lazucirnon (AKST4290) / Grifols - LARVOL DELTA

Advancements in Bullous Pemphigoid Treatment: A Comprehensive Pipeline Update. (PubMed, Am J Clin Dermatol) - "Rituximab, a CD20 monoclonal antibody, depletes B-lymphocytes and has shown efficacy in severe cases. Dupilumab, targeting interleukin (IL)-4 receptor α and thus blocking IL-4 and IL-13, downregulates type 2 helper (Th2) responses and has demonstrated promising results. Targeting eosinophil-related molecules using bertilimumab and AKST4290 has yielded positive results in clinical trials. Omalizumab, an immunoglobulin (Ig) E antibody, can reduce disease severity and allows corticosteroid tapering in a number of cases. Complement inhibitors such as nomacopan and avdoralimab are being investigated. IL-17 and IL-23 inhibitors such as secukinumab and tildrakizumab have shown potential in a limited number of case reports. Neonatal Fc receptor antagonists such as efgartigimod are under investigation. Additionally, topical therapies and Janus kinase inhibitors are being explored as potential treatments for BP. These novel therapies offer promising alternatives for managing..."

Clinical • Journal • Pipeline update • Review • Bullous Pemphigoid • Dermatology • Dermatopathology • Immunology • Pruritus • IL13 • IL17A • IL23A • IL4

A Study to Evaluate the Efficacy of Oral AKST4290 in Participants With Moderately Severe to Severe Diabetic Retinopathy (CAPRI) (clinicaltrials.gov) - P2 | N=3 | Terminated | Sponsor: Alkahest, Inc. | Suspended ➔ Terminated; Study terminated due to safety findings in other AKST4290 studies

Trial termination • Diabetic Retinopathy • Retinal Disorders

A Study to Assess the Therapeutic Effect and Safety of Adjunctive AKST4290 in Subjects With Bullous Pemphigoid (clinicaltrials.gov) - P2 | N=6 | Terminated | Sponsor: Alkahest, Inc. | N=30 ➔ 6 | Completed ➔ Terminated; The study was prematurely terminated by the Sponsor due to operational challenges stemming from the coronavirus disease 2019 (COVID-19) pandemic, treatment limitations, rarity of the disease, and drug supply considerations.

Enrollment change • Trial termination • Bullous Pemphigoid • Dermatology • Dermatopathology • Immunology

Safety and therapeutic effects of orally administered AKST4290 in newly diagnosed neovascular age-related macular degeneration. (PubMed, Retina) - "To evaluate the safety and therapeutic effects of orally administered AKST4290 (formerly BI 144807 and ALK4290) in treatment-naive patients with neovascular age-related macular degeneration (nAMD). All adverse events (AEs) were mild or moderate in severity and no safety issues were identified. Treatment of nAMD with AKST4290 warrants further investigation in randomized, placebo-controlled trials."

Journal • Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AKST4290 IN PARKINSON’S DISEASE (ADPD 2022) - "Conclusions Improvements with AKST4290 treatment were evident in select important assessments of relevance to PD patients. The results of this study support continued investigation of AKST4290 in neuroinflammation in PD."

Clinical • CNS Disorders • Immunology • Inflammation • Movement Disorders • Parkinson's Disease • CCL11

A Study to Evaluate the Efficacy of Oral AKST4290 in Participants With Moderately Severe to Severe Diabetic Retinopathy (CAPRI) (clinicaltrials.gov) - P2 | N=3 | Suspended | Sponsor: Alkahest, Inc. | N=80 ➔ 3 | Trial completion date: Oct 2022 ➔ Jul 2022 | Recruiting ➔ Suspended | Trial primary completion date: Sep 2022 ➔ Feb 2022

Enrollment change • Trial completion date • Trial primary completion date • Trial suspension • Diabetic Retinopathy • Retinal Disorders

CCR3 inhibition reduces recruitment of peripheral immune cells to the eye and brain in inflammatory disease models (Neuroscience 2021) - "AKST4290, a CCR3 inhibitor, is a promising oral drug for AMD treatment...Preclinical studies using the sodium iodate (NaIO 3 ) induced oxidative stress model were subsequently conducted to examine whether the efficacy observed in nAMD patients was in part due to blocking CCR3-mediated retinal homing of damage-promoting immune cells from the periphery. This in turn could dampen local inflammation and may subsequently modify disease progression."

