Attillaps Pharmaceuticals · Dermatology & Ophthalmology

The AChM Platform Acetylcholine Modulators that kill Demodex

Targeting the unified biological driver of rosacea, blepharitis, and the cutaneous autoimmune spectrum.

100+Assay Runs

>7,000Mites Tested

10+Lethal Compounds

>1,000Molecules Screened

Section 1

The Demodex–Immune Dysregulation Spectrum

One parasite. Multiple antigens. A spectrum of inflammatory disease from rosacea to lupus — and a 70-year mystery finally explained.

Every adult human carries Demodex mites. DNA-based detection finds them on 100% of adults over 18. For most people the immune system silently tolerates them. But for millions of patients, a breakdown in immune regulation allows the mite’s primary structural component — chitin — to trigger a chronic inflammatory cascade. What medicine calls “rosacea,” “cutaneous lupus,” or “blepharitis” may all be expressions of the same immunological event at different severity levels.

✓

Tolerance

No symptoms · Most adults

→

Rosacea

Facial flushing, papulopustules

→

Blepharitis

Eyelid mite infestation

→

Lupus

Cutaneous & systemic

→

Autoimmune

Full spectrum · RA · Sjögren’s

Same root cause — Demodex antigen hypersensitivity — expressed at increasing immune dysfunction severity

The Demodex Immune Cascade

Each link in this chain is independently confirmed in published literature. This is not a hypothesis about the cascade — it is a hypothesis about what HCQ is actually interrupting.

Demodex sheds chitin continuously into the pilosebaceous unit

Chitin is absent from all mammalian tissue and mite allergens are among the most important worldwide inducers of allergic disease — released during mite molting, feeding, and decomposition. When mites die, gut contents including bacterial antigens are released directly into the follicle.

Chitin activates TLR-2 on keratinocytes

Chitin acts as a PAMP (pathogen-associated molecular pattern), binding TLR-2 and triggering NF-κB activation. TLR-2 expression is markedly elevated in rosacea and lupus skin.

TLR-2 drives the full cytokine cascade

IL-17, IL-23, TNF-α, IL-1β, KLK5, and LL-37 production cascade. Mast cell degranulation, neutrophil recruitment, NLRP3 inflammasome activation, and angiogenesis follow — the full inflammatory architecture of rosacea and cutaneous lupus.

Kill the mite → chitin and associated bacterial antigens load collapses → all downstream signals fall

When the mite population is eliminated, chitin shedding ceases. TLR-2 ligand load drops to zero. IL-17, TNF-α, ANA production, and Th17 skewing resolve — not because immune cells were suppressed, but because they no longer have anything to react to.

Is Rosacea a Systemic Autoimmune Disease?

The Venn diagram below illustrates the substantial overlap between rosacea and lupus — sharing cytokines, immune pathways, and critically, the same treatments. The two conditions differ not in kind but in severity, consistent with a single shared driver: Demodex-mediated chitin immune dysregulation expressed at different points on the spectrum.

Figure 1 — Etiopathogenesis and Related Clinical Findings of Rosacea and Lupus

Figure 1. Etiopathogenesis and Related Clinical Findings of Rosacea and Lupus. The Venn diagram illustrates the substantial overlap between rosacea (left) and lupus (right), with Demodex proposed as the central unifying driver. Overlapping features include inflammation in the T and U zones, ocular involvement, upregulated ANA titers, innate immune dysregulation, PDC and neutrophil activation, TLR signaling, and shared cytokines (IL-1, IL-6, IL-17, TNF-α, TGF-β, INF-α). Overlapping treatments — anti-parasitic drugs (hydroxychloroquine) and energy devices (PDL, IPL) known to kill Demodex — further support the unified etiology. Rosacea-only features (red box) represent localized cutaneous/ocular inflammation; lupus-only features (green box) represent systemic organ involvement — consistent with differing severity of the same Demodex chitin-driven immune dysregulation spectrum. Adapted from Dursun et al. Dermatologic Therapy 2020.

The 70-Year Mystery Explained

Hydroxychloroquine has been used to treat lupus, RA, and 8+ autoimmune diseases for 70 years with no definitive mechanistic explanation. Attillaps proposes the answer: HCQ kills Demodex in the pilosebaceous unit using the same anti-parasitic mechanism it uses against Plasmodium. The immunological effects attributed to HCQ are not primary drug actions — they are downstream readouts of an immune system that no longer has a parasite driving its activation.

