A Study to Learn About the Medicine Ponsegromab in Adults With Cancer of the Pancreas Which Has Spread and Caused Significant Body Weight Loss and Fatigue

A Phase 2b/3, randomized, double-blind, multicenter, multinational study to investigate

the efficacy, safety and tolerability of systemic chemotherapy plus ponsegromab versus

systemic chemotherapy plus placebo for the first-line treatment in adult participants

with cachexia and mPDAC. The first-line chemotherapies will either be nab-paclitaxel plus

gemcitabine or FOLFIRINOX (or mFOLFIRINOX). The double-blind period is followed by an

optional open-label extension period.

Initial enrollment will be in Phase 2b. If all eligibility criteria are met, participants

will be randomized in a 1:1:1 allocation to study intervention (one of the two doses of

ponsegromab, or placebo) plus first-line systemic chemotherapy. Participants must have

completed their first-line pre-randomization systemic chemotherapy (1 x 28-day cycle of

nab-paclitaxel and gemcitabine or 2 x 14-days cycles of FOLFIRINOX) prior to the start of

receiving their first dose (Day 1) of study intervention (ponsegromab or placebo). Day 1

study intervention must be taken on the same day participants start their next cycle of

nab-paclitaxel and gemcitabine chemotherapy or FOLFIRINOX chemotherapy and prior to

receiving chemotherapy. All chemotherapy dosing is to be determined by the participant's

health care provider in accordance with local guidelines. Study intervention will be

administered Q4W SC.

Following enrollment completion of Phase 2b, Phase 3 enrollment will begin, and eligible

participants will be randomized in a 1:1:1 allocation to study intervention (one of the

two doses of ponsegromab, or placebo). Participants must have completed their first-line

pre-randomization systemic chemotherapy (1 x 28-day cycle of nab-paclitaxel and

gemcitabine or 2 x 14-day cycles of FOLFIRINOX) prior to the start of receiving their

first dose (Day 1) of study intervention (ponsegromab or placebo). Day 1 study

intervention must be taken on the same day participants start their next cycle of

nab-paclitaxel and gemcitabine chemotherapy or FOLFIRINOX chemotherapy and prior to

receiving chemotherapy. All chemotherapy dosing is to be determined by the participant's

health care provider in accordance with local guidelines. Study intervention will be

administered Q4W SC.

Once all Phase 2b participants have completed Week 12 procedures, an analysis of Phase 2b

will be performed, from which one of the 2 ponsegromab doses will be selected. After the

Phase 3 ponsegromab dose has been selected, continuing Phase 2b participants will:

- Continue the ponsegromab dose selected for Phase 3 if already randomized to that

dose, OR

- Be switched to the ponsegromab dose selected for Phase 3 if randomized to the

non-selected ponsegromab dose, OR

- Continue receiving placebo if randomized to placebo

- Remain blinded to study treatment

After the ponsegromab dose has been selected, continuing Phase 3 participants will:

- Continue the ponsegromab dose selected for Phase 3 if already randomized to that

dose, OR

- Be switched to the ponsegromab dose selected for Phase 3 if randomized to the

non-selected ponsegromab dose, OR

- Continue receiving placebo if randomized to placebo

- Remain blinded to study treatment Phase 3 participants enrolled after dose selection

will be randomized 1:1 (ponsegromab selected dose: placebo). Participants must have

completed their first-line pre-randomization systemic chemotherapy (1 x 28-day cycle

of nab-paclitaxel and gemcitabine or 2 x 14-days cycles of FOLFIRINOX) prior to the

start of receiving their first dose (Day 1) of study intervention (selected Phase 3

ponsegromab dose or placebo). Day 1 study intervention must be taken on the same day

participants start their next cycle of nab-paclitaxel and gemcitabine chemotherapy

or FOLFIRINOX chemotherapy and prior to receiving chemotherapy.

During the Phase 3 portion of the study, there will be an optional sub-study for primary

caregivers of participants with cachexia and mPDAC to evaluate the effectiveness of

ponsegromab in improving the quality of life and well-being of the primary caregivers.

Study intervention (ponsegromab selected dose or placebo) will continue regardless of

chemotherapy treatment until permanent discontinuation of study intervention, withdrawal

of consent, death, or the end of the Phase 3 double-blind portion of the study has been

reached when the approximate number of overall survival events have been accrued for the

Phase 3 analysis of overall survival.

Participants will have tumor assessments performed approximately every 6 to 8 weeks

during the double-blind period by blinded, independent, central reader radiologists.

When the number of overall survival events has been accrued to terminate the Phase 3

double-blind portion of the study, active participants can continue in the optional

open-label extension where they will receive ponsegromab for up to 12 months.