XPro (pegipanermin) / Xencor, INmune Bio - LARVOL DELTA

UNDERSTANDING MECHANISMS OF ARIA - INSIGHTS FROM HUMAN AND MOUSE (ADPD 2026) - "ARIA, remains a significant concern with amyloid-targeted therapies (ATTs) such as lecanamab and donanemab...In one study, we have administered XPro1595, a soluble TNFα inhibitor, for the duration of anti-Aβ antibody treatment, to examine the potential role of TNFα in ARIA occurrence, In a second study, we have administered GM6001, an MMP inhibitor with high affinity for MMP9, for the duration of anti-Aβ antibody treatment, to determine the role of MMP9 in ARIA occurrence...These data suggest that the increases in TNFα with ATTs is likely not causative in ARIA development, but MMPs do seem to have a role in ARIA. Spatial multi-omic analysis of tissue from these studies is in process to gain further insights into ARIA development and modification."

Preclinical • Hematological Disorders • Inflammation • MMP9

INmune Bio…announced that it received the official minutes from its End-of-Phase 2 (Type B) meeting with the U.S. Food and Drug Administration (FDA) (GlobeNewswire) - "The Phase 2b portion will enroll approximately 300 participants over a nine-month evaluation period designed to validate key efficacy and biomarker assumptions before expansion into the Phase 3 registration segment. The full program is expected to enroll approximately 1,000 participants, with the Phase 3 portion evaluating XPro1595 over 18 months....The FDA raised no objection to the use of Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) as the sole primary efficacy endpoint for the Phase 3 portion of the study....The FDA raised no objection to the Company’s inflammation-based enrichment strategy....INmune Bio is incorporating the FDA’s feedback into the final Phase 2b/3 protocol and anticipates submitting the protocol to the Agency for review."

Clinical protocol • FDA event • Alzheimer's Disease

Developing Topics. (PubMed, Alzheimers Dement) - P2 | "MINDFuL is a proof-of-concept study evaluating the efficacy and safety of XPro1595 (1.0 mg/kg/wk) in patients with early AD and biomarkers of inflammation. Detailed results of unblinded cognitive, functional, safety, and biomarker data will be presented."

Biomarker • Clinical • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Oncology • TNFA

XPro1595, a Selective Soluble TNF Neutralizer, in Early Alzheimer's Disease with Inflammation (ADi): Results from the Phase 2 MINDFuL Trial (CTAD 2025) - No abstract available

P2 data • Alzheimer's Disease • CNS Disorders • Inflammation

TNFR1 Suppression by XPro1595 Reduces Peripheral Neuropathies Associated with Perineural Invasion in Female Mice. (PubMed, Cells) - "Transcriptomic analysis revealed that XPro1595 in females with PNI upregulated mitochondrial, myelination, motor function, and immune regulation gene pathways while it downregulated inflammatory, extracellular matrix, and tumor progression pathways. Overall, we demonstrated that XPro1595 exhibited antitumor, neuroprotective, and analgesic properties in female mice, likely by promoting neuronal regeneration and mitochondrial function, while reducing inflammation and extracellular remodeling."

Journal • Preclinical • Oncology • Pain • TNFA • TNFRSF1A

INmune Bio Announces Two Presentations at the Upcoming 18th Annual CTAD Conference (The Manila Times)

Clinical data • Alzheimer's Disease

The effect of the nonselective TNF inhibitor etanercept, and of the selective TNF inhibitor XPro1595 on lesioned supraspinatus muscle. (PubMed, Biosci Rep) - "Though  both inhibitors had an effect on mitochondrial proteins, particularly etanercept tended to modulate mitochondrial function, and eternacept also influezed  NF-κB signaling. Modulation of mitochondrial proteome, and the  influence on  NF-κB signaling seen after etanercept treatment could correspond with its known effect on apoptosis."

Journal • Oncology • Myogenin

Inhibition of T cell infiltration and soluble TNF signaling is neuroprotective in the alpha-synuclein overexpressing mouse model of Parkinson's disease. (PubMed, NPJ Parkinsons Dis) - "In a chronic model induced with a low viral dose, treatment with either fingolimod (FTY720), which prevents T cell infiltration, or XPro1595, a selective inhibitor of soluble TNF signaling, led to improved motor function and resulted in partially protected dopaminergic cell bodies. Our results support the contribution of CD4+ T cells to αSyn-induced neurodegeneration and suggest that immune modulation can provide neuroprotection in chronic neurodegenerative conditions, offering a wider therapeutic window. Further studies are needed to determine the optimal timing and conditions for implementing immunomodulatory strategies in PD."

Journal • Preclinical • CNS Disorders • Immune Modulation • Immunology • Inflammation • Movement Disorders • Parkinson's Disease • CD4 • IFNG • TNFA

DN-TNF Platform Highlights (XPro) (GlobeNewswire) - "The company is on track to request an End of Phase 2 meeting with the FDA which is anticipated to occur in Q1, 2026....Upcoming Events and Milestones:...Imaging data from the phase 2 MINDFuL trial in Alzheimer’s Disease should be released in Q4 2025."

