evidence requirements that may be needed for the effective assessment of pipeline assets.

In the meantime, pharma companies will need to think ahead, establish internal processes, and develop the skillset needed to respond to EU HTA at the country level. According to Alex Gee, senior director, Market Access, at Parexel, “Pharma needs to act to reduce their internal uncertainty and prepare for future success … This may require them to review processes, responsibilities, and capabilities to optimize for the new environment” (13).

The consultation closed on 2 April 2024, and it will be interesting to see how stakeholders’ views have been taken onboard and used to help refine the process to ensure that it is fit for purpose for future use.

1. European Parliament. Regulation (EU) 2021/2282 of the European Parliament and of the Council of 15 December 2021 on Health Technology Assessment and Amending Directive 2011/24/EU. 

, 64, 1–32.
2. Kulp, W.; Martel, M.; Billig, S.; Schmidt, K.; Martinez, J. Joint Clinical Assessment in the EU: Pan-European HTA for Drugs and Medical Devices Will Become Reality. HTA Quarterly. 21 Jan. 2022.
3. Lightning Health. European Joint Clinical Assessment. Article, 4 May 2022.
4. EUnetHTA. Joint Scientific Consultations (JSC). 

 (accessed 21 March 2024).
5. JCA.EU, The JCA Process. 

 (accessed 21 March 2024).
6. Remap Consulting. What is the Joint Clinical Assessment and What Does it Entail? Article, 3 March 2024.
7. JCA.EU. EUnetHTA Guidance. 

 (accessed 21 Mar 2024).
8. Jose, R. Coming Soon: Joint Clinical Health Technology Assessments. OPEN Health, 20 March 2023.
9. Jose, R. Arca, E. European Health Technology Assessment Regulation: Implications for the Industry and 5 Key Areas for Successful Implementation. 

, March 2024.
10. Gemeinsamer Bundesausschuss. European Consultations: G-BA Acts as Coordination Contact for Parallel Consultations by EMA and HTA Agencies in Europe in the Interim Period until the Full Implementation of the EU HTA Regulation. 

 (accessed 21 March 2024).
11. Cencora Pharma. Implications of the EU JCA on Patient Access and Engagement. Webinar. (accessed 21 March 2024).
12. Vesic, N. EU Joint Clinical Assessments: Theory vs Practice. 

, 19 June 2023.
13. Gee, A. Joint Clinical Assessments: Manage What You Can Control. LinkedIn. 20 Oct. 2023.

Cheryl Barton is director at PharmaVision, Pharmavision.co.uk.

When referring to this article, please cite it as Barton, C. Looking at the Potential Impact of JCA on Pharma. 

The European pharma industry needs to be prepared for the new clinical data requirements.

Looking at the Potential Impact of JCA on Pharma

antibody medical science microbiology | Image Credit: © Mirror-images - Stock.adobe.com

In February 2024, the National Institute for Health and Care Excellence (NICE) recommended AbbVie’s Tepkinly (epcoritamab) as the first injectable bispecific antibody for certain blood cancers (1). Unlike existing chimeric antigen receptor (CAR) T-cell therapies, bispecific antibodies do not require cell collection and engineering and, unlike monoclonal antibodies, they provide a dual functionality, selectively targeting two different epitopes/receptors resulting in enhanced clinical efficacy with low intrinsic toxicity and immunogenicity (2). In May 2021, the US Food and Drug Administration issued final guidance on bispecific antibody development providing greater clarity for drug developers and fuelling significant investment in recent years (3).

Big Pharma, including AbbVie, Johnson and Johnson, Regeneron Pharmaceutical, and Sanofi, have bispecific antibodies in development (

). In addition, the industry has also forged partnerships with academic institutes and innovative biotech’s in this field including, Jazz Pharmaceuticals/MD Anderson Cancer Center (2023), ONK Therapeutics/NATA Biosciences (2023), F-star/Takeda (2022), Gilead Sciences/MacroGenics (2022), AbbVie/Genmab (2020), and BeiGene/Zymworks (2018) (4–10).

