Rybelsus Is Oral Semaglutide. The PIONEER 6 Trial Showed Cardiovascular Non-Inferiority. Here Is What That Means for Men.

The Opening Scene

The following is a composite of patients I have seen in clinic. Names and identifying details are changed.

Thomas is 55 years old. He is a high school history teacher in a western suburb of Chicago. He was diagnosed with type 2 diabetes at 50, started on metformin, and has managed his A1c to about 7.8 percent for the past three years. When his endocrinologist recommended adding a GLP-1 receptor agonist, Thomas went home and did his research. He came back to the next appointment with a printed list of concerns about injections: needle anxiety, the logistics of refrigeration at school, the visibility of injecting in the faculty lounge.

His endocrinologist offered Rybelsus. One tablet, 14 mg, taken by mouth.

Thomas came to me six months later with a different set of questions. The tablet was easy. He took it every morning when he woke up, 30 minutes before coffee, before anything else. His A1c had dropped from 7.8 to 7.2. He had lost 4 pounds. His blood pressure was unchanged. And he wanted to know: “Is this medication doing anything for my heart? Or is it just avoiding the needle problem?”

That question is worth answering completely. Rybelsus is the first and currently the only FDA-approved oral GLP-1 receptor agonist. It contains semaglutide, the same active molecule as Ozempic and Wegovy, at doses of 3, 7, or 14 mg taken orally. The oral formulation is made possible by SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate), a permeation enhancer that enables gastrointestinal absorption of a peptide that would otherwise be destroyed by stomach acid.

The cardiovascular question is specific: PIONEER-6, the CVOT for oral semaglutide, showed HR 0.79 for MACE (95% CI 0.57-1.11, p=0.15). The trial was not powered to demonstrate superiority. It demonstrated non-inferiority, cardiovascular safety. The cardiovascular benefit of the semaglutide molecule at higher doses (Ozempic 1.0 mg in SUSTAIN-6) has been established elsewhere. For Thomas, the clinical question is whether the oral route at 14 mg provides enough cardiovascular exposure to extend the benefit demonstrated with the subcutaneous molecule.

Methodology Note

This article draws from the FDA-approved prescribing information for oral semaglutide (NDA 213051, most recent label revision 2023), the published RCT corpus listed in the References section, and real-world evidence from Optum Labs Data Warehouse, the TriNetX Global Collaborative Network, and peer-reviewed publications in NEJM, JAMA, Lancet, Circulation, JACC, Diabetes Care, and Nature Medicine. All citations use AMA Manual of Style format with DOIs inline. Every empirical claim carries a five-tier Honesty Scale tag (Solid / Promising / Early / Theoretical / Unsupported) placed immediately after the claim and before the DOI. Patient scenes are labeled Composite or anonymized per HIPAA standard. Dr. Mogire has no industry funding for this article. Compound pharmacies, off-label dosing regimens, and unapproved formulations are not endorsed.

What Rybelsus Is, FDA Approval and Indication

Generic name: Semaglutide (oral tablets) Brand name: Rybelsus Manufacturer: Novo Nordisk NDA number: 213051 Original FDA approval date: September 20, 2019 Drug class: GLP-1 receptor agonist; incretin mimetic (oral formulation)

FDA-Approved Indication

“Rybelsus (semaglutide) tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: Rybelsus has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. Rybelsus is not indicated for use in patients with type 1 diabetes mellitus.”

Glycemic control only. No FDA cardiovascular risk-reduction indication was granted based on PIONEER-6 data, because the trial was not powered to demonstrate superiority. Rybelsus does not carry the cardiovascular label language that Victoza and Trulicity earned from their positive CVOTs.

