Icovamenib Shows Durable HbA1c Reduction in Type 2 Diabetes Trial | Endocrine Today

A once-daily oral medication, icovamenib, has demonstrated sustained reductions in HbA1c and improvements in insulin secretion in adults with insulin-deficient type 2 diabetes, according to findings from the COVALENT-111 phase 2 trial presented at the International Conference on Advanced Technologies & Treatments for Diabetes. The benefits observed during 12 weeks of treatment were maintained for up to a year, offering a potential new approach for managing this challenging condition.

Durable Glycemic Effect in a Difficult-to-Treat Population

Type 2 diabetes is a chronic metabolic disorder characterized by high blood sugar levels, often resulting from insulin resistance and impaired insulin secretion. As the disease progresses, many individuals experience a decline in beta-cell function – the cells in the pancreas responsible for producing insulin – leading to insulin deficiency. This subset of patients often requires insulin therapy to manage their blood glucose. Icovamenib, developed by Biomea Fusion, is a novel compact molecule menin inhibitor designed to address this underlying beta-cell dysfunction. Menin is a protein that plays a role in gene regulation, and inhibiting it can potentially restore insulin production.

The COVALENT-111 trial enrolled 216 adults with type 2 diabetes, aged 18 to 65, who had an HbA1c between 7% and 10.5% and a body mass index (BMI) between 25 kg/m² and 40 kg/m². Participants had previously been treated with up to three diabetes medications, excluding insulin and sulfonylureas, indicating a degree of treatment failure with conventional therapies. The trial utilized a randomized, controlled design, comparing icovamenib to placebo across three arms with varying treatment durations.

Key Findings: HbA1c Reduction and Insulin Secretion

The per-protocol analysis, including 114 participants receiving icovamenib and 49 receiving placebo, revealed a significant reduction in HbA1c in the icovamenib group at 26 weeks. Specifically, those receiving icovamenib for 12 weeks experienced a 0.5 percentage point decline in HbA1c, while the placebo group showed no change. Remarkably, this reduction was sustained at the one-year mark, with the icovamenib group maintaining a 0.4 percentage point decrease compared to baseline, while the placebo group experienced a slight increase of 0.1 percentage points.

Perhaps even more encouraging was the observed improvement in insulin secretion. In a subgroup analysis of patients with severe insulin deficiency, those treated with icovamenib (across the 12-week and 8-week/every-other-day arms) demonstrated a 24% increase in insulin secretion, as measured by the C-peptide index, compared to a mere 2% increase in the placebo group (P = .01). C-peptide is a byproduct of insulin production, serving as a marker of the pancreas’s ability to secrete insulin. The strong correlation between increased C-peptide levels and improved HbA1c suggests that the observed glycemic control was directly linked to enhanced beta-cell function.

Juan Pablo Frias, MD, medical director and principal investigator at Los Angeles Institute for Metabolic Research, highlighted the durability of the treatment effect, particularly in patients with severe insulin deficiency. “We saw an increase in endogenous insulin secretion as shown by increase in stimulated C-peptide,” he stated during his presentation. “The higher the pharmacokinetic exposure that was seen in this cohort, the greater the HbA1c response and the C-peptide response.”

Pharmacokinetic Exposure and GLP-1 Medication Use

The study also explored the relationship between drug exposure and treatment response. Participants with higher pharmacokinetic exposure to icovamenib – meaning they had higher concentrations of the drug in their system – experienced greater reductions in HbA1c and larger increases in C-peptide index. This suggests that optimizing drug dosage may be crucial for maximizing therapeutic benefits.

Interestingly, the benefits of icovamenib were also observed in patients already using GLP-1-based medications, a class of drugs commonly used to treat type 2 diabetes. Those receiving icovamenib in addition to a GLP-1 medication experienced a 1.19 percentage point drop in HbA1c at one year, compared to a 0.55 percentage point increase in the placebo group (P = .05). They exhibited a 35% increase in C-peptide index, compared to a 4% decline with placebo. This suggests that icovamenib may offer additive benefits when combined with existing therapies.

Safety Profile and Regulatory Considerations

The safety profile of icovamenib appeared to be generally favorable. Treatment-emergent adverse events occurred in 27% of the placebo group and 27% of the pooled icovamenib group. Severe adverse events were reported by 1% of participants in each group. The most common adverse events associated with icovamenib were hyperglycemia (4%) and diarrhea (3%).

It’s key to note that the FDA had temporarily placed a clinical hold on the COVALENT-111 trial in June 2024 due to concerns about drug-induced hepatotoxicity (liver damage) observed during the dose escalation phase. Yet, the hold was lifted in September 2024 after further investigation. The trial data indicated that 2% of participants receiving icovamenib experienced increases in liver enzymes (alanine aminotransferase or aspartate aminotransferase), but these levels returned to normal in all cases without requiring discontinuation of treatment.

Future Directions and Ongoing Research

Based on the promising results of the COVALENT-111 trial, Biomea Fusion is planning two additional phase 2 trials. The COVALENT-211 trial will evaluate icovamenib in insulin-deficient patients with type 2 diabetes who have not achieved adequate glycemic control with standard therapies. The COVALENT-212 trial will investigate the drug in patients with type 2 diabetes who are not meeting their glycemic goals despite being treated with GLP-1-based medications. These trials will further assess the efficacy and safety of icovamenib in broader patient populations.

Dr. Frias concluded that icovamenib “may provide durable glycemic effect, and it has a potential to delay insulin therapy in these patients.” The ongoing research will be crucial in determining the long-term benefits and potential role of this novel therapy in the management of insulin-deficient type 2 diabetes.