Eli Lilly (NYSE: LLY) saw its shares climb 5% this past week after announcing that its history-making oral obesity candidate, orforglipron aced the Phase III ATTAIN-2 trial (NCT05872620), which assessed the small molecule glucagon-like peptide-1 (GLP-1) receptor agonist in adults who were obese or overweight and had type 2 diabetes.
All three doses of orforglipron (6 mg, 12 mg, and 36 mg) met the primary and all key secondary endpoints by showing significant weight loss, meaningful A1C reductions, and improvements in cardiometabolic risk factors compared with placebo at 72 weeks.
In the primary endpoint of mean percent change in body weight from an average baseline of 223.5 lb., orforglipron 36 mg, taken once daily without food and water restrictions, lowered weight by an average of 10.5% (22.9 lbs) vs. 2.2% (5.1 lbs) with placebo. The 36 mg dosage also produced A1C reduction of 1.8% from an average baseline of 8.1%.
“Overall, we think this is an acceptable profile & orfo[rglipron] 36 mg generally looks in line vs Wegovy® 2.4 mg/oral sema[glutide] 50 mg,” Akash Tewari, global head of biopharmaceutical research with Jefferies, wrote in a research note. Wegovy is the version of semaglutide marketed to treat obesity by the longtime market leader in sales of GLP-1 diabetes and obesity treatments Novo Nordisk (NASDAQ Copenhagen: NOVO-B), which also markets semaglutide to treat type 2 diabetes under the name Ozempic®.
Tewari and Jefferies are projecting peak-year sales of $25 billion for orforglipron—about double the DKK 120.342 billion ($18.84 billion) generated by Ozempic last year, and more than double the $11.54 billion racked up by Lilly’s tirzepatide as a type 2 diabetes drug marketed as Mounjaro®. Those figures do not include the DKK 58.206 billion ($9.112 billion) in sales generated last year by semaglutide as the obesity drug Wegovy and $4.926 billion by tirzepatide as an obesity drug under the name Zepbound®.
Ozempic and Mounjaro made enough in sales to rank on GEN‘s most recent A-List of Top 10 Best-Selling Drugs, published in July and based on 2024 sales.
In observing orforglipron to have an acceptable profile vs. Wegovy and Ozempic, Tewari cited average weight loss for the Novo Nordisk treatments of 10% to about 11%, and A1 reduction of 1.6 to ~2.2%.
The low dose of orforglipron yielded average weight loss of about 5.5% (12.1 lbs) and A1C reduction of 1.6%, while the middle dose resulted in 7.8% average weight loss (17.4 lbs) and 1.3% A1C reduction. Additional detailed data will be presented at a future medical conference and published in a peer-reviewed journal, Lilly said.
“With these positive data in hand, we are moving with urgency toward global regulatory submissions to potentially meet the needs of patients who are waiting. If approved, we are ready to offer a convenient, once-daily pill that can be scaled globally, removing barriers and redefining how obesity is treated around the world,” Kenneth Custer, PhD, Lilly executive vice president and president of Lilly Cardiometabolic Health, said in an August 26 statement.
A regulatory submission is expected for orforglipron in obesity before the end of the year.
“The ATTAIN-2 results reinforce the potential for orforglipron, as a once-daily oral, to deliver meaningful weight loss and A1C reduction, consistent with similar landmark trials for injectable GLP-1s,” Custer added.
Andy T. Hsieh, PhD, a partner and biotechnology analyst with William Blair, and a colleague were similarly positive in a research note: “Orforglipron outperformed investor expectations in patients living with both overweight/obesity and type 2 diabetes, which we view as the higher-risk and more difficult-to-treat population.”
Mini-surge
Investors agreed with those upbeat assessments, touching off a mini-surge that sent Lilly shares rising 6% Tuesday, from $695.33 to $736.03. Shares stayed all but flat, dipping 0.1% since then, to $732.20 on Thursday, before inching up 0.6%, finishing the week at $732.58.
“Near term, we’re not sure the stock meaningfully breaks out until the orfo[rglipron] launch. To that end, we’re curious whether LLY can accelerate orfo’s launch timeline,” added Tewari.
The Jefferies analyst said Lilly could accelerate that timeline by pursuing priority review—and by entering the FDA’s new Commissioner’s National Priority Voucher program. Launched by Commissioner Martin Makary in June, the program enables the agency to award vouchers to drug developers whose work addresses a health crisis in the United States, delivers more innovative cures, addresses unmet public health needs, and increases domestic drug manufacturing as a national security issue. The vouchers entitle companies to reviews of their final applications in 1–2 months rather than the current 10–12 months.
“If LLY is able to get this, our illustrative analysis suggests orfo launch could be YE’25~February ’26,” Tewari predicted.
David Risinger, a senior managing director and senior research analyst covering diversified biopharmaceuticals with Leerink Partners, and three colleagues called the results from ATTAIN-2 “compelling,” and maintained an earlier prediction that orforglipron will attain sales that more than reach multi-billion-dollar “blockbuster” heights.
