AG-181 for Healthy Subjects

Overseen By Agios Medical Affairs

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Agios Pharmaceuticals, Inc.

Must not be taking: Prescription drugs, OTC medication

Disqualifiers: Pregnancy, Drug allergy, Alcohol, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The primary purpose of this study is to assess the safety and tolerability of AG-181 in healthy participants after oral administration of single ascending dose (SAD) of AG-181 in Part 1 and multiple ascending dose (MAD) in Part 2 along with the effect of food on the pharmacokinetics (PK) of single oral doses of AG-181 in healthy participants in Part 3.

Will I have to stop taking my current medications?

Yes, participants must stop using prescription drugs at least 2 weeks before the first dose of the study drug and over-the-counter medications (except routine vitamins) 7 days before, unless the study team agrees it's not clinically relevant.

How does the drug AG-181 differ from other treatments for its condition?

AG-181 is unique because it is a human anti-α 4 β 7 monoclonal antibody, which targets specific receptors involved in inflammatory bowel diseases, potentially offering a more targeted approach compared to other treatments. This specificity may lead to different efficacy and safety profiles. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for healthy individuals who want to participate in a study testing the safety of a new medication, AG-181. The study will involve taking single or multiple doses of the drug with and without food to see how it's absorbed and tolerated.

Inclusion Criteria

Body mass index in the range of 18.0 to 30.0 kilograms per square meter (kg/m^2)

All values for hematology and clinical chemistry tests of blood and urine within the normal range or showing no clinically relevant deviations, as judged by the Investigator

For women of childbearing potential (WOCBP), have a negative serum or urine pregnancy test at Screening and during admission to the clinic

Exclusion Criteria

History of long-QT syndrome, torsade de pointes, or any risk factors for torsades de pointes in the opinion of the investigator

Use of tobacco or nicotine products in the 48 hours (2 days) prior to administration of the first dose of study drug

Use of any investigational drug or device within 30 days before administration of the first dose of study drug

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Single Ascending Dose (SAD)

Participants receive a single oral dose of AG-181 or placebo under fasted conditions

1 day

1 visit (in-person)

Multiple Ascending Dose (MAD)

Participants receive AG-181 or placebo twice daily for 13 days and a single dose on Day 14 under fasted conditions

14 days

Daily visits (in-person)

Food Effect Study

Participants receive single oral doses of AG-181 under fasted and fed conditions, separated by a 72-hour washout period

2 periods of 1 day each, separated by 72 hours

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-4 weeks

Treatment Details

Interventions

• AG-181 (Anti-metabolites)

Trial Overview AG-181 is being tested in this trial. Participants will take either AG-181 or a placebo (a pill without any active drug) to compare effects. The study has three parts: one for single doses, another for multiple doses, and a third part to see how food affects the drug's absorption.

Participant Groups

Group I: Part 3: Food Effect - Sequence 2: BA Experimental Treatment 1 Intervention

Participants will receive a single oral dose of AG-181 on Day 1 of Period 1 under fed (high fat meal) condition (B) followed by single oral dose of AG-181 on Day 1 of Period 2 under fasted condition (A). Each period will be separated by a washout period of 72 hours.

Group II: Part 3: Food Effect - Sequence 1: AB Experimental Treatment 1 Intervention

Participants will receive single oral dose of AG-181 on Day 1 of Period 1 under fasted condition (A) followed by single oral dose of AG-181 on Day 1 of Period 2 under fed (high fat meal) condition (B). Each period will be separated by a washout period of 72 hours.

Group III: Part 2: Multiple Ascending Dose (MAD) Experimental Treatment 2 Interventions

Participants will receive a range of doses of AG-181 or placebo twice daily (BID) for 13 days and a single dose on Day 14 under fasted conditions.

Group IV: Part 1: Single Ascending Dose (SAD) Experimental Treatment 2 Interventions

Participants will receive a range of doses of AG-181 or placebo, orally, once on Day 1. AG-181 will be given under fasted conditions.

