A FEASIBILITY ASSESSMENT OF AN ANCHORED INDIRECT TREATMENT COMPARISON BETWEEN ENEBOPARATIDE (CALYPSO) AND PALOPEGTERIPARATIDE (PATHWAY) IN CHRONIC HYPOPARATHYROIDISM
Author(s)
Michelle Erdmann, BSc, BNSc, MBA1, Soraya Allas, MD, PhD2, Ellen Colman, PharmD, BCCCP3, Ying Kong, MD, PhD3, Tommy Lan, MSc4, Kayleen Ports, MS4, Kristina B. Lindsley, MS4, Maria Luisa Brandi, PhD5.
1Alexion, AstraZeneca Rare Disease, Mississauga, ON, Canada, 2Alexion, AstraZeneca Rare Disease, Lyon, France, 3Alexion, AstraZeneca Rare Disease, Boston, MA, USA, 4IQVIA Canada, San Francisco, CA, USA, 5European Institute of Oncology (IEO), Milan, Italy.
1Alexion, AstraZeneca Rare Disease, Mississauga, ON, Canada, 2Alexion, AstraZeneca Rare Disease, Lyon, France, 3Alexion, AstraZeneca Rare Disease, Boston, MA, USA, 4IQVIA Canada, San Francisco, CA, USA, 5European Institute of Oncology (IEO), Milan, Italy.
OBJECTIVES: Indirect treatment comparisons (ITCs) may inform comparative effectiveness when head-to-head trials are unavailable. This case study assessed the comparability of two randomized trials in chronic hypoparathyroidism (HypoPT).
METHODS: We reviewed the CALYPSO (eneboparatide) and PaTHway (palopegteriparatide) phase III trials, both of which used placebo plus standard care as the comparator, making an anchored comparison theoretically possible. We examined features affecting estimand alignment, including eligibility criteria, supplement withdrawal algorithms, serum calcium targets, study-drug titration and rescue rules, and primary endpoint components.
RESULTS: Although both trials enrolled patients with HypoPT, compared active treatment versus placebo plus standard-of-care, and defined response using the same composite elements (albumin-adjusted serum calcium within range, independence from active vitamin D and therapeutic oral calcium, and no increase in prescribed study drug during the last 4 weeks of the blinded phase), important differences in study design and patient characteristics raised concerns regarding homogeneity and transitivity, precluding a valid ITC. CALYPSO defined chronic HypoPT as duration >12 months and baseline calcium 7.8-9.0 mg/dL based on 2 consecutive measurements; PaTHway used broader criteria (duration >6 months; baseline calcium 7.8-10.6 mg/dL). Protocol- and guideline-defined treatment strategies also differed substantially, meaning patients with the same serum calcium and supplement status could be managed differently between trials. CALYPSO used supplement-dependent serum calcium targets, up-titration algorithms at predefined time-points, and mandatory rescue supplementation; PaTHway used a uniform serum calcium target, permitted up-titration throughout the treatment period, and utilized conditional rescue supplements. These differences influence how endpoint components are achieved and how response is classified across trials.
CONCLUSIONS: Differences in eligibility criteria, baseline demographics, and protocol/guidelines-defined management strategies led to non-aligned estimands. Statistical adjustment cannot fully account for endpoints influenced by differing treatment strategies where achieving response is partly protocol-dependent and not solely reflective of treatment effect.
METHODS: We reviewed the CALYPSO (eneboparatide) and PaTHway (palopegteriparatide) phase III trials, both of which used placebo plus standard care as the comparator, making an anchored comparison theoretically possible. We examined features affecting estimand alignment, including eligibility criteria, supplement withdrawal algorithms, serum calcium targets, study-drug titration and rescue rules, and primary endpoint components.
RESULTS: Although both trials enrolled patients with HypoPT, compared active treatment versus placebo plus standard-of-care, and defined response using the same composite elements (albumin-adjusted serum calcium within range, independence from active vitamin D and therapeutic oral calcium, and no increase in prescribed study drug during the last 4 weeks of the blinded phase), important differences in study design and patient characteristics raised concerns regarding homogeneity and transitivity, precluding a valid ITC. CALYPSO defined chronic HypoPT as duration >12 months and baseline calcium 7.8-9.0 mg/dL based on 2 consecutive measurements; PaTHway used broader criteria (duration >6 months; baseline calcium 7.8-10.6 mg/dL). Protocol- and guideline-defined treatment strategies also differed substantially, meaning patients with the same serum calcium and supplement status could be managed differently between trials. CALYPSO used supplement-dependent serum calcium targets, up-titration algorithms at predefined time-points, and mandatory rescue supplementation; PaTHway used a uniform serum calcium target, permitted up-titration throughout the treatment period, and utilized conditional rescue supplements. These differences influence how endpoint components are achieved and how response is classified across trials.
CONCLUSIONS: Differences in eligibility criteria, baseline demographics, and protocol/guidelines-defined management strategies led to non-aligned estimands. Statistical adjustment cannot fully account for endpoints influenced by differing treatment strategies where achieving response is partly protocol-dependent and not solely reflective of treatment effect.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
CO153
Topic
Clinical Outcomes, Methodological & Statistical Research, Study Approaches
Topic Subcategory
Comparative Effectiveness or Efficacy
Disease
Musculoskeletal Disorders (Arthritis, Bone Disorders, Osteoporosis, Other Musculoskeletal), No Additional Disease & Conditions/Specialized Treatment Areas, Rare & Orphan Diseases