Despite the advent of more physiologic insulin analogs, continuous glucose monitoring (CGM), and continuous subcutaneous insulin infusion (CSII) therapy, glycemic control in type 1 diabetes remains suboptimal. Only a minority of patients with type 1 diabetes achieve the American Diabetes Association goal of glycated hemoglobin (HbA_1c) <7% (<53 mmol/mol), and hospitalizations for diabetic ketoacidosis (DKA) and hypoglycemia are increasing globally (1–3). An unmet need exists for adjunctive therapies that improve glycemic control in type 1 diabetes without increasing the risk of hypoglycemia or ketoacidosis.

Glucokinase (GK), a hexokinase that catalyzes glucose phosphorylation, has long been a target of interest because of the observation that human mutations lead to dysglycemia (4). Heterozygous inactivating mutations in GK raise the set point for insulin secretion, resulting in maturity onset diabetes of the young type 2, and homozygous mutations in GK result in severe neonatal diabetes (5–7). Conversely, activating mutations cause hyperinsulinemic hypoglycemia (8).

Compared with other hexokinases, the unique kinetics of glucose binding and lack of inhibition by downstream products allow GK to act as a glucose sensor (4,9). In pancreatic islet cells, GK is constitutively expressed and sets the threshold for glucose-stimulated insulin release (10). In the hepatocyte, GK regulates the R_g and glycolysis (10–13). At low glucose concentrations, hepatic-specific GK regulatory protein (GKRP) binds GK into an inactive form and sequesters it within the nucleus (14). At high glucose concentrations, GK is released by GKRP into its active form in the cytosol, thus restricting hepatic GK activity to periods of hyperglycemia (15,16).

Additionally, hepatic GK expression is insulin dependent. Individuals with type 1 diabetes who have little or no endogenous insulin secretion have low portal vein concentrations of insulin, less GK expression, and impaired liver uptake and metabolism of glucose (17). In insulinopenic mice, restoring GK expression in the liver improves glycemic control without increasing hypoglycemia or ketoacidosis (18).

Numerous small-molecule GK activators have been developed, but their use has been limited by severe hypoglycemia and hypertriglyceridemia, because unfettered activation of GK results in unregulated release of insulin and increased lipogenesis. We previously described the development of TTP399, which selectively targets hepatic GK without disrupting the GKRP/GK interaction (19). Treatment with TTP399 improves glycemic control in both animal models and individuals with type 2 diabetes, primarily through lowering postprandial glucose levels, without increasing hypoglycemia, plasma triglycerides, or hepatic fat (19). It is unknown how GK activation will affect glycemia in individuals who have minimal endogenous insulin secretion.

The SimpliciT1 study, an adaptive three-part phase 1b/2 proof-of-concept study, was designed to explore the effect of TTP399 as an adjunctive therapy for the treatment of type 1 diabetes. We hypothesized that hepatoselective GK activator treatment, adjunctive to insulin, would improve glycemic control in patients with type 1 diabetes without increasing the risk of hypoglycemia or ketoacidosis.

Five adults with type 1 diabetes using CGM and CSII underwent dose escalation to ensure safety during the sentinel phase; 800 mg TTP399 was selected as the dose for subsequent phases. Sentinel phase results are provided in Supplementary Tables 1 and 2.

Participant disposition for parts 1 and 2 is shown in Supplementary Fig. 2. Twenty participants in part 1 and 85 participants in part 2 were randomly assigned. One participant in part 1 was randomly assigned in error but completed the study and contributed safety data only. All randomly assigned participants took at least one dose of study medication, which was observed at the first study visit.

Baseline characteristics and demographics were comparable in both parts (Table 1). Prespecified outcomes are shown in Table 2. In part 1, the change in HbA_1c from baseline after 12 weeks of treatment was 0.08 percentage points (SE 0.2) with placebo and −0.60 percentage points (SE 0.2) with TTP399, resulting in a placebo-adjusted change in HbA_1c from baseline to 12 weeks of −0.69% (95% CI −1.3, 0.07%; P = 0.032) (Fig. 1A). In part 2, the change from baseline after 12 weeks of treatment was 0.07 percentage points (SE 0.06) with placebo and −0.14 percentage points (SE 0.06) with TTP399, resulting in a placebo-adjusted change of −0.21% (95% CI −0.39, −0.04%; P = 0.018) (Table 2). Analysis of the second estimand resulted in a placebo-adjusted change in HbA_1c of −0.32% (95% CI −0.50, −0.13%; P = 0.0017) (Fig. 1B).

