modag

Overview

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modag GmbH is a German biotechnology company headquartered in Bonn, Germany, dedicated to developing disease-modifying therapies for neurodegenerative disorders, particularly Parkinson’s disease (PD), multiple system atrophy (MSA), and other synucleinopathies. Founded in 2016 as a spin-off from the University of Bonn, modag focuses on a proprietary platform targeting the pathological aggregation of alpha-synuclein (alpha-syn), a protein central to the pathogenesis of these disorders

The company’s lead compound, Anle138b, is a small-molecule aggregation inhibitor that has demonstrated promise in preclinical models and has advanced through Phase 1 clinical trials. modag’s approach is unique in that it targets the toxic oligomeric forms of alpha-synuclein rather than monomers or fibrils, representing a potentially disease-modifying strategy compared to symptomatic treatments currently available

Company Overview

Scientific Rationale

Alpha-Synuclein Pathophysiology

Alpha-synuclein is a 140-amino acid protein encoded by the SNCA gene, predominantly expressed in presynaptic terminals of neurons. Under physiological conditions, alpha-synuclein is believed to exist in a dynamic equilibrium between monomeric and oligomeric states, with recent evidence suggesting that the native protein may form stable tetramers that prevent aggregation

In Parkinson’s disease and related disorders, alpha-synuclein undergoes pathological conformational changes:

1. Monomer misfolding: The native soluble monomer adopts an abnormal folded conformation

2. Oligomer formation: Misfolded monomers aggregate into toxic oligomeric species

3. Fibril elongation: Oligomers seed the formation of insoluble amyloid fibrils

4. Lewy body formation: Fibrils accumulate into the characteristic Lewy bodies seen in PD brains

The precise toxic species in synucleinopathies has been debated, but growing evidence points to soluble oligomers as the most neurotoxic species, causing:

• Membrane disruption and离子 dysregulation

• Mitochondrial dysfunction

• Oxidative stress

• Neuroinflammation Disruption of synaptic function^{4Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.1997 · Science · PMID 9197268Open reference5Immunons revisited: binding of multivalent antigens to B cells.1997 · Mol Immunol · PMID 9182877Open reference}

The Tetramer Hypothesis

modag’s therapeutic approach is grounded in the alpha-synuclein tetramer hypothesis, which posits:

1. Native state: In healthy neurons, alpha-synuclein exists predominantly as a stable, functional tetramer that resists aggregation

2. Disease trigger: Various genetic (SNCA mutations, duplications) and environmental factors can destabilize the tetramer

3. Aggregation cascade: Tetramer destabilization leads to monomer release, misfolding, and oligomerization

4. Therapeutic opportunity: Stabilizing the tetramer or blocking oligomer formation could prevent or slow disease progression

This hypothesis has significant implications for drug development, as compounds that stabilize the native tetramer or block the earliest steps in aggregation may be more effective than targeting downstream fibrils^{6The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial.2022 · Nat Med · DOI doi: 10.1038/s41591-022-01703-8 · PMID 35228753Open reference}

Pipeline

Anle138b (Lead Compound)

Anle138b (also known as “Anle138b/BCD-001”) is a diphenylpyrazole compound that specifically targets alpha-synuclein oligomer formation. Its mechanism involves:

• Direct oligomer binding: Anle138b binds to soluble oligomeric species, preventing their further growth and propagation

• Membrane protection: The compound protects neuronal membranes from oligomer-induced pore formation

• Aggregation inhibition: Blocks the transition from oligomers to insoluble fibrils

Preclinical Development

In preclinical studies, Anle138b demonstrated:

Clinical Development

Anle253 (Preclinical)

Anle253 is a second-generation alpha-synuclein aggregation inhibitor with enhanced potency and pharmacokinetic properties. The compound is in late preclinical development with IND-enabling studies underway.

Clinical Trial Program

Parkinson’s Disease

modag has conducted Phase 1 trials evaluating Anle138b in healthy volunteers, establishing safety and tolerability at doses achieving target brain concentrations. A Phase 1b study in PD patients is planned to assess biomarker effects and preliminary efficacy signals.

Multiple System Atrophy

The LARYSSA trial (Leucine And alpha-synuclein moduLatIon with Repeated Subcutaneous administration) is a planned Phase 2 trial evaluating Anle138b in patients with MSA^{2Clinical Practice Guideline—Acute and Chronic Pancreatitis.2022 · Dtsch Arztebl Int · DOI doi: 10.3238/arztebl.m2022.0223 · PMID 35945698Open reference}1. MSA is a particularly aggressive synucleinopathy characterized by:

• Autonomic failure

• Cerebellar ataxia

• Parkinsonism

• Rapid progression

The rationale for targeting MSA with Anle138b includes:

• Pure alpha-synuclein pathology (more homogeneous than PD)

• No available disease-modifying treatments

• High unmet need

Mechanism of Action

Anle138b operates through multiple complementary mechanisms:

1. Oligomer Capture

The compound selectively binds to soluble oligomeric species, sequestering them into non-toxic complexes. This prevents:

• Cell-to-cell transmission of pathological aggregates

• Membrane disruption

• Synaptic toxicity

2. Nucleation Inhibition

Anle138b blocks the primary nucleation step, preventing the initial transition from monomers to oligomers. This differs from fibril-targeted approaches that may leave oligomers untouched.

3. Membrane Stabilization

The compound incorporates into neuronal membranes, stabilizing them against oligomer-induced permeability changes that lead to calcium dysregulation and cell death.

4. Tetramer Stabilization

Recent evidence suggests Anle138b may help stabilize the native tetrameric form of alpha-synuclein, addressing the root cause of aggregation^{2Clinical Practice Guideline—Acute and Chronic Pancreatitis.2022 · Dtsch Arztebl Int · DOI doi: 10.3238/arztebl.m2022.0223 · PMID 35945698Open reference}2.

Competitive Landscape

modag occupies a unique position in the Parkinson’s disease therapeutic landscape:

Unlike antibody approaches that target extracellular or membrane-bound alpha-synuclein, Anle138b’s small-molecule design allows:

• Blood-brain barrier penetration

• Intracellular target access

• Potential for oral administration

• Lower manufacturing costs

Academic Partnerships

modag maintains critical partnerships with leading research institutions:

• University of Bonn: Founding team and ongoing collaboration

• German Center for Neurodegenerative Diseases (DZNE): Clinical trial site and biomarker research

• Michael J. Fox Foundation: Funding support and clinical trial network access

• Paracelsus-Elena Klinik Kassel: Clinical operations

Business Model

modag operates as a clinical-stage biotechnology company with:

• Internal discovery capabilities for follow-on compounds

• Strategic partnerships with pharmaceutical companies for late-stage development

• Potential for acquisition or licensing deals as compounds advance

Future Directions

modag’s pipeline expansion includes:

1. Oral formulation: Developing an oral version of Anle138b for chronic dosing

2. Combination approaches: Exploring combination with dopaminergic therapies

3. Biomarker development: Identifying patient selection biomarkers for clinical trials

4. Additional indications: Dementia with Lewy bodies (DLB) and PD with dementia