Aeterna Zentaris Achieves Proof-of-Concept for the Treatment of NMOSD With AIM Biologicals Program

Aeterna Zentaris Inc. recently announced its Autoimmunity Modifying (AIM) Biologicals program has achieved preclinical proof-of-concept for the potential treatment of neuromyelitis optica spectrum disorder (NMOSD) (also known as Devic disease), a chronic autoimmune disorder of the brain and spinal cord dominated by inflammation of the optic nerve and spinal cord and which can be fatal in approximately 30% of patients within 5 years of diagnosis. These findings were presented at the 13^th International Congress on Autoimmunity held June 10-13, 2022, in Athens, Greece.

The abstract presented at the Congress, titled Antigen presentation on MHC class Ib-related molecules induces Aquaporin-4-specific regulatory T cells in PBMC and prevents experimental autoimmune encephalomyelitis in mice, was presented in a poster format and as an oral presentation by Aeterna’s research collaborator, Valentin Bruttel, PhD, Senior Researcher, Department of Obstetrics and Gynecology, School of Medicine, University of Wuerzburg..

“There remains strong unmet medical need to provide treatment options for patients diagnosed with NMOSD, a rare but potentially devastating autoimmune condition. Given the severe impact NMOSD can have on people, we are very encouraged by the proof-of concept our AIM Biologicals program has demonstrated in both in vitro and mouse models,” said Dr. Klaus Paulini, Chief Executive Officer of Aeterna. “We are grateful for the collaborative work being done with Dr. Bruttel, Prof. Wischhusen and their team, and we look forward to continue further developing Aeterna’s AIM Biologicals for the potential treatment of NMOSD.”

Aquaporin-4 (AQP-4) is the autoimmune antigen implicated in neuromyelitis optica (NMO), a demyelinating and inflammatory autoimmune disorder of the central nervous system (CNS). AIM Biologicals are based on a mechanism that is physiologically important for feto-maternal immune tolerance during pregnancy. These new biomolecules utilize the α3 domain of the human MHC class Ib molecule HLA-G to inhibit antigen-specific T cells via the human ILT-2 or the murine PIRB receptor. As part of Aeterna’s ongoing pre-clinical studies in collaboration with the University, researchers at the University generated fusion proteins comprising an AQP-4-derived antigenic peptide, MHC class I α1-α2 antigen presenting domains, the HLA-G α3 domain and b2-microglobulin to investigate whether these novel single-chain biomolecules can induce antigen-specific tolerance towards presented AQP-4 and other neuroinflammatory peptide antigens. Various AIM Biologicals were then tested and shown to induce antigen-specific regulatory T cells (Treg) in vitro and to inhibit CD8⁺ driven experimental autoimmune encephalomyelitis (EAE) models and optic neuritis in 2D2 mice in vivo.

“We are very pleased with these pre-clinical proof-of-concept results which help to inform our research moving forward to define a development candidate. As demonstrated in these pre-clinical studies, we believe that Aquaporin-4-specific AIM Biologicals have the potential to provide targeted immunosuppression in NMOSD. We look forward to advancing this important program with our exclusive licensee, Aeterna, to potentially meet an indication where there remains unmet medical need,” added Dr. Bruttel, who has just received the audience prize and the German innovation award at the recent German Biotechnology Days 2022.

Summary of Key Highlights

• HLA-G elicits specific tolerance towards presented peptides. AIM Biologicals use this mechanism to induce tolerance to autoimmune antigens.
• Mouse-adapted AIM Biologicals molecules selectively induce IL-10, inhibit IFN-γ secretion in cognate T cells, inhibit EAE symptoms and spinal cord inflammation.
• Mouse-adapted AIM Biologicals constructs presenting MOG44 peptide elicit a strong bystander immunosuppression in OT-I ODC-Ova mice models and prevent EAE and MOG-specific autoantibodies in CD4⁺ T cell driven MOG EAE models.
• AQP4_HLAG AIM Biologicals induce IL10-secreting CD8⁺CD28^–CD127^– Treg in hPBMC.
• Preliminary data with mouse 2D2 models of spontaneous EAE indicate that mouse-adapted AIM Biologicals may reduce optic neuritis, loss of inner nuclear layer neurons and EAE symptoms.