CNS Disorders

Pharmacokinetics and distribution of AKST4290, a CCR3 antagonist with anti-inflammatory properties in the eye and brain (Neuroscience 2021) - "LC-MS/MS analysis also showed very low levels in the brain, together demonstrating that it is non-brain penetrant drug. These data suggest that AKST4290 treatment for nAMD can act both systemically as well as centrally in the RPE/choroid, where action may occur through inflammatory pathways."

PK/PD data • CNS Disorders • CXCL9

PHTHALO-205: A Study to Assess the Efficacy and Safety of AKST4290 With Aflibercept in Patients With Newly Diagnosed nAMD (clinicaltrials.gov) - P2; N=107; Completed; Sponsor: Alkahest, Inc.; Recruiting ➔ Completed

Clinical • Trial completion • Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

A Study to Evaluate the Efficacy of Oral AKST4290 in Participants With Moderately Severe to Severe Diabetic Retinopathy (CAPRI) (clinicaltrials.gov) - P2; N=80; Recruiting; Sponsor: Alkahest, Inc.

Clinical • New P2 trial • Diabetic Retinopathy • Retinal Disorders

PHTHALO-205: A Study to Assess the Efficacy and Safety of AKST4290 With Aflibercept in Patients With Newly Diagnosed nAMD (clinicaltrials.gov) - P2; N=100; Recruiting; Sponsor: Alkahest, Inc.; Trial completion date: Apr 2021 ➔ Sep 2021; Trial primary completion date: Apr 2021 ➔ Sep 2021

Clinical • Trial completion date • Trial primary completion date • Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

A Study to Assess the Therapeutic Effect and Safety of Adjunctive AKST4290 in Subjects With Bullous Pemphigoid (clinicaltrials.gov) - P2; N=30; Completed; Sponsor: Alkahest, Inc.; Recruiting ➔ Completed

Clinical • Trial completion • Bullous Pemphigoid • Complement-mediated Rare Disorders • Dermatology • Dermatopathology • Immunology

[VIRTUAL] AKST4290, a CCR3 Inhibitor, Reduces Age-Related Inflammation and Immune Cell Infiltration (IMMUNOLOGY 2021) - "In contrast, Dexamethasone produced a broad, non-specific, decrease of total white blood cells and critical subpopulations. These findings suggest that AKST4290 is a potent immunomodulator that normalizes immune cell populations related to inflammation to healthy levels, both in the context of disease and aging. These immune modulatory and anti-inflammatory effects have functional consequences in aging models, indicating its therapeutic potential in multiple age-related disorders."

CNS Disorders • Immune Modulation • Immunology • Inflammation • Multiple Sclerosis • CCL11

[VIRTUAL] CCR3 inhibition reduces recruitment of peripheral immune cells to the eye in the sodium iodate model of age- related macular degeneration (ARVO 2021) - "These data demonstrate that systemic inhibition of CCR3 by AKST4290 reduces the accumulation of peripheral immune cells in the RPE, which is the primary injury site in the NaIO3 model and in nAMD. This reduction in recruitment of immune cells was associated with a decrease in chemokines in the degenerating RPE. These findings help illustrate the mechanism of action for AKST4290, supporting its observed efficacy as a drug candidate in clinical trials of nAMD patients."

Age-related Macular Degeneration • Macular Degeneration • Ocular Inflammation • Ophthalmology • Retinal Disorders • CD4 • CXCL9

[VIRTUAL] Determining the pharmacokinetics and ocular distribution of AKST4290, a clinical stage oral therapeutic for age-related macular degeneration (ARVO 2021) - "These data show a preferential accumulation of AKST4290 in the RPE/choroid, the primary site of nAMD pathologies. Moreover, these data show a strong effect of retinal pigmentation on the levels of drug accumulation in the eye. These data support the RPE/choroid as a potential site of AKST4290 action in nAMD and contextualize treatment efficacy observed in clinical trials."