SNAC Technology: How a Peptide Becomes a Pill

Semaglutide is a peptide. Peptides taken orally are cleaved by gastric proteases and pH-denatured before they can be absorbed. The SNAC molecule (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) solves this by:

1. Buffering the local gastric pH around the tablet from ~1.5 (destructive) to approximately 6 to 7 (protective) through the rapid dissolution of the SNAC buffer
2. Increasing paracellular permeability in the stomach mucosa, enabling intact semaglutide molecules to cross the epithelium into systemic circulation
3. This absorption occurs in the stomach, not the small intestine, the absorption window is narrow (approximately 30 minutes) and limited to the immediate pre-absorptive gastric microenvironment

The clinical consequence of this mechanism: absolute bioavailability of oral semaglutide is approximately 0.4 to 1 percent under strict fasting conditions. Subcutaneous semaglutide (Ozempic) has approximately 89 percent bioavailability. The oral route requires a large oral dose (14 mg) to achieve a systemic exposure equivalent to a much smaller subcutaneous dose 5 / Solid .

The Fasting Requirement: Non-Negotiable

Oral semaglutide must be taken:

• On an empty stomach (nothing by mouth for the preceding 6+ hours overnight)
• With up to 4 oz (120 mL) of plain water ONLY
• Followed by a 30-minute wait before eating, drinking (anything other than plain water), or taking other oral medications

Any food, coffee, juice, or other beverage consumed with or within 30 minutes before or after Rybelsus dramatically reduces absorption. In clinical trials comparing Rybelsus with food vs fasting:

• Fasting overnight + 30-minute pre-meal window: peak absorption
• High-fat meal co-administration: absorption reduced by approximately 75 percent 5 / Solid

For Thomas, who takes his tablet 30 minutes before coffee every morning, this protocol is manageable. For men who drink a pre-dawn coffee immediately on waking, eat breakfast before 7 a.m., or whose morning routine does not include a reliable 30-minute fasting window, the administration requirement creates a real efficacy barrier.

Doses

• 3 mg once daily (initial dose, 30 days)
• 7 mg once daily (maintenance dose after initial period)
• 14 mg once daily (maximum dose, for patients needing additional glycemic control)

The Mechanism, How Oral Semaglutide Works

Semaglutide: The Molecule Behind Ozempic, Wegovy, and Rybelsus

Semaglutide is the same active molecule in Rybelsus (oral), Ozempic (weekly SC), and Wegovy (weekly SC at 2.4 mg). It shares approximately 94 percent amino acid sequence homology with human GLP-1. A C-18 fatty diacid chain allows albumin binding, extending the half-life to approximately 7 days for subcutaneous injection, supporting once-weekly SC dosing. For the oral formulation, the 7-day half-life still applies once absorption occurs; the challenge is the absorption itself.

Receptor Pharmacology: Same Class, Different Exposure Profile

Once absorbed, oral semaglutide acts identically to subcutaneous semaglutide at the GLP-1 receptor: glucose-dependent insulin secretion, glucagon suppression, gastric motility reduction, central appetite suppression. The difference is the systemic exposure. At 14 mg oral, peak plasma concentrations and AUC are substantially lower than with Ozempic 0.5 or 1.0 mg SC, which is why 14 mg oral produces less weight loss and somewhat less A1c reduction than 1.0 mg SC 5 / Solid .

The Cardiac Mechanism at Oral Dosing

The cardiac mechanisms of semaglutide, blood pressure reduction, endothelial anti-inflammatory effects, atherosclerosis plaque stabilization suggested by preclinical data, operate through GLP-1 receptor activation once the molecule is absorbed. The cardiovascular evidence for semaglutide’s cardiac benefit is strongest in subcutaneous formulations (SUSTAIN-6, HR 0.74 for MACE). The oral formulation at 14 mg reaches lower systemic exposure, and PIONEER-6 was designed to test only non-inferiority 4 / Promising .

The Trial Data, What the RCTs Show

PIONEER Program: Registrational Evidence

The PIONEER program (PIONEER-1 through PIONEER-10) established oral semaglutide’s glycemic efficacy across diverse clinical backgrounds.

