The landscape of obesity treatment is undergoing a revolution, largely fueled by the emergence of highly effective, injectable incretin-based pharmacotherapies. However, oral obesity treatments are poised to play a pivotal role in addressing the challenges associated with injectables, offering a convenient option for long-term maintenance therapy, particularly after an initial, time-limited induction phase using injectables. Currently, the obesity pipeline, encompassing pre-clinical to phase 3 stages, features 50 assets specifically designed for oral administration, constituting 33% of all assets in development for this indication.
Many innovators are exploring incretin mimetics and amylin analogues, both single and multi-acting agents, in their quest for effective oral obesity treatments. These efforts also include the exploration of CB1 receptor blockers, which modulate appetite and energy homeostasis. Peripherally restricted CB1 inverse agonists are garnering significant interest due to their potentially cleaner psychiatric side effect profile compared to centrally acting CB1 blockers.
Beyond their mechanism of action (MoA), the modality of oral obesity assets, whether small molecules or peptides, is a crucial factor determining their commercial viability and overall impact.
Small Molecules vs. Peptides: A Key Differentiator
Small molecules constitute the majority of the oral obesity pipeline, accounting for 60% of the assets. They offer several advantages over oral peptides in terms of pharmacology, manufacturing, and economics.
Pharmacology: Small molecules typically exhibit better bioavailability and food compatibility, negating the need for fasting, unlike oral peptides. This allows for lower dosing, potentially leading to a more favorable tolerability profile.
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Manufacturing: Small molecules are generally simpler to manufacture than peptide-based therapies. This enables rapid scaling up of production to meet the increasing demand.
Economics: Small molecules have significantly lower costs of goods sold (COGS) compared to peptides, primarily due to less complex manufacturing requirements. Their improved bioavailability also translates to a lower requirement of active ingredients per treatment.
Efficacy of Oral Therapies: Competing with Injectables
Several mid- to late-stage oral assets, including Novo Nordisk’s oral semaglutide, Lilly’s orforglipron, Pfizer’s danuglipron, and Structure Therapeutics’ GSBR-1290, are demonstrating competitive levels of weight loss compared to injectable Wegovy at the highest tested doses. Furthermore, orforglipron and GSBR-1290 appear competitive against Zepbound at the 12-week time point, again at the highest dose. However, they still trail behind leading next-generation, high-potency injectables like CT-388, retatrutide, or MariTide.
Peptide amycretin has shown the most impressive efficacy among oral obesity assets to date, based on early data. However, recent phase 1 data for CT-996 suggest the small molecule modality is not intrinsically inferior.
Tolerability: Addressing Gastrointestinal Side Effects
Some first-generation oral obesity assets were plagued by severe gastrointestinal (GI) side effects, leading to high discontinuation rates. This prompted innovators to explore reformulations and dose optimization. Early clinical data suggests that newer oral agents possess a cleaner tolerability profile. For instance, Viking reported no clinically meaningful difference in GI side effects for oral VK2735 compared to placebo in its phase 1 readout. This clean tolerability profile potentially allows innovators to safely explore higher doses to enhance efficacy without causing severe treatment-related adverse events, thereby closing the gap with injectables.
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It is important to note that many of these observations are directional and based on limited phase 1 data.
The Promise of Oral Anti-Obesity Pharmacotherapies
Oral anti-obesity pharmacotherapies offer many compelling advantages over injectables, making them critical in addressing the global obesity health crisis. Several key questions remain:
- How durable is the weight loss achieved with ongoing oral therapies, and at what level?
- What trade-off between efficacy, oral convenience, and tolerability would be considered clinically meaningful and acceptable to patients?
- How will the competitive dynamics between oral therapies and injectables play out? Will they coexist in distinct market segments based on patient need (e.g., baseline BMI) or therapy goal (induction vs. maintenance)? Or will oral therapies cannibalize injectables, shrinking the commercial window for injectables as induction therapies, with patients eager to switch to orals sooner? Or will they supplant injectables altogether in some patient segments that don’t require significant weight loss via potent injectables?
- How will a leaner cost structure for manufacturing small molecule-based oral therapies translate into differentiated pricing strategies?
The first oral obesity treatments are expected to enter the market around 2026/27, with Lilly’s orforglipron and Novo Nordisk’s oral semaglutide, both in phase 3, as the current frontrunners. However, timelines for the current early- and mid-stage pipeline are more fluid.
Orforglipron: A Promising Oral GLP-1 Receptor Agonist
In a large, international phase III clinical trial (ATTAIN-1), patients taking the experimental oral GLP-1 drug orforglipron experienced significant weight loss and improvements in heart and metabolic risk factors. The trial, which included 3,127 non-diabetic patients with obesity or overweight with obesity-related complications, randomized participants to receive a placebo or one of three daily doses (6mg, 12mg, 36mg) of orforglipron, along with a healthy diet and physical activity.
Over 72 weeks, patients in the low-, medium-, and high-dose orforglipron groups lost an average of 7.8%, 9.3%, and 12.4% of their initial body weight, respectively, compared to 2.1% for the placebo group. Side effects were similar to other GLP-1 drugs: mild to moderate gastrointestinal symptoms such as nausea, vomiting, and diarrhea.
