The Rise of Oral Peptide Drugs: Industry Analysis

The Pill Problem: Why Peptides Were Injection-Only for Decades
SNAC Technology: The Breakthrough Behind Oral Semaglutide
Oral Semaglutide: From Rybelsus to the Wegovy Pill
Orforglipron: The Small-Molecule Challenger
The Competitive Field: Who Else Is in the Race
Patient Preference: Why Pills Matter
Market Projections and Economics
Technical Challenges Still Standing
What This Means for the Peptide Industry
FAQ
The Bottom Line
References

The Pill Problem: Why Peptides Were Injection-Only for Decades

Peptides are chains of amino acids. So is your lunch. The digestive system treats both the same way — it breaks them apart.

That biological reality kept peptide drugs confined to injections for most of pharmaceutical history. The gastrointestinal tract presents a gauntlet of destruction: stomach acid (pH as low as 1.5), pepsin and other proteolytic enzymes that cleave peptide bonds, a thick mucus barrier that blocks large molecules, and an epithelial lining that's selectively permeable to small, lipophilic molecules. Peptides are typically large, hydrophilic, and structurally fragile. They are, in other words, everything the gut is designed to destroy.

Insulin, discovered in 1921, has been injected for over a century despite persistent efforts to develop an oral formulation. The history of oral peptide delivery is littered with failed approaches — enteric coatings that protected against acid but not enzymes, enzyme inhibitors that caused unacceptable GI side effects, absorption enhancers that couldn't achieve reliable bioavailability.

That history makes what happened in 2019 — and what is happening right now — remarkable.

SNAC Technology: The Breakthrough Behind Oral Semaglutide

The key technology enabling oral semaglutide is SNAC: sodium N-(8-[2-hydroxybenzoyl] amino) caprylate. Developed by Emisphere Technologies through its Eligen platform, SNAC is a synthetic derivative of salicylic acid that acts as a transcellular permeation enhancer.

The FDA granted SNAC "generally regarded as safe" (GRAS) status. Its first approved application was in an oral vitamin B12 formulation in 2014. But its real significance emerged when Novo Nordisk licensed the technology for semaglutide.

How SNAC Works

According to a review in Reviews in Endocrine and Metabolic Disorders, SNAC operates through three complementary mechanisms:

Local pH buffering. SNAC creates a zone of elevated pH around the dissolving tablet in the stomach, protecting semaglutide from acid-mediated degradation and pepsin activity (pepsin is most active at low pH).

Enzyme inhibition. SNAC directly inhibits pepsin, the primary protease in gastric fluid. Without this inhibition, pepsin would cleave semaglutide's peptide bonds before absorption could occur.

Membrane permeability enhancement. SNAC increases the fluidity of gastric epithelial cell membranes, facilitating transcellular absorption. It forms non-covalent complexes with semaglutide and improves membrane diffusion by increasing lipophilicity. A 2025 study in Nature Communications provided molecular-level evidence that SNAC induces membrane defects — essentially creating temporary pathways through cell membranes — that allow polar peptides like semaglutide to cross the epithelial barrier.

Critically, absorption happens in the stomach, not the intestines. Studies in dogs with pyloric ligation (preventing any intestinal transit) showed plasma semaglutide levels comparable to non-ligated controls, and splenic vein concentrations (draining the stomach) were significantly higher than portal vein concentrations (draining the intestines).

The Bioavailability Trade-Off

SNAC works, but it works inefficiently. Only about 0.4–1% of the oral semaglutide dose reaches the bloodstream. That explains the dose math: the oral formulation requires 25 mg of semaglutide to achieve plasma levels comparable to 2.4 mg injected subcutaneously — roughly a 10-fold dose escalation.

That low bioavailability creates real constraints. Patients must take the pill on an empty stomach, with no more than 4 ounces of plain water, and then wait at least 30 minutes before eating, drinking, or taking any other medication. These requirements, detailed in the FDA prescribing information, exist because food, beverages, or other drugs in the stomach would interfere with the delicate SNAC-semaglutide absorption process.

