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Show VRDN-001, a Full Antagonist Antibody to IGF-1 Receptor for Thyroid Eye Disease (TED): Phase 1/2 Clinical Study in Patients Raymond S. Douglas*, Chantal Boisvert, Kimberly Cockerham, David Kaufman, Andrea Kossler, Wendy W. Lee, Navdeep Nijhawan, Rosa Tang, Roger Turbin, Shoaib Ugradar, Michael T. Yen, Michael Yoon, Barrett Katz *Professor of Surgery, Division of Ophthalmology Director, Orbital and Thyroid Eye Disease Program Cedars-Sinai Medical Center (Los Angeles, CA) Financial Disclosures Consultant for the following companies: • Horizon Therapeutics • Viridian • ValenzaBio TED: Inflammation, Tissue Expansion, and Remodeling in the Orbit Adipose tissue expansion TED results in inflammation and tissue expansion in the fixed bony orbit. These changes result in shortterm and long-term consequences including proptosis and dysmotility. Extraocular muscle expansion Insulin-like Growth Factor-1 Receptor • Overexpressed on Graves’ Disease (GD) fibroblasts • Signaling of fibroblasts and immune cells mimics pathologic findings • Antibodies to these receptors in GD patients IGF-1R Overexpression is a Hallmark of GD Douglas RS, et al. J Immunology, 2007. 178(5):3281-3287. Medical Treatment of Moderate-to-Severe TED • • • • Intravenous corticosteroids: Utilized in TED with inflammatory signs including conjunctival injection, chemosis, eyelid erythema and edema. Does not address proptosis or significant impact on dysmotility. Radiotherapy: Utilized in conjunction with corticosteroids in some patients with inflammatory signs. Does not reduce proptosis or have significant impact on dysmotility. Teprotumumab: Preferred treatment, if available, when significant proptosis, dysmotility with or without inflammatory signs. Rituximab and tocilizumab: May be considered for glucocorticoid-resistant patients but not FDA approved and not widely used. Burch HB, Perros P, Bednarczuk T, Cooper DS, Dolman PJ, Leung AM, Mombaerts I, Salvi M, Stan MN. Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the European Thyroid Association. Thyroid. 2022 Dec;32(12):1439-1470. Antigen Specific (IGF-1R) Therapies for Active and Chronic TED Delivery Phase Status IV infusion IV infusion Approved in US Approved in US since 2020 Phase 3 Positive phase 1/2 data, phase 3 expected in 2024 Linsitinib PO Phase 2b Phase 2b data expected in 2023 VRDN-002 SC Phase 2 Phase 2 data expected in 2023 Lonigutamab SC Phase 1b Phase 1b data expected in 2023 Teprotumumab SC Phase 1 Phase 1 underway VRDN-003 SC Preclinical Phase 1 data expected in 2023 Teprotumumab mAb VRDN-001 mAb Small molecule mAb mAb mAb mAb VRDN-001 Proof-of-Concept Study Tested 3 Different Doses in Active TED Randomized, Double-Blind Trial vs Placebo Active TED • Clinical activity score (CAS) of ≥4 • Onset of symptoms within past 12 months Cohort 1 VRDN-001 10 mg/kg Q3W x 2 (n=6) Placebo (n=2) Cohort 2 VRDN-001 20 mg/kg Q3W x 2 (n=6) Placebo (n=2) Cohort 3 VRDN-001 3 mg/kg Q3W x 2 (n=9) Placebo (n=1)* *2 patients were randomized to the placebo arm, with 1 patient in the 3 mg/kg cohort’s placebo arm discontinuing the study before week 6. Data contained within presentation are interim data as not all patients have completed the study. Baseline Patient Characteristics VRDN-001 VRDN-001 3 mg/kg VRDN-001 10 mg/kg VRDN-001 20 mg/kg Placebo 21 9 6 6 5 42 41 Proptosis, mean (SEM) 23.7 (0.7) 23.1 (1.2) 24.8 (1.2) 23.6 (1.3) 22.8 (2) 23.4 