Danuglipron

iStock, Golden Sikorka While Eli Lilly brushed off concerns about gastrointestinal side effects for oral weight loss candidate orforglipron, analysts from William Blair worried that adverse events are not tapering off as expected. As industry watchers eagerly await Eli Lilly’s third quarter obesity data drop for the oral candidate orforglipron, type 2 diabetes data released at the American Diabetes Association has analysts reading the tea leaves for what to expect. In investor notes over the weekend and on Monday, one firm zeroed in on a signal that suggests adverse events are not tapering off over time as is the case with the GLP-1 drugs that have taken the world by storm. Meanwhile, others dubbed the safety data clean. Orforglipron was featured in a session on next-generation oral weight loss drugs at ADA on Saturday. While much of the data from the Phase III ACHIEVE-1 trial had previously been released , clinical investigators had more to say on liver enzymes and tolerability. The results were simultaneously published in The New England Journal of Medicine . Analysts had been worried about the potential of seeing liver enzyme elevations, which could have suggested damage to the organ. But that was not the case—in fact, liver markers actually decreased from baseline by about two to four points, Jefferies noted. Addressing liver enzymes during an investor event over the weekend, Lilly’s management said the FDA is actually pushing companies to include patients with higher baseline liver enzymes to better match the typical patient population. Patients who had higher levels at the start of the trial did not experience elevations, according to the company. All these patients stayed on the study drug and their enzymes normalized or returned to baseline during the trial. “Overall, orfo has a clean pro detailed events of interest showed no real concerns, and [gastrointestinal] tolerability was deemed fine and numerically lower or in line with the injectables (except for diarrhea),” Jefferies wrote. Truist Securities spoke to key opinion leaders at ADA who still voiced concerns about liver enzymes, because the drug will likely be used for chronic weight management. Truist, however, said the concern is “likely overblown.” Leerink Partners similarly heralded the liver data as “clean.” But William Blair took issue with another part of the safety profile: gastrointestinal adverse events. While the firm believes orforglipron will “change practice in T2D,” obesity is a murkier indication, they contend. At the highest dose, nausea, vomiting and constipation did not appear to taper off as it typically does in patients taking GLP-1 drugs like Novo Nordisk’s semaglutide (marketed for weight loss as Wegovy) and Lilly’s own tirzepatide (Zepbound for weight loss), William Blair noted. “We are concerned by the persistence of both severe and frequent gastrointestinal adverse events beyond the titration period,” William Blair wrote. Truist, however, said the gastrointestinal side effects were mostly mild to moderate and mostly occurred during dose escalation as is typical of GLP-1s. The trial was designed to mitigate the symptoms after they were observed in the earlier Phase II trial. Patients in the orforglipron group discontinued the drug because of gastrointestinal side effects at a rate of 2.2% to 5.7%, depending on the dose arm. Truist said it’s notable that the highest dose had a dropout rate of under 6%, a “strong indication of the tolerability of the drug, in our view.” During a call with investors on Saturday, Lilly executives denied the characterization of diarrhea in the study as “persistent.” Jeff Emmick, senior vice president of product development, said there were geographic variabilities in the study, with higher rates of diarrhea seen in patients in India and China and extremely low rates in Japan. The U.S. was “midrange,” he added. The placebo groups in India and China also had fairly high rates of diarrhea, which Emmick said indicates differences in diet. He compared the gastrointestinal adverse events to that of tirzepatide. “Less than 6% at the highest dose discontinued due to a GI adverse event,” Emmick said. “If it had been such a big problem, [we] would have expected higher rates of discontinuation.” The Phase III ATTAIN trial is set to read out in the third quarter, which will finally give investors a glimpse at the weight loss data for orforglipron. Truist believes the diabetes data, which showed the drug significantly lowered blood sugar, has set up a positive readthrough to the obesity indication. The drug is easier to manufacture and for patients to take given it’s an oral, and they can take it without any food restrictions. Lilly plans to approval of orforglipron in obesity by the end of this year, followed by T2D in 2026. Emmick explained the rationale for filing for the weight management indication first. The FDA requires 24 months of exposure data for T2D, and only 18 for weight management. Therefore, since the trials started in parallel, the weight management data will be ready earlier. Lilly Still Believes in Triple G Lilly also used the ADA fanfare to tout its overall cardiometabolic pipeline during the call. Ken Custer, the newly minted president of cardiometabolic health at Lilly, told investors the company expects patient preference to dictate the future of the obesity market. “We fully expect the obesity market will segment into several logical categories based on things like the patient’s preferred route of administration, maybe less frequent dosing, tolerability, maybe a patient wants greater weight loss, different quality of weight loss,” Custer said. Besides weight management and diabetes, Lilly is also testing orforglipron in sleep apnea, similar to what was done with Zepbound. That drug earned a sleep apnea nod from the FDA in December 2024 . Lilly is also testing orforglipron for hypertension as well as examining maintenance dosing with the drug, including switching to the drug after injectables. One asset that caught the eye of BMO Capital Markets is the oral GLP-1 called naperiglipron, a triple G agonist that Lilly has said could unlock higher efficacy, according to BMO. But it uses the same “scaffold” as danuglipron, the failed obesity asset that Pfizer removed from its pipeline in April due to a case of drug-induced liver injury. BMO said Lilly’s continued interest shows the company’s “remaining belief in its potential.” “While history for the scaffold has been challenging, we are interested to learn more why Lilly believes it can evade these past pitfalls,” BMO wrote. If successful, naperiglipron could bring better efficacy in the oral class.