Oral Semaglutide: From Rybelsus to the Wegovy Pill

Rybelsus: The First Oral GLP-1

Rybelsus, the oral semaglutide formulation for type 2 diabetes, reached the market in 2019 at a 14 mg dose. It was the first oral peptide GLP-1 receptor agonist — a genuine milestone.

But commercially, Rybelsus told a cautionary story. Despite being the same active ingredient as the wildly successful injectable Ozempic, Rybelsus generated approximately $2.7 billion in 2024 sales compared to Ozempic's nearly $14 billion. That 5:1 gap for drugs with identical pharmacology reflected the real-world friction of SNAC-related dosing requirements: patients found the fasting protocol inconvenient, and physicians often defaulted to the more reliable injectable.

The Wegovy Pill: Oral Semaglutide for Obesity

In December 2025, the FDA approved the Wegovy pill — making it the first oral GLP-1 for weight management. This higher-dose (25 mg) formulation delivered meaningfully better results than Rybelsus.

The key OASIS 4 trial, involving 307 adults with obesity or overweight, demonstrated 13.6% mean weight loss at 64 weeks on an intent-to-treat basis. For patients who adhered to the treatment protocol throughout the trial, mean weight loss reached 16.6%. That puts the pill's efficacy in the same range as injectable Wegovy (2.4 mg subcutaneous), which typically achieves 15–17% weight loss.

Novo Nordisk launched the Wegovy pill in the US in January 2026 at an introductory cash-pay price of $149 per month — a fraction of the branded injectable's list price. For insured patients, co-pays could drop to $25 per month.

The approval also included a cardiovascular indication: reducing the risk of major cardiovascular events (death, heart attack, or stroke) in adults with obesity and established cardiovascular disease.

Orforglipron: The Small-Molecule Challenger

While Novo Nordisk solved the oral peptide problem with SNAC, Eli Lilly took a fundamentally different approach with orforglipron: skip the peptide entirely.

Orforglipron is a non-peptide, small-molecule GLP-1 receptor agonist. It binds and activates the same GLP-1 receptor as semaglutide but is chemically a small organic molecule rather than an amino acid chain. That distinction eliminates the entire oral peptide delivery challenge at the molecular level.

Why Small Molecules Change the Equation

Because orforglipron is not a peptide, it sidesteps every problem SNAC was designed to solve:

No fasting required. Orforglipron can be taken at any time of day, with or without food.
No water restrictions. Patients don't need to limit fluid intake.
Higher bioavailability. Small molecules are absorbed through standard intestinal pathways with dramatically better efficiency.
Simpler manufacturing. Small-molecule synthesis is cheaper and more scalable than peptide synthesis.

Clinical Results

In the Phase 3 ACHIEVE-1 trial for type 2 diabetes, orforglipron demonstrated HbA1c reductions of 1.3–1.6% and average weight loss of 7.9% at the highest dose. The ATTAIN-MAINTAIN trial showed that patients switching from semaglutide to orforglipron maintained their previously achieved weight loss — an important result suggesting the small molecule can serve as an oral "step-down" from injectable therapy.

Eli Lilly submitted its new drug application for orforglipron to the FDA and received a Commissioner's National Priority Review Voucher, cutting the standard 10–12 month review period to one or two months. FDA approval is expected by March 2026.

The Competitive Field: Who Else Is in the Race

The oral GLP-1 market is attracting a crowded field of competitors.

Amycretin (Novo Nordisk)

Novo Nordisk's amycretin is a novel unimolecular GLP-1 and amylin receptor agonist — a single molecule that hits two distinct biological targets. The company has announced plans to move both subcutaneous and oral formulations into Phase 3 for obesity in Q1 2026. Novo Nordisk calls amycretin a potential "best-in-class" profile, though the clinical data to support that claim is still early.

