ALS-205 / Alsonex - LARVOL DELTA

Targeting the C5-C5aR1 Axis: A promising therapeutic strategy for Alzheimer's disease and amyotrophic lateral sclerosis by Unlocking Neuroprotection. (PubMed, Biochem Pharmacol) - "Preclinical studies show that C5aR1 antagonists, such as PMX205, which mitigate disease progression in AD and ALS animal models by reducing neuroinflammation and preserving synaptic function. These findings underscore the C5-C5aR1 axis as a promising target for neurodegenerative disease therapy and highlight the need for further development of potential antagonists of C5aR1."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • IL1B • IL6 • TNFA

C5aR1 inhibition alleviates cranial radiation-induced cognitive decline. (PubMed, Cancer Res) - "Importantly, C5aR1 blockade in two syngeneic, orthotopic glioblastoma-bearing mouse models protected against RICD and elevated gene signatures associated with neuroprotection without interfering with the therapeutic efficacy of RT in reducing tumor volume in vivo. As PMX205 has been found to be safe in clinical trials with healthy individuals, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need."

Journal • Brain Cancer • Cognitive Disorders • Glioblastoma • Oncology • Solid Tumor

Synergistic Effects of Complement Modulation and Hypothermia in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy (AAP-NCE 2025) - "C5a facilitates inflammation by binding C5aR1, and PMX205 is a small molecule inhibitor of this interaction. We aimed to determine if complement modulation following hypoxic-ischemic-injury in conjunction with therapeutic hypothermia (TH) improves structural and functional outcomes on neonatal rats... Overall, TH demonstrated more improvement in female rats, CT demonstrated more improvement in male rats, and combining the two treatments showed additive improvement in both sexes. These results help us better understand the sex-specific differences in HIE pathology and response to treatment and may translate to an adjuvant to TH."

Preclinical • CNS Disorders • Cognitive Disorders • Inflammation • Reperfusion Injury

The Crosstalk Between Sepsis-Associated Encephalopathy and Alzheimer's Disease: Identifying Potential Biomarkers and Therapeutic Targets for Cognition. (PubMed, Mol Neurobiol) - "Pharmacological inhibition of the hub gene product C5aR1 using PMX205 improved cognitive and emotional dysfunction in CLP-induced septic mice and reduced BBB damage and microglial activation...In summary, the neuroimmune dysregulation caused by sepsis is correlated with potential pathological mechanisms in AD. This study provides additional molecular evidence for potential biomarkers and therapeutic targets for drug intervention in the risk of AD among sepsis survivors."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Infectious Disease • Inflammation • Septic Shock • C5AR1 • CCL2 • CD163 • CXCL1 • HSPA1A • HSPB1 • ICAM1 • IL6 • MPZL2 • SERPINA3 • SOCS3 • ZFP36

Colon-targeted complement C5a1 receptor inhibition using pH-sensitive nanoparticles ameliorates experimental colitis. (PubMed, Br J Pharmacol) - "This novel colon-targeted formulation therefore offers a potent therapeutic strategy for translating C5a1 receptor antagonists for IBD conditions such as ulcerative colitis."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

Structural and functional effects of combination complement modulation and hypothermia therapies in a rat model of neonatal HIE (PAS 2025) - "C5a facilitates inflammation by binding C5aR1, and PMX205 is a small molecule inhibitor of this interaction... While brain lesion measurements in NT and TH were significantly larger than Sham, treatment with CT and CT+TH mitigated injury, with lesion sizes not significantly different from Sham values. CT reduced lesion area in male rats and demonstrated synergy with TH. In male rats, treatment with CT reduced cortical and hippocampal levels of astrocytes, and treatment with CT+TH reduced levels of activated microglia (Fig."

Preclinical • Cognitive Disorders • Inflammation • Reperfusion Injury

Sex-Specific Quantification of Lymphocyte Subsets in a Rat model of Neonatal HIE (PAS 2025) - "Cohorts of rats received no treatment (NT, normothermia), complement therapy (CT, C5aR1 antagonist PMX205+C3a), therapeutic hypothermia (TH), or combination (CT+TH)... TH and CT males showed a significant increase in total CD3+CD45+ lymphocytes compared to Sham males (Fig 1c). Between treatment groups and sexes, there was no difference in proportion of Thelper cells, defined as CD3+, CD45+, and CD4+ (Fig 2a). Within CD4+ cells, there was a decrease in CD25 cells seen in treated groups compared to NT (Fig 2b)."

Preclinical • CNS Disorders • Inflammation • GATA3 • IL2RA • PTPRC

Complement C5a and C5a receptor 1 mediates glomerular damage in focal segmental glomerulosclerosis. (PubMed, Clin Immunol) - "These findings highlight the pathogenic role of the complement system in the development of FSGS through the C5a-C5aR1 axis on podocytes and PECs. The C5aR1 antagonist represents a promising therapeutic intervention for FSGS patients."

