Overcoming Barriers to Delivering Large Molecules to the Brain

Episode Summary

Executive Summary: The episode examines Alieta Therapeutics’ approach to overcoming the blood-brain barrier with its MODEL platform, which can attach small delivery modules to large biologics like antibodies. CSO John Dunlap explains the science behind the platform, the company’s Janssen/J&J origins, and lead Alzheimer’s asset ALIA-1758, as well as the rationale for biomarker-driven trials, partnering, and future pipeline expansion.

Main Topics: The blood-brain barrier as the central CNS drug-delivery obstacle: Dunlap explains how the barrier protects the brain while also blocking many therapeutics, especially large biologics, from reaching CNS targets. Alieta’s MODEL platform and modular delivery strategy: The company’s platform uses small protein delivery modules to hijack normal nutrient transport mechanisms and ferry large cargo molecules across the blood-brain barrier. Origins of the technology at Janssen and company formation: The platform was developed inside Janssen, and Alieta emerged after discussions with JJDC and scientific founders to build a company focused solely on the technology. Alzheimer’s disease biology, diagnosis, and treatment gap: The conversation outlines amyloid pathology, the long preclinical phase, limited current treatment options, and why better CNS delivery could improve outcomes. ALIA-1758 lead program and early clinical strategy: Dunlap describes ALIA-1758 as a bispecific antibody targeting pyroglutamate amyloid beta, enhanced by MODEL to improve brain exposure, with a first-in-human study imminent. Biomarkers, endpoints, and patient selection in trials: The trial will rely on amyloid imaging and blood markers to enroll patients more likely to truly have Alzheimer’s pathology, with safety and PK as initial endpoints. Partnering and pipeline expansion beyond antibodies: Alieta is looking at collaborations across antibodies, oligonucleotides, enzymes, peptides, and other proteins, while remaining capital-aware.

Key Arguments: The blood-brain barrier is the key limiting factor in developing effective therapies for brain diseases because it tightly regulates what enters and exits the brain. Large molecules and biologics have transformative potential in CNS disease, but they have historically been difficult to deliver across the blood-brain barrier. Alieta’s MODEL platform is differentiated because it can be attached to essentially any antibody or large biologic without altering the cargo’s core function. Alzheimer’s patients benefit from better-targeted therapies, but disease progression begins years before symptoms, making early diagnosis and biomarker-based enrollment critical. Prior clinical failures were partly driven by poor diagnostic certainty; modern amyloid imaging improves trial design and confidence in patient selection. ALIA-1758 is designed to bind pyroglutamate amyloid beta, an especially aggregation-prone form of amyloid, and MODEL should increase brain concentration versus non-enabled antibodies. The first clinical study is intended primarily to establish safety, tolerability, CSF exposure, and pharmacokinetics before advancing further in Alzheimer’s patients. Alieta sees broader platform potential in oligonucleotides, enzymes, peptides, and partner-owned antibodies where delivery is the main bottleneck.

Data Points: Estimated U.S. Alzheimer’s prevalence: around 7 million individuals - Dunlap cites the number of people currently living with Alzheimer’s disease in the United States. Trial timing: second quarter of 2024 - Alieta said it was on target to start the first clinical trial for ALIA-1758 in Q2 2024. Preclinical pathology timing: a couple of decades - Amyloid pathology may begin this long before the first clinical signs of memory impairment. Initial study focus: safety, tolerability, CSF exposure, and pharmacokinetics - These are the main endpoints/objectives of the early ALIA-1758 clinical trial. Funding runway: next 12 to 18 months - Dunlap says the company is currently well funded to advance planned studies over this period. Company status: clinical stage company - Alieta expects to become a clinical-stage company with the initiation of its trial.

Pivotal Quotes: "The blood-brain barrier is a specialized set of cells that really prevent toxic material from getting into the brain and have procedures for how they allow essential nutrients to get into the brain." — John Dunlap: Definition of the barrier and why it matters for CNS drug delivery. "We can actually alter essentially any antibody or large molecule biologic cargo because the protein delivery modules are very small." — John Dunlap: Why MODEL is flexible and broadly applicable across biologic cargos. "There are some medications that provide modest symptomatic benefit to patients, but I would emphasize that's very modest." — John Dunlap: Assessment of the current treatment landscape for Alzheimer’s disease.

Implications: If successful, Alieta’s platform could materially expand what types of biologics can treat brain diseases, improve Alzheimer’s trial success rates, and create partnering opportunities across multiple CNS modalities.