Volagidemab improves glycaemic control in T1D patients

Phase II data presented at ADA 2021 showed the potential of the GRA* volagidemab to improve glycaemic control in patients with type 1 diabetes (T1D).

“[In our previous study,] volagidemab decreased daily insulin use and average glucose, increased time in range, and did not increase time in hypoglycaemia in T1D patients,” said Dr Jeremy Pettus from the University of California San Diego in California, US, during his presentation. [Diabetes Obes Metab 2018;20:1302-1305]

The team further evaluated volagidemab in a phase II programme comprising two trials (n=75 and 78 for trials 1 and 2 [T1 and T2], respectively). In both trials, participants were randomized 1:1:1 to receive once-weekly SC volagidemab 35 or 70 mg or placebo for 12 weeks. T1 involved unblinded CGM** whereas in T2, it was blinded. [ADA 2021, abstract 236-OR]

 

Consistent HBA_1c reductions

Week 12 saw greater HBA_1c reductions with volagidemab 35 and 70 mg vs placebo in T1 (–0.67 percent and –0.66 percent vs –0.43 percent) and T2 (–0.64 percent and –0.60 percent vs –0.11 percent).

“[In T2,] I think we accomplished our goal [of trying] to mitigate the placebo reduction while still maintaining the HBA_1c reduction with treatment … [This] reduction of a little over 0.5 percent [is something we] have not seen with adjunctive therapies in T1D,” said Pettus.

About 28 percent of placebo recipients achieved an HbA_1c of <7 percent. With volagidemab, up to 59 percent of recipients achieved this goal. “That is a little more than a twofold increase [vs placebo]. I think it is clinically meaningful if you can double the number of patients that are getting to goal,” Pettus said.

 

Subgroup analysis

Among patients with a slightly higher baseline HBA_1c (>7.5 percent), volagidemab 35 mg reduced HBA_1c by 1.02/0.97 percent (T1/T2). “In type 2 diabetes, the higher the HBA_1c, the higher the fall. It is interesting to see [this] in the T1D population,” said Pettus.

Albeit the slightly lower HBA_1c reductions with volagidemab 70 mg vs the 35-mg dose (–0.94/–0.59 percent [T1/T2]), these were still higher than those achieved with placebo (–0.68/–0.08 percent).

 

Hyperglycaemia, hypoglycaemia, insulin use

With volagidemab 70 mg, absolute increases in time in range (70–180 mg/dL) were 7.0/6.2 percent (T1/T2). However, when looking at time above range (>180 mg/dL), there were reductions in time in hyperglycaemia (–7.0/–7.6 percent).

T1 saw an overall reduction in hypoglycaemia in each arm (change in percent time in <70 mg/dL, from –0.2 to –0.44 percent). In T2, there was a reduction with volagidemab 35 mg (–2.75 percent) and an increase with the 70-mg dose (1.57 percent).

There was a greater reduction in overall (T1/T2) insulin usage with volagidemab vs placebo (–5 to –8 [both doses] vs –1.4 U/day). “Compared with baseline, that is roughly a 15-percent reduction in total daily dose taken primarily from the bolus compartment, but still with some reductions in the basal insulin dose,” said Pettus.

 

ALT, BP

While serum ALT*** increased by about 20 U/L, it dropped even with continued treatment and normalized after treatment discontinuation. “The increases were partially reversible … [Whether] this is a way of the liver compensating for the increased amino acid metabolism … remains to be seen,” explained Pettus.

Another effect that must be explored further, noted Pettus, were the spikes in blood pressure (3–4 and 2–3 mm Hg [systolic and diastolic, respectively]).

 

Why block glucagon?

When T1D patients have a glucose challenge, there is a paradoxical spike in glucagon. Consequently, hepatic glucose output increases even when there is no need for the liver to produce glucose, explained Pettus.

“[This ultimately leads] to hyperglycaemia, poor control, and microvascular complications … It is one reason why T1D patients struggle; blocking glucagon might help that,” he continued, adding that the current findings appear to align with this hypothesis. “It was a real pleasure to … see the effects of this new compound in this patient population with a high unmet need.”