Journal • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Nephrology • Renal Disease • C5AR1 • CD44 • NOTCH1

C5a-C5aR1 axis mediates lung inflammation and fibrosis induced by single-walled carbon nanotubes via promoting neutrophils recruitment. (PubMed, Ecotoxicol Environ Saf) - "Furthermore, inhibition of C5a-C5aR1 axis with C5aR1 antagonist PMX205 treatment not only dramatically reduced neutrophils recruitment and inflammatory cytokines secretion at early phase, but also effectively alleviated early lung inflammation and late pulmonary fibrosis induced by SWCNT exposure. In conclusion, our study provides novel insights into the underlying biological mechanism that C5a-C5aR1 axis regulates neutrophils recruitment-mediated lung injury induced by SWCNT, may help to develop therapeutic strategies for SWCNT-provoked lung injury."

Journal • Fibrosis • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

A ROLE FOR THE C5 COMPLOSOME IN KUPFFER CELL POLARIZATION IN ALCOHOL ASSOCIATED LIVER DISEASE (AASLD 2024) - "These data potentially suggesting mtC5aR1 localization as an important sensitization step proceeding detection of pathogen-associated molecules (LPS) and the C5 complosome may be an important mediator of KC hyperinflammatory response in the context of ALD."

Hepatology • Inflammation • CD86 • MRC1

Intracellular C5aR1 inhibits ferroptosis in glioblastoma through METTL3-dependent m6A methylation of GPX4. (PubMed, Cell Death Dis) - "More importantly, in an intracranial xenograft mouse model, PMX205, a C5aR1 inhibitor, promoted alterations in ferroptosis in GBM cells and inhibited GBM progression...Our study reveals a novel mechanism by which the intracellular complement receptor C5aR1 suppresses ferroptosis induction and promotes GBM progression. These findings may facilitate the identification of a potential therapeutic target for glioma."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • C5AR1 • GPX4 • METTL3

Sex-specific effects of complement modulation in a rat model of neonatal hypoxic-ischemic encephalopathy (AAP-NCE 2024) - "These results demonstrate that complement modulation with PMX205 may be a viable therapeutic in neonatal HIE, but results are sexually dimorphic. This underscores the need to stratify results by sex in preclinical and clinical trials, enabling the development of much needed custom therapeutics for neonatal HIE. Future studies include long-term neurobehavioral assays to test if anatomical neuroprotection translates to long-term functional improvement."

Preclinical • CNS Disorders • Inflammation • Reperfusion Injury • Vascular Neurology • C5AR1

Exploration of compounds to inhibit the Panton-Valentine leukocidin of Staphylococcus aureus. (PubMed, Med Microbiol Immunol) - "Avacopan, PMX205 and W-54,011 showed protection against PVL-induced cytotoxicity and suppressed IL-1β secretion by monocytes. Clinical studies are needed to prove whether these substances can be used therapeutically as repurposed drugs."

Journal • Infectious Disease • IL1B • PTPRC

C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer's disease mouse model. (PubMed, Nat Commun) - "Finally, although hippocampal plaque load was unaffected, PMX205 prevented deficits in short-term memory in female Arctic mice. In conclusion, C5aR1 inhibition prevents cognitive loss, limits detrimental glial polarization while permitting neuroprotective responses, as well as leaving most protective functions of complement intact, making C5aR1 antagonism an attractive therapeutic strategy for AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation

Complement C5a receptor 1 blockade reverses cognitive deficits following cranial radiation therapy for brain cancer. (PubMed, bioRxiv) - "PMX205 is currently in clinical trials for amyotrophic lateral sclerosis (ALS). Thus, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need."

Journal • Amyotrophic Lateral Sclerosis • Astrocytoma • Brain Cancer • CNS Disorders • CNS Tumor • Cognitive Disorders • Glioblastoma • Glioma • Oncology • Pediatrics • Solid Tumor

Structural and functional effects of C5aR1 antagonism in a rat model of neonatal hypoxic-ischemic encephalopathy. (PubMed, Dev Neurosci) - "In a dose-response experiment, cerebral area loss from injury was improved only in female rats, suggesting underlying sexual dimorphisms in the complement response. Conclusion These results demonstrate proof-of-concept for targeting C5aR1 signaling in neonatal HIE with PMX205 and underscore the role of sex in hypoxic-ischemic injury."

Journal • Preclinical • CNS Disorders • Inflammation • Vascular Neurology

C5aR1 signaling promotes region- and age-dependent synaptic pruning in models of Alzheimer's disease. (PubMed, Alzheimers Dement) - "C5aR1 ablation restores long-term potentiation in the Arctic model of AD. C5aR1 ablation rescues region specific excessive pre-synaptic loss. C5aR1 antagonist, PMX205, rescues VGlut1 loss in the Tg2576 model of AD. C1q tagging is not sufficient to induce VGlut1 microglial ingestion. Astrocytes contribute to excessive pre-synaptic loss at late stages of the disease."

Journal • Alzheimer's Disease • CNS Disorders • SLC2A1

C5a/C5aR1 axis as a key driver promotes epithelial-to-mesenchymal transition in airway epithelial cells in silica nanoparticles-induced pulmonary fibrosis. (PubMed, Int Immunopharmacol) - "Finally, treatment of SiNPs-exposed mice with the C5aR1 inhibitor PMX205 effectively reduced C5aR1 levels and inhibited the activation of HMGB1/RAGE signaling and the expression of EMT-related proteins, culminating in a significant alleviation of pulmonary fibrosis. Taken together, our results suggest that C5a/C5aR1 is the main signaling pathway for SiNPs-induced pulmonary fibrosis, which induces EMT in airway epithelial cells via the HMGB1/RAGE axis."