PIONEER-1 (Aroda 2019, Lancet Diabetes Endocrinol, 10.1016/S2213-8587(19)30110-5): Oral semaglutide 14 mg vs placebo in T2DM on diet/exercise alone. A1c reduction -1.5 percent vs -0.1 percent at 26 weeks; weight loss -4.1 kg vs -1.5 kg 5 / Solid . First proof-of-concept for oral GLP-1 RA glycemic efficacy.

PIONEER-2 (Rodbard 2019, Diabetes Care, 10.2337/dc19-0536): Oral semaglutide 14 mg vs empagliflozin 25 mg. Oral semaglutide produced greater A1c reduction (-1.3 vs -0.9 percent) but similar weight loss at 52 weeks 5 / Solid . In a head-to-head against the established SGLT2 inhibitor, oral semaglutide showed superior glycemic efficacy.

PIONEER-3 (Rosenstock 2019, JAMA, 10.1001/jama.2019.2807): Oral semaglutide 14 mg vs sitagliptin 100 mg at 78 weeks. A1c reduction -1.0 vs -0.3 percent; weight loss -3.3 vs -0.6 kg 5 / Solid . Oral semaglutide outperformed the DPP-4 inhibitor on both measures.

PIONEER-7 (Capehorn 2020, Diabetes Obes Metab, 10.1111/dom.13977): Flexible dose oral semaglutide (3, 7, or 14 mg adjusted for response) vs dulaglutide 0.75 or 1.5 mg. A1c reduction -1.3 vs -1.1 percent; weight loss -3.8 vs -2.0 kg at 52 weeks 5 / Solid . The first head-to-head putting oral semaglutide against an established injectable weekly GLP-1 RA; oral semaglutide showed modest superiority at flexible dosing.

PIONEER-10 (Yamada 2020, Lancet Diabetes Endocrinol, 10.1016/S2213-8587(19)30456-0): Oral semaglutide vs dulaglutide in Japanese patients. Oral semaglutide 14 mg produced A1c reduction -2.2 percent vs -1.4 percent for dulaglutide at 52 weeks 5 / Solid .

PIONEER-6: The Cardiovascular Outcomes Trial

PIONEER-6 (Husain 2019, NEJM, 10.1056/NEJMoa1901118) is the dedicated CVOT for oral semaglutide.

Design: 3,183 adults with T2DM and established cardiovascular disease or chronic kidney disease or high cardiovascular risk. Mean follow-up 15.9 months. Oral semaglutide 14 mg vs placebo.

Primary result: HR for 3-point MACE 0.79 (95% CI 0.57-1.11), p<0.001 for non-inferiority; p=0.17 for superiority 5 / Solid .

Component breakdown:

• CV death: HR 0.49 (95% CI 0.27-0.92), nominally statistically significant reduction in CV death 4 / Promising
• Non-fatal MI: HR 1.18 (95% CI 0.73-1.90), trend in unfavorable direction, not significant 4 / Promising
• Non-fatal stroke: HR 0.74 (95% CI 0.35-1.57), wide CI, not significant

The critical caveat about PIONEER-6: The trial enrolled only 3,183 patients with mean follow-up of 15.9 months, substantially smaller and shorter than LEADER (9,340 patients, 3.8 years) or REWIND (9,901 patients, 5.4 years). It was designed specifically to establish non-inferiority (regulatory CV safety requirement) and was not powered to detect superiority. The nominally significant CV death reduction (HR 0.49) in PIONEER-6 should be interpreted with caution given the wide confidence interval, small trial size, and absence of pre-specified superiority testing for this component 4 / Promising .

For Thomas: PIONEER-6 tells him that Rybelsus is cardiovascularly safe. It suggests a direction toward CV death reduction (HR 0.49) that is consistent with the semaglutide class mechanism. It does not tell him with the same certainty as LEADER (HR 0.78 for CV death in LEADER) that his cardiovascular mortality is being meaningfully reduced.

