March 2, 2024

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Challenges in the Development of Oral Weight Loss Medication

Challenges in the Development of Oral Weight Loss Medication: Focus on Drug Tolerance



Challenges in the Development of Oral Weight Loss Medication: Focus on Drug Tolerance

2023 appears to be a milestone year for the development of weight loss medications, with significant market success for Novo Nordisk’s Wegovy and Eli Lilly’s Zepbound gaining approval and entering the market towards the year-end, creating a competitive landscape alongside Wegovy.

Challenges in the Development of Oral Weight Loss Medication: Focus on Drug Tolerance


  1. The Unfulfilled Ambition of Danuglipron

Despite the flourishing era, Pfizer faces a somber situation, particularly concerning their weight loss drug, danuglipron. In addition to a drastic decline in sales of their COVID-19 vaccine, the highly anticipated GLP-1 receptor agonist danuglipron experienced a setback at the end of the year. The Phase 2 clinical trial, involving twice-daily dosages, was abruptly terminated, leading Pfizer to abandon plans for Phase 3 clinical studies.

Danuglipron held Pfizer’s fervent hope to venture into the obesity market, replacing their earlier terminated oral GLP-1 receptor agonist, lotiglipron, with a shift in focus to danuglipron, already in Phase 2 clinical trials by mid-year. However, six months later, the termination of the Phase 2 clinical trial for twice-daily danuglipron was announced. The news caused Pfizer’s stock to plummet by 5%, wiping nearly $10 billion off its market value. Prior to this, Pfizer’s stock had already experienced a decline of over 40% for the year. The once-promising danuglipron, predicted by JPMorgan to achieve $1.5 billion in annual sales, concluded with only a once-daily clinical trial remaining as a lingering hope.

A closer examination of danuglipron’s data reveals that its Phase 2 clinical readings actually met the primary clinical endpoints. The downfall of this oral small molecule drug was not due to lack of efficacy but rather issues related to tolerance.

Danuglipron’s weight loss effects aligned with analysts’ expectations. While it was not anticipated to match the weight reduction data of GLP-1 peptides like semaglutide and tirzepatide, or compete with Novo Nordisk’s CagriSema (a combination therapy of 2.4 mg semaglutide and 2.4 mg cagrilintide, achieving a 16% weight reduction over 32 weeks), danuglipron achieved a 7-12% weight reduction in Phase 2 studies, depending on the dosage.

Despite lagging in weight reduction data, the real issue for danuglipron was its tolerability. Even with a titration plan in place, the dropout rate for participants receiving twice-daily danuglipron was 10% higher than the placebo group. Similar to semaglutide and tirzepatide, danuglipron faced gastrointestinal disturbances due to its mechanism of action as a GLP-1 receptor agonist.


  1. Tolerance Issues with GLP-1 Drugs

GLP-1 drugs have become integral in the management of type 2 diabetes and obesity, offering dual benefits by simulating natural insulin responses to promote insulin secretion, inhibit glucagon release, reduce insulin resistance, lower gastric emptying, and suppress appetite. However, tolerance issues with GLP-1 drugs have gained increasing importance in clinical studies and drug development.

a. Significance of Drug Tolerance

Drug development is a complex and rigorous process aimed at finding medications that can treat diseases and improve patients’ quality of life. In this process, drug tolerance becomes a crucial factor directly impacting the long-term safety of the drug and the overall health of the patients. Drug tolerance refers to the patients’ response to the drug during treatment, including the response to different doses, the occurrence and severity of adverse reactions, and the maintenance of tolerance during long-term use.

• Drug Tolerance and Drug Safety

Drug safety is a primary consideration in the drug development process. Adverse reactions to drugs can have severe impacts on patients, potentially leading to treatment failure. Therefore, a comprehensive and systematic assessment of drug tolerance is a fundamental step in ensuring drug safety. In clinical trials, researchers need to monitor patients’ responses to different drug doses, promptly detect and report any adverse events. By comprehensively assessing individual differences, drug metabolism, and drug interactions, among other factors, a better prediction of patients’ tolerance to the drug can be achieved, enabling the early identification of potential safety risks.

• Drug Tolerance and Drug Efficacy

In addition to safety, drug efficacy is another crucial aspect. Patients’ tolerance to the drug directly influences the therapeutic effects of the drug. If patients cannot tolerate the drug, it may lead to drug discontinuation or adjustment, affecting the continuity and effectiveness of the treatment. Therefore, in the early stages of drug development, a careful assessment of patients’ tolerance to the drug is necessary to ensure that patients can maintain tolerance throughout the entire treatment process, thereby achieving optimal therapeutic results.

• Monitoring and Evaluating Drug Tolerance

To better understand patients’ tolerance to the drug, both in clinical trials and subsequent monitoring, are essential. Regular monitoring of physiological indicators, the occurrence of adverse events, and changes in drug concentrations can help identify potential problems and take appropriate measures.

Drug tolerance is of undeniable importance in drug development. It directly relates to the safety and efficacy of the drug, making it a key factor that must be seriously considered in the drug development process.

b. Tolerance Issues with GLP-1 Drugs

Although GLP-1 drugs have shown significant effects in the treatment of type 2 diabetes and obesity, tolerance remains a concern. Patients using GLP-1 drugs may experience gastrointestinal discomfort, injection site reactions, and other adverse reactions, factors that can impact patient compliance and even lead to treatment interruption.

In a 16-week trial evaluating the safety, efficacy, and tolerance of danuglipron for adults with type 2 diabetes, 411 participants underwent a double-blind trial, receiving different doses of twice-daily danuglipron or a placebo.