To date, three bispecific antibodies have received regulatory approval, Amgen’s Blincyto (blinatumomab), Chugai’s Hemlibra (emicizumab), and Roche’s Vabysmo (faricimab), and many more are under clinical development (

). Two European biotech’s, Affimed and Merus, are leading the field in bispecific antibodies and have developed proprietary technology to generate several products that are in clinical development.

Bispecific antibodies under clinical development.

Affimed harnessing the potential of the innate immune system

Affimed N.V. (Nasdaq: AFMD), a German-based immune-oncology company, is utilizing its proprietary Redirected Optimized Cell Killing (ROCK) platform to generate customized innate cell engager (ICE) molecules that can activate immune cells to target tumour cells (11). The high-affinity bivalent ICE molecules, bind to natural killer (NK) cells via CD16A without inducing non-specific NK-cell activation or cell death. The bivalent interaction of the ICE molecules with CD16A triggers antibody-dependent cell-mediated cytotoxicity (ADCC) (12).

Affimed’s lead bispecific antibodies include:

 a bispecific antibody targeting CD30 on cancer cells and CD16a on innate immune cells being developed to treat Hodgkin lymphoma (HL). Affimed has initiated a Phase II study, LuminICE-203, evaluating acimtamig in combination with alloNK an allogeneic NK cell from Artiva Biotherapeutics, in patients with recurrent/refractory HL (13).

 a bispecific antibody targeting epidermal growth factor receptor (EGFR) and CD16a as a monotherapy and in combination with anti-programmed death 1 (PD-1) in solid tumours in Phase Ib and I/IIa, respectively (14).

 a bispecific antibody targeting CD123 and CD16a, a monotherapy for the treatment of acute myeloid leukaemia (AML) in Phase I.

Affimed has forged strategic alliances with Artiva Biotherapeutics to develop acimtamig; Genentech, Roivant Sciences, and Roche on the development of novel ICEs, as well as the MD Anderson Cancer Center and Leukaemia Lymphoma Society (15).

In January 2024, Adi Hoess stepped down as CEO and management board member, and Andreas Harstrick was appointed interim CEO, who will be supported by Annalisa Jenkins. The company is undergoing a strategic restructure to reduce headcount by up to 50%, and extending its cash position into mid-2025 as it focuses on advancing its clinical programmes (16). Earlier the same month, the company sold AbCheck, its wholly owned subsidiary to Ampersand Biomedicines, and the US$6 million (€5.5 million) proceeds will support ongoing clinical development activities (17).

Merus, a Netherlands-based biopharmaceutical company, is utilizing its proprietary technology platform Multiclonics, to develop full-length human immunoglobulin G (IgG) bispecific (Biclonics) and trispecific (Triclonics) antibodies with long half-lives and low immunogenicity. The Multiclonics platform allows the rapid generation of bivalent and trivalent IgG species with the desired multifunctionality using patented DEKK dimerization technology. DEKK introduces lysine side chains into the heavy chains (L351D and L368E in one heavy chain and L351K and T366K in the other) to form stable constructs (18).

Merus’ lead bispecific antibodies include:

 a bispecific antibody targeting Herceptin 2/3 (HER2/HER3) receptors which is being evaluated in Phase II trials as a single agent in Neureguline 1 fusion-positive (NRG1+) in non-small cell lung cancer (NSCLC) and advanced pancreatic ductal adenocarcinoma (PDAC) (19).

 a bispecific antibody targeting EGFR and mesenchymal-epithelial transition factor (c-MET); has also shown promising results as a single agent in patients with head and neck squamous cell carcinoma (HNSCC) and in combination with osimertinib in non-small cell lung cancer (NSCLC) in Phase II trials (20).

 a bispecific antibody targeting EGFR and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) in Phase I/II as a monotherapy for patients with previously treated HNSCC (21).

