Slide 1: Encaleret (CLTX-305) Phase 2B Results in ADH1
Encaleret (CLTX- 305) Phase 2B Results in ADH1 June 2022 Encaleret is an investigational drug. Its safety and efficacy Alexis and Jackson have not been fully evaluated by any regulatory authority. Living with ADH1
Slide 2: Forward-Looking Statements and Disclaimer
Forward-Looking Statements and Disclaimer Statements in this Presentation that are not statements of historical fact are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Such fo
Slide 3: Encaleret Development Program
Encaleret Neil Kumar, Ph.D. Development Founder and CEO Program 3
Slide 4: Encaleret program history: From IND to Phase 3-ready program in less than 3 years
Encaleret program history: From IND to Phase 3-ready program in less than 3 years Sep 2020 Jun 2021 Q1 2022 Jun 2022 FDA fast track FDA end of Phase 2b study initiated Report Phase 2 designation Phase 2 in ADH1 results at ENDO announced meeting Mar 2021 Dec 2019 2H 2022 Proof-of-concept data IND ope
Slide 5: ADH1 is a serious condition for which treatable patient numbers may grow meaningfully
ADH1 is a serious condition for which treatable patient numbers may grow meaningfully as diagnosis rates increase ~12k carriers of ADH1 causing variants in the US Analogous ADH1 market includes XLH Estimated US Prevalence1 (K) XLH ADH1 14000 Prevalence (US) 12K4 12K 12000 Acute hypocalcemia Disease
Slide 6: ADH1 unmet need is large with significant disease burden and no interventions specifically approved
ADH1 unmet need is large with significant disease burden and no interventions specifically approved >70% of ADH1 cases exhibit symptoms of Current treatments inadequately address hypocalcemia1 symptom burden1 ADH1 cases (n=192) Individuals receiving calcium and/or active vitamin D (n=58) % % Asympto
Slide 7: Phase 2 Results
Phase 2 Rachel Gafni, M.D. Results Senior Research Physician and Head of the Mineral Homeostasis Studies Group National Institute of Dental and Craniofacial Research of the National Institutes of Health (NIH) Encaleret is an investigational drug. Its safety and efficacy have not been fully evaluated
Slide 8: Encaleret Restored Mineral Homeostasis in a Phase 2 Study in ADH1
Encaleret (CLTX-305) Restored Mineral Homeostasis in a Phase 2 Study in Autosomal Dominant Hypocalcemia Type 1 (ADH1) [NCT04581629] RI Gafni, IR Hartley, KL Roszko, EF Nemeth, KA Pozo, R Sani-Grosso, AS Mathew, AV Sridhar, MS Roberts, JC Fox, MT Collins Prepared for presentation at the ENDO 2022 Ann
Slide 9: Blood calcium is maintained by four organs regulated by CaSR and PTH
Blood calcium is maintained by four organs regulated by the calcium- sensing receptor (CaSR) and parathyroid hormone (PTH) 9 Ca2+ = ionized calcium; PTH = parathyroid hormone; CaSR = calcium-sensing receptor
Slide 10: Activating variants in the CASR cause Autosomal Dominant Hypocalcemia Type 1
Activating variants in the CASR cause Autosomal Dominant Hypocalcemia Type 1 (ADH1) Activating variants in the CASR increase Hyperactive CaSR causes dysregulation Clinical Manifestations tissue sensitivity to Ca2+ of Ca homeostasis Acute symptoms Parathyroid Hypocalcemic seizures Wild Decreased para
Slide 11: Encaleret, an investigational oral calcilytic, may be a potential treatment for ADH1
Encaleret, an investigational oral calcilytic, may be a potential treatment for ADH1 • Calcilytics are negative allosteric modulators of the CaSR that decrease CaSR sensitivity to extracellular calcium • Normalizing CaSR sensitivity could correct hypocalcemia, hypercalciuria, and low PTH in individu
Slide 12: Encaleret Phase 2B Study Design – CLTX-305-201
Encaleret Phase 2B Study Design – CLTX-305-201 Period 1 1 Period 2 1 Period 3 LTE Individualized dose Individualized dose Long-term extension Outpatient extension (LTE) escalation titration 5 days, inpatient (N=6) cv 5 days, inpatient (N=13) 24 weeks, outpatient cv (N=13) cv Outpatient Phase 2B Resu
Slide 13: Baseline Characteristics
Baseline Characteristics Characteristic Study Population (N = 13) Normal Range Age, mean, yr (range) 39 (22-60) Female, n (%) 8 (62%) Nephrocalcinosis/Nephrolithiasis, n (%) 10 (77%) eGFR (mL/min/1.73 m2) 84 ± 25 >60 Calcium1,2 (mg/dL) 7.1 ± 0.4 8.4 –10.2 Intact PTH2 (pg/mL) 6.3 ± 7.8 15 – 65 Phosph
Slide 14: Phase 2B Oral Encaleret Dosing Summary