“We continue to model 2030 E[stimated] orforglipron sales of $13.5B,” Risinger said—a figure 35% above the $10 billion forecast offered by a consensus of analysts assembled through the Visible Alpha equities research platform. Risinger maintained Leerink’s “Market Perform” rating on Lilly shares.
Rajesh Kumar, head of European life sciences and healthcare equity research with HSBC, and colleagues upgraded the firm’s rating on Lilly shares from “Reduce” to “Hold,” citing what it called greater clarity on the commercial potential of orforglipron. HSBC has projected that orforglipron will generate close to $10 billion in peak-year sales, according to Morningstar. Kunmar also raised HSBC’s 12-month price target on Lilly shares by roughly 4%, from $675 to $700.
Bad news and bounce back
Lilly’s surge was bad news for Novo Nordisk, which saw its main shares fall 4.5% Tuesday from DKK 367.30 ($57.50) to DKK 350.95 ($54.94). However, Novo shares bounced back 1.6% to DKK 356.70 ($55.84) on Wednesday, inched up another 0.6% Thursday to DKK 358.80 ($56.17), and finished Friday trading unchanged.
For Lilly, the clinical win in ATTAIN-2 was its latest in three Phase III trials since April. Back then, the company basked in the glow of orforglipron becoming the first oral GLP-1 drug to ace a Phase III trial when it reported results from ACHIEVE-1 (NCT05971940) showing that orforglipron met the trial’s primary endpoint of superior A1C reduction vs. placebo at 40 weeks. Patients treated with orforglipron showed an average of 1.3% to 1.6% lower A1C compared with a baseline of 8.0%.
ACHIEVE-1 was a 40-week, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of orforglipron 3 mg, 12 mg, and 36 mg vs. placebo in adults with type 2 diabetes and inadequate glycemic control with diet and exercise alone.
In between those studies, Lilly shared results on August 7 from its Phase III ATTAIN-1 trial (NCT05869903) that were positive but which disappointed investors, causing the stock to skid 16% over two days. ATTAIN-1 was a 72-week, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of orforglipron (6 mg, 12 mg, and 36 mg) as monotherapy vs. placebo in 3,127 adults with obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidemia, OSA, or cardiovascular disease, who did not have diabetes.
Orforglipron met ATTAIN-1’s primary endpoint by lowering weight by an average of 12.4% (27.3 lbs) vs. 0.9% (2.2 lbs) with placebo, at the highest dose of 36 mg. However, investors expected to see about 15% weight loss. Leerink’s Risinger chopped his 2030 sales forecast 38% from $21.6 billion based on the news, while a consensus of analysts cited by MarketWatch sliced its 2032 sales forecast for the drug from $20 billion to $15.5 billion.
In what Lilly said was a key secondary endpoint, 59.6% of participants taking the 36 mg dose of orforglipron lost at least 10% of their body weight, while 39.6% lost at least 15% of their body weight.
Leaders and laggards
- Immuneering (NASDAQ:IMRX)shares jumped 22% on August 25 after the clinical-stage oncology company announced a clinical supply agreement with Eli Lilly (NYSE: LLY) for its second-generation KRAS G12C inhibitor, olomorasib (LY3537982). The supply agreement is designed to support the evaluation of Immuneering’s lead candidate, atebimetinib (IMM-1-104), a novel dual MEK inhibitor, in combination with olomorasib in a planned Phase II trial in patients with locally advanced or metastatic KRAS G12c-mutant non-small cell lung cancer (NSCLC) who have progressed on prior therapy. The agreement marks the second such collaboration by the company with a biopharma giant: In February, Immuneering announced a clinical trial agreement with Regeneron Pharmaceuticals (NASDAQ: REGN) to evaluate atebimetinib in combination with the anti-PD-1 therapy Libtayo® (cemiplimab) in patients with advanced non-small cell lung cancer.
- Invivyd (NASDAQ: IVVD) shares rocketed 84% from 56 cents to $1.03 on August 26, a day after The Daily Beast reported that President Donald Trump’s administration plans to withdraw messenger RNA (mRNA)-based COVID-19 vaccines from the U.S. market in coming months, citing unnamed sources. Investors appeared to also respond to an August 14 company announcement that it had aligned with the FDA on a rapid pathway to potential Biologics License Application (BLA) approval for its monoclonal antibody (mAb) candidate VYD2311 for the prevention of COVID-19. VYD2311 has been developed from the same antibody construct as Pemgarda® (pemivibart), which received FDA emergency use authorization (EUA) last year. The FDA told Invivyd that one Phase II/III randomized, double-blind, placebo-controlled trial evaluating mAb efficacy could support a BLA submission for VYD2311 in people ages 12 and older weighing at least 40kg (88 lbs), including immunocompromised people, subject to agreement on safety database size and a full protocol review.