Introduction

Substantial genetic and clinical evidence indicates that TL1A has a key role in the molecular pathology of IBD. Variants in TNFSF15, the gene encoding TL1A, are associated with IBD, rheumatic, and other diseases. Circulating levels of the protein are elevated in patients with CD and UC. Proof-of-concept for TL1A inhibition in IBD is provided by positive Phase 2 trials of monoclonal antibodies targeting and inhibiting the cytokine in patients with UC and CD (1–3).
SPY002 is an investigational fully human IgG1 monoclonal antibody that specifically binds to TL1A at an epitope that is distinct from other TL1A antibodies in development. SPY002 blocks the interaction of TL1A with its receptor, known as death receptor 3 (DR3), and includes a YTE modification in the Fc domain to increase the binding affinity to FcRn and thereby extend the antibody half-life. A Phase 1, first-in-human study in healthy volunteers is being conducted to characterize the safety, tolerability, PK, and PD properties of SPY002.

Aims & Methods

SPY002-101 is a randomized, double-blind, placebo-controlled single ascending dose (SAD) Phase 1 study in healthy volunteers aged 18 to 65. Study participants were randomized to either SPY002 or placebo in a 3:1 ratio as in dose cohorts as follows: 100 mg SC, 300 mg SC, 300 mg IV, 1000 mg IV, or 1500 mg IV. Blood was collected to evaluate safety, PK, PD (serum soluble TL1A levels), and ADA assessments at scheduled study visits. Interim safety and bioanalytical data with up to three months of follow-up from the first SAD cohort were analyzed.

Results

Interim PK data from Cohorts 1-3 demonstrated dose-proportional pharmacokinetics for SPY002. Noncompartmental[BW1] [JF2] [JL3] [BW4] [JL5] analysis and population PK modeling suggested a half-life extension of approximately 3-fold relative to typical monoclonal antibodies. PD analysis demonstrated saturating effects on soluble TL1A levels beginning with the lowest dose tested (100 mg SC) that extend to the latest time points assessed thus far. Blinded safety data from all cohorts thus far demonstrated SPY002 to be well tolerated with no serious or severe adverse events, with most adverse events being mild in severity and unrelated to study agent.

Conclusion

Interim PK analysis following single doses of SPY002 demonstrated half-life extension supporting potential maintenance dosing at a frequency of every 3 to 6 months with a single SC injection. SPY002 resulted in saturating changes in soluble TL1A levels. SPY002 was well tolerated, with all adverse events being non-serious and typical of a Phase 1 study in healthy volunteers. These results support advancement of SPY002 into clinical trials in IBD, rheumatic, and other potential indications as a monotherapy and as a component of combination therapy.

References

1. B. Sands, L. Peyrin-Biroulet, S. Danese, D. T. Rubin, S. Vermeire, O. Laurent, A. Luo, D. Nguyen, J. D. Lu, A. Wiechowska-Kozlowska, J. Leszczyszyn, R. Kempinski, J. Kierkus, C. Ma, T. Ritter, B. G. Feagan, S. Targan, OP40 PRA023 Demonstrated Efficacy and Favorable Safety as Induction Therapy for Moderately to Severely Active UC: Phase 2 ARTEMIS-UC Study Results. J. Crohn’s Colitis 17, i56–i59 (2023).
2. B. G. Feagan, B. E. Sands, C. A. Siegel, M. C. Dubinsky, R. Longman, J. Sabino, O. Laurent, A. Luo, J. D. Lu, D. D. Nguyen, F. Towfic, A. DuVall, M. Woynarowski, H. A. Kharrat, D. McGovern, S1143 The Anti-TL1A Antibody PRA023 Demonstrated Proof-of-Concept in Crohn’s Disease: Phase 2a APOLLO-CD Study Results. Am. J. Gastroenterol. 118, S875–S876 (2023).
3. S. Danese, M. Klopocka, E. J. Scherl, J. Romatowski, J. R. Allegretti, E. Peeva, M. S. Vincent, U. Schoenbeck, Z. Ye, M. Hassan-Zahraee, N. Rath, G. Li, S. Neelakantan, C. Banfield, C. Lepsy, D. E. Chandra, K. E. Hung, Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study. Clin. Gastroenterol. Hepatol. 19, 2324-2332.e6 (2021).