Phase 2B Oral Encaleret Dosing Summary Period 1 Dosing Period 2 Dosing Period 3 Dosing Defined dose escalation Individualized dose titration Optimized dose adjustments Day 5 Mean: 350.0±22.4 mg/day Day 5 Mean: 178.3±123.7 mg/day Wk 24 Mean: 172.0±140 mg/day Individual Patient Dosing Mean encaleret s
Slide 15: Encaleret was well-tolerated with no serious adverse events reported
Encaleret was well-tolerated with no serious adverse events reported Period 1 Periods 2 and 3 N=6 N=13 Number of subjects experiencing any Serious Adverse Event 0 (0%) 0 (0%) Number of subjects experiencing any Adverse Event 6 (100%) 13 (100%) Mild 6 (100%) 13 (100%) Moderate 0 2 (15%) Severe 0 0 Nu
Slide 16: Period 1 Results: Encaleret increased PTH secretion and normalized blood and urine calcium
Period 1 Results (n=6): Encaleret increased PTH secretion and normalized blood and urine calcium Baseline Value (Day 1) Mean Value (Day 5) on encaleret 180 mg BID1 Albumin-corrected blood calcium Urine calcium Intact parathyroid hormone mg/dL mg/day pg/mL 11 1000 120 ** ULN 10 ** 800 ** 90 9 600 ULN
Slide 17: Periods 2 and 3 Results: BID encaleret restored and maintained blood and urine calcium
Periods 2 and 3 Results (n=13): BID encaleret restored and maintained mean blood and urine calcium in the normal range over a 24-week period ULN Blood cCa (mg/dL) ** LLN (mg/24 h) Urine Ca ** ULN Days Weeks Period 2 Period 3 Data as of Mar 8, 2022 reported as mean+SD. Values below limit of assay qua
Slide 18: BID encaleret increased mean PTH and decreased mean blood phosphate
Period 2 and 3 Results (n=13): BID encaleret increased mean PTH and decreased mean blood phosphate into the normal range (pg/mL) iPTH ** 6 5 Phosphate ** (mg/dL) 4 3 2 1 0 0 1 2 3 4 5 63 8 119 16 175 24 Days Weeks Period 2 Period 3 Data as of Mar 8, 2022 reported as mean+SD. Values below limit of as
Slide 19: BID encaleret increased mean blood magnesium and 1,25-(OH)2-vitamin D
Period 2 and 3 Results (n=13): BID encaleret increased mean blood magnesium and mean 1,25-(OH)2-vitamin D Magnesium ** (mg/dL) 1, 25-(OH)2-vitamin D ** (pg/mL) Days Weeks Period 2 Period 3 19 Data as of Mar 8, 2022 reported as mean+SD. Gray shading reflects normal range. The measures shown for weeks
Slide 20: BID encaleret increased bone turnover markers and had minimal effects on bone density
Period 3 Results: BID encaleret increased bone turnover markers (n=13) and had minimal short-term effects on bone density (n=11) P1NP Relative to ULN CTX Relative to ULN (P1NP/ULN) (CTX/ULN) Weeks Weeks Period 3 Period 3 DXA Anatomical Site Screening Z-score Period 3, Week 24 Z-score n = 11 Mean ± S
Slide 21: Summary
Summary • In 13 individuals with ADH1, encaleret administered twice daily for 24 weeks restored mineral homeostasis as demonstrated by: o Increase in PTH o Correction of hypocalcemia o Normalization of mean 24-hr urine calcium o Reduction in blood phosphate o Increase in mean magnesium and 1,25-(OH)
Slide 22: Phase 3 Registrational Study Design
Phase 3 Mary Scott Roberts, M.D. Registrational Sr. Director, Clinical Development, Study Design Cardiorenal Encaleret is an investigational drug. Its safety and efficacy have not been fully evaluated by any regulatory authority. 22
Slide 23: Phase 3 Registrational Study Design
Phase 3 Registrational Study Design CLTX-305-302: global, multi-center, randomized, open-label, two-arm study Encaleret Screening Period Encaleret Titration Period Maintenance (N ~ 30) Period • Age > 16 years of age Long-Term • Documented Extension pathogenic variant, or SoC Randomization 2:1 varian
Slide 24: 69% of participants responded to encaleret as intended by the planned Phase 3 primary endpoint
Based on Phase 2 results, 69% of participants responded to encaleret as intended by the planned Phase 3 primary composite endpoint Individuals achieving both blood Ca and urine Ca in the target range SoC vs Encaleret (n=13) 100% 80% 69% % of Participants 60% 40% 20% 0% 0% SoC Encaleret Screening Wee
Slide 25: Summary of encaleret Phase 2 data and next steps
Summary of encaleret Phase 2 data and next steps Phase 2 Data Anticipated Next steps ■ Encaleret maintained normalized mean corrected blood ■ 2H 2022: Initiate Phase 3 CALIBRATE registrational study calcium and 24-hour urine calcium excretion for 24 weeks ■ Mean PTH increased and phosphate decreased