The poster can be accessed on the Publications page of the company’s website.

NMOSD is an antibody mediated inflammatory central nervous system (CNS) disorder that affects about one per 100,000 population per year. NMOSD, also known as Devic’s disease, is a chronic disorder of the brain and spinal cord dominated by inflammation of the optic nerve (optic neuritis) and of the spinal cord (myelitis). Typical symptoms include vision loss, muscle spasms, paraparesis, and incontinence. If left untreated, 50% of individuals with NMOSD may become wheelchair bound and blind, and 30% may have died within five years after the first attack. The water channel protein AQP4 is widely expressed in the brain, spinal cord, and optic nerves. Auto-antibodies directed against AQP4 play an important role in the pathogenesis of NMOSD.

Currently there are only three approved medications available for the treatment of NMOSD, all with very high annual treatment costs and the risk of the patient contracting serious infections. Therefore, the company believes there remains a strong medical need to offer new therapeutic options to the patients.

In the US and Europe there are currently approximately 10,000 to 15,000 patients living with NMOSD. Of these the AQP4 antibody seropositive patients who represent about 80% of the NMOSD population are the targeted patients for a potential therapy based on the AIM Biologicals technology.

AIM Biologicals are targeted, highly specific autoimmunity modifying therapeutics. This platform technology utilizes a mechanism that is physiologically required for “feto-maternal immune tolerance” during pregnancy. Despite 50% paternal antigens, the maternal immune system tolerates a fetus, while protection against pathogens is retained. This requires selective tolerance induction against fetal antigens. During pregnancy, this goes along with an amelioration of autoimmune diseases.

AIM Biologicals utilize a novel technique which is based on the presentation of antigens on immunosuppressive MHC class I molecules to selectively and efficiently induce antigen-specific tolerance. Based on this mechanism, targeted immunomodulatory therapeutics are designed as optimized soluble molecules and adapted to selectively induce tolerance to various autoantigens. Pre-clinical studies conducted thus far indicate that tolerance induction may be achieved via selective elimination of antigen-specific immune effector cells and via induction of antigen-specific regulatory T cells from naïve T cells.

For the potential treatment of NMOSD, AIM Biologicals presenting a specific antigen derived from the water channel protein aquaporin-4 (AQP4) loaded onto a soluble immunoregulatory HLA-G protein has the potential to selectively induce immunological tolerance in the central nervous system. AIM Biologicals thus have the potential to become highly specific and effective yet not personalized treatment options for NMOSD.

Aeterna Zentaris is a specialty biopharmaceutical company developing and commercializing a diversified portfolio of pharmaceutical and diagnostic products focused on areas of significant unmet medical need. The company’s lead product, macimorelin (Macrilen; Ghryvelin), is the first and only US FDA and European Commission approved oral test indicated for the diagnosis of adult growth hormone deficiency (AGHD). The Company is leveraging the clinical success and compelling safety profile of macimorelin to develop it for the diagnosis of childhood-onset growth hormone deficiency (CGHD), an area of significant unmet need, in collaboration with Novo Nordisk.

Aeterna Zentaris is dedicated to the development of therapeutic assets and has recently taken steps to establish a growing pre-clinical pipeline to potentially address unmet medical needs across a number of indications, including neuromyelitis optica spectrum disorder (NMOSD), Parkinson’s disease (PD), hypoparathyroidism and amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease). Additionally, the Company is developing an oral prophylactic bacterial vaccine against SARS-CoV-2 (COVID-19) and Chlamydia trachomatis. For more information, visit www.zentaris.com.