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☆ The clinical phase II results of glucagon receptor antibody Vola conceptually verify the possibility of treating patients with type 1 diabetes mellitus who do not meet the standard insulin monotherapy by reducing the excessive activation of
the glucagon pathway.
, reached a significant level, and after correction for insulin monotherapy, it was reduced by 0.
53% in the 35mg group and 0.
49%
in the 70mg group.
Recently, Beijing Kexin Meide and American Ruimed released its clinical phase II.
proof-of-concept data
for the treatment of type 1 diabetes with its research glucagon receptor antibody REMD-477 (Volagidemab, abbreviated as "Vola") in the international top medical journal Nature Medicine.
Vola plus insulin has shown positive results in reducing glycated hemoglobin, and for the first time in clinical practice the hypothesis of the double hormone theory proposed by the late Professor Roger Unger nearly 50 years ago, that is, hypoglycemic insulin and glycemic glucagon jointly regulate blood glucose concentration
。 The editorial board of Nature Medicine invited Professor Michelle Van Name and Jennifer Sherr of the Department of Endocrinology at Yale University School of Medicine to comment
on this important development.
Because the body's own islet β cells are destroyed and cannot produce insulin, type 1 diabetes has been treated
with various forms of exogenous insulin for more than 100 years.
However, most patients with type 1 diabetes still have difficulty achieving glycated haemoglobin levels after insulin monotherapy, and there is a risk
of insulin-induced hypoglycemia.
Therefore, the industry has been developing drugs that can be combined with insulin for many years to meet the clinical need
for better sugar control without increasing the risk of hypoglycemia.
But so far, the development of such drugs has had little
success.
The exploration of effective drugs for type 2 diabetes in combination with insulin for type 1 diabetes is not ideal
.
Can Vola's Phase II clinical data eventually translate into new options for treatment? Can it meet the clinical need for better glycaemic control and reduce the risk of hypoglycemia? Can it bring new development ideas to the field of insulin combination therapy for type 1 diabetes? Industry experts are constantly exploring these questions
.
Glycated hemoglobin reduces the clinical potential by 0.
5%.
of type 1 diabetes.
The patients were randomized to 35 mg+ insulin therapy, 70 mg+ insulin therapy, and insulin monotherapy (control
).
The medication group injected Vola once a week and tracked data for all enrolled patients for 12 and 13 weeks
.
The selection of the primary clinical endpoint was based on clinical data obtained by Vola in Phase I.
, i.
e.
, the change
in insulin dosage after Vola injection.
Secondary clinical endpoints included HbA1c change level, mean daily blood glucose concentration, and incidence of hypoglycemic events
.
The results showed that the daily insulin dosage was reduced by 7.
59 (P=0.
040) in the 35mg group and 6.
64 (P=0.
084)
in the 70mg group.
Although the primary clinical endpoint did not reach a pre-set significance level (p<0.
025), the reduction in the secondary clinical endpoint HbA1c reached a significant level, with a reduction of 0.
53% in the 35 mg group and 0.
49%
in the 70 mg group after correction for insulin monotherapy.
Further subgroup analysis showed that the proportion of patients with HbA1c reduction of more than 0.
4% was 54.
2% and 54.
5% in the 35 mg and 70 mg groups, respectively, while the proportion of patients with HbA1c control below 7% was 50% and 36.
4% in the 35 mg and 70 mg groups, respectively.
For enrolled patients with a base of HbA1c ≥ 7.
5%, HbA1c was reduced by an average of 0.
93% in the 35 mg treatment group and 0.
54%
in the 70 mg treatment group.
Professor Ji Linong, director of the Department of Endocrinology at Peking University People's Hospital, director of the Peking University Diabetes Center, and chairman of the Western Pacific Region of the International Diabetes Federation, told the developer that by reducing the overactivation of the glucagon pathway, the treatment of insulin monotherapy patients with type 1 diabetes is a new exploration, and Vola's clinical phase II results conceptually prove this possibility
.
When interpreting this clinical trial, it mainly looks at the clinical design and clinical endpoints
.
Vola's phase II clinical trial is based on the indicator of insulin dose reduction obtained in phase I clinical trial as the primary clinical endpoint, and the number of
clinical enrollments is extrapolated.