FDA event • P2 data • Alzheimer's Disease

Systemic inhibition of soluble TNF significantly changes glial cell populations leading to improved myelin integrity and better functional outcome after experimental stroke. (PubMed, Biomed Pharmacother) - "We previously demonstrated that XPro1595, a selective solTNF inhibitor, decreased inflammation and improved functional outcome in the acute phase of experimental stroke...These changes were followed by increased hippocampal pro-brain-derived neurotrophic factor levels and an improvement in cognitive function, seen as better recognition memory, as well as improved motor asymmetry. In conclusion, these findings support a long-term protective effect of inhibiting solTNF in experimental ischemic stroke."

Journal • Alzheimer's Disease • Cardiovascular • Cognitive Disorders • Inflammation • Ischemic stroke • Oncology • Solid Tumor • TNFRSF1A

Targeting necroptosis protects against astrocyte death and hippocampal sclerosis in experimental temporal lobe epilepsy. (PubMed, J Physiol) - "The results show that pharmacological inhibition of necroptosis using Nec-1s, a specific inhibitor of RIPK1, or selective inhibition of soluble TNFα by XPro1595, as well as genetic knockout of TNFR1, effectively rescued CA1 astrocyte loss caused by kainate-induced status epilepticus...Immunohistochemical analysis revealed that Nec-1s treatment reduced the extent of hippocampal sclerosis in experimental TLE-HS. Our results provide further insights into the molecular mechanisms underlying the development and progression of TLE."

Journal • CNS Disorders • Epilepsy • Oncology • RIPK1 • TNFA • TNFRSF1A

INmune Bio Reports Key Findings from Phase 2 MINDFuL Trial of XPro in Early Alzheimer’s Disease (GlobeNewswire) - P2 | N=201 | MINDFuL (NCT05318976) | Sponsor: Inmune Bio, Inc. | "Key Findings in the Amyloid positive Early AD participants with two or more biomarkers of inflammation (N=100): (i) Cognition: A clinical benefit of XPro over placebo was observed on the primary endpoint EMACC (effect size: 0.27) and on the secondary endpoint Neuropsychiatric Inventory (effect size: -0.24); (ii) Alzheimer’s Disease Biomarkers: A biological benefit of XPro over placebo was observed in blood levels of pTau217 (effect size: -0.20), the gold standard measure of AD pathology in blood; (iii) Safety and tolerability: XPro treatment was safe and well tolerated, without any occurrences of ARIA-E or ARIA-H. Injection site reactions (ISR) were common (80% of XPro group compared to placebo group (<20%).....Additional analyses will be presented at Alzheimer’s Association International Conference (AAIC)...and the Company will submit for Breakthrough Therapy designation with the FDA."

Biomarker • FDA event • P2 data • Alzheimer's Disease

INmune Bio Inc. to Announce Top Line Results from MINDFuL Phase 2 Trial in Early Alzheimer’s on Monday, June 30th (GlobeNewswire) - "INmune Bio...will host a conference call on Monday, June 30 beginning at 8:00am EDT to present top line data from the Phase 2 MINDFuL trial in early Alzheimer’s Disease....The MINDFuL trial is an international, blinded, randomized Phase 2 trial in patients with Early AD with biomarkers of elevated neuroinflammation. Early AD includes patients with MCI (mild cognitive impairment) and mild AD. Patients must have at least one of four biomarkers of inflammation – elevated CRP, HgbA1c, ESR or ApoE4 allele. Patients receive either XPro or placebo (2:1 ratio) for 6 months."

P2 data • Alzheimer's Disease

INmune Bio Inc. Announces First Quarter 2025 Results and Provides Business Update (GlobeNewswire) - "Upcoming Events and Milestones: (i) Top-line data from the Phase 2 Alzheimer’s trial is expected in the second half of June...; (ii) Initiation of Phase 2 trial of XPro in patients with treatment-resistant depression once NIH funding is made available."

New P2 trial • P2 data • Alzheimer's Disease • Depression

Unraveling the Immune Puzzle: Role of Immunomodulation in Alzheimer's Disease. (PubMed, J Neuroimmune Pharmacol) - "Preclinical studies of immunomodulatory agents, including salidroside, festidinol, astragalin, sulforaphane, BM-MSC, simvastatin, Ab-T1, hTREM2, and XENP345, demonstrate promising effects. Additionally, clinical investigations of drugs such as simufilam, AL002, TB006, VGL101, DNL919, XPro1595, astragalus, and IBC-Ab002 underscore the therapeutic potential of targeting immune pathways in AD. This review emphasizes how neuroinflammation, microglial activation, and peripheral immune responses contribute to disease progression. By exploring immunomodulatory mechanisms, the article sheds light on potential therapeutic targets that could help mitigate AD pathology which may pave the way for novel interventions preventing neurodegeneration in AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Immunology • Oncology • CTNNB1 • TNFA