Clinical • PK/PD data • Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

TEAL: Study Assessing Efficacy and Safety of AKST4290 in Subjects With Parkinson's Disease on Stable Dopaminergic Treatment (clinicaltrials.gov) - P2; N=110; Completed; Sponsor: Alkahest, Inc.; Recruiting ➔ Completed

Clinical • Trial completion • CNS Disorders • Movement Disorders • Parkinson's Disease

"Live at #ARVO2021 RPE/choroid as potential site of action in nAMD for CCR3 inhibitor AKST4290 from Alkahest" (@Cortellis)

TEAL: Study Assessing Efficacy and Safety of AKST4290 in Subjects With Parkinson's Disease on Stable Dopaminergic Treatment (clinicaltrials.gov) - P2; N=120; Recruiting; Sponsor: Alkahest, Inc.; Trial completion date: Nov 2020 ➔ Mar 2021; Trial primary completion date: Nov 2020 ➔ Mar 2021

Clinical • Trial completion date • Trial primary completion date • CNS Disorders • Movement Disorders • Parkinson's Disease

[VIRTUAL] A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AKST4290 in Subjects with Parkinson’s Disease on Stable Dopaminergic Treatment (TEAL Study) (MDS Congress 2020) - "The current study is ongoing. AKST4290 has the potential to provide an alternative treatment option for patients with PD. TEAL will be the first Phase II randomized study to establish efficacy and safety of AKST4290 in PD."

Clinical • CNS Disorders • Parkinson's Disease • CCL11

Grifols Moves Deeper Into Proteome R&D With $146M Deal for Alkahest (Xconomy) - "Alkahest, a company that analyzes blood proteins to develop therapies that address neurological disorders including Alzheimer’s disease, is set to be acquired by partner Grifols in a $146 million deal.....Alkahest drug candidates, GRF-6019 and GRF-6021, are intended to enhance the growth and development of nerve tissue, improve the deficits in learning and memory that come with aging, and reduce neuroinflammation....The other Alkahest lead compound, GRF-6021, is being evaluated in separate a Phase 2 study in Parkinson’s disease. The company’s pipeline also includes AKST4290, in mid-stage tests for the wet form of age-related macular degeneration as well as Parkinson’s..."

M&A • Alzheimer's Disease • CNS Disorders • Parkinson's Disease

A Study to Assess the Therapeutic Effect and Safety of Adjunctive AKST4290 in Subjects With Bullous Pemphigoid (clinicaltrials.gov) - P2; N=30; Recruiting; Sponsor: Alkahest, Inc.

Clinical • New P2 trial • Complement-mediated Rare Disorders • Dermatology • Dermatopathology

Alkahest Provides Corporate Update (GlobeNewswire) - "Alkahest, Inc., a clinical stage biotechnology company focused on discovering and developing transformative therapies to treat age-related diseases, today provided a corporate update....Ongoing Studies: AKST6021-201 (NCT03713957), a Phase 2 clinical trial of GRF6021 in patients with Parkinson’s disease with cognitive impairment; AKST4290-211 (TEAL) (NCT04369430), a Phase 2 clinical trial in patients with Parkinson’s disease."

Trial status • CNS Disorders • Cognitive Disorders • Parkinson's Disease

Emerging Therapies in Neovascular Age-Related Macular Degeneration in 2020. (PubMed, Asia Pac J Ophthalmol (Phila)) - "For nAMD: Abicipar pegol, an intravitreal anti-vascular endothelial growth factor based on designed ankyrin repeat proteins (DARP) in protein, is currently pending approval. Conbercept and Faricimab, 2 intravitreal anti-growth factors, are currently in phase 3. Nine other upcoming agents have at least produced results in the 2A phase including intravitreal injections (KSI-301, OPT-302, RGX-314, ICON-1, and DE-122), depot (GB-102), drug reservoir (PDS), topical drops (PAN-90806), and oral formulations (AKST4290). We summarize all the newer molecules."

Journal • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Gene Therapies • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

TEAL: Study Assessing Efficacy and Safety of AKST4290 in Subjects With Parkinson's Disease on Stable Dopaminergic Treatment (clinicaltrials.gov) - P2; N=120; Recruiting; Sponsor: Alkahest, Inc.

Clinical • New P2 trial • CNS Disorders • Gene Therapies • Genetic Disorders • Movement Disorders • Parkinson's Disease

PHTHALO-205: A Study to Assess the Efficacy and Safety of AKST4290 With Aflibercept in Patients With Newly Diagnosed nAMD (clinicaltrials.gov) - P2; N=100; Recruiting; Sponsor: Alkahest, Inc.

Clinical • New P2 trial