Who Is Running the Clinical Trial?

Agios Pharmaceuticals, Inc.

Lead Sponsor

Trials

55

Recruited

4,200+

Findings from Research

In a study involving 62 healthy volunteers, the maximum tolerated dose of astragalosides injection (AGI) was determined to be 600 mL for a single dose and 400 mL for multiple doses over 7 days, indicating a safe range for future clinical trials.

The study reported 40 adverse events, primarily mild, including abnormal liver function and low blood potassium, suggesting that while AGI is generally well-tolerated, monitoring for specific side effects is necessary in further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and Tolerance of Healthy People to Injection of Astragalosides-a New Drug for Coronary Heart Disease]. Zou, C., Liu, F., Jiang, M., et al.[2018]

A pharmacokinetic and pharmacodynamic model based on cynomolgus monkey data was successfully developed to predict a safe starting dose of AMG 181, an anti-α 4 β 7 antibody for inflammatory bowel diseases, with a starting dose of 0.7 mg in humans.

The model predicted that this starting dose would achieve significant receptor occupancy while maintaining safety, as confirmed by matching predictions with actual human pharmacokinetic data from initial clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prediction of clinical pharmacokinetics of AMG 181, a human anti-α 4 β 7 monoclonal antibody for treating inflammatory bowel diseases. Li, H., Köck, K., Wisler, JA., et al.[2018]

SPH3127 demonstrated a dose-dependent increase in exposure and effectively suppressed plasma renin activity by up to 90% for 24 hours, indicating its potential efficacy in managing conditions related to renin activity.

The drug was well tolerated among healthy individuals, with only mild adverse events reported in 29.2% of single-dose and 33.3% of multiple-dose participants, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SPH3127: A Phase I, Randomized, Double-Blind, Placebo-Controlled Trial. Jing, S., Xu, R., Yang, K., et al.[2021]

TAK-357, a potential treatment for Alzheimer's disease, showed a long half-life in plasma and high distribution to adipose tissues in non-clinical studies with rats and dogs, indicating prolonged presence in the body after administration.

The primary route of elimination for TAK-357 was through metabolism, and its slow release from adipose tissues contributes to its extended half-life, suggesting that body weight changes may influence its plasma levels during clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disposition of the Highly Fat Distributed Compound 1-(4-Methoxyphenyl)-4-(2,2,4,6,7-Pentamethyl -2,3-Dihydro-1-Benzofuran-5-yl)Piperazine (TAK-357) in Rats and Dogs. Goto, A., Moriya, Y., Mandai, T., et al.[2017]

A study involving 19 healthy male volunteers found that KC-404 sustained release tablets and capsules have similar pharmacokinetic profiles, indicating they are bioequivalent.

The relative bioavailability of the KC-404 sustained release tablets was found to be 102.6%, suggesting that they are effectively absorbed in the body just like the capsules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacokinetics and relative bioavailability of KC-404 sustained release tablets in healthy volunteers]. Li, T., Pang, Y., Wang, Z., et al.[2012]

References

1. China pubmed.ncbi.nlm.nih.gov

[Safety and Tolerance of Healthy People to Injection of Astragalosides-a New Drug for Coronary Heart Disease]. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Prediction of clinical pharmacokinetics of AMG 181, a human anti-α 4 β 7 monoclonal antibody for treating inflammatory bowel diseases. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SPH3127: A Phase I, Randomized, Double-Blind, Placebo-Controlled Trial. [2021]

4. Germany pubmed.ncbi.nlm.nih.gov

Disposition of the Highly Fat Distributed Compound 1-(4-Methoxyphenyl)-4-(2,2,4,6,7-Pentamethyl -2,3-Dihydro-1-Benzofuran-5-yl)Piperazine (TAK-357) in Rats and Dogs. [2017]

5. China pubmed.ncbi.nlm.nih.gov

[Pharmacokinetics and relative bioavailability of KC-404 sustained release tablets in healthy volunteers]. [2012]