Foundayo (orforglipron calcium): NDA 220934

We recommend approval for the proposed indication based on findings from the submitted results.

DDLO concludes that the benefit-risk evaluation of orforglipron for weight reduction in adults is favorable and recommends approval.

However, the placebo-adjusted percentage change in body weight was of borderline clinical significance in the 12 mg group (-4.5%) and not clinically significant in the 6 mg group (-2.6%).

FDA assessment of liver safety in the three Phase 3 orforglipron weight management trials (ATTAIN-1, ATTAIN-2 and ATTAIN-J) showed no substantial evidence of increased risk of idiosyncratic liver injury associated with orforglipron (there was potential for liver injury due to acute gallbladder events as expected).

In summary, the weight loss efficacy of orforglipron was statistically significant and clinically meaningful.

ATTAIN-1 and ATTAIN-2 were the pivotal studies that provided substantial evidence of effectiveness and appropriate safety for orforglipron for the proposed indication.

Orforglipron led to clinically meaningful reductions in mean percent change in body weight compared with placebo using the treatment regimen estimand.

Additional laboratory assessments demonstrated dose-dependent reductions in hsCRP, the inflammatory and CV risk marker, and improvements in fasting glucose, insulin, and HbA1c for orforglipron versus placebo.

On balance, the benefit-risk assessment for orforglipron for the indication of weight reduction and maintenance in adults with overweight/obesity appears favorable.

The Applicant's analyses comparing the incidence of Level 2 and 3 hypoglycemia in subjects receiving sulfonylurea therapy at baseline (Appendix - FDA Table 114) versus subjects not receiving sulfonylurea therapy at baseline (Appendix - FDA Table 115) confirmed that hypoglycemia risk for OFG ALL is higher with sulfonylurea therapy (6.7%) versus without (0.5%).

It is the opinion of this clinical reviewer that the TEAE consistent with an immediate hypersensitivity reaction be described in Section 6 (ADVERSE REACTIONS) of the label.

No cases of MTC or C-cell hyperplasia were identified in completed studies, and evaluation of cases of orforglipron-treated participants with postbaseline increases in calcitonin did not indicate increased risk of C-cell malignancy.

A risk evaluation and mitigation strategy is not necessary for this NDA as the safety issues can be addressed through labeling, postmarket requirements, and routine pharmacovigilance.

Therefore, the positive benefit-risk profile supports authorization of orforglipron as a meaningful therapeutic option for adults with obesity or overweight.

A PMR will be issued for the Applicant to conduct a clinical pharmacology trial that uses ultrasound to measure the effect of both temporary withholding of orforglipron and fasting duration on retained gastric contents.

Listed below are 6 other PMRs that will be issued for orforglipron; no postmarket commitments (PMCs) are recommended for this application.