VK2735 (Viking Therapeutics)

Viking Therapeutics is developing VK2735, an oral dual agonist of the GIP and GLP-1 receptors. It mimics the mechanism of injectable tirzepatide but in a once-daily pill. Viking's entry is significant because it represents an oral path to the dual-agonist approach that tirzepatide has validated in injected form.

Danuglipron (Pfizer)

Pfizer's oral GLP-1 program has been more troubled. The company initially targeted twice-daily dosing with danuglipron but shifted development toward a modified-release once-daily formulation after tolerability concerns with the twice-daily regimen. The program remains in clinical development, though Pfizer's timeline lags significantly behind Lilly and Novo.

Emerging Permeation Enhancer Research

Beyond SNAC, researchers are exploring next-generation absorption enhancement strategies. A 2024 study in ScienceDirect showed that combining SNAC with sodium caprate (C10) in a single tablet significantly improved peptide permeability compared to either enhancer alone, using gastric organoid-based cell models. This combination approach could eventually improve oral bioavailability beyond the current sub-1% ceiling.

Patient Preference: Why Pills Matter

The clinical case for oral GLP-1s isn't just about efficacy — it is about adherence.

Injection aversion is real and widespread. Surveys consistently show that 20–30% of patients eligible for injectable GLP-1 therapy decline treatment due to needle phobia or discomfort with self-injection. Even among patients who start injectable therapy, discontinuation rates are high — real-world data shows 20–50% of GLP-1 RA users stop within the first year, with injection burden cited as a contributing factor.

For primary care physicians — who prescribe the majority of metabolic drugs — pills fit existing workflows far better than injectable biologics. A primary care practice already writes hundreds of pill prescriptions daily. Adding an injectable requires patient education on injection technique, refrigeration, needle disposal, and reconstitution (for some formulations). An oral option removes that entire layer of complexity.

The convenience gap between oral semaglutide (with its fasting requirements) and orforglipron (no restrictions) is itself clinically meaningful. A drug that patients actually take consistently at the prescribed dose will outperform a theoretically superior drug that patients skip, forget, or abandon.

Market Projections and Economics

The financial stakes are staggering. Goldman Sachs projects that oral GLP-1s will generate roughly $22 billion in annual sales by 2030, capturing about 24% of the global weight-loss drug market expected to reach $95 billion.

Within the oral segment, the bank predicts a striking split: Eli Lilly's orforglipron is projected to capture approximately 60% market share (~~$13.6 billion), while Novo Nordisk's oral semaglutide is projected at about 21% (~~$4 billion). That 3:1 disadvantage for oral semaglutide — despite Novo's first-mover advantage — reflects analyst consensus that orforglipron's lack of dosing restrictions will prove commercially decisive.

The broader oral options are expected to capture around 20% of the $80 billion obesity GLP-1 market by decade's end, with the remaining 80% staying with injectable formulations that offer higher doses and, in some cases, superior weight loss.

Pricing Dynamics

Novo Nordisk's decision to launch the Wegovy pill at $149/month cash-pay signals a pricing strategy aimed at volume over margin. For context, branded injectable Wegovy carries a list price exceeding $1,300/month. The oral formulation's lower manufacturing costs (smaller required quantities of API per dose notwithstanding the low bioavailability) and Novo's desire to establish market share before orforglipron's approval are both driving the aggressive pricing.

Eli Lilly's pricing for orforglipron has not been announced, but the small-molecule manufacturing advantage should allow competitive pricing. Lilly has already demonstrated willingness to compete on price through its LillyDirect program for injectable tirzepatide.

Technical Challenges Still Standing

Despite the progress, oral peptide delivery remains technically constrained.

Bioavailability ceiling. SNAC-enabled oral semaglutide achieves less than 1% oral bioavailability. That means over 99% of the active ingredient is destroyed or unabsorbed. This isn't just wasteful — it contributes to higher API requirements and manufacturing costs, and it means the dose-response relationship is subject to high inter-patient variability depending on individual gastric conditions.

