Novo Nordisk Initiates Phase 3 Clinical Program of High-Dose Oral Semaglutide for Alzheimer’s Disease Treatment

December 18, 2020 /BioValleyBIOON/ -- Novo Nordisk recently announced its decision to enter Phase 3 clinical development to evaluate 14 mg oral semaglutide (Chinese generic name: semaglutide) for the treatment of Alzheimer’s disease (AD). The 14 mg oral formulation of semaglutide is a once-daily oral preparation of the long-acting GLP-1 analog semaglutide. This decision was made following an evaluation of GLP-1 data from preclinical models, real-world evidence studies, post hoc analyses of large cardiovascular outcome trials, and discussions with regulatory authorities.

Novo Nordisk plans to initiate a pivotal Phase 3a clinical program, enrolling approximately 3,700 patients with early Alzheimer’s disease (AD). The program is scheduled to commence in the first half of 2021 and will evaluate the efficacy and safety of once-daily oral semaglutide versus placebo. In this trial, the expected main treatment period is approximately two years.

Alzheimer's Disease - AD (Image source: tecake.in)

Mads Krogsgaard Thomsen, Executive Vice President and Chief Scientific Officer at Novo Nordisk, stated: “We are eager to address the high unmet medical needs in serious chronic diseases; therefore, we are pleased to initiate Phase 3 clinical development of semaglutide for Alzheimer’s disease. Over the past few decades, Alzheimer’s disease has been extensively studied, yet unfortunately, no major medical breakthroughs have been achieved. Given the growing unmet medical needs and increasing evidence suggesting the potential therapeutic role of GLP-1, we will investigate the benefits of oral semaglutide in treating early-stage Alzheimer’s disease.”

Alzheimer’s disease (AD) is a rapidly growing public health concern, causing significant adverse consequences for affected individuals and their families, and has led to substantial and increasingly severe socioeconomic impacts worldwide. An estimated 70 million to 100 million people globally are living with early-stage Alzheimer’s disease (mild cognitive impairment and mild dementia stages).

AboutData from Preclinical Models, Real-World Evidence Studies, and Post Hoc Analyses:

Animal studies have highlighted the critical role of GLP-1 in AD, including improving memory function and reducing phosphorylated tau accumulation. Semaglutide has been clearly demonstrated to reduce neuroinflammation, which may affect cognition and function.

Furthermore, from two nationwide registries in Denmark, the US Truven claims database, and the USFDAReal-world evidence from the FAERS database supports a potential link between GLP-1 therapy and a reduced risk of dementia.

Finally, in a post hoc analysis of data from three large cardiovascular outcome trials (LEADER, SUSTAIN 6, and PIONEER 6) conducted by Novo Nordisk, a total of 47 participants were identified as having dementia, including 32 in the placebo group and 15 in the GLP-1 receptor agonist group (liraglutide or semaglutide). The data favored GLP-1 receptor agonists, demonstrating a statistically significant 53% reduction in the incidence of dementia.

AboutSemaglutide (Semaglutide):

Semaglutide (Chinese generic name: semaglutide) is a human glucagon-like peptide-1 (GLP-1) analog that promotes insulin secretion and inhibits glucagon secretion through a glucose concentration-dependent mechanism, enabling type 2DiabetesThe patient's blood glucose levels improved significantly, with a low risk of hypoglycemia. Furthermore, semaglutide can induceWeight Loss. In addition, semaglutide can also significantly reduce type 2DiabetesPatient risk of major adverse cardiovascular events (MACE).

Currently, Novo Nordisk has developed an injectable formulation (Ozempic) and an oral formulation (Rybelsus) for semaglutide:

——Ozempic (semaglutide, injection): is a once-weekly subcutaneous injection formulation (0.5 mg or 1 mg), indicated for: (1) as an adjunct to diet and exercise to improve type 2DiabetesGlycemic control in adult patients; (2) for type 2 diabetes with cardiovascular disease (CVD)DiabetesTo reduce the risk of major adverse cardiovascular events (MACE, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in adult patients.

Ozempic was first approved by the U.S. FDA in December 2017 and is currently marketed in many countries and regions worldwide. The drug’s second indication was approved by the U.S.FDAApproved. Data from the cardiovascular outcomes trial (CVOT) SUSTAIN 6 demonstrated that, in patients with type 2 diabetes at high cardiovascular (CV) risk, Ozempic, when added to standard care, significantly reduced the risk of the composite major adverse cardiovascular events (MACE) endpoint by 26% compared with placebo.

——Rybelsus (semaglutide, oral tablets): is a once-daily oral formulation containing the absorption-enhancing excipient SNAC. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Rybelsus is the world’s first and only oral GLP-1 receptor agonist, administered once daily, with two therapeutic doses: 7 mg and 14 mg.

In the United States, the Rybelsus label was updated in January 2020 to include additional information from the PIONEER 6 cardiovascular outcomes trial (CVOT), which demonstrated cardiovascular (CV) safety. This trial was conducted in patients with type 2 diabetes at high cardiovascular risk. The data showed that Rybelsus, when added to standard care, met the primary endpoint of non-inferiority for the composite major adverse cardiovascular events (MACE) endpoint compared with placebo, thereby establishing CV safety. In the study, the proportion of patients who experienced at least one MACE was 3.8% in the Rybelsus group and 4.8% in the placebo group.

Currently, Novo Nordisk is also investigating a once-weekly 2.4 mg subcutaneous injection formulation of semaglutide as a treatment for adult obesity. Semaglutide helps people eat less and reduce calorie intake by reducing hunger and increasing satiety, thereby inducingWeight Loss。

Earlier this month, Novo Nordisk to the United StatesFDAA New Drug Application (NDA) was submitted for the 2.4 mg subcutaneous injection formulation of semaglutide, a once-weekly glucagon-like peptide-1 (GLP-1) analog indicated for long-term weight management. Notably, Novo Nordisk also submitted a Priority Review Voucher (PRV) to expedite the NDA review process, which would shorten the review timeline from the standard 10 months to 6 months.

The indication applied for the semaglutide 2.4 mg subcutaneous injection formulation is: as an adjunct to a reduced-calorie diet and increased physical activity, for the treatment of adult patients with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity. (Bioon.com)

Original Source: Novo Nordisk to enter phase 3 development in Alzheimer’s disease with oral semaglutide