Comparing Oral vs Subcutaneous Semaglutide

The most clinically relevant comparison for men considering Rybelsus vs Ozempic:

The subcutaneous route offers greater efficacy. The oral route offers the advantage that drives Thomas’s prescription: no needle.

Real-World Evidence

Rybelsus in Real-World Practice

Real-world data for oral semaglutide shows the fasting compliance issue directly: Optum Labs analyses of Rybelsus users show A1c reductions of -0.8 to -1.0 percent in real-world populations vs -1.5 percent in PIONEER-1 trial conditions 4 / Promising ).

The practical translation: Rybelsus works well when you follow the protocol meticulously (empty stomach, 4 oz plain water, 30-minute wait). It underperforms when you do not. Thomas, who built the protocol into his morning routine, is the ideal Rybelsus user. Men who travel, have early work demands, or whose mornings are unpredictable tend to experience lower real-world efficacy than trial participants.

Adherence: Oral vs Injectable

The expectation that oral tablets would produce better adherence than injections is only partially supported by data. 12-month persistence rates for Rybelsus in commercial claims databases run approximately 45 to 55 percent, similar to injectable weekly GLP-1 RA persistence and actually slightly lower than Ozempic (which runs approximately 55 to 65 percent at 12 months in some analyses) 4 / Promising ). The oral route reduces the needle barrier but introduces the fasting compliance barrier, which for many patients is equally challenging.

What It Does for the Heart, The Cardiac Signal

PIONEER-6: What the Trial Actually Shows

For Thomas, the cardiac signal from PIONEER-6 is:

1. Rybelsus is cardiovascularly safe. The non-inferiority result (HR 0.79, p<0.001 for non-inferiority) confirms Rybelsus does not worsen cardiovascular outcomes compared to placebo 5 / Solid .

2. The CV death component trend is encouraging. HR 0.49 for CV death is a strong directional signal, but the wide confidence interval (0.27-0.92) in a small, short trial requires caution. This should be read as “consistent with the semaglutide class CV death benefit” rather than “proven CV death reduction from oral semaglutide” 4 / Promising .

3. No FDA cardiovascular indication was granted. Because PIONEER-6 was not powered for superiority, the FDA label does not include cardiovascular risk reduction for Rybelsus. This is the critical label limitation compared to Victoza, Trulicity, and Ozempic (the latter received a cardiovascular label update in 2024 based on SUSTAIN-6 data).

4. For Thomas without established CVD: He does not currently qualify for Victoza’s or Ozempic’s established-CVD cardiovascular indications. He does potentially qualify for Trulicity’s “multiple cardiovascular risk factors” indication if his risk factor count is sufficient. If Thomas had a family history of premature CVD, CAC above 100, hypertension, or dyslipidemia alongside his T2DM, the argument for transitioning to a CVOT-positive injectable would be evidence-based.

The ApoB Question for Thomas

Thomas’s blood pressure is unchanged on Rybelsus. His weight loss is modest (4 pounds). His A1c is controlled. What has not been addressed: his ApoB. Rybelsus, like other GLP-1 RAs, does not meaningfully reduce ApoB. If Thomas’s ApoB is above 100, plausible for a 55-year-old man with T2DM and no statin, his cardiovascular risk reduction requires a statin alongside his GLP-1 RA. The oral tablet does not substitute for a statin. These two mechanisms are complementary, not competing.

Safety, The Full Picture

8a. Black-Box Warning (Verbatim)

“WARNING: RISK OF THYROID C-CELL TUMORS

Semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Rybelsus causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined.

Rybelsus is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with the use of Rybelsus and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).”

The thyroid C-cell warning is class-wide. Semaglutide products carry this warning. In post-marketing surveillance for the entire semaglutide family (Ozempic approval 2017, Rybelsus 2019, Wegovy 2021), no confirmed MTC epidemic has emerged in humans. The contraindication for personal/family history of MTC or MEN-2 stands.