Compound specificity. Research published in Clinical Diabetes demonstrates that SNAC's absorption-enhancing effect is highly compound-specific. What works for semaglutide may not work for other peptides. Each new oral peptide formulation requires its own exhaustive optimization process — SNAC is not a universal oral delivery solution.

Formulation complexity. The SNAC-semaglutide tablet is an engineered system, not simply semaglutide mixed with an excipient. The tablet's erosion profile, SNAC-to-drug ratio, and manufacturing tolerances all affect absorption. Scaling this formulation while maintaining batch-to-batch consistency is a non-trivial manufacturing challenge.

Limited pipeline. Beyond semaglutide, no other peptide has been successfully formulated for oral delivery using SNAC or any other permeation enhancer at commercial scale. The small-molecule approach (orforglipron) avoids these issues entirely but is limited to targets where a non-peptide agonist can be designed — which is not possible for all peptide drug targets.

What This Means for the Peptide Industry

The oral GLP-1 race is reshaping the peptide industry in several ways.

Manufacturing investment. The demand for oral semaglutide requires substantially more semaglutide API per patient than injectable formulations (25 mg/day oral vs. ~0.34 mg/day injectable equivalent). This has driven massive investment in peptide synthesis capacity, with CDMOs like CordenPharma committing over EUR 1 billion to expansion.

Competitive pressure from small molecules. If orforglipron succeeds commercially, it will demonstrate that peptide targets can sometimes be captured by small molecules — raising questions about the long-term competitive position of peptide drugs in markets where small-molecule alternatives exist. For the broader peptide industry, this underscores the importance of targets where peptides offer unique advantages (selectivity, multi-target engagement, specific binding geometries) that small molecules cannot replicate.

Regulatory precedent. The FDA's approval pathway for oral semaglutide has established a regulatory template for oral peptide drugs. Companies developing oral formulations of other peptides now have a clearer roadmap for the preclinical and clinical data packages needed to support approval.

Compounding implications. The shift toward oral formulations also intersects with the FDA's crackdown on peptide compounding. As branded oral options become available at lower price points, the regulatory and commercial arguments for compounded alternatives weaken — though cost and access barriers will persist for many patients.

FAQ

How effective is the oral semaglutide pill compared to the injection?

In the OASIS 4 trial, oral semaglutide (25 mg daily) achieved 13.6% mean weight loss at 64 weeks on an intent-to-treat basis (16.6% among treatment-adherent patients). This is comparable to injectable Wegovy (2.4 mg weekly), which achieves approximately 15–17% weight loss in clinical trials. The two formulations contain the same active ingredient and have consistent exposure-response relationships once the drug is absorbed.

What is the difference between orforglipron and oral semaglutide?

Oral semaglutide is a peptide (amino acid chain) that requires SNAC, a permeation enhancer, for stomach absorption, and must be taken on an empty stomach with specific water restrictions. Orforglipron is a small organic molecule (not a peptide) that activates the same GLP-1 receptor but can be taken at any time with or without food. Both are once-daily pills, but orforglipron's lack of dosing restrictions represents a significant convenience advantage.

Why does oral semaglutide require fasting?

Food, beverages, and other medications in the stomach interfere with SNAC's ability to create the local conditions needed for semaglutide absorption — specifically, the pH buffering, enzyme inhibition, and membrane permeability enhancement that allow the peptide to cross the gastric epithelium. Even a small amount of food can dramatically reduce absorption.

When will orforglipron be available?

Eli Lilly submitted its new drug application to the FDA and received a priority review voucher. FDA approval is expected by approximately March 2026, with commercial availability likely shortly after.

Will oral GLP-1 drugs replace injectable versions?