Eli Lilly detailed safety results for its oral GLP-1 asset orforglipron at the American Diabetes Association (ADA) meeting Saturday, highlighting the absence of liver toxicity, a problem that forced Pfizer to abandon its rival pill earlier this year."This convenient once-daily pill with no restrictions on food and water intake could be an option for millions of people with type 2 diabetes who prefer oral medications over injectables," said Jeff Emmick, Lilly's head of product development. "The positive ACHIEVE-1 results position orforglipron as a potential treatment option with meaningful A1C and weight reduction, and a safety profile similar to injectable GLP-1 therapies."The Phase III study is evaluating once-daily doses of orforglipron (3 mg, 12 mg, and 36 mg) as monotherapy in 559 adults with type 2 diabetes who have not achieved adequate glycaemic control through diet and exercise alone. Toplined earlier this year, patients taking orforglipron saw average reductions in HbA1c between 1.3% and 1.6% after 40 weeks, compared to just 0.1% for those on placebo, meeting the primary endpoint.On the key secondary endpoint of weight loss, patients receiving the 36-mg dose shed an average of 16 pounds, or up to 7.9% of their body weight. Lilly noted that weight loss did not appear to have plateaued by week 40, indicating the possibility for more reductions over time.Cardiometabolic gains"Beyond glycaemic control and bodyweight reduction, we observed reductions in cardiometabolic risk factors, including lipid levels, waist circumference, and systolic blood pressure, findings that indicate a favourable cardiovascular risk profile," researchers wrote in an NEJM paper, which was published Saturday.However, safety remains a central focus, with discontinuation rates and overall tolerability likely to serve as key measures for a therapy meant to be an option for chronic dosing.Lilly reiterated Saturday that orforglipron's overall safety profile in ACHIEVE-1 was consistent with the GLP-1 class as a whole, with gastrointestinal (GI) side effects such as diarrhoea (occurring in 19% to 26% of patients), nausea (13% to 18%), and dyspepsia (11% to 20%) being the most common. The events were generally mild-to-moderate and occurred mainly during dose escalation, researchers wrote.Gradual dosing escalationTo help minimise GI side effects seen in earlier studies, Lilly opted for a gradual dose-escalation strategy, starting with a lower dose and increasing every four weeks.Discontinuation rates due to side effects ranged from 4.4% to 7.8% across orforglipron doses, compared to 1.4% with placebo, and no cases of severe hypoglycaemia or liver safety concerns were reported. The incidence of elevated liver enzymes – three times the upper limit of normal or higher – was similar across all trial groups. In all orforglipron-treated participants, these levels returned to normal or near baseline while they were still receiving the drug, researchers wrote.Pfizer's withdrawal of danuglipron in April due to liver safety concerns had cast a shadow over the entire class of oral small-molecule GLP-1 agonists.Obesity results in Q3Lilly expects to report topline results from ACHIEVE-2, comparing orforglipron to AstraZeneca's SGLT2 inhibitor Farxiga (dapagliflozin), and ACHIEVE-3, comparing it to Novo Nordisk's oral semaglutide, later this year. The company also plans to share results from ATTAIN-1 and ATTAIN-2, evaluating orforglipron for weight management, in the third quarter.