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These findings suggest that orforglipron could be an important new option for people with obesity, especially those reluctant to use injections or who live in places where cold storage for injectable medications is limited. Orforglipron, a "small molecule" drug, is designed to be taken orally.
While the average weight loss was somewhat less than that seen with injectable GLP-1 therapies such as semaglutide or tirzepatide, the improvements in heart and metabolic risk factors were substantial. Individuals treated with the drug had greater reductions in waist circumference, systolic blood pressure, non-HDL cholesterol and triglyceride levels, glycated hemoglobin and other measures, compared to the placebo group.
Concerns Regarding Compounded GLP-1 Receptor Agonists
The FDA is aware that some patients and health care professionals may seek unapproved versions of GLP-1 receptor agonists, including semaglutide and tirzepatide, as a weight loss option. This can be risky because unapproved versions do not undergo FDA review for safety, effectiveness, and quality. The FDA recommends that compounded drugs be used only when a patient's medical needs cannot be met by an FDA-approved drug.
The agency has identified several concerns regarding compounded GLP-1 drugs, including:
- Improper storage during shipping: Injectable GLP-1 drugs require refrigeration, and the FDA has received complaints that certain compounded GLP-1 drugs have arrived warm or with inadequate ice packs.
- API supply chain: The FDA has issued an import alert to prevent compounded drugs containing potentially unsafe active pharmaceutical ingredients (APIs) from entering the U.S. This alert does not apply to GLP-1 API from manufacturers that comply with FDA standards.
- Products with false information on the label: In some cases, the compounding pharmacies identified on the labels of fraudulent compounded medicines do not exist or did not compound the products.
- Dosing concerns: The FDA has received reports of adverse events related to dosing errors with compounded injectable semaglutide products, resulting from patients measuring and self-administering incorrect doses or health care professionals miscalculating doses.
- Use of unauthorized ingredients: Retatrutide and cagrilintide cannot be used in compounding under federal law. Also, the FDA is aware that some semaglutide products sold by compounders may be salt forms, which are different active ingredients than those used in the approved drugs.
The FDA urges consumers to be vigilant and know the source of their medicine, carefully check labels for warning signs, and ensure their medicine is provided by a licensed pharmacy and prescribed by a licensed health care provider.
Naturally Occurring Molecules: A Novel Approach
Researchers at Stanford Medicine have identified a naturally occurring molecule that appears similar to semaglutide in suppressing appetite and reducing body weight. This molecule, identified through the use of artificial intelligence, targets receptors in the brain, gut, pancreas, and other tissues.
The researchers focused on the prohormone convertase 1/3, which separates prohormones at specific amino acid sequences and is known to be involved in human obesity. One of the peptide products is glucagon-like peptide 1, or GLP-1, which regulates appetite and blood sugar levels; semaglutide works by mimicking the effect of GLP-1 in the body.
The researchers designed a computer algorithm they named Peptide Predictor to identify typical prohormone convertase cleavage sites in all 20,000 human protein-coding genes. They then focused on genes that encode proteins that are secreted outside the cell - a key characteristic of hormones - and that have four or more possible cleavage sites.
Peptide Predictor predicted that prohormone convertase 1/3 would generate 2,683 unique peptides from the 373 proteins. A small peptide made up of just 12 amino acids increased the activity of neuronal cells tenfold over controls. When the researchers tested the effect of BRP on lean mice and minipigs, they found that an intramuscular injection of BRP prior to feeding reduced food intake over the next hour by up to 50% in both animal models. Obese mice treated with daily injections of BRP for 14 days lost an average of 3 grams - due almost entirely to fat loss - while control animals gained about 3 grams over the same period.
Skate Skin Collagen Peptides: A Natural Anti-Obesity Agent
Recent animal studies have indicated the potential of collagen peptides derived from skate skin to have anti-obesity effects through the suppression of fat accumulation and regulation of lipid metabolism. A human randomized, placebo-controlled, and double-blinded study investigated the efficacy and tolerability of skate skin collagen peptides (SCP) for the reduction of body fat in overweight adults.
Ninety healthy volunteers were assigned to the intervention group (IG), receiving 2000 mg of SCP per day, or to the control group (CG), receiving a placebo for 12 weeks. After 12 weeks, the percentage of body fat and body fat mass (kg) in IG were significantly better than those of subjects in CG. Application of SCP was well tolerated, with no notable adverse effects reported in either group.
The study found that oral SCP of 2000 mg daily for 12 weeks decreased a small amount of body fat and was tolerated without reducing calorie intake and increasing physical activities. Previous animal studies have shown that fish collagen peptide (FCP) significantly reduced body weight gain induced by a high-fat diet without a significant difference in food intake, confirming that FCP has an anti-adipogenic effect.
The major amino acids of skate skin are arginine, proline, and glutamic acid. The stability of collagen is proportional to the total amount of collagen and associated with the pyrolidine (proline + hydroxyproline) content, thus it can be enhanced by using skate skin.
More recent findings specifically using collagen peptide derived from skate skin were consistent with previous research. A reduced increase in body weight and visceral adipose tissue was observed in SCP-fed groups compared to the control group. Additionally, the researchers observed that the intake of SCP increased the hepatic protein expression of phosphorylated 5’ adenosine monophosphate-activated protein kinase (p-AMPK) with elevated adiponectin and reduced leptin levels.