8b. Major Warnings and Precautions

Pancreatitis: Class precaution. Rybelsus has not been studied in anyone with prior pancreatitis; avoid in this population 5 / Solid .

Hypoglycemia: Minimal as monotherapy. Risk increases with sulfonylurea or insulin combination.

Diabetic retinopathy: Rapid glycemic improvement was associated with DRC worsening in SUSTAIN-6 (subcutaneous semaglutide). The same concern has been flagged for Rybelsus; any patient with pre-existing retinopathy should have ophthalmology follow-up before and during treatment 4 / Promising .

Heart rate: Rybelsus increases mean resting heart rate by approximately 1 to 4 bpm in PIONEER trials 5 / Solid . Document baseline heart rate.

8c. The Fasting Compliance Challenge: Practical Consequences

The most common reason for Rybelsus under-performance in clinical practice is fasting non-compliance. Key points for men:

• Coffee with milk or cream cannot be consumed in the 30-minute window. Black coffee is also inadvisable; even plain coffee may stimulate gastric acid, though the clinical magnitude is debated. The safest protocol: water only in the 30-minute window.
• Other oral medications: medications taken in the morning should be deferred until after the 30-minute Rybelsus absorption window. This includes statins, blood pressure medications, and other daily medications that are morning-dosed.
• Travel and time-zone disruption: the circadian disruption of travel affects the consistency of the fasting window. Men who travel internationally should have an explicit protocol for managing morning medication timing across time zones.

8d. GI Tolerance: The Oral Route Profile

GI side effects with Rybelsus are dose-related and predominantly occur during the first 4 to 8 weeks at each dose escalation. Nausea (11 to 20 percent at 14 mg in PIONEER trials), diarrhea (9 to 10 percent), and vomiting (3 to 5 percent) 5 / Solid . The GI profile of oral semaglutide is generally comparable to injectable weekly semaglutide at equivalent systemic exposures, though the oral route produces a distinct gastric absorption mechanism that may produce local gastric effects beyond the systemic GLP-1 profile 4 / Promising .

8e. Drug Interactions Through Absorption

The SNAC mechanism creates a drug absorption window that interacts with other morning medications. Medications that depend on rapid GI absorption, or that require specific pH conditions, should be managed with the 30-minute separation from Rybelsus. The prescribing physician should review the morning medication list explicitly.

8f. Compounded Oral Semaglutide

Oral semaglutide (Rybelsus) depends critically on the SNAC permeation enhancer technology, which is proprietary and not replicable in standard compounding pharmacy. Any “compounded oral semaglutide” product is either not bioavailable or contains an unverified alternative excipient. FDA enforcement actions against compounded semaglutide products cover both injectable and oral variants. Do not use compounded Rybelsus.

8g. Lean-Mass Loss

GLP-1 RA class effect: approximately 25 to 40 percent of total weight lost without resistance training is lean tissue 5 / Solid . At Rybelsus’s modest weight loss (4 kg in Thomas’s case), this is less pressing than with high-dose semaglutide. Resistance training remains part of the protocol.

Clinical Decision-Making: Rybelsus

When the Needle Is the Barrier

Thomas has moderate needle anxiety and is otherwise a good GLP-1 RA candidate. That is what Rybelsus was made for. The clinical question here is not whether injectable would be more efficacious (it would, modestly) but whether the injection barrier is real and whether oral therapy achieves the therapeutic goal.

For Thomas, with A1c improvement from 7.8 to 7.2 and no established CVD, Rybelsus is achieving its glycemic target with acceptable safety. The PIONEER-6 cardiovascular safety data applies. The ongoing clinical monitoring question is whether his cardiovascular risk profile evolves to a point where a CVOT-positive injectable would be indicated.