INHIBITION OF TNFA SHOWS PATHOLOGY SPECIFIC ALTERATIONS OF INFLAMMATION IN VCID MODELS (ADPD 2025) - "XPro1595, a novel soluble TNF α inhibitor, was administered subcutaneously twice weekly at 2mg/ml throughout this timeframe... Inhibition of soluble TNF α differentially impacts gene expression in models of cSVD and CAA compared to vehicle controls. Interestingly, this inhibition affects each disease model differently and suggests distinct mechanistic roles of T NFα-driven inflammation in cSVD and CAA."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Hematological Disorders • Inflammation • Metabolic Disorders • ITGA7 • TNFA • TNFRSF1B

ALZHEIMER'S DISEASE (AD) AND INFLAMMATION: BASELINE DEMOGRAPHICS AND DISEASE CHARACTERISTICS IN A PHASE -2 STUDY OF XPRO1595 IN EARLY AD (ADPD 2025) - P2 | "Innovative study designs are required for determination of treatment effects in early -stage AD. These include patient enrichment st rategies and the use of treatment -sensitive endpoints. The MINDful trial is enriched for patients with biomarker confirmed neuropathological AD and systemic inflammation deemed likely to benefit from treatment with XProTM."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • Oncology • TNFA

INmune Bio Inc. Announces Year End 2024 Results and Provides a Business Update (GlobeNewswire) - "Upcoming Events and Milestones: Top line cognitive results and secondary endpoints from the AD02 trial in Alzheimer’s Disease will be available in June 2025....Data from the ongoing INKmune trial in mCRPC will be released as they become available. The next data set should be released in Q2 or Q3, 2025. A Phase II trial of XPro in patients with Treatment-Resistant Depression will begin enrollment soon once the NIH releases funds for the trial."

Enrollment status • P1/2 data • P2 data • Alzheimer's Disease • Castration-Resistant Prostate Cancer • Depression

Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn + PFFs-induced rat model for Parkinson's disease. (PubMed, Neurobiol Dis) - "An increase in IL-6 and IL-1β levels in CSF was observed in rats treated with XPro1595, possibly explaining a lack of protective effects following treatment. Our results highlight the need to determine the importance of timing of treatment initiation, which is crucial for future applications of sTNF therapies in PD patients."

Journal • Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • HLA-DRB1 • IL1B • IL6

MINDFuL: A Study of XPro1595 in Patients with Early Alzheimer's Disease with Biomarkers of Inflammation (clinicaltrials.gov) - P2 | N=201 | Active, not recruiting | Sponsor: Inmune Bio, Inc. | Recruiting ➔ Active, not recruiting

Biomarker • Enrollment closed • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Developmental Disorders • Inflammation • Mental Retardation • Psychiatry

Peripherally administered TNF inhibitor is not protective against α-synuclein-induced dopaminergic neuronal death in rats. (PubMed, Neurobiol Dis) - "To do so, we administered the DN-TNF agent XPro1595 subcutaneously for a period of 12 weeks...Therefore, despite an apparently immunomodulatory effect, this did not suffice to protect against viral vector-derived α-synuclein-induced neurotoxicity. Further studies are warranted to better elucidate the therapeutic potential of soluble TNF inhibitors in PD."

Journal • Preclinical • CNS Disorders • Movement Disorders • Oncology • Parkinson's Disease • CD68

Developing Topics. (PubMed, Alzheimers Dement) - P1b | "Synaptic dysfunction is associated with both the clinical symptoms and core pathologies of AD. These findings provide further evidence of disease-specific and dose-related target engagement for XProTM in AD."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders • Oncology • TNFA

Ablation of CCL17-positive hippocampal neurons induces inflammation-dependent epilepsy. (PubMed, Epilepsia) - "In conclusion, our data demonstrate that sterile pyramidal neuronal death is sufficient to cause epilepsy in the absence of other pathological processes. The CCL17-DTR mouse line may thus be a valuable model for further mechanistic studies on epilepsy and assessment of antiseizure medication."

Journal • Absence Seizure Disorder • CNS Disorders • Epilepsy • Infectious Disease • Inflammation • Oncology • CA3 • TNFA • TNFRSF1A

INmune Bio Inc. Announces Third Quarter 2024 Results and Provides Business Update (GlobeNewswire) - "Top-line data from the Phase 2 Alzheimer’s trial is expected in the second quarter of 2025."

P2 data • Alzheimer's Disease • CNS Disorders

INmune Bio Inc. Announces Publication in Cell Reports Demonstrating XPro Promotes Remyelination (GlobeNewswire) - "INmune Bio, Inc...announces the publication of a seminal paper in the journal Cell Reports that demonstrates XPro1595 promotes remyelination in an animal model of demyelinating disease...'Our data identify solTNF as a critical cytokine checkpoint that converts microglia from a reparative, remyelinating cell to a damaging, demyelinating cell. These data suggest that blocking soluble TNF is a promising strategy for treating demyelinating diseases.'...'These new data further support the potential for XPro1595 in neurodegenerative diseases by restoring glia function to improve key components of neurodegeneration at multiple levels, including restoration of synaptic function, remyelination, and ceasing cell loss.' INmune anticipates reporting top-line cognitive results of an ongoing blinded randomized Phase II in Early AD patients in the first half of 2025."

P2 data • Preclinical • Alzheimer's Disease • CNS Disorders