A Phase 2, Multicenter, Randomized, Double Blind, Placebo-controlled Study to Assess the Efficacy, Safety, and Tolerability of NGM120 in Participants With Colorectal Cancer Who Have Cancer Cachexia

A multi-center evaluation of NGM120 in a randomized, double-blind, placebo-controlled study in participants with colorectal cancer who have cancer cachexia.

More details:

Evaluation of Efficacy, Safety and Tolerability of NGM120 in a Phase 2, Randomized, Double-blind, Placebo-controlled, Multi-center Study in Participants with Colorectal Cancer who have Cancer Cachexia

Overview

NGM120 is an investigational human monoclonal antibody that antagonizes GFRAL, the cognate brainstem receptor for the stress-response hormone GDF15. It is being developed for oncology (including cancer cachexia) and, more recently, hyperemesis gravidarum (HG). First-in-human studies began in 2019; a Phase 1/1b program in advanced solid tumors included metastatic pancreatic cancer (in combination with gemcitabine/nab‑paclitaxel) and metastatic castration‑resistant prostate cancer (mCRPC). A randomized Phase 2 study in HG (EMERALD) began dosing in February 2025, and a randomized Phase 2 study in colorectal cancer cachexia opened in mid‑2025. (news.ngmbio.com)

Mechanism of action

• Target: GFRAL (glial cell–derived neurotrophic factor receptor alpha‑like), expressed in the area postrema/nucleus of the solitary tract. GDF15 binding to GFRAL signals via RET to reduce food intake and mediate aversive responses. NGM120 blocks GDF15–GFRAL signaling. (pubmed.ncbi.nlm.nih.gov)
• Rationale in cancer and cachexia: Elevated GDF15 is linked to poor outcomes, tumor progression/immune effects, and cancer‑associated anorexia/cachexia; blocking the pathway is expected to counter weight loss and may have antitumor effects. (pubmed.ncbi.nlm.nih.gov)
• Rationale in HG: Genetic and clinical data implicate high maternal exposure/sensitivity to GDF15 from the feto‑placental unit in nausea/vomiting of pregnancy, motivating GFRAL blockade for symptom relief. (pubmed.ncbi.nlm.nih.gov)

Efficacy

• Metastatic pancreatic cancer (Phase 1b; first‑line with gemcitabine/nab‑paclitaxel; patients selected for elevated GDF15): Among 8 treated and 6 evaluable patients at the March 25, 2022 cutoff, objective response rate was 50% (3/6 partial responses), disease control rate 100% (3 PR, 3 SD), 12‑month overall survival 83.3%, and median PFS not reached. Body weight and lean mass were maintained or increased in most evaluable patients. Results were presented at the AACR Special Conference: Pancreatic Cancer. (aacrjournals.org)

• Advanced prostate cancer (Phase 1a monotherapy; heavily pretreated mCRPC): In an ESMO 2022 abstract (n=5), two patients had PSA reductions (−32% and >99% to <0.1 ng/mL). One MSI‑H patient achieved a RECIST partial response with sustained PSA and GDF15 reductions and weight gain; overall, 1/5 PR and 2/5 PSA responses were reported. (oncologypro.esmo.org)

Note: The Phase 1/1b trial (NCT04068896) completed in 2024 with summary results posted to ClinicalTrials.gov in May 2025. (cdek.pharmacy.purdue.edu)

Safety

• Across Phase 1a/1b cohorts, NGM120 was reported as well tolerated with no dose‑limiting toxicities; most adverse events were grade 1–2 and, in the pancreatic combination cohort, consistent with gemcitabine/nab‑paclitaxel. (aacrjournals.org)
• ClinicalTrials.gov summary results (NCT04068896) indicate treatment‑related TEAEs were recorded in both experimental and placebo arms; for example, in Part 2 (pancreatic cancer combo), related TEAEs occurred in 17/31 patients in the NGM120 100‑mg arm versus 12/20 on placebo. Detailed event types/severity are posted with the registry results. (cdek.pharmacy.purdue.edu)

No pregnancy safety or efficacy data are yet available; the randomized Phase 2 EMERALD HG study began dosing on February 24, 2025. (news.ngmbio.com)

Ongoing/Planned studies

• HG: EMERALD Phase 2 randomized, placebo‑controlled study of NGM120 added to standard/supportive care in pregnant patients with HG (initiated 2025). (news.ngmbio.com)
• Cancer cachexia: Phase 2 randomized, double‑blind, placebo‑controlled study in colorectal cancer with cachexia (NCT07033026; started June 2025; planned n≈136). (fdaaa.trialstracker.net)

Further reading

• Mechanistic foundation for the GDF15–GFRAL–RET pathway in body‑weight regulation and aversion: Nature/Nature Medicine/PNAS. (pubmed.ncbi.nlm.nih.gov)
• Phase 1b pancreatic cancer results (AACR abstract). (aacrjournals.org)
• Phase 1a prostate cancer results (ESMO abstract 1402P). (oncologypro.esmo.org)
• Phase 1/1b trial registry with posted results (NCT04068896). (cdek.pharmacy.purdue.edu)
• HG rationale and EMERALD Phase 2 initiation. (pubmed.ncbi.nlm.nih.gov)

Sources: - AACR Cancer Research abstract PR006 (pancreatic cancer cohort). (aacrjournals.org) - ESMO 2022 OncologyPRO abstract 1402P (prostate cancer cohort). (oncologypro.esmo.org) - ClinicalTrials.gov-linked summary (CDEK) for NCT04068896, results posted May 29, 2025. (cdek.pharmacy.purdue.edu) - Foundational GDF15–GFRAL papers. (pubmed.ncbi.nlm.nih.gov) - HG genetics/biology and EMERALD Phase 2 announcement. (pubmed.ncbi.nlm.nih.gov)

Notes on evidence maturity: Published peer‑reviewed clinical results specific to NGM120 are limited to conference abstracts and registry postings as of October 2025; larger randomized efficacy readouts (HG and colorectal‑cachexia Phase 2 trials) are pending. (news.ngmbio.com)

Last updated: Oct 2025

Inclusion Criteria:

1. Documented active diagnosis of colorectal cancer.

2. Cachexia defined by Fearon criteria of weight loss.

3. Signed informed consent.

Exclusion Criteria:

1. Current active reversible causes of decreased food intake.

2. Receiving tube feedings or parenteral nutrition at the time of Screening or Randomization.

3. Have cachexia caused by other reasons.