22.6 CAS, mean (SEM) 5.4 (0.2) 5.4 (0.4) 5.2 (0.3) 5.5 (0.4) 5.0 (0.5) 5.1 5.1 Diplopia, n (%) 13 (62%) 5 (56%) 4 (67%) 4 (67%) 3 (60%) 38 (90%) 28 (67%) Diplopia, mean (SEM) 1.3 (0.3) 1.3 (0.4) 1.3 (0.5) 1.3 (0.4) 1.6 (0.7) 1.8 Not reported Months since onset of TED signs/symptoms, mean (SEM) 7.4 (0.8) 7.7 (1.1) 7.3 (1.7) 6.9 (1.7) 7.0 (2.0) 4.7 6.2 Age, years (SEM) 47 (3.3) 51.2 (4.8) 38.7 (5.2) 48.8 (7.0) 44.2 (4.3) 51.6 51.6 Female, n (%) 19 (90%) 8 (89%) 4 (67%) 6 (100%) 3 (60%) 28 (65%) 29 (71%) (3, 10, and 20 mg/kg) n SEM = Standard error of the mean Teprotumumab Phase 2 data: Smith TJ, et al, NEJM 376:18, May 2017. Teprotumumab Phase 3 data: Douglas RS, et al, NEJM 382:4, Jan 2020. FDA clinical review of teprotumumab (BLA 761143) All data regarding teprotumumab in this presentation are from separate teprotumumab studies. Conclusions are not based on head-to-head results. Teprotumumab Ph2 Teprotumumab Ph3 VRDN-001 Efficacy Measures Signs Symptoms Improvement in proptosis Overall response: Signs + symptoms Proptosis: Responder rate (Improvement in proptosis & clinical activity score) (% with ≥2mm reduction from baseline to week 6) 67% 71% VRDN-001 (3, 10 or 20 mg/kg; week 6) n=21 3 mg/kg / 10 mg/kg / 20 mg/kg n=9 n=6 n=6 Teprotumumab (at 10 mg/kg 20 mg/kg; week 6) 56% 83% 44% 67% 67% 83% 56% Improvement in clinical activity score (CAS) and diplopia score Proptosis: Mean change by exophthalmometry (change from baseline to week 6) CAS: Score of 0 or 1 CAS: Mean change (% achieving CAS of 0 or 1 at week 6) (change from baseline to week 6) 62% -4.1 -2.3 mm 67% -2.7 mm -2.4 mm -1.9 mm -1.7 mm 67% 83% 22% Clinical Activity Score (CAS) = a composite 0-7 scale scoring signs and symptoms of TED *Diplopia was present at baseline in 13 out of 21 drug-treated patients; 4 in 10 mg/kg cohort, 4 in 20 mg/kg cohort and 5 in the 3 mg/kg cohort All data regarding teprotumumab in this presentation are from separate teprotumumab studies. Conclusions are not based on head-to-head results. 33% -4.2 -4.3 Diplopia: Complete resolution* (% improved to a score of 0 at week 6) 54% -3.7 20% -2.1 Teprotumumab Phase 3 data: Douglas RS, et al, NEJM 382:4, Jan 2020, Douglas RS, et al, Ophthalmology 129:4, Apr 2022 75% 36% 75% Exophthalmometry and MRI Together Provide Robust Assessment of Proptosis Hertel Exophthalmometer • Most commonly used • Successfully used as primary endpoint in prior clinical trials in TED • THRIVE Phase 3 trial primary endpoint Magnetic Resonance Imaging • More precise • 3D reconstruction algorithm used • Centrally read by 2 masked reviewers • Exploratory measure to potentially differentiate overall data findings VRDN-001 Proptosis Improvement by Exophthalmometer and MRI Mean proptosis change (from baseline to week 6) (by MRI) 1 * 0 * * * * -2 -4 Placebo VRDN-001 -6 Blinded, centrally reviewed MRI data were available for 5/5 placebo patients and 16/21 VRDN-001 patients. All MRI images were reviewed centrally by 2 independent, blinded readers. *2 placebo patients and 3 VRDN-001 patients were proptosis responders by exophthalmometer, but response was not confirmed by MRI. Change from baseline proptosis (mm) Change from baseline proptosis (mm) 2 Placebo n=5 +0.03mm 0 -1 -2 VRDN-001 n=16 -2.76mm -3 0 Time (weeks) 6 Preliminary top line data as not all patient MRI’s have been fully analyzed Adj. mean proptosis change (by exophthalmometer) 1 Change from baseline proptosis (mm) Proptosis change by MRI Placebo