Roche Holding Ltd · SIX:RO
Roche — 60th European Association for the Study of Diabetes (EASD) Annual Meeting 2024
20 slides from Roche's conference presentation, Sep 11, 2024
Slide 1: Safety, Pharmacokinetics, and Pharmacodynamics of CT-996 Over 4 Weeks in Adults With Obesity
Safety, Pharmacokinetics, and Pharmacodynamics of CT-996, an Oral Small-Molecule, Signal-Biased GLP-1 Receptor Agonist Over 4 Weeks in Adults With Obesity Manu V Chakravarthy,1 Paul Wabnitz,2 Jingtao Wu,1 Stacey Toussaint Touson,1 Michael A Elliott, 1 Christina C Chang,3 Jason Lickliter 3 1F. Hoffma
Slide 2: Disclosures
Disclosures ■ MV Chakravarthy, J Wu, and S Toussaint Touson are full-time employees of Roche and may hold Roche stock and/or stock options ■ P Wabnitz is an employee of Avance Clinical, which has a consulting agreement with Carmot/Roche ■ MA Elliott is a former employee of Carmot Therapeutics (now R
Slide 3: Challenges and Opportunities in the Treatment of Obesity
Challenges and Opportunities in the Treatment of Obesity Worldwide adult Approved medications are effective for weight loss3–5 prevalence (2020) 1 However, challenges remain: With obesity or overweight 2.2B (growing to 3.3B by 2035) Access6,7 | Adherence7 | Tolerability6,7 With obesity 810M (growing
Slide 4: CT-996 Is a Small-Molecule Oral GLP-1 Receptor Agonist
CT-996 Is a Small-Molecule Oral GLP-1 Receptor Agonist Intended for once-daily oral administration for T2D, obesity, and obesity-related comorbidities GLP-1 Required design elements to achieve receptor meaningfully differentiated attributes CT-9961,2 Highly potent, cAMP biased, selective GLP-1 recep
Slide 5: CT-996: In Vitro and In Vivo Properties
CT-996: In Vitro and In Vivo Properties hGLP-1 Receptor cAMP hGLP-1 Receptor β-arrestin-2 hGLP-1 Receptor Internalization CT-996 is a potent and cAMP-biased GLP-1 receptor agonist1 Sub-nM potency on hGLP-1 receptor ~20-fold weaker β-arrestin-2 ~200-fold weaker internalization recruitment to hGLP-1 r
Slide 6: Study CT-996-201
Study CT-996-201 First-in-Human, 3-Part, Multi-Cohort, Phase I, Randomized, Double-Blind, Placebo-Controlled Study Part 1: SAD (Overweight/Obesity, n = 40) | Part 2: MAD (Obesity, n = 25) | Part 3: MAD (Obesity + T2D, n = ~30) Overall Study Objective To investigate the safety, tolerability, pharmaco
Slide 7: CT-996-201 MAD: 3 Sequential Dose Escalation Cohorts Over 4 Weeks
CT-996-201 MAD: 3 Sequential Dose Escalation Cohorts Over 4 Weeks Eligibility • Adults aged 18–65 years n = 8 per cohort planned criteria: • BMI ≥ 30 kg/m 2 and otherwise healthy 3:1 randomization [CT-996 (6):Placebo (2)] Single-center MAD study Placebo 4-week follow-up conducted in Australiaa 90 mg
Slide 8: Rationale for Rapid Up-Titration Design in the Phase 1 Study
Rationale for Rapid Up-Titration Design in the Phase 1 Study “Fail fast” approach early in development ra o approa e a “ ar low a d o low” ave been known to improve the tolerability profile of incretin therapies Objective Rapid determination if unexpected safety signals or efficacy patterns might ex
Slide 9: The MAD Portion of the Study Included Participants With Obesity and Without T2D
The MAD Portion of the Study Included Participants With Obesity and Without T2D Study enrolled 25 participants in 3 sequential cohorts 3:1 randomization [CT-996 (6):Placebo (2)] in each cohort Placebo Cohort 1a Cohort 2b Cohort 3c Category (n = 6) (n = 6) (n = 7) (n = 6) Age, years 42.8 (9.3) 40.0 (
Slide 10: 92% of Participants Completed Study Drug Treatment