Because comparing the magnitude reduction in insulin dosage between two doses and placebo at the same time involves multiple tests of statistical analysis, a more rigorous significance judgment method is set up—P values < 0.
05 in both dose groups or 0.
025 in one group <
.
From the perspective of reducing insulin dosage alone, the study itself did not reach the primary clinical endpoint, but from the overall study data, there are the following impressions: first, Vola can significantly reduce the amount of insulin used in patients with type 1 diabetes; Second, there was a significant improvement in HbA1c, with a reduction of nearly 1% in enrolled patients with a HbA1c base ≥ 7.
5%; Third, on the basis of reducing the insulin dose and improving HbA1c, there was no increased risk
of hypoglycemia.
Better glycemic control without increasing or even reducing the risk of hypoglycemia is precisely the most important principle and goal
of developing drugs for type 1 diabetes in combination with insulin.
Michelle Van Name and Jennifer Sherr also pointed out in the review article that in the planning phase of clinical trials, in order to estimate the sample size, it is necessary to define a primary clinical endpoint based on existing clinical data, but this primary clinical endpoint may not be the best indicator of the clinical importance of a new therapy or technology, and the real benefit of Vola is in the reduction of glycated hemoglobin levels
。
Ji Linong also noticed that Vola's improvement in HbA1c is not inferior to other drug candidates, and the weekly use also greatly increases
patient compliance.
At present, Pramlintide, a drug approved for adjuvant therapy for type 1 diabetes, reduces HbA1c by 0.
25%~0.
34%.
。 In the class of SGLT-2 inhibitors that were not approved by the FDA, phase III clinical trials of sotagliflozin showed an average reduction in HbA1c of 0.
36% and 0.
41% in both dose groups after placebo correction; Phase III clinical data of empagliflozin showed that after placebo correction, its 2.
5mg reduced HbA1c by 0.
28%, 10mg and 25mg by 0.
54% and 0.
53%, respectively
.
For the clinical significance of Vola's reduction of HbA1c, it may also refer to the standards
set by regulators for the development of such drugs.
In June this year, the Center for Drug Evaluation of the State Food and Drug Administration issued a draft of the "Technical Guidelines for Clinical Research and Development of Drugs for Type 2 Diabetes in Adults", which requires that the reduction in HbA1c in the development of new drugs for type 2 diabetes must reach 0.
5% after correcting for the placebo effect to prove effective
.
Specific guidelines for drug development for type 1 diabetes are currently being developed
.
Ji Linong believes that its criteria may be similar to the development of type 2 diabetes drugs, with a reduction of 0.
5% as the standard of efficacy and 0.
4% as the standard of non-inferior efficacy
.
The reduction in the low-dose group was 0.
53% in all enrolled patients in this study, and even higher in HbA1c≥7.
5% of enrolled patients, close to 1%.
Exploration of new mechanisms in the development of combination drugs
.
Professor Ji Linong said that type 1 diabetes needs to be completely dependent on exogenous insulin, but exogenous insulin is absorbed into the blood through the subcutaneous, and the rate of absorption is difficult to match the patient's blood sugar changes, which is very different
from the physiological secretion of insulin by normal people (from pancreatic islets to liver to blood) to regulate the balance of blood sugar.
If you blindly increase the amount of insulin to control the blood glucose concentration of type 1 diabetes patients to reduce HbA1c, it will lead to hypoglycemia problems, and the risk of hypoglycemia is still the most difficult problem
for blood sugar control in type 1 diabetes.
At present, the ultra-fast-acting insulin and long-acting basal insulin developed still fail to meet the clinical needs in solving the problem of hypoglycemia, which leads to the inability of many patients to control blood glucose and HbA1c at normal levels
.
Type 1 diabetes usually requires an HbA1c control below
7.
0%.
According to Ji Linong, the average HbA1c of patients with type 1 diabetes in the United States is controlled at about
7.
5%.
In China, he did a study showing that the average HbA1c is about 9%, and these patients have an increased risk
of complications due to poor blood sugar control.
"Therefore, the main problem in the field of type 1 diabetes is that there is no drug that can replace insulin, and secondly, despite everyone's efforts, there is still no combination drug
that can significantly improve blood sugar, do not increase the risk of hypoglycemia or even reduce the risk of hypoglycemia.
" Professor Ji Linong said
.