Responder analysis revealed a greater percentage of responders among participants treated with TTP399 as compared with placebo in both parts 1 (75% vs. 9%; P = 0.006) and 2 (42% vs. 12%; P = 0.001) (Fig. 1C). CGM data are provided in Table 2. Participants randomly assigned to TTP399 demonstrated increased daytime TIR from before randomization to week 12, whereas participants in the placebo arm experienced decreased daytime TIR. The difference between the effect of TTP399 on daytime TIR compared with placebo was significant (Table 2) (part 1: 11.8%; 95% CI 2.58, 20.98%; P = 0.016; part 2: 7.8% 95% CI 0.93, 14.68%; P = 0.027). Time in hypoglycemia was numerically lower in both treatment groups after 12 weeks.

In part 1, total insulin was numerically reduced by 1.7% with TTP399 compared with 0.1% with placebo. In part 2, total insulin was numerically reduced by 7.6% with TTP399 compared with 1.6% with placebo. Bolus insulin was numerically reduced by 8.4% and 3.9% in the TTP399 and placebo groups, respectively (Table 2).

To explore the effect of alterations in insulin dose in part 2, we conducted a prespecified subgroup analysis based on changes in total insulin (Supplementary Fig. 3A). Numerically more participants in the TTP399 arm decreased their insulin dose, and fewer participants in the TTP399 arm increased insulin. In the subgroup that reduced total insulin dose by >15%, TTP399 significantly reduced HbA_1c relative to placebo by 0.4% (Supplementary Fig. 3B left) (P = 0.017). In the subgroup that maintained the same insulin dose, TTP399 reduced HbA_1c by 0.35% relative to placebo (Supplementary Fig. 3B middle; P = 0.041). Pharmacokinetic samples suggested adherence in at least 95% of patients randomly assigned to TTP399. Two of 43 patients randomly assigned to TTP399 had no detectable levels of TTP399 in their plasma when measured at any of the study visits. Both of these participants experienced numerically increased insulin.

A post hoc analysis was conducted to better understand the relationship of change in insulin dose to change in HbA_1c. A positive correlation was observed between reduction in HbA_1c and reduction in total insulin (Fig. 1D blue circles) (P = 0.008) and bolus insulin (P = 0.004) in the TTP399-treated group. Conversely, an inverse correlation was observed in the placebo group.

No events of severe or symptomatic hypoglycemia were reported in part 1. In part 2, one patient in the placebo group reported an event of severe hypoglycemia. Fewer participants in the TTP399 group reported events of symptomatic hypoglycemia compared with the placebo-treated group. In total, 27 severe or symptomatic patient-reported hypoglycemic events were identified in the placebo-treated group compared with 12 in the TTP399-treated arm (Table 3 and Fig. 1E) (nominal P < 0.05). Twenty percent of the participants in the placebo group and 12% of participants in the TTP399 group experienced at least one hypoglycemic event, resulting in a 40% reduction in severe and symptomatic events compared with placebo in part 2 (Table 3).

Two treatment-emergent events of ketosis occurred in part 2 of the study: one participant receiving placebo and one participant receiving TTP399. The ketosis event in the participant on TTP399 occurred during hospitalization for worsening chronic obstructive pulmonary disease and was not considered drug related. A trend toward reduction in ketone events in the TTP399 group was observed. In part 1, three participants (27%) had at least one elevated serum β-hydroxybutyrate level, compared with no participants in the TTP399 group (Table 3). In part 2, 11 participants in the placebo group compared with five participants in the TTP399 group had an elevated serum β-hydroxybutyrate. In the pooled cohort, 25% and 10% of participants treated with placebo and TTP399, respectively, experienced one elevated serum β-hydroxybutyrate during dosing (Table 3 and Fig. 1F). When participants were grouped by change in insulin, regardless of insulin subgroup, the incidence of hypoglycemia and ketone events was lower in participants treated with TTP399 (Supplementary Tables 3 and 4). The incidence of treatment-emergent AEs was otherwise similar between the groups, with no change in liver function or plasma lipids (Table 3 and Supplementary Tables 5–7).

The SimpliciT1 study evaluated and confirmed the safety and efficacy of TTP399 as an adjunctive therapy to insulin in type 1 diabetes. We used an adaptive proof-of-concept design to enhance efficiency and a hierarchic testing strategy to evaluate regulatory end points, clinical benefits, and safety.

In part 1, TTP399 therapy was associated with a 0.7% greater reduction from baseline HbA_1c to a mean end-of-trial HbA_1c of 6.7% (50 mmol/mol) while numerically reducing total insulin. In part 2, the second estimand demonstrated a 0.3% reduction in HbA_1c. Although the reductions in HbA_1c observed in part 2 were more modest, the sample sizes in both parts of the study were small, and the CIs overlapped. The observed reductions in HbA_1c were coupled with a favorable safety profile. At 6 and 12 weeks in both parts 1 and 2 of the study, participants randomly assigned to TTP399 had continued reductions in HbA_1c, despite a numeric reduction in bolus insulin, whereas participants on placebo returned to baseline HbA_1c.