Among the 411 participants, 224 (55%) experienced a total of 538 treatment-emergent adverse events (TEAE). The proportion of participants in the danuglipron group experiencing TEAE ranged from 46% to 64%, while the placebo group was 48%. The proportion of participants discontinuing the study drug due to TEAE showed a dose-dependent trend in the danuglipron group (3%-34%, compared to 8% in the placebo group).

Of the 538 TEAE instances, 365 (68%) were reported as mild, 154 (29%) as moderate, and 19 (4%) as severe. Thirteen participants (3%) experienced serious TEAE, with one participant (from the 80 mg twice-daily group) developing acute cholecystitis 42 days after the last dose.

The most common TEAEs were nausea (7%-33% in the danuglipron group, 3% in the placebo group), diarrhea (4%-18% in the danuglipron group, 3% in the placebo group), and vomiting (0%-25% in the danuglipron group, 0% in the placebo group). The tendency for TEAEs showed a dose-dependent characteristic, with more TEAEs occurring in the high-dose group.


  1. Prospects of Danuglipron Amid Tolerance Issues

In the face of the setback for twice-daily danuglipron, Pfizer is redirecting its efforts to focus on the development of once-daily danuglipron, aiming to alleviate tolerance issues by reducing the dosing frequency. Establishing a precise titration plan may offer assistance in resolving this issue, but the road ahead is challenging.

The tolerance issues encountered with twice-daily danuglipron suggest that the impact on the local gastrointestinal tract at higher doses, despite achieving satisfactory therapeutic efficacy, is unacceptable. Consequently, reducing dosing frequency (e.g., from twice daily to once daily) and adjusting the dosage may bring about improved tolerance and adherence. However, this might come at the cost of reduced effectiveness. Unless once-daily oral administration can achieve similar systemic pharmacokinetic characteristics as twice-daily administration, lower doses and titration plans may lead to poorer efficacy.

The dilemma between tolerance and efficacy may be a challenge faced by all developers of oral GLP-1 weight loss drugs. Lower oral bioavailability resulting in higher doses contributes to more severe tolerance issues. Considering safety concerns, the need to address both dosage and dosing frequency might compromise efficacy. This situation resembles the plight of Sisyphus, repeatedly pushing a boulder uphill only to witness it roll back down.


  1. Outlook for Oral GLP-1

Despite the arduous path in the development of oral GLP-1 drugs, the anticipated rewards are undoubtedly enticing. This explains why leaders in the GLP-1 field, such as Novo Nordisk and Eli Lilly, continue to vigorously pursue the development of oral versions while sitting atop their golden thrones.

In fact, not only are industry giants like Novo Nordisk and Eli Lilly making strides, but the field of oral GLP-1 drugs also witnesses new entrants. Roche is a notable newcomer, entering the race by acquiring Carmot Therapeutics Inc. for $2.7 billion, including its Phase 1 oral gut hormone CT-996, to expedite their entry into the oral weight loss drug arena.

While the giants make their moves, it’s essential to recognize that oral GLP-1 drugs already have a pioneer in the form of Novo Nordisk’s oral semaglutide drug Rybelsus. Like Wegovy and Ozempic, Rybelsus also contains semaglutide, achieving oral delivery through the use of an absorption enhancer (SNAC, as shown in Figure 2), targeting patients with type 2 diabetes.

Rybelsus is the first and currently the only oral incretin drug (GLP-1 being one type of incretin). Approved by the FDA in 2019, it marked a milestone in GLP-1 drug development. Various doses of Rybelsus are currently being used by Novo Nordisk for the development of obesity therapy.

Novo Nordisk is awaiting data from the OASIS clinical study on Rybelsus. OASIS comprises a series of studies targeting obesity patients in different regions, including other East Asian subgroups and the Chinese subgroup, with most doses at 50 mg. Notably, the OASIS-4 trial uses a 25 mg Rybelsus oral drug, and its data is expected to be released in the first half of 2024. If the data demonstrates satisfactory effectiveness and safety, Rybelsus may receive approval for obesity treatment a year later (potentially under a different brand name).

Eli Lilly’s oral GLP-1 candidate is a small molecule drug called Orforglipron (Figure 3), rather than their peptide tirzepatide. Analysts predict that by 2028, Orforglipron’s sales for treating diabetes will reach $1.3 billion, and sales for treating obesity will reach $525 million.

On the road to developing oral GLP-1 receptor agonist drugs, there seems to be a consensus that expecting oral versions to have the same tolerance and efficacy as subcutaneous versions at the current stage is unrealistic.

Accepting this reality may involve a strategic redeployment: oral drugs targeting high BMI patients without diabetes or high cardiovascular risk, while more effective injectables target diabetes, clinical obesity patients, and cardiovascular disease prevention.

Although this strategy might lack the grandiosity of solving all problems at once, it could be a feasible solution for overcoming the development challenges of oral GLP-1 drugs, saving substantial funds for their development.

Challenges in the Development of Oral Weight Loss Medication: Focus on Drug Tolerance

References:

1.Smith, A. Stock Watch: GLP-1 Expectations Dashed. Scrip. 12. 12. 2023.

2.Efficacy and Safety of Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron for Glycemic Control Among Patients With Type 2 Diabetes. A Randomized Clinical Trial. JAMA Netw Open. 2023;6(5):e2314493. doi:10.1001/jamanetworkopen.2023.14493.

3.McConaighie, A. Roche Looks To Muscle Into Obesity Market With $2.7bn Carmot Buyout. Scrip. 04. 12. 2023.

4.Cairns, E. Time For Oral Incretins To Prove Their Worth. Scrip. 05. 12. 2023.

(source:internet, reference only)


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