Frontrunners in CNS Drug Delivery

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 (Table I [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 Aducanumab has also been withdrawn from the US market as a result of low uptake and payor challenges.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).

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.

Drug delivery to the CNS

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) (Figure 1). 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.

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:

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

VectorY’s lead programmes include:

• VTx-002—VecTab vectorized antibody programme targeting TDP-43 for the treatment of amyotrophic lateral sclerosis (ALS)
• VTx-003—VecTab/VecTron vectorized antibody targeting misfolded and aggregated huntingtin (HTT) proteins for the treatment of Huntington’s disease (HD)
• VTx-004—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.

References

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. Am J Epidemiol. 2022, 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. Health Psychol Res. 2022, 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. Nat. Rev. Mater. 2022, 7, 314–331.
7. Wu, D.; Chen, Q.; Chen, X.; et al. The Blood-Brain Barrier: Structure, Regulation, and Drug Delivery. Sig. Transduct. Target Ther. 2023, 8, 217.
8. Terstappen, G.C.; Meyer, A.H.; Bell, R.D.; et al. Strategies for Delivering Therapeutics Across the Blood-Brain Barrier. Nat. Rev. Drug Discov. 2021, 20, 362–383.
9. Sheridan, C. Drugs Catch a Ride Through the Blood-Brain Barrier. Nat. Biotechnol. 2023, 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.

About the author

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

Article details

Pharmaceutical Technology Europe
Vol. 36, No. 5
May 2024
Pages: 15–19

Citation

When referring to this article, please cite it as Barton, C. Frontrunners in CNS Drug Delivery. Pharmaceutical Technology Europe, 2024, 36 (5), 15–19.