Disclosure

All authors are employees of and own stock in Spyre Therapeutics.

Introduction

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease characterized by intestinal inflammation, mainly including Crohn’s Disease (CD) and Ulcerative Colitis (UC), both of which will cause swelling and ulceration in the inner wall of gastrointestinal tract ^[1]. ISM5411 is an oral gut-restrictive small molecule inhibitor targeting PHD2 to stabilize hypoxia inducible factors (HIF-1α), thus promoting the expression of intestinal mucosal protective genes, maintaining the integrity and functions of intestinal barrier to finally achieve the purpose of protecting and repairing intestinal mucosal barrier together with anti-inflammation. Preclinical studies demonstrated that ISM5411 can significantly alleviate the symptoms of multiple animal models of colitis without significant increase in systemic erythropoietin (EPO) or vascular endothelial growth factor (VEGF) ^[2]. The first-in-human Phase I study in Australia was completed to evaluate safety, tolerability, pharmacokinetics and food effect in healthy subjects.

Aims & Methods

ISM5411-101 was a randomized, double-blinded, placebo-controlled, single and multiple-dosed and food effect first-in-human Phase I study conducted in healthy subjects at a single site in Australia. Seven dose levels from 50 mg to 1000 mg of single ascending doses and three dose levels from 200 mg to 800 mg once daily for 14 days of multiple doses of ISM5411 were administrated. Safety and tolerability, pharmacokinetics (PK) parameters (plasma, urine and feces) and biomarkers (EPO and VEGF levels) were evaluated.

Results

Seventy-six subjects were dosed with no serious adverse events (SAEs) or deaths recorded. One treatment emergent adverse event (TEAE) leading to discontinuation of ISM5411 occurred (Grade 1, rectal hemorrhage) in 200 mg once daily ISM5411 cohort was reported and judged as not related to ISM5411. The incidence of TEAEs was 25.0% and 55.0% in ISM5411 pooled cohort (n=56) and placebo cohort (n=20). All TEAEs reported in ISM5411 pooled cohorts were Grade 1. After single and multiple doses administration, ISM5411 was rapidly absorbed and metabolized to metabolite (ISM5411-M15). The plasma exposure of both analytes was very low without apparent dose-proportional manner. ISM5411 was excreted in the feces in its prototypic form by more than 30%. Systemic EPO level increased post-dose in most cohorts then decreased, and most changes were within normal range. No clear trend was observed in the change of mean systemic VEGF levels across cohorts.

Conclusion

ISM5411 tablets were safe and well-tolerated and demonstrated good gut-restrictive property, consistent with the intended PK profile. Another Phase I study in China was also completed. Phase 2a proof of concept study of ISM5411 is under planned in patients with ulcerative colitis to explore the safety, PK and clinical efficacy.

References

1. Chang JT. Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med, 2020 Dec 31;383(27): 2652-2664
2. Fu, Y., Ding, X., Zhang, M. et al. Intestinal mucosal barrier repair and immune regulation with an AI-developed gut-restricted PHD inhibitor. Nat Biotechnol (2024).

Introduction

Existing treatments aim to induce and maintain remission in Ulcerative Colitis (UC); however, 30–55% of patients remain refractory during the induction phase, highlighting an unmet need for novel therapeutic options(1). Phosphodiesterase-4 (PDE4) is a cyclic adenosine monophosphate (cAMP)-specific enzyme expressed by immune and inflammatory cells. Abnormal expression of PDE4 and dysregulated signal transduction have been reported in colonic biopsies from patients with UC (2,3). Orismilast is an oral, B/D-selective PDE4 inhibitor with a modified-release formulation.

Aims & Methods

This study (the UCORIS study) was a phase 2a, open-label, single-arm exploratory clinical study assessing the efficacy and safety of orismilast in patients with moderate to severe UC. Patients with UC currently on stable 5-ASA treatment and experiencing moderate-severe disease activity (defined as a Mayo endoscopic sub score of 2 or 3) were eligible for inclusion. Orismilast was administered twice daily for 12 weeks, with investigators allowed to individualize the dose based on body weight, treatment response and side effects. Responding patients could extend treatment to a total duration of 52 weeks.
A last-observation-carried-forward (LOCF) approach was applied to early discontinuers when com-paring to those who completed treatment. No hypothesis testing was performed due to the small sample size. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or lower, with no individual sub score exceeding 1.