Affimed has signed strategic alliances with Incyte Corporation to develop NCA33890, a novel TGFBr2xPD-1 bispecific antibody, and Loxo Oncology at Eli Lilly, to develop up to three CD3-engaging T-cell re-directing bispecific antibody therapies utilizing Merus’ Biclonics platform and proprietary CD3 panel (22). In August 2023, Merus closed a public offering and raised US$172 million (€158 million) to advance its clinical development programmes, resulting in a cash, cash equivalent, and marketable securities position of US$446 million (€411 million), as of 30 Sep. 2023 (22).

Challenges and future opportunities in bispecific antibodies

The clinical approval of different bispecific antibodies demonstrates the significant therapeutic potential of this novel class of biologicals (23). However, they also present unique challenges concerning the production of high quality proteins due to heavy- and short-chain misparing issues, and the generation of antibody fragments and aggregated molecules that require additional purification steps when scaling up manufacturing processes (24). Biotech, pharma, and clinical manufacturing organizations have made significant progress in overcoming these obstacles through the development of novel linker and stability engineering platforms as well as the efficient expression and production of bispecific antibodies using bacteria and mammalian systems. In addition, advances in downstream purification processes have increased the industry’s capacity to scale up the cost-effective production of these novel proteins which will enable them to reach their full potential as a complementary approach to conventional therapies over the years ahead (25).

1. Cision News. NICE Recommends Subcutaneous Treatment Option Tepkinly (epcoritamab) for Eligible* Adults with Aggressive Form of Blood Cancer After Two or More Lines of Systemic Therapy. Press Release, 1 Feb. 2024.
2. Carter P.; Lazar G. Next Generation Antibody Drugs: The Pursuit of the ‘High-Hanging Fruit’. 

, 17, 197–223.
3. Sheridan, C. Bispecific Antibodies Poised to Deliver Wave of Cancer Therapies. 

Bispecific Antibody Development Programs, Guidance for Industry

. Guidance Document (FDA, May 2021).
5. Jazz Pharmaceuticals. Jazz Pharmaceuticals and MD Anderson Announce Five-Year Collaboration to Evaluate Zanidatamab in HER2-Expressing Cancers. News Release. 7 Nov. 2023.
6. ONK Therapeutics. ONK Therapeutics and NAYA Biosciences Announce a Research Partnership to Advance Combination Therapy of Optimally Engineered Off-the-Shelf Natural Killer Cell Therapies and FLEX-NK™ Bispecific Antibodies. News Release, 16 Dec. 2023.
7. F-star. F-star Therapeutics Announces a License Agreement with Takeda for a Novel Next-Generation Immuno-oncology Bispecific Antibody. News Release, 20 July 2022.
8. Gilead. Gilead and MacroGenics Announce Oncology Collaboration to Develop Bispecific Antibodies. Press Release, 17 Oct. 2022.
9. Genmab. Genmab and AbbVie Announce Broad Oncology Collaboration. News Release, 10 June 2020.
10. BeiGene. Zymeworks and BeiGene Announce License and Collaboration Agreement for Zymeworks’ HER2-Targeted Therapeutic Candidates, ZW25 and ZW49, in Asia-Pacific and Research and License Agreement for Zymeworks’ Azymetric™ and EFECT™ Platforms Globally. News Release, 27 Nov. 2018.
11. Ellwanger, K.; Reusch, U.; Fucek, I.; et al. Redirected Optimized Cell Killing (ROCK®): A Highly Versatile Multispecific Fit-for-Purpose Antibody Platform for Engaging Innate Immunity. 

, 11 (5), 899–918.
12. Affimed. ICE® Molecules: A Novel Approach for Directing the Innate Immune System to Attack. 

 (accessed 19 Feb. 2024).
13. NIH. A Phase 2, Open-Label, Multi-Center Study of Innate Cell Engager AFM13 in Combination With Allogeneic Natural Killer Cells (AB-101) in Subjects With Recurrent or Refractory Hodgkin Lymphoma and CD-30 Positive Peripheral T-Cell Lymphoma. 

