Retatrutide

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Eli Lilly’s retatrutide is a next-generation investigational drug that targets obesity, demonstrating remarkable weight loss and metabolic benefits in clinical studies. It is a “triagonist,” activating three key receptors: GLP-1, GIP, and glucagon. This unique combination allows it to improve glucose control, enhance insulin sensitivity, and increase energy expenditure, distinguishing it from other drugs in its class, like semaglutide (Wegovy) and tirzepatide (Mounjaro).

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In a Phase 2 study involving 338 participants with obesity or weight-related conditions, retatrutide showed impressive results. Patients on the highest dose (12 mg) experienced a 24.2% reduction in body weight over 48 weeks, averaging 58 pounds of weight loss. Notably, the study ended before participants reached a weight plateau, indicating the potential for even greater efficacy in longer trials. The drug also improved cardiometabolic measures, including cholesterol, blood pressure, and blood sugar levels, making it a promising option for comprehensive metabolic management.

 

The safety profile of retatrutide is consistent with other incretin-based therapies, with gastrointestinal side effects being the most common and dose-dependent. To mitigate side effects, the trial employed a gradual dose escalation strategy.

 

The Phase 3 TRIUMPH program is currently underway, aiming to further evaluate retatrutide’s efficacy and tolerability for long-term weight management, as well as its impact on related conditions such as sleep apnea and knee osteoarthritis.

 

Overall, retatrutide represents a significant advancement in obesity treatment and is positioned to play a key role in Eli Lilly’s expanding pipeline of metabolic therapies.

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The U.S. Food and Drug Administration (FDA) oversees a series of clinical trial phases to evaluate new drugs for safety, efficacy, and overall benefit-risk profile before approval for public use.

Here are the phases:

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1. Preclinical Studies

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•               Goal: Assess initial safety and biological activity in non-human models.

•               Process: Conducted in laboratory and animal studies to determine toxicity, dosage, and pharmacokinetics (how the drug moves through the body).

•               Outcome: If promising, the drug sponsor submits an Investigational New Drug (IND) application to the FDA to begin human trials.

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2. Phase 1: First-in-Human Trials

 

•               Goal: Evaluate safety, dosage range, and pharmacokinetics in humans.

•               Participants: 20–100 healthy volunteers or people with the disease/condition (depending on the drug’s nature).

•               Key Activities: Escalating doses to find the maximum tolerable dose and understand side effects.

•               Outcome: Identify a safe dosage range and observe drug behaviour in the human body.

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3. Phase 2: Proof-of-Concept Trials

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•               Goal: Assess drug efficacy and side effects in a targeted patient population.

•               Participants: 100–300 individuals with the disease/condition.

•               Process: Typically randomized and controlled, comparing the drug to a placebo or standard treatment.

•               Outcome: Gather preliminary data on efficacy and confirm safety findings from Phase 1.

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4. Phase 3: Pivotal Trials

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•               Goal: Confirm effectiveness, monitor side effects, and compare the drug to current standard treatments.

•               Participants: 300–3,000+ patients across multiple sites.

•               Design: Double-blind, randomized controlled trials to minimise bias.

•               Outcome: Comprehensive data for submission in a New Drug Application (NDA) or Biologics License Application (BLA) to the FDA for approval.

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5. FDA Review and Approval

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•               Review: After submission of the NDA or BLA, the FDA evaluates all trial data to decide on approval.

•               Advisory Committees: External experts may provide recommendations, though the FDA makes the final decision.

6. Phase 4: Post-Marketing Surveillance

•               Goal: Monitor long-term safety and effectiveness after FDA approval.

•               Participants: Broad population using the drug in real-world settings.

•               Activities: Detect rare side effects, ensure ongoing efficacy, and evaluate additional uses.

•               Outcome: This may lead to label changes, additional warnings, or even withdrawal of the drug.

This phased approach ensures new drugs are rigorously evaluated for both safety and efficacy before reaching the market.

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