Section 2

Hydroxychloroquine: The Established Standard of Care

HCQ is not a competitor to the AChM platform — it is the proof-of-concept reference compound and the current standard of care.

Ex Vivo Kill Data: Chloroquine 10% Kaplan-Meier Survival Analysis

Attillaps has confirmed statistically significant chloroquine miticidal activity against Demodex in standardised ex vivo LT50 assays. Chloroquine diphosphate is the validated aqueous surrogate for HCQ in water-based assay conditions, by virtue of structural equivalence: the two compounds are congeners differing by a single hydroxyl substituent on the ethyl side chain, conferring shared pharmacological mechanisms. The basis for surrogate selection is structural and mechanistic, not solubility-driven — the hydroxyl group in HCQ increases rather than decreases aqueous solubility relative to chloroquine. Permutation testing on the primary LT50 endpoint confirms the treatment effect at p = 0.0012.

Figure 2 — Chloroquine 10% Kaplan-Meier Survival Analysis

Figure 2. Kaplan-Meier survival analysis. Orange: chloroquine-treated mites. Blue: water vehicle control. Shaded bands: 95% confidence intervals. Attillaps internal ex vivo assay data, N > 50 mites per arm.

Key Findings

Primary outcome: 1,896 min vs. 2,688 min LT50Chloroquine 10% reached LT50 at 1,896 minutes (31.6 hours) versus 2,688 minutes (44.8 hours) for the vehicle — a 792-minute acceleration and 1.42× LT50 ratio. Permutation test p = 0.0012 (100,000 iterations).

Early divergence at 111–125 minFive chloroquine-treated mites died before any vehicle death occurred (first vehicle death at 267 min). Fisher’s exact test at 250 minutes: p = 0.0036. Consistent with ion-trap accumulation kinetics reaching lethal intracellular threshold.

Progressive step-wise mortality gradientCharacteristic of multi-mechanism kill — lysosomotropic disruption, mitochondrial depolarization, and autophagy inhibition each activate at different thresholds over time. Peak kill rate (17.9%) at 500–1,000 minutes. No plateau.

Sustained activity through 31.6-hour observation windowIrreversible mechanism — no recovery, tolerance, or plateau observed. Mean death time 7.0 hours faster in the chloroquine arm (893 vs. 1,315 min; Welch’s t-test p = 0.0045).

Consistent curve separation throughout observationChloroquine survival tracks below vehicle at every measured timepoint. Survival gap widens progressively from +5.4 percentage points at 500 minutes to +13.4 percentage points at the 1,896-minute endpoint.

Four independent tests confirm treatment effect at p < 0.01Permutation test on LT50 (p = 0.0012) · Mann-Whitney U on death-time distributions (p = 0.0095) · Welch’s t-test on mean death times (p = 0.0045) · Fisher’s exact at 250 min (p = 0.0036).

Conservative Lower Bound

The water-based assay has no lipid partitioning or follicular depot effect. Chloroquine’s lipophilicity (logP ≈ 4.6) predicts preferential partitioning into follicular sebum, concentrating the effective mite-surface dose well above the nominal 10% applied concentration. The in vitro LT50 of 1,896 minutes is a conservative floor — the true in vivo LT50 in a sebum-formulated preparation would be expected to be substantially shorter.

HCQ vs. AH-300 (AChM Platform) — Head-to-Head Comparison

Parameter	Hydroxychloroquine (HCQ) — Systemic Standard	AH-300 (AChM) — Attillaps Platform
Molecular Weight	Note335.9 Da — Below 500 Da rule	Advantage<500 Da — Full follicular penetration
Kill Mechanism	SingleLysosomal pH disruption — anti-parasitic · systemic delivery only	Multi-targetMultiple cholinergic pathways · confirmed contact kill
Direct Contact Kill	IndirectConfirmed ex vivo — but only via slow systemic depot	LT50 <12 hrsAll compounds confirmed · rapid contact activity
Sebum Drug Level	SlowBuilds over weeks — depot-dependent, months to therapeutic sebum levels	ImmediateTopical application delivers drug directly to site of action
Resistance Risk	LowSingle mechanism — decades of use, no known Demodex resistance	Very LowMultiple independent neuro-targets
Route of Administration	Oral onlyRetinal toxicity risk with long-term use	TopicalNo systemic exposure · known safety via 505(b)(2) path
Indications	Lupus · RA · Malaria — off-label for some autoimmune, not approved for rosacea/blepharitis	Full SpectrumRosacea · Lupus · Blepharitis · Acne · RA · Full DCIDS