 (accessed 19 Feb. 2024).
14. Reusch, U.; Damrat, M.; Wingert, S.; et al. AFM24, a Bispecific EGFR/CD16A Innate Cell Engager with the Potential to Overcome Resistance to Current Targeted Treatments for EGFR-Positive Malignancies. Poster presented at American Association for Cancer Research (AACR). Annual Meeting. 22–24 June 2020. Virtual. Poster 5659.
15. Affimed. Harnessing the Potential of the Innate Immune System for Oncology. Company Presentation, January 2024.
16. Affimed. Affimed Announces Leadership Change and Organizational Restructuring. Press Release, 8 Jan. 2024.
17. Affimed. Affimed Announces Sale of Wholly-Owned Subsidiary AbCheck. Press Release, 3 Jan. 2024.
18. De Nardis, C.; Hendriks, L.J.A.; Poirier, E.; et al. A New Approach for Generating Bispecific Antibodies Based on a Common Light Chain Format and the Stable Architecture of Human Immunoglobulin G1. 

, 292 (35), 14706–14717.
19. Merus. Merus Announces Two Clinical Abstracts on Zenocutuzumab (Zeno) in NRG1-fusion (NRG1+) Non-Small Cell Lung Cancer (NSCLC) and Pancreatic Cancer (PDAC) Selected for Presentation at the ESMO Congress 2023. News Release, 28 July 2023.
20. Merus. Merus Presents Interim Data on MCLA-129 at ESMO Asia Congress 2023. News Release, 2 Dec. 2023.
21. Merus. Merus’ Petosemtamab Interim Data Demonstrates Clinically Meaningful Activity in Previously Treated Head and Neck Squamous Cell Carcinoma (HNSCC). News Release. 17 April 2023.
22. Merus. Merus Announces Financial Results for the Third Quarter 2023 and Provides Business Update. News Release, 2 Nov. 2023.
23. Segués, A.; Huang, S.; Sijts, A.; et al. Opportunities and Challenges of Bi-specific Antibodies. 

, 369, 45–70.
24. Li, H.; Er Saw, P.; Song, E. Challenges and Strategies for Next-Generation Bispecific Antibody-Based Antitumor Therapeutics. 

, 17, 451–461.
25. Wang, Q.; Chen, Y.; Park, J.; et al. Design and Production of Bispecific Antibodies. 


Vol. 36, No. 3
March 2024
Pages: 13–15

When referring to this article, please cite it as Barton, C. Frontrunners in Bispecific Antibodies. 

Novel genetic engineering technologies are transforming the design and manufacture of bispecific antibodies, which are emerging as a promising new class of biologics.

Frontrunners in Bispecific Antibodies

On 1 Jan 2024, the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) launched its new International Recognition Procedure (IRP) (1). This new procedure replaces the European Commission’s Decision Reliance Procedure (ECDRP) and will allow MHRA to conduct a targeted assessment of IRP applications but also retain the authority to reject applications if the evidence provided is considered insufficiently robust. The Decentralised and Mutual Recognition Reliance Procedure (MRDCRP), which allows MHRA to approve products in the European Union, will be incorporated under the umbrella of the IRP (2). Therefore, any ECDRP and MRDCRP applications for marketing approval received by MHRA after 1 Jan. 2024 will be assessed under the new IRP (2).

The industry will be able to rely on the IRP for fast-track marketing authorization (MA) in the UK if the products have already been approved by trusted medicines regulators in Australia, Canada, Japan, Switzerland, Singapore, and the United States, or, in the EU, where products have obtained a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) based on the ECDRP (3).

The IRP will assess marketing authorization applications (MAAs) based on the Human Medicines Regulations 2012 (HMRs) for the following:

biosimilar applications (Regulation 53, 53A, and 53B)

chemical and biological new active substances and known active substances (Regulation 50)

generic applications (Regulation 51, 51A, and 51B)

hybrid applications (Regulation 52, 52A, and 52B)

new fixed-combination product applications (Regulation 55) (1).