Glycemic benefits were confirmed by analysis of CGM data, where treatment with TTP399 improved daytime TIR. Because GK is critical for glucose metabolism in the postprandial state, physiologic GK activation is expected to disproportionally affect postprandial hyperglycemia (19). To proactively prevent hypoglycemia, bolus insulin was reduced on the 1st day of randomized drug in all participants. Despite an aggressive treat-to-target design, participants randomly assigned to placebo experienced less daytime TIR at the end of the treatment period. Conversely, consistent with the mechanism of GK activation, daytime TIR was improved in participants randomly assigned to TTP399 despite numerically decreased bolus insulin.

Adjunctive therapies in type 1 diabetes, if effective, require insulin dose adjustment. Therefore, the change in HbA_1c observed in part is a function of study product and in part results from the blinded adjustment of insulin therapy to achieve desired glycemic control. On average, participants randomly assigned to TTP399 achieved better glycemic control while numerically reducing insulin doses. The observed positive correlation between the largest responses in HbA_1c reduction and the largest reduction in insulin suggests that there is a subpopulation of people who respond particularly well to TTP399. In contrast, a negative correlation was observed with participants on placebo, such that reduction in insulin was associated with increases in HbA_1c. At baseline, HbA_1c was near the American Diabetes Association–recommended target of 7% (53 mmol/mol) in both parts 1 (7.3%, 56.3 mmol/mol) and 2 (7.6%, 59.6 mmol/mol). Small reductions in HbA_1c therefore represent improvement in already good glycemic control. It is unknown whether TTP399 would have a larger impact in participants with higher baseline HbA_1c.

Importantly, despite further reduction in HbA_1c, TTP399 administration was associated with a nominal reduction in patient-reported hypoglycemia events. Tight glycemic control is often compromised by patient and provider fear of hypoglycemia (22). Given that hypoglycemia remains a leading cause of morbidity in the treatment of insulin-dependent diabetes, an adjunctive therapy that improves glycemia while reducing hypoglycemia would represent a significant advance.

The smaller numbers of hypoglycemic events may be related to the lower insulin dose with TTP399; however, subgroup analysis does not support this idea, because hypoglycemia events were not generally observed in patients on increased insulin doses. Furthermore, the incidence of hypoglycemia was lower in participants randomly assigned to TTP399 regardless of the magnitude of change in insulin dose. Instead, we speculate that by restoring hepatic glycogen stores, TTP399 enhances the ability of the liver to release glucose in response to falling glucose concentrations.

There were no drug-related DKA events, and treatment-emergent events of ketosis in urine or blood were few. However, abnormal β-hydroxybutyrate and urine ketones were detected more frequently in participants on placebo than on TTP399. This finding is compatible with the hypothesis that GK activation has a direct metabolic effect that prevents hepatic ketogenesis in the setting of insulin deficiency (23). GK activation increases postprandial hepatic glycogen synthesis. Increased glycogen stores in the fasting state may increase the proportion of energy provided to the liver via glycolysis rather than through free fatty acid oxidation, thus protecting against ketosis. Consistently, preclinical studies in insulin-dependent Göttingen mini-pigs demonstrate that GK activation prevents ketosis in this animal model during insulin withdrawl (24).

The favorable safety profile of TTP399 stands in contrast to what has been observed in trials of other promising adjunctive agents, such as sodium-glucose co-transporter 1 and 2 inhibitors and glucagon-like peptide-1 receptor agonists, for the treatment of type 1 diabetes (25–27). Although both classes improve glycemic control with placebo-adjusted changes in HbA_1c comparable to those observed with TTP399, sodium-glucose co-transporter inhibitors are associated with increased rates of ketosis and DKA, and glucagon-like peptide-1 receptor agonists are associated with increased rates of hypoglycemia and frequent hyperglycemic episodes associated with ketosis (25–30). The scarcity of AEs during treatment with TTP399 underscores the potential for TTP399 in the treatment of type 1 diabetes. Although the study was limited to 12 weeks, TTP399 has been tested in patients with type 2 diabetes for 6 months without substantial AEs. Longer clinical trials are necessary to confirm the long-term safety and efficacy of TTP399 in type 1 diabetes.

The SimpliciT1 study suggests that TTP399 is a candidate for further development as an adjunctive therapy for the treatment of type 1 diabetes. The study, although conducted under one adaptive protocol, is representative of two independent trials showing that TTP399 significantly, although modestly, lowers HbA_1c when used as an adjunctive therapy to insulin. The improvement in glycemia was achieved despite a rigorous treat-to-target approach. Treatment with TTP399 also displayed a favorable safety profile and demonstrated potential benefit in reduction of hypoglycemia and ketosis events. An adjunctive therapy that protects against these complications would be a substantial advance in the treatment of type 1 diabetes. To our knowledge, this observation is unique. If confirmed in larger and longer phase 3 studies, these data suggest that TTP399 will both improve glycemia and reduce risks of hypoglycemia and ketosis in patients with type 1 diabetes.