Clinical Development Framework

Patients with SLE, RA, and autoimmune conditions are already receiving HCQ as standard of care. Attillaps clinical studies will evaluate AChM compounds added to standard HCQ therapy — measuring whether topical Demodex eradication at the primary site of antigen production produces incremental immunological normalization over and above what systemic HCQ alone achieves.

Section 3

The Downstream Measurement Hypothesis

A reframing of 70 years of HCQ mechanistic research — and why it matters for the entire autoimmune therapeutic landscape.

Central Hypothesis

The immunological effects attributed to hydroxychloroquine in autoimmune disease — TLR inhibition, reduced antigen presentation, suppressed cytokines, diminished ANA titers — are not primary pharmacological actions of the drug. They are downstream readouts of one upstream event: the elimination of Demodex mites and the removal of their chitin antigenic load. What the field has been measuring for 70 years is the immune system returning to baseline after the parasite driving its activation is killed.

The multiple-indication mystery

HCQ works in Cutaneous Lupus Erythematosus, DLE, SLE, RA, Sjögren’s, sarcoidosis, and 6+ more. No direct immunosuppressive mechanism explains this breadth. A single anti-parasitic mechanism does. Demodex moderates a neurimmune-microbiome axis that can drive inflammatory and immune mediated diseases.

The infection protection paradox

HCQ is a supposed immunosuppressant that paradoxically reduces infection rates. Eliminating a chronically immune-activating parasite — and reducing immune exhaustion — explains this precisely.

The TLR7/9 selectivity puzzle

HCQ’s TLR inhibition is selective for nucleic-acid-sensing TLR7/9. When mites die and release bacterial endosymbionts (B. oleronius, C. acnes), their DNA/RNA are potent TLR7/9 ligands — killing the mite eliminates both chitin (TLR2) and bacterial DNA (TLR7/9) loads simultaneously.

The slow-onset kinetics

HCQ takes 6–12 weeks for clinical effect — difficult to reconcile with rapid direct cell pharmacology but entirely consistent with sebum depot loading kinetics and 2–3 Demodex lifecycle cycles (18–24 days each) needed to collapse mite populations.

The critical scientific implication: If acaricidal action alone — without HCQ’s lysosomal chemistry — produces equivalent immunological normalisation, then the AH-300 AChM series provides the ideal experimental instrument to test this hypothesis. Compounds with confirmed Demodex kill activity and no direct immune cell pharmacology would distinguish the two models definitively.

Section 4

Platform Advantages

The AChM platform is the first integrated IP estate targeting the root cause of Demodex-driven inflammatory disease across dermatology, ophthalmology, and rheumatology.

⊕

Sub-500 Da Follicular Penetration

All AChM candidates comply with Lipinski’s 500 Da rule, reaching Demodex deep in the follicular canal where oral HCQ takes weeks to achieve adequate sebum levels.

⊗

Multi-Target Resistance Profile

Multiple independent cholinergic kill mechanisms. Resistance requires simultaneous mutations across unrelated biological systems — virtually impossible.

✓

FDA-Approved Safety Base

All AH-300 candidates are FDA-approved drugs repositioned topically via 505(b)(2) — known human safety profiles and an accelerated regulatory path.

♦

Proven Out-License Model

AH-100 assets licensed to Glaukos Corporation as GLK-321, currently in active dose range study for Demodex Blepharitis. AH-300 platform is fully unencumbered.

⊞

Platform Breadth

One IP estate covers the entire DCIDS spectrum: Rosacea · Blepharitis · Cutaneous Lupus · Acne · RA adjunct — 10+ indications from a single mechanistic platform.

▣

Deep IP Moat

Granted U.S. patents and pending applications covering compound class, mechanism, formulation, and indication. Built over 12 years — 2014 to 2026.

Contact Us to Learn More

The first integrated IP estate targeting the root cause of Demodex-driven inflammatory disease — across dermatology, ophthalmology, and rheumatology.