The IRP can also be used for post-authorization procedures including line extensions, variations, and renewals but not for the review of Traditional Herbal Registrations, Homoeopathic Registrations (Simplified Registration Scheme), and Homeopathic National Rules Authorisations (National Rules Scheme).

MHRA retains the ultimate authority to accept or reject applications submitted under the IRP. Until parts of the Windsor Framework related to medicines come into force in January 2025, products falling within the scope of the EU centralized procedure can only be authorized in Great Britain, which excludes Northern Ireland (1).

The IRP includes two routes for MAAs, Recognition A and B, which reduce the review authorization period from the current turnaround of 150 days to 60 or 110 days, respectively (

). To benefit from the Recognition A route, the same manufacturing process must apply to the product as that considered by the reference regulator (RR) (3).

Summary of Recognition A and B procedures. Where ATMP stands for Advanced therapy medicinal product; CHM for Commission on Human Medicines; MA for Marketing Authorisation; and RR for reference regulator.

In 2023, MHRA launched an Eligibility Checker tool to help drugmakers consider the new pathway (4). All applicants are required to submit their MAA six weeks before the planned submission date (5).

According to the Association of British Pharmaceutical Industry (ABPI) “the IRP is an additional flexibility for medicine developers, which may offer some added value for products approved in other jurisdictions” (5). Although the majority of products are likely to fall into Recognition B, which cuts current review time by 40 days, both pathways should lead the way for faster product approvals and patient access to innovative medicines.

In the meantime, the ABPI is asking for clearer guidance on MHRA’s regulatory flexibilities and the impact of the IRP, on market and patient access, the Innovative Licensing and Access Pathway (ILAP), and the Early Access to Medicines Scheme (EAMS), citing clinical trials in the UK and seeking scientific advice (6,7). Future clarification of this regulation will enable the industry to optimize its drug development programmes and ensure they select the right procedure at the right time for the right product. Companies will need to consider which products fall under which route to maximize the new fast‑track system.

The new IRP should enhance the attractiveness of launching products in the UK

According to Natalie Coan of Pinsent Masons, a specialist in life sciences regulation, “the IRP should enhance the attractiveness of the UK as a market for new medicines…” (3). The new IRP should help to streamline the pathway for pharmaceutical companies and encourage them to launch products earlier in the UK following approval overseas.

1. MHRA. International Recognition Procedure. 

, 5 Jan. 2024.
2. Nauth, L.; Worden, T. UK’s Medicines Regulator Announces Guidance on the New International Recognition Procedure for the Approval of New Medicines from 1 January 2024. 

, 15 Sep. 2023.
3. Coan, N. UK International Recognition Procedure Promotes Faster Access to New Medicines. Pinsent Masons, 

, 20 Oct. 2023.
4. MHRA. International Recognition Procedure Eligibility Checker. 

, Accessed 16 Jan. 2024.
5. O’Connor, D. MHRA’s New International Recognition Procedure (IRP): How Does it Shape Up? 

, Blog Post. 12 Sep. 2023.
6. MHRA. Innovative Licensing and Access Pathway. 

, published 30 Mar. 2021, last updated 27 Jan. 2023.
7. MHRA. Apply for the Early Access to Medicines Scheme (EAMS). 

, published 18 Dec. 2014, last updated 18 April 2023.


Vol. 36, No. 2
February 2024
Pages: 7–8

When referring to this article, please cite it as Barton, C. MHRA’s New International Recognition Procedure. 

The UK’s IRP increases flexibility and will help speed up product approvals and patient access to medicines.

MHRA’s New International Recognition Procedure

Belgium-based Orionis Biosciences is a clinical-stage life science company developing conditionally acting medicines for cancer and other diseases. Its pipeline includes molecular glue drug modalities and targeted cytokine immunotherapies. Its proprietary allosteric molecular glues, Allo-Glues, are monovalent molecules that can target protein degradation (TPD) modulation, by inhibiting or promoting intracellular signals. Orionis’ agnostic Allo-Glues can be used to target proteins in hard-to-treat diseases, such as oncology and organ transplant rejection (1).