Results

10 patients were included in the study. Six participants discontinued the study prematurely - three due to lack of efficacy and three due to adverse events. Clinical remission at week 12 was achieved by one patient, who continued orismilast for 50 weeks, maintaining endoscopic remission.
In the completed trial group, mean Total Mayo Score decreased from 9.75 to 5.25 (Δ– 4.50, [95% CI: -4.17;13.17], p=0.20), and Partial Mayo Score from 7.25 to 3.75 (Δ –3.5, [95% CI: -2.66;9.66], p=0.17). In the early determination group, Partial Mayo Score declined from 5.83 to 4.17 (Δ–1.66, [95% CI: -2.46;5.79], p=0.35); follow-up Total Mayo Scores were unavailable. Faecal calprotectin levels showed modest reductions in both groups.
A total of 75 adverse events (AEs) were recorded. Of these, 48 were mild (68%), consistent with previous findings(4). The most common ADRs were nausea (15% of AEs; 8 patients (80%)), abdominal pain (12%; 5 patients (50%)), dizziness (5%; 2 patients (20%)), and headache (4%; 2 patients (20%)). Three serious AEs occurred in one patient but did not result in discontinuation. None of the serious AEs were considered related to orismilast. The overall safety profile aligned with known effects of PDE4 inhibitors(4–6), although the frequency of nausea was higher, potentially reflecting overlap with underlying disease symptoms.

Conclusion

Orismilast demonstrated reductions in both Total and Partial Mayo scores among patients who completed the trial, and a reduction in Partial Mayo score among those who discontinued early. Although only one patient, who completed the full 12-week regimen, achieved both clinical and endoscopic response, three out of ten patients achieved remission based on Partial Mayo score, faecal calprotectin, and SCCAI. Adverse drug reactions were common; although none were severe, nausea had a notable impact on daily life. Effective management of this adverse event may be essential to improving tolerability and supporting the therapeutic potential of orismilast in the treatment of ulcerative colitis.

References

1. Zhao M, Sall Jensen M, et al. Trends in the use of biologicals and their treatment outcomes among patients with inflammatory bowel diseases – a Danish nationwide cohort study. Aliment Pharmacol Ther. 2022 Mar 1;55(5):541–57.
2. Spina D. PDE4 inhibitors: Current status. Vol. 155, British Journal of Pharmacology. 2008. p. 308–15.
3. Li H, Zhang Y, Liu M, et al. Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis. Acta Pharm Sin B. 2022 Jan 1;12(1):228–45.
4. Silverberg JI, Eichenfield LF, et al. Orismilast, a PDE4B/D inhibitor, in moderate-to-severe atopic dermatitis: Efficacy and safety from a multicenter, randomized, placebo-controlled, phase 2b dose-ranging study (ADESOS). Br J Dermatol [Internet]. 2025 Jan 7;
5. Warren RB, French LE, et al. Orismilast in moderate-to-severe psoriasis: Efficacy and safety from a 16-week, randomized, double-blinded, placebo-controlled, dose-finding, and phase 2b trial (IASOS). J Am Acad Dermatol. 2024 Mar 1;90(3):494–503.
6. Frederiksen CG, Sedeh FB, et al. Orismilast for the treatment of mild to severe hidradenitis suppurativa: Week 16 data from OSIRIS, a Phase 2a, open-label, single-centre, single-arm, dose-finding clinical trial. Journal of the European Academy of Dermatology and Venereology. 2024 May 1;38(5):920–30.

Disclosure

TVH: No disclosures
JBS: Research grants from Takeda and Johnson and Johnson, national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim.
JB: Dr. Burisch reports grants from AbbVie, Janssen-Cilag, MSD, Takeda, Tillots Pharma, Bristol Myers Squibb, and Novo Nordisk Foundation; personal fees from AbbVie, Janssen-Cilag, Celgene, MSD, Pfizer, Takeda, Tillots Pharma, Bristol Myers Squibb, Samsung Bioepis, Pharmacosmos, Ferring, Galapagos, Eli Lilly, Dr Falk Pharma, Celltrion and Orion Pharma.