In fact, there have been many attempts in the development of combination drugs, but the results are not ideal
.
Pramlintide was approved in combination with insulin in the United States in 2005 and has not yet entered China and the European Union
.
This drug requires 4 injections per day, and it is difficult to promote
clinical application.
SGLT-2 (sodium-glucose co-transporter) inhibitors, which have shown good efficacy in type 2 diabetes, have been explored
in type 1 diabetes.
The two products mentioned above have carried out phase III clinical trials
of combination insulin.
These two drugs perform better than pramlintide in reducing HbA1c, but the mechanism of action of these drugs is to block the kidneys from recycling blood sugar in the urine, and the increase in urine glucose leads to an increased risk of ketoacidosis (DKA), which has been confirmed
in clinical studies.
Although sopagliflozin is approved in Europe, neither drug has been approved by the US FDA for type 1 diabetes
.
The GLP-1 receptor agonist liraglutide, which also has a good effect in type 2 diabetes, has also been studied
for type 1 diabetes.
Compared with placebo, high doses (1.
2 or 1.
8mg) of liraglutide can reduce HbA1c by 0.
2~0.
3%, but increase the risk of
hypoglycemia.
As a result, Novo Nordisk also abandoned its application
for this indication extension early.
GLP-1 receptor agonists lower glucose by stimulating the cells β islets to secrete insulin, and this class of drugs is generally considered to have a limited
role in type 1 diabetes because they β cell damage in patients with type 1 diabetes.
The common problem of these failed cases is still that the mechanism of action of the drug and the pathology of type 1 diabetes do not match very well, so the clinical effect
is not achieved.
Therefore, drug development based on new mechanisms has gradually become a new trend in the field, including Vola antibody and glucokinase activators
that have entered the clinical stage.
Dr.
Yan Hai, CEO of Kexinmeide and Remead, said that after healthy people eat, the β cells in the islets produce high concentrations of insulin, which directly acts on the α cells of the islets and inhibits the production of glucagon (inhibits the glycemic function).
。 In patients with type 1 diabetes, the function of inhibiting glucagon production is lost due to damage to β cells and inability to produce insulin; To make matters worse, the islets of type 1 diabetes patients are accompanied by α cell proliferation, resulting in a further rise in glucagon, which is one of
the pathogenic mechanisms of blood sugar increase after the lack of its own insulin in type 1 diabetes.
The concentration of exogenously injected insulin cannot block the rise of glucagon in the islets, causing blood sugar to continue to rise
.
Vola's mechanism of action is to reduce the activity of the glucagon pathway and block the rise
of blood sugar.
Another recently completed clinical trial demonstrated that Vola can also reduce the formation of ketones in the blood of patients with type 1 diabetes, reduce the risk of diabetic ketoacidosis, and have the potential to be combined with insulin to treat type 1 diabetes
.
Global multi-center phase III clinical trial preparations began
.
Yan Hai said that Vola is the world's first drug molecule based on blocking the glucagon pathway and insulin combination for the treatment of type 1 diabetes, clinical phase II results have fully shown the potential to reduce HbA1c, with relevant data, according to FDA requirements, clinical phase III will take the decline of HbA1c as the main clinical endpoint
.
According to the suggestions of Professor Ji Linong and other relevant experts, the selection of HbA1c baseline for enrolled patients will be adjusted
appropriately based on the clinical needs of patients with type 1 diabetes and clinical phase II.
results.
Phase II clinical trials have shown that the higher the patient's HbA1c baseline, the greater the improvement in HbA1c
.
In addition, it is worth noting that in phase II clinical trials, the 35mg dose group showed better efficacy than the 70mg dose group, which will also lead to the adjustment
of the dose in phase III clinical trials.
According to Yan Hai, this is a very interesting clinical finding, Vola is a competitive blocker of glucagon receptors, which can prevent glucagon from binding to receptors, but when the concentration of Vola is too high, its blockade will cause islets to secrete more glucagon, affecting the hypoglycemic effect
.
In subsequent phase III clinical trials, a dose group below 35 mg will be increased while retaining the 35 mg per week dose group
.
"Blood sugar regulation emphasizes balance, not blindly pursuing high doses of medication, through clinical we need to find an optimal dose
.
" Dr.
Yan Hai concluded
.
Issue 1765
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