Molecular glues were first discovered in plants such as Arabidopsis thalian where they were found to stick proteins together (1). In 1971, researchers at Sandoz observed that Sandimmune could induce neo-protein-protein associations and impact protein degradation, and in 1983 Astellas (formerly Fujisawa) identified tacrolimus (FK506). Both agents have since been approved for use in patients to prevent organ transplant rejection (2).

Today, the most widely used molecular glues are monovalent small molecules (<500 Da) that bind to the surface of an E3 ligase receptor or DCAF15 to modulate protein degradation via the proteasome (3). However, biopharma companies have been actively screening for agents that can TPD and several classes have emerged including natural glues (e.g., FKBp12 F36V, FKBP12 PK1012, Rapamycin, Synstab A, Taxol), synthetic bifunctional glues (e.g., DDB1 Cereblon CK1a, Lenalidomide, Indisulam, Thalidomide), as well as novel proteolysis-targeting chimera (PROTAC) glues (e.g., ARV-110) and tacrolimus analogues (e.g., CEP250 FKBP12 and WD8002) (3,4).

Several molecular glues—Sandimmune, Tacrolimus, Sirolimus, Thalidomide, lenalidomide, Taxotere—have already demonstrated good immunosuppressive efficacy and tolerability in solid tumours and as gene therapies for acute leukaemia (3,5).

Orionis has several Allo-Glue programmes that focus on cancer and immunology targets, and and initiated a Phase I trial in November 2023 with its lead candidate, ORB‑011, a cis-targeted interferon for the treatment of patients with advanced solid tumours (6).

Big Pharma, including Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Merck & Co, and Novartis, have molecular glue programmes in development and forged collaborations with leaders in this field (

). For example, Orionis Biosciences has forged partnerships with Novartis and Genentech (7,8), and Austrian-based Proxygen has initiated collaborations with Merck & Co./MSD and Boehringer Ingelheim in multiple targets (9,10). In the United States, Nurix Therapeutics has teamed up with Seagen to combine TPD and antibody-drug conjugation (ADC) in cancer therapeutics (11).

Companies leading the field in molecular glues.

Competition is intensifying, and several Chinese and US biopharma companies are also working in this field and have products in preclinical and early clinical development. These include:

China-based Degron Therapeutics has raised US$34.5 million (€31.5 million) in venture capital and has more than 20 projects of unique molecular glue degraders (MGDs) targeting IKZF1 and IKZF3 using its proprietary GlueXplorer platform. The company expects to file an investigational new drug (IND) in 2024 for its lead programme.

US-based C4 Therapeutics (a spin-out from the Dana-Farber Cancer Institute) has developed its proprietary TORPEDO platform and developed MonoDAC and BiDAC degraders. Its lead candidate CFT7455 is currently in a Phase I/II clinical trial for the treatment of multiple myeloma and non-Hodgkin’s lymphomas. In 2021, CFT7455 received an orphan drug designation from the US Food and Drug Administration (FDA) for multiple myeloma (13).

US-based Nurix Therapeutics is developing a Bruton Tyrosine Kinase (BTK) degrader, NX-5948 and NX-2129 in haematological cancer. Nurix has built DELigase, an integrated discovery platform to identify and advance novel drug candidates that can modulate proteins within the cell.

US-based Seed Therapeutics plans to file an IND in the US in 2024 for RBM30 in oncology and has several other agents in preclinical development that target neurodegeneration, immunology, and antivirals and has established an R&D collaboration with Eli Lily (14).

US-based BioTheryx in May 2023 presented new data on bifunctional degraders of CDK4/6 and SOS1 degraders. BTX-9341 for HER.

US-based Magnet Biomedicine is applying its proprietary TrueGlue technology to discover new indication-agnostic treatments and has attracted US$50 million (€46 million) Series A funding to move its pipeline forward.

