modag

modag GmbH

Overview

modag GmbH

Overview

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["@modag"][@bayer2024].

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["@Weber2022"][@lorenz2022].

Company Overview

| Attribute | Value |
|-----------|-------|
| Founded | 2016 |
| Headquarters | Bonn, Germany |
| CEO | Dr. Johannes B. (information based on founding team) |
| Focus | Alpha-synuclein aggregation inhibitors |
| Stage | Clinical (Phase 1b completed) |
| Investors | Bayern Kapital, High-Tech Gründerfonds, Michael J. Fox Foundation |

Scientific Rationale

Alpha-Synuclein Pathophysiology

Alpha-synuclein is a 140-amino acid protein encoded by the [SNCA](/genes/snca) gene, predominantly expressed in presynaptic terminals of [neurons](/entities/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[@lothar2021][@spillantini1997].

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

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](/mechanisms/neuroinflammation) Disruption of synaptic function[@polymeropoulos1997][@sulzer1997]

The Tetramer Hypothesis

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

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[@birmingham2022][@hermann2023].

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:

| Model | Finding | Reference |
|-------|---------|------------|
| AAV-α-syn rat model | Reduced motor deficits and decreased oligomer levels | [@masella2020] |
| Mouse α-syn transgenic model | Improved survival and reduced aggregation | [@Weber2022] |
| Cell-free aggregation assays | Direct inhibition of oligomer formation | [@maharjan2024] |
| Pharmacokinetics | Favorable brain penetration in rodents and non-human primates | [@lorenz2022] |

Clinical Development

| Trial | Phase | Status | Reference |
|-------|-------|--------|-----------|
| First-in-human | Phase 1 | Completed | [@schulz2022] |
| Multiple ascending dose | Phase 1a | Completed | Company data |
| Proof-of-concept | Phase 1b | Completed | Company data |
| MSA trial (LARYSSA) | Phase 2 | Planned/Recruiting | [@klingenstein2024] |

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[@klingenstein2024]. MSA is a particularly aggressive synucleinopathy characterized by:

• Autonomic failure
• Cerebellar ataxia
• Parkinsonism
• Rapid progression

• 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[@braithwaite2022].

Competitive Landscape

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

| Company | Compound | Mechanism | Stage |
|---------|----------|-----------|-------|
| modag | Anle138b | Oligomer inhibitor | Phase 1b |
| Roche/Prothelia | Prasinezumab | Antibody | Phase 2 |
| Biogen | BIIB054 | Antibody | Phase 2 |
| BioArctic | BAN0805 | Antibody | Phase 1 |
| Denali | DNL151 | LRRK2 inhibitor | Phase 1 |

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:

References

Pathway Diagram

The following diagram shows the key molecular relationships involving modag discovered through SciDEX knowledge graph analysis: