The Race for Oral GLP-1: Eli Lilly’s Disappointing Trial Results Turn the Spotlight to Polypid’s Innovative Approach

Last Thursday's bloodbath for Eli Lilly’s shares (LLY) tells a sobering story about the rushed pursuit of oral GLP-1 solutions. The pharmaceutical giant's much-anticipated weight loss pill, orforglipron, delivered only 12.4% weight loss over 72 weeks, a far cry from the 23% achieved by its injectable Zepbound and dramatically below the 13.7-15% that Wall Street had expected. The disappointment was swift and brutal, with shares plummeting more than 14% and wiping out approximately $98-100 billion from the company's market capitalization.

The market's harsh reaction reveals a fundamental truth that the pharmaceutical industry has been reluctant to acknowledge: while oral GLP-1 solutions do address the real problem of patient deterrence from frequent injections, they may not justify the considerable hype or represent the optimal solution. While companies have poured billions into developing pills that promise the convenience of swallowing a tablet daily, they've largely ignored other critical issues plaguing patients who rely on these life-changing medications.

The genuine problems with weekly GLP-1 injections are well-documented and severe. Gastrointestinal side effects including nausea, vomiting, diarrhea and constipation affect more than one in 10 patients, often persisting for several days after each injection. Research from Prime Therapeutics found that nearly half of patients discontinue GLP-1 therapy within the first year, with three out of four stopping treatment by year two. The burst release pattern of current weekly formulations has been linked to these intense side effects, as the sudden flood of medication into the bloodstream triggers severe nausea and other gastrointestinal distress.

But perhaps most critically, patients experience what amounts to a therapeutic roller coaster. The efficacy of weekly injections peaks shortly after administration and then gradually diminishes, leaving many patients struggling with reduced appetite control and cravings in the days leading up to their next dose. This creates a cycle where patients face their most challenging moments, when willpower alone must carry them through, precisely when the medication's effects are at their weakest.

Polypid (NASDAQ: PYPD), an under the radar biopharma player company with a market cap of just ~$59 million recently unveiled an innovative potential solution to both problems with an elegantly simple approach. Rather than abandoning the proven efficacy of injections for the convenience of pills, Polypid's proprietary technology aims to extend  the injection interval from weekly to approximately every 60 days while delivering medication in a linear, controlled fashion that eliminates the burst release responsible for side effects.

The company's technology offers a sophisticated drug delivery system that forms a protected drug reservoir. The unique architecture of the delivery system enables controlled and continuous drug delivery over prolonged periods, providing patients with consistent therapeutic levels of the GLP-1 receptor agonist for approximately 60 days with a single administration.

Notably, PolyPid is no stranger to biopharma disruption. The Company recently released phase 3 results for its lead candidate, D-PLEX100, which seeks to prevent surgical site infections. In the recent phase 3 clinical trial, which focused on patients with large abdominal surgery incisions, the company reported a 38% reduction in deep and superficial surgical site infections.

The timing couldn't be more fortuitous. Just months ago, Eli Lilly demonstrated exactly how much value it places on extended-dosing technology when it agreed to pay up to $870 million to Camurus for similar long-acting delivery capabilities. That deal, which could reach $870 million in total value, gives Lilly access to technology that can extend dosing intervals to once monthly. Polypid's 60-day platform potentially offers even greater patient convenience.

By reducing injection frequency from 52 times yearly with current weekly dosing to just six times yearly with bi-monthly administration, Polypid's platform addresses medication adherence challenges while maintaining consistent therapeutic levels. The linear release pattern overcomes the burst release seen with current weekly delivered molecules that trigger side effects like nausea and vomiting, two of the most common reasons patients discontinue therapy.

For pharmaceutical giants still reeling from today's reminder that oral solutions may not live up to their promise, Polypid represents a potentially transformative acquisition opportunity. The company's ~$59 million market cap would be negligible for companies like Lilly or Novo Nordisk, who are generating billions quarterly from their GLP-1 franchises. Given that Eli Lilly was willing to commit nearly $1 billion for monthly dosing technology, the premium for a 60-day solution with proven clinical validation could justify a significantly higher valuation.

Recent News Highlights from PolyPid:

PolyPid Provides Corporate Update and Reports Second Quarter 2025 Financial Results

PolyPid Unveils a Long-Acting GLP-1 Receptor Agonists Delivery Platform Targeting the Diabetes and Weight Loss Market

PolyPid Announces Positive Topline Results from Phase 3 SHIELD II Trial: D-PLEX₁₀₀ Demonstrated Significant Reduction in Surgical Site Infections and Successfully Met Primary and All Key Secondary Endpoints

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