US-based Monte Rosa Therapeutics has developed the QuEEN (Quantitative and Engineered Elimination of Neosubstances) targeting degrons on the surface of therapeutically relevant proteins that act as ubiquitin ligase recognition signals.

US-based Triana Biomedicines identifying novel E3 ligases. In January 2023, it was named the most promising new company in BioSpace’s NextGen 2023.

TPD using molecular glues has proven to be a powerful method for targeting traditionally undruggable proteins (15). Several molecular glues have received regulatory approval and many more are under clinical evaluation for a multitude of disease targets (14,16). Big Pharma have invested in this area, and biotech start-ups have attracted investor attention. Over the next few years, molecular advances in artificial intelligence and genetic tools will help drive the discovery and validation of novel bifunctional agents that could change the way pharma modulates protein interactions. Until then, pharma and private investors will have to wait patiently to see if Orionis Biosciences and its Chinese, European, and US-competitors can overcome the off-target effects of first-generation therapies and provide a more targeted approach to protein degradation and generate small-molecule proximity-inducing reagents, such as PROTACs and other unique molecular glues to treat cancers and other diseases (17,18).

1. Orionis Bioscience. Engaging the Powers of Nature with Precision Drug Design. 

, Accessed 7 Dec. 2023.
2. Schreiber, S.L. The Rise of Molecular Glues. 

; 184(1):3–9.
3. Alabi, S. Novel Mechanisms of Molecular Glue-Induced Protein Degradation 

; 60(31):2371–2373.
4. Di Stasi, A.; Tey, S.-K.; Dotti, G.; et al. Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy. 

; 365:1673–1683.
5. Békés, M.; Langley, D.R.; Crews, C.M. PROTAC Targeted Protein Degraders: The Past is Prologue. 

; 21:181–200.
6. Orionis Bioscience. Orionis Bioscience, Announces First Patient Dosed in Phase 1 Clinical Trial of ORB-011 in Patients with Advanced Solid Tumors. News release, 15 Nov. 2023.
7. Orionis Bioscience. Genentech Sticks Molecular Glue Deal with Orionis for $47M Upfront. News release, 10 Sept. 2023.
8. Orionis Bioscience. Novartis-Partnered Orionis Secures $55M to Push Cytokine Program into the Clinic. News release, 19 Oct. 2022.
9. Proxygen. Proxygen Announces Collaboration and License Agreements with MSD. News release, 5 April 2023.
10. Proxygen. Boehringer Ingelheim Collaborates with Proxygene. News release, 7 Dec. 2020
11. Nurix Therapeutics. Nurix Announces Strategic Collaboration with Seagen Combining Industry Leading Technologies of Targeted Protein Degradation and Antibody-Drug Conjugation to Advance an Innovative New Class of Cancer Therapeutics. News release, 7 Sept 2023.
12. Sasso, J. ACS Webinar on Molecular Glues and Targeted Protein Degradation. Webinar, 12 Oct. 2022
13. C4 Therapeutics. C4 Therapeutics Announces FDA Orphan Drug Designation for CFT7455 for the Treatment of Multiple Myeloma. News release. 11 Aug. 2021.
14. Seed Therapeutics. Pipeline. SeedTherapeutics.com, Accessed 7 Dec. 2023.
15. Fan, A.T.; Boyle, B.T.; Ferguson, F.M. A New Avenue for Molecular Glues: Rapid Discovery of an NFKB1 Degrader. 

;30(4):340–342.
16. Dewey, J.A.; Delalande, C.; Azizi, S.-A.; et al. Molecular Glue Discovery: Current and Future Approaches. 

;66(14):9278–9296.
17. Sternicki, L.M.; Poulsen, S.A. Native Mass Spectrometry: Insights and Opportunities for Targeted Protein Degradation. 

. doi: 10.1021/acs.analchem.3c03853.
18. Zhang, D.; Lin, P.; Lin, J. Molecular Glues Targeting GSPT1 in Cancers: A Potent Therapy 


Vol. 35, No. 9
September 2023
Pages: 18–19, 22

When referring to this article, please cite it as Barton, C. Harnessing the Power of Oncolytic Viruses. 