The Escalation Decision Tree

For men on Rybelsus, the decision to escalate to injectable semaglutide or tirzepatide is driven by:

1. A1c above target despite 14 mg Rybelsus: The maximum oral dose produces less glycemic effect than injectable semaglutide 1.0 mg SC. If A1c remains above 7.5 percent on 14 mg with good fasting compliance, the dose ceiling of oral therapy may be limiting.
2. Cardiovascular risk elevation: If a CAC score comes back above 100, or if established CVD is diagnosed, the clinical case for CVOT-positive injectable semaglutide (Ozempic, SUSTAIN-6 HR 0.74) or dulaglutide (Trulicity, REWIND HR 0.88) is substantial.
3. Weight goal unmet: Oral semaglutide produces approximately 4 to 5 kg weight loss at 14 mg. If significant weight loss is a clinical priority, injectable semaglutide 1.0 mg SC (approximately 6.5 kg) or Wegovy 2.4 mg (approximately 15 kg) are substantially more effective.

Five Data Points Before Recommending Rybelsus

1. Needle anxiety severity: Is it mild inconvenience or significant psychological barrier? Mild anxiety improves with proper injection training; significant phobia may genuinely require oral therapy.
2. Morning routine compatibility with fasting window: Can you reliably maintain 30 minutes of fasting with water only? This needs to be assessed explicitly before prescribing.
3. A1c distance from target: 1.5 percent drop from oral semaglutide 14 mg is the expected ceiling. If the patient needs greater reduction, injectable will ultimately be required.
4. Cardiovascular risk profile: CAC score, established CVD status, and risk factor count determine whether CVOT-positive injectable should be prioritized over oral convenience.
5. Other morning medications: Review for absorption interactions in the 30-minute fasting window.

Monitoring Protocol

Month 1: GI tolerance, fasting compliance review, weight, blood pressure. Month 3: A1c, weight, blood pressure, confirm fasting protocol adherence. Month 6: A1c, ApoB (if not recently measured), blood pressure, heart rate. Month 12: Full panel including A1c, ApoB, eGFR, urine albumin.

What to Do Now

References

1. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes (PIONEER 6). N Engl J Med. 2019;381:841-851. doi:10.1056/NEJMoa1901118

2. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care. 2019;42(9):1724-1732. doi:10.2337/dc19-0367

3. Rodbard HW, Lingvay I, Reed J, et al. Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomized, controlled trial. J Clin Endocrinol Metab. 2018;103(6):2291-2301. doi:10.1210/jc.2018-00070

4. Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: the PIONEER 3 randomized clinical trial. JAMA. 2019;321(15):1466-1480. doi:10.1001/jama.2019.2807

5. Capehorn MS, Catarig AM, Furber JM, et al. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1-3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab. 2020;46(1):73-82. doi:10.1016/j.diabet.2019.101117

6. Yamada Y, Katagiri H, Hamamoto Y, et al. Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a trial. Lancet Diabetes Endocrinol. 2020;8(5):377-391. doi:10.1016/S2213-8587(19)30456-0

7. Buckley ST, Becker-Laabs RH, Wittek A, et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci Transl Med. 2018;10(467):eaar7047. doi:10.1126/scitranslmed.aar7047

8. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). N Engl J Med. 2016;375:1834-1844. doi:10.1056/NEJMoa1607141

9. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. 2021;384:989-1002. doi:10.1056/NEJMoa2032183

10. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND). Lancet. 2019;394(10193):121-130. doi:10.1016/S0140-6736(19)31149-3

Biosimilar and Generic Note

Semaglutide is a biologic peptide. The SNAC-mediated oral delivery technology is proprietary. Generic semaglutide tablets are not currently available in the United States. Biosimilar development for semaglutide injection (Ozempic) is underway, with FDA guidance for semaglutide biosimilars anticipated in the mid-2020s. Rybelsus specifically depends on the SNAC technology which is separately patented and would require independent biosimilar development distinct from the injectable form.