Journal • Cardiovascular • Fibrosis • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • HMGB1

Complement Component 5 (C5) Deficiency Improves Cognitive Outcome After Traumatic Brain Injury and Enhances Treatment Effects of Complement Inhibitors C1-Inh and CR2-Crry in a Mouse Model. (PubMed, Neurotrauma Rep) - "Agents acting at different levels of the complement system, including 1) C1 esterase inhibitor (C1-Inh), 2) CR2-Crry, an inhibitor of all pathways acting at C3, and 3) the selective C5aR1 antagonist, PMX205, were administered at 1 h post-TBI...Our findings support critical roles for C3 in motor deficits, the C3/C5/C5aR1 axis in cognitive deficits, and C5aR1 signaling in brain damage after TBI. Findings suggest the combination of C5 inhibition with C1-Inh and CR2-Crry as potential therapeutic strategies in TBI."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Vascular Neurology

An open-label, phase 1b study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of a single dose of PMX205 in patients with amyotrophic lateral sclerosis (ANZCTR) - P1 | N=8 | Completed | Sponsor: Alsonex Pty Ltd | Not yet recruiting ➔ Completed

Trial completion • Amyotrophic Lateral Sclerosis • CNS Disorders • Movement Disorders • Parkinson's Disease

Complement System Inhibitory Drugs in a Zebrafish (Danio rerio) Model: Computational Modeling. (PubMed, Int J Mol Sci) - "For this, we analyzed molecular docking interactions between peptides and target molecules. Our study demonstrated that Cp40 and the cyclic peptide PMX205 have positive interactions with their respective zebrafish targets, thus suggesting that zebrafish can be used as an animal model for therapeutic studies on these inhibitors."

Journal • Inflammation

Influence of complement protein C1q or complement receptor C5aR1 on gut microbiota composition in wildtype and Alzheimer's mouse models. (PubMed, J Neuroinflammation) - "Similarly, pharmacologic treatment with the C5aR1 antagonist, PMX205, beginning at the onset of beta-amyloid plaque deposition in the Arctic and Tg2576 mice, demonstrated no impact of C5aR1 inhibition on the microbiome. This study demonstrates the importance of C1q in microbiota homeostasis in neurodegenerative disease. In addition, while demonstrating that constitutive deletion of C5aR1 can significantly alter the composition of the fecal microbiome, these differences are not present when C5aR1-deficient mice are cohoused with C5aR1-sufficient animals with or without the AD phenotype and suggests limited if any contribution of the microbiome to the previously observed prevention of cognitive and neuronal loss in the C5aR1-deficient AD models."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation

The complement-inflammasome axis mediates neuronal pyroptosis in neonatal hypoxic-ischemic encephalopathy (PAS 2023) - "T reatment with PMX205 results in a significant decrease in cortical loss when compared to untreated controls in a rat model of neonatal HIE (Fig 2 A,B). P rimary cortical rat neurons subjected to OGD followed by treatment with C5a resulted in significantly greater neuronal death compared to untreated neurons, and inhibition of C5a-C5aR1 signaling with PMX205 rescued neuronal death to levels comparable to untreated controls (Fig. 2C)."

Cardiovascular • CNS Disorders • Inflammation • Reperfusion Injury • Vascular Neurology • IL1B • MPO • NLRP3

C5a / C5aR1 signaling in spinal mechanisms of neuropathic pain (Neuroscience 2022) - "Multiphoton Ca2+ imaging in an ex vivo intact spinal cord preparation of these mice demonstrated that C5a application induced rapid [Ca2+]i increases in superficial dorsal horn microglia in a dose-dependent manner, which were blocked by co-application of a C5aR1 competitive antagonist, PMX205...At the same time, C5a produced a significant decrease in the threshold of action potential generation in a subpopulation of dorsal horn neurons, which further enhances the spinal cord output to supraspinal structures. Overall, these findings demonstrate that C5a/C5aR1 signaling results in an increased intrinsic excitability of dorsal horn neurons likely via microglial activation and plays an important role in SNI-induced neuropathic pain."

CNS Disorders • Neuralgia • Pain

Loss of Perineuronal Nets in Alzheimer’s Disease Mouse Models are not mediated by C5a-C5aR1 signaling (Neuroscience 2022) - "Brain sections from 10-month Arc and Arc C5aR1 knockout mice and 15-month Tg2576 mice treated with the C5aR1 inhibitor PMX205 for 12-weeks were stained for PV and PNNs, imaged at 10X and quantified using IMARIS...These results indicate that C5a-C5aR1 signaling does not contribute to PNN loss in the Arc mice model. Our results also indicate there are differences among the mouse models in damage to PNNs, providing opportunities to dissect pathways that lead to PNN loss."

Preclinical • Alzheimer's Disease • CNS Disorders