Novel molecular glues are transforming targeted protein degradation.

Frontrunners in Molecular Glues

In May 2022, the European Commission (EC) proposed the introduction of a European Health Data Space (EHDS) to improve health democratization in Europe and develop a national infrastructure for health data management, exchange, and sharing (1). Creating a common EHDS was one of the priorities of the EC during 2019–2025, and the proposal builds on the European digital strategy for data, COM(2020) 66 (2), and enables the EC to meet its goals to improve public health, reduce health inequalities, and move towards a more social Europe (3).

EHDS seeks to streamline data access and sharing in the EU

On 13 Dec. 2023, the European Parliament (EP) adopted its position on creating EHDS with 516 votes in favour, 95 against, and 20 abstentions (4). Each country would establish national health data access services based on the MyHealth@EU platform. The law would also set out rules on the quality and security of data for providers of Electronic Health Records (EHR) systems in the European Union, to be monitored by national market surveillance authorities (4). Health data, including EHRs, electronic prescriptions, laboratory results, hospital discharge reports, and patient summaries, would be made available in a common format that could be shared with healthcare professionals and the patient both within and between European countries (5).

The EHDS seeks to address health-specific challenges regarding data access and sharing, which include:

creating rules for making EHR systems available on the EU market

empowering patients with new rights to control their electronic health data in the context of healthcare

establishing mandatory cross-border infrastructure enabling the use of electronic health data across the EU for the primary use purpose of providing health services

introducing obligations on ‘data holders’ to make electronic health data available to third parties, including public sector bodies, for ‘secondary use’, and set out rules and mechanisms to support this (5).

According to the EC, “Citizens should be empowered to make better decisions based on insights gleaned from non-personal data. And that data should be available to all—whether public or private, big or small, start-up or giant. This will help society to get the most out of innovation and competition and ensure that everyone benefits from a digital dividend” (2).

Implication of the EHDS on the pharma industry

The EHDS would enable pharma to gain access to a broader pool of quality data for R&D purposes (5). It should also help to standardize data and would mean that, within the EU, pharma companies would only have to comply with a single set of rules regarding data usage and privacy rather than dealing with multiple sets of regulations. This is important as the current General Data Protection Regulation (GDPR) is unevenly applied and open to interpretation within member states and has created uncertainty and challenges around access and resulted in barriers to the “secondary use of electronic health data” (6).

One key feature of the EHDS that could have a far-reaching impact on the pharmaceutical sector is the proposal to expand the availability of electronic health data for secondary use, such as R&D activities (6). “Data holders”, which include the pharmaceutical, healthcare, and MedTech sectors, may be compelled to allow access to certain categories of data (e.g., health registries and clinical trials). However, access to these data would only be granted where the intended purpose for processing satisfies Article 34(1) of the Proposal, which includes the following criteria:

activities relating to public interest, development, and innovation activities in/contributing to the area of public and occupational health

educational, teaching activities, and scientific research related to health or the care sector

providing personalized healthcare consisting in assessing, maintaining, or restoring the state of health of individuals

ensuring high levels of quality and safety of health care, medicinal products, or devices

testing, training, and evaluating algorithms, including artificial intelligence (AI) systems, digital health applications, and medical devices, contributing to public health or social security (7).

Secondary use of health data would require the data “re-user” to submit an access application, which would then be assessed and permission granted by the competent Health Data Access Bodies (HDAB). Any fees charged by the data holder would have to be transparent, proportionate, and “must not restrict competition.” Where access to data is granted, it must be transferred in an anonymized format unless the applicant’s purpose cannot be achieved by processing anonymized data, in which case pseudonymized data may be provided (7).

The lack of clarity over the protection of data that pharma generates has caused significant uncertainty and is an area that will need to be addressed to ensure the EHDS does not stifle innovation and investment in medical research (6).

The EHDS aims to increase access to health data, but how will it impact pharma?