92% of Participants Completed Study Drug Treatment No study drug-related discontinuations Participant Disposition Titrations in study completers who MAD received CT-996 (N = 25) Cohort Actual vs planned dosing Cohort 1 Cohort 2 Cohort 3 All participants followed the Placebo CT-996 CT-996 CT-996 Coho
Slide 11: Once-Daily Oral Dosing of CT-996 Over 4 Weeks Yielded Weight Loss of up to 7.3%
Once-Daily Oral Dosing of CT-996 Over 4 Weeks Yielded Weight Loss of up to 7.3% Percent change in body weight appears to be linear Clinically meaningful placebo-adjusted weight over time (~2.0% [~1.8 kg] per week), with no plateau loss of -6.1% for cohort 3 (P < 0.001)a 0 0 Change From Baseline Chan
Slide 12: CT-996 Reduced Blood Glucose and Insulin During Mixed Meal Tolerance Test
CT-996 Treatment Over 28 Days Resulted in Reductions in Blood Glucose and Insulin During a Mixed Meal Tolerance Test Glucose Concentration vs Time 2 Glucose AUC LS Mean (SE) Change From 9 0.3 Day -1 to Day 28 Glucose AUC0-240m in (mmol/L*min) 1 During MMTT (mmol/L) Mean (SD) Glucose 8 7 0 6 -1 5 -2
Slide 13: PK Parameters Support Once-Daily Dosing
PK Parameters Support Once-Daily Dosing Day 28 – time-concentration profile Day 28 – PK parameters 1E+04 (semi-log scale) Mean Concentration, ng/mL Parameters, Cohort 1a Cohort 2b Cohort 3c mean (SD) 1000 Cmax, 1070 1550 1620 ng/mL (275) (752) (1130) 100 AUClast, 22,900 23,900 37,900 h*ng/mL (3560)
Slide 14: All TEAEs Were Mild or Moderate Across MAD Cohorts
All TEAEs Were Mild or Moderate Across MAD Cohorts ■ All TEAEs were mild or moderate in severity; no severe (Grade 3) TEAEs ■ 1 serious AE (unrelated to study drug) ■ No discontinuations related to study drug Placebo Cohort 1a Cohort 2b Cohort 3c Category, n (%) (n = 6) (n = 6) (n = 7) (n = 6) Parti
Slide 15: The Most Common TEAEs Were GI-Related, Consistent With Other Incretin Therapies
The Most Common TEAEs Were GI-Related, Consistent With Other Incretin Therapies ■ Frequency of GI-related TEAEs consistent with brisk up-titration and early stage of development* Higher-dose cohorts exhibited more frequent TEAEs, and ■ Higher-dose cohorts exhibited more TEAEs, and a more gradual tit
Slide 16: GI-Related TEAEs Were Mostly Mild
GI-Related TEAEs Were Mostly Mild Placebo Cohort 1a Cohort 2b Cohort 3c TEAE, n (%) (n = 6) (n = 6) (n = 7) (n = 6) Nausea 1 (16.7) 5 (83.3) 6 (85.7) 5 (83.3) There were no Grade 3 (severe) Grade 1 1 (16.7) 5 (83.3) 6 (85.7) 5 (83.3) Grade 2 0 0 0 0 GI-related AEs Grade 3 0 0 0 0 Constipation 1 (16.
Slide 17: Despite Rapid Up-Titration Approach, No Unexpected Safety Signals Were Observed
Despite Rapid Up-Titration Approach, No Unexpected Safety Signals Were Observed Changes in laboratory parameters and vital signs Laboratory investigations were generally NCS ECG findings (including QTc) were NCS, except for 1 participant who experienced an No signals of liver injury RBBB, reported a
Slide 18: Summary
Summary ■ CT-996 treatment produced robust weight loss of up to 7.3% (7 kg) over 4 weeks – Slowing the pace of titration in cohort 3 tended to yield more weight loss than cohort 2 → suggests slower titration approaches may not compromise the weight loss efficacy of CT-996 – Magnitude of weight loss
Slide 19: Next Steps
Next Steps Complete part 3 of the ongoing phase 1b study Initiate phase 2 (4-week cohorts in studies in 2025 participants with obesity and T2D) T2D, type 2 diabetes. 19
Slide 20: Acknowledgments
Acknowledgments ■ We thank the participants and their families ■ Study site staff ■ This study was funded by Carmot Therapeutics, a member of the Roche group. Medical writing assistance was funded by Roche and provided by Alicia Salinero, PhD, ISMPP CMPP, of JB Ashtin 20