n=3 -0.3mm 0 -1 VRDN-001 n=18 -2.22mm -2 -3 0 6 Time (weeks) Patients where MRI did not confirm exophthalmometer response were excluded from this analysis. Improvement in Signs and Symptoms as Measured by CAS Mean change in CAS (from baseline to week 6) Placebo VRDN-001 10 mg/kg: 83% 20 mg/kg: 33% -1 Placebo n=5 -1.75 -2 ≥5 62% Responders Change from baseline score (from baseline to week 6) 3 mg/kg: 67% 0 -3 -4 Reduction in CAS CAS of 0 or 1 at week 6 3 mg/kg: -4.2 10 mg/kg: -4.3 20 mg/kg: -3.7 VRDN-001 n=21 -4.10 20% ≥4 ≥3 43% 76% 9/21 16/21 19/21 90% 2/5 40% -5 0 6 Time (weeks) VRDN-001 n=21 Placebo n=5 -100% -50% 0% 50% 100% 54% of VRDN-001 Patients Had Complete Diplopia Resolution at Week 6 Complete diplopia resolution at week 6 3 mg/kg: 20% 10 mg/kg: 75% 20 mg/kg: 75% Diplopia resolution rate defined as % of patients with diplopia at baseline that improved to a score of 0 54% S 0% VRDN-001 n=13 Placebo n=3 For patients with diplopia at baseline, complete diplopia resolution defined as Gorman subjective diplopia score of zero Favorable Safety Profile VRDN-001 3 mg/kg (n=9), n No serious adverse events (SAEs), no infusion reactions, and no discontinuations in patients treated with VRDN-001 Teprotumumab label VRDN-001 10 mg/kg (n=6), n VRDN-001 20 mg/kg (n=6), n Placebo (n=6), n Teprotumumab (n=84), n (%) Placebo (n=86), n (%) Muscle spasms 2 2 2** - 21 (25%) 6 (7%) Nausea 2 - - - 14 (17%) 8 (9%) Alopecia - - - 1 11 (13%) 7 (8%) Diarrhea 1 2** 1* - 10 (12%) 7 (8%) Fatigue - 1 - 3 10 (12%) 6 (7%) Hyperglycemia 1 - 1* - 8 (10%) 1 (1%) Hearing impairment 1 1 - - 8 (10%) 0 (0%) Dysgeusia - - 1 - 7 (8%) 0 (0%) Headache 2 1 1 2** 7 (8%) 6 (7%) Dry skin 1 - 1 - 7 (8%) 0 (0%) Infusion reactions - - - - 4% N/A *Deemed unrelated to study drug by the masked investigators ** One patient deemed related and one patient deemed unrelated to study drug by the masked investigators Data are as of data cut-off of December 19, 2022. Other AE that occurred in more than one patient and deemed related to study drug by masked investigators was acne (n=2). Instances were mild and did not require intervention. Muscle spasms were mild and did not require intervention; hearing impairment (n=2) resolved without intervention in both cases. Both patients with hyperglycemia were diabetic at baseline; in 1 case glucose variability was determined by masked PI to be unrelated to drug. All data regarding teprotumumab in this presentation are from separate teprotumumab studies. Conclusions are not based on head-tohead results. Patient Case Report after 2 Infusions of 3 mg/kg VRND-001 Baseline patient characteristics • Proptosis: 29 mm • CAS: 7 Photo taken by patient 2 days before first dose of VRDN-001 Case report patient information and photos taken by patient used with patient and investigator permission. Patient received 2 infusions in the study; in extended follow-up off treatment, TED symptoms have returned for this patient. Following VRDN-001 treatment, at week 6 • Change in proptosis by Hertel: -5 mm • Change in proptosis by MRI: -5.2 mm • Change in CAS: -6 points Photo taken by patient 2 days following second dose of VRDN-001 Conclusion • Based on the results of this phase 2 proof-of-concept study of 3 different doses of VRDN-001, VRDN-001 shows promise for the treatment of TED. • The efficacy and safety of VRDN-001 for the treatment of TED will be further assessed in the ongoing THRIVE Phase 3 clinical trial (NCT05176639) |
