Full Press Release Details
Stanley H. Appel, MD Jason Thonhoff,
MD, PhD David Beers, PhD Houston Methodist Research Institute 2023 MDA Clinical & Scientific Conference Novel Treg-modulating Immunotherapy Targets Inflammation in ALS Exhibit 99.1
Disclosures Mitsubishi Tanabe Pharma
- Member of Clinical Advisory Board; Eledon Pharmaceuticals - Consultant; Implicit Bioscience - Consultant; Coya Therapeutics - Chair of Scientific Advisory Board
Disclosures The Houston Methodist
Hospital has entered into an exclusive license agreement with Coya Therapeutics, Inc. for the know-how and patents related to its investigational product COYA 302 (IL-2/CTLA4-Ig). The development of this technology and the clinical study has been
funded in part by Coya Therapeutics.
- Neuroinflammation - Propagating
Neuronal Injury in Amyotrophic Lateral Sclerosis
Blood monocytes/macrophages and CNS
microglia are proinflammatory. Th1 and Th17 lymphocytes are activated and proinflammatory Neuroprotective FoxP3 regulatory T lymphocytes are decreased and dysfunctional. Systemic Immune Alterations Promote Inflammation in ALS Augmenting Burden of
Disease and Rates of Progression M1 FoxP3
Activated Macrophage Regulatory T Cell
FoxP3 x Activated Th1-Th17 IL-1 NO, O2- IL-18 4-HNE IL-6 H2O2 TNF Activated Macrophages Promote Dysfunction of Treg Numbers + Suppressive Functions Releasing Proinflammatory Cytokines and Markers of Oxidative Stress Proinflammatory
cytokines and oxidative stress and lipid peroxides contribute to the pathophysiology of neuronal injury and cell death in ALS.
In vivo expansion of Tregs in ALS In
vivo Treg expansion strategy with IL-2/CTLA4-Ig was applied for 48 weeks Four ALS patients were enrolled Changes in Treg Suppressive function, Treg numbers, ALSFRS, and biomarkers of lipid peroxides and proinflammatory cytokines were monitored
Lipid Peroxide Biomarkers of
Inflammation in ALS * p<0.05 ** p<0.01 n.s.: not significant ** * * ** n.s. ** ** 4-Hydroxynonenal (4-HNE) Oxidized Low-Density Lipoprotein (ox-LDL)
Expanded Treg Combination Therapy for
ALS - IL-2/CTLA4-Ig Th1,Th17 80-90% IL-1 NO, O2- IL-18 4-HNE IL-6 H2O2 TNF CTLA4Ig Proinflammatory Macrophages 30-40% CD80 FoxP3 FoxP3 FoxP3 FoxP3 IL-2
Proof-of-Concept Clinical Study
Open-label, single-arm in 4 patients with ALS IL-2/CTL4-Ig was administered via subcutaneous injection over 48 weeks
Patients' Demographics and
Baseline Characteristics Age (years) Sex Type Onset ALS Progression Prior to Baseline (ALSFRS-R score) Respiratory Status Respiratory Support Patient 1 47 Female Familial Limb -1.6 points / month No Respiratory Insufficiency None Patient 2 54 Male
Sporadic Limb -1 points / month Respiratory Insufficiency Non-invasive Ventilation Patient 3 57 Female Sporadic Bulbar -1 point / month Respiratory Insufficiency Non-invasive Ventilation Patient 4 84 Female Sporadic Bulbar -0.7 points / month
Respiratory Insufficiency None
IL-2 and CTLA4-Ig significantly
increased Treg suppressive function in vivo Treatment Period Follow-Up IL-2 and CTLA4-Ig significantly upregulates Treg suppressive function as early as 4 weeks after initiation of treatment and maintained a significantly increased Treg function
over the course of treatment. * p<0.05 ** p <0.01 (paired t test) ** ** *
IL-2/CTL4-Ig Significantly Increased
Treg Numbers in vivo Consistent with the significant increase in Treg function, IL-2 and CTLA4-Ig increased Treg numbers as early as 4 weeks after initiation of treatment and maintained a higher number over the course of treatment. ** * n.s. n.s. *
p<0.05 ** p <0.01 n.s.: not significant (paired t test) Treatment Period Follow-Up
IL-2/CTLA-Ig - Lipid Peroxide
Biomarkers (interim data) * n.s. * p<0.05 n.s.: not significant (paired t test)
IL-2/CTLA4-Ig - Biomarkers by
Patient (interim data)
The mean ALSFRS-R scores at 24 and
48 weeks after initiation of treatment were not statistically different, compared to the baseline score n.s. 48-Week Treatment Follow-Up B: baseline n.s.: not significant (paired t test) IL-2 and CTLA4-Ig appeared to ameliorate disease progression
over the course of the 48-week treatment n.s.
Safety Summary Overall, treatment
with IL-2 and CTL4-Ig was well tolerated over 48 weeks. Most common adverse event was mild injection site reaction. All patients completed the study. No death or other serious adverse event occurred over the course of the study.
Conclusions: Biomarkers and
Therapeutic Targets in ALS In ALS Treg's normal neuroprotective functions are impaired and macrophages/microglia are proinflammatory. Macrophage/myeloid-mediated inflammatory cytokines, oxidative stress, and lipid peroxides are increased
promoting neuronal injury and cell death in ALS. IL-2 expands Tregs and suppresses the proliferation of T effector cells and to a much lesser extent the proinflammatory macrophages responsible for oxidative stress and cytotoxic cytokines. The
deleterious effects of heightened proinflammatory secretions mandates the use of CTLA4-Ig in combination with IL-2 to provide suppression of activated macrophages as well as Tcells, not accomplished by IL-2 alone. In the present study in ALS,
administration of IL-2 and CTLA4Ig over 48 weeks enhanced suppression of biomarkers of macrophage-mediated oxidative stress and proinflammatory cytokines as well as T cells. Overall, IL-2 and CTLA4-Ig administration was well tolerated. IL-2 and
CTLA4-Ig appeared to ameliorate disease progression for 48 weeks. These data suggest that IL-2 and CTLA4-Ig together provide a potentially meaningful approach for the "unmet therapeutic need" in ALS.