Not entirely. Analysts project oral formulations will capture about 20–24% of the total GLP-1 market by 2030. Injectable versions will continue to offer advantages in some scenarios — higher achievable doses, more predictable pharmacokinetics, and combination formulations (like CagriSema) that may not be feasible in oral form. For many patients, however, the convenience of a pill will outweigh the theoretical advantages of injection.

Are there oral peptide drugs beyond GLP-1 agonists?

Currently, no other peptide has been commercially formulated for oral delivery at scale. Research is ongoing into oral formulations of insulin, calcitonin, and other therapeutic peptides, but none has matched semaglutide's clinical and commercial success. The SNAC approach appears to be highly compound-specific, meaning each new oral peptide requires its own optimization process.

The Bottom Line

The oral peptide drug market has arrived, and it is already reshaping the pharmaceutical industry's most lucrative therapeutic category. Novo Nordisk's SNAC-enabled oral semaglutide proved that peptides can survive the gut — even if inefficiently — while Eli Lilly's orforglipron demonstrated that sometimes the best solution to delivering a peptide orally is to not use a peptide at all.

For patients, the practical impact is straightforward: within 2026, two distinct oral GLP-1 options will be available for obesity and diabetes, each with different trade-offs around convenience, efficacy, and cost. For the pharmaceutical industry, the competition between peptide-based and small-molecule approaches to the same receptor target is a case study in how molecular strategy shapes commercial outcomes.

The broader lesson for the peptide field is nuanced. Oral delivery expands the addressable market for peptide drugs, but it also exposes peptides to direct competition from small molecules on their home turf. The peptide industry's long-term advantage lies in biological targets where small molecules simply cannot match peptide selectivity — targets that oral delivery technology may eventually unlock.

References

A new era for oral peptides: SNAC and the development of oral semaglutide. Reviews in Endocrine and Metabolic Disorders (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9515042/
Current understanding of SNAC as an absorption enhancer. Clinical Diabetes (2024). https://pmc.ncbi.nlm.nih.gov/articles/PMC10788673/
Permeation enhancer-induced membrane defects assist oral absorption of peptide drugs. Nature Communications (2025). https://www.nature.com/articles/s41467-025-64891-0
FDA approves oral semaglutide as first GLP-1 pill for weight loss. AJMC (2025). https://www.ajmc.com/view/fda-approves-oral-semaglutide-as-first-glp-1-pill-for-weight-loss
Novo Nordisk Wegovy pill FDA approval. MedCity News (2025). https://medcitynews.com/2025/12/novo-nordisk-wegovy-pill-fda-approved-oral-glp-1-drug-obesity-weight-loss-nvo/
Novo Nordisk launches first GLP-1 pill for obesity. Drug Discovery Trends. https://www.drugdiscoverytrends.com/novo-nordisk-launches-first-glp-1-pill-for-obesity-but-lilly-may-dominate-the-oral-market-eventually/
What's driving the remarkable rise of the oral GLP-1 market today? GlobeNewsWire (2025). https://www.globenewswire.com/news-release/2025/12/05/3200759/0/en/What-s-Driving-the-Remarkable-Rise-of-the-Oral-GLP-1-Market-Today.html
The leading GLP-1 contenders in pharma's race for an obesity pill. PharmaVoice. https://www.pharmavoice.com/news/glp-1-pharma-obesity-pill-drug-novo-viking-structure-lilly/808195/
Combining SNAC and C10 in oral tablet formulations for gastric peptide delivery. ScienceDirect (2024). https://www.sciencedirect.com/science/article/pii/S016836592400837X
FDA Wegovy pill prescribing information (2025). https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218316Orig1s000lbl.pdf
Real-world evidence on GLP-1RA utilization and effectiveness. PMC (2025). https://pmc.ncbi.nlm.nih.gov/articles/PMC12000858/
What to watch for in weight loss drugs in 2026. NBC News. https://www.nbcnews.com/health/health-news/weight-loss-drug-prices-2026-glp-1-pills-trumprx-what-expect-rcna249520

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