Amgen's new generation of calcimimetic Etecatide will soon be approved for marketing in China

Recently, CDE's official website announced that the listing application of Amgen's new drug etelcalcetide hydrochloride injection (etelcalcetide, trade name Parsabiv) has been accepted by CDE [1]
.

The drug was approved in the United States in 2017 for the treatment of secondary hyperparathyroidism (SHPT) for adults with chronic kidney disease (CKD) who are on hemodialysis

Before understanding this drug, let's first understand why patients with lower kidney disease develop SHPT
.

SHPT is one of the common complications in patients with chronic kidney disease (CKD) that seriously affects the prognosis and quality of life of patients [2]
.

When renal function declines, due to factors such as reduced active vitamin D, hyperphosphatemia, hypocalcemia and other factors, the parathyroid glands are stimulated to make them hypertrophy and secrete too much parathyroid hormone (PTH)

SHPT can be treated with drugs to control hyperphosphatemia and maintain blood calcium levels up to the standard
.

If the level of parathyroid hormone still does not reach the target value, active vitamin D and calcimimetic drugs can be used for treatment

At present, three calcimimetic agents have been approved for marketing worldwide, namely Cinacalcet (Cinacalcet), Etelcalcetide, and Evocalcet
.

Cinacalcet is currently the only calcimimetic that has entered the Chinese market

01

01

The mechanism of action of three calcimimetic agents

The mechanism of action of three calcimimetic agents

A calcimimetic is an allosteric agonist that acts on calcium sensitive receptors (CaSR).
By binding to CaSR in organs and tissues, it increases the sensitivity of CaSR to calcium ions, thereby activating CaSR to produce corresponding pharmacological effects
.

On the one hand, Cinacalcet can increase the sensitivity of extracellular calcium ion by regulating the calcium-sensitive receptors of the parathyroid glands, thereby inhibiting the synthesis of PTH.
On the other hand, it can up-regulate the parathyroid calcium-sensitive receptor mRNA and vitamins.
The transcription and translation of D receptor mRNA to inhibit the synthesis of PTH [3]
.

The mechanism of action of etecartide is similar to that of cinacalcet.
The cysteine ​​at its end can directly interact with the cysteine ​​at position 482 of the calcium-sensitive receptor through a disulfide bond to cause the allosteric activation of the calcium-sensitive receptor, thereby Play a role in reducing the concentration of PTH and calcium ions in the circulating blood
.

Etecatide is a long-acting preparation [4]

Evocalcet is currently the latest calcimimetic with similar pharmacological effects to cinacalcet.
The purpose of its research and development is to reduce adverse reactions in the digestive tract
.

At present, there are few researches on Evocalcet, and we still look forward to follow-up research

02

02

Clinical Efficacy of Etecartide

Clinical Efficacy of Etecartide

Etecatide vs placebo [5]

The approval of etacatide was mainly based on a phase 3 randomized controlled study, which included 1023 patients with moderate to severe SHPT
.

The average age of the subjects was 58.

The results showed that the number of patients in the etacatide group who reached the primary endpoint was significantly higher than that in the placebo group (74.
0% vs 8.
3%, P <0.
001, 95% CI: 65.
7%)
.

The most common adverse event is a decrease in blood calcium, which requires calcium supplementation, calcium-containing phosphate binders, or active vitamin D analogs

Etecatide vs Cinacalcet [5]

In a study comparing the efficacy of etecartide and cinacalcet, a total of 683 patients with moderate to severe SHPT were included
.
The average age of the subjects was 54.
7 years old, and males accounted for 56.
2%
.
Etecartide + placebo (n = 340) and cinacalcet + placebo (n = 343) were randomly given
.
The starting dose of etercartide is 5 mg, 3 times a week, after hemodialysis, it can be increased by 2.
5 mg or 5 mg depending on the PTH level
.
The starting dose of cinacalcet is 30 mg/day
.
The primary end point was the non-inferiority of etercartide when the PTH level decreased by more than 30% from baseline at 20-27 weeks
.

The results found that the effectiveness of etecartide was similar to that of cinacalcet, and the proportion of patients whose PTH level dropped by more than 30% from baseline was 68.
2% vs 57.
7% (95% CI: -17.
5% to -3.
5%, non-inferior Effectiveness P <0.
001)
.
In addition, the proportion of patients in the etecartide group whose PTH level decreased by more than 50% from baseline was 52.
4%, while the proportion of patients with cinacalcet PTH level dropped by more than 50% from baseline was 40.
2%.
The sex is higher (P = 0.
001; 95%CI: 4.
7%-19.
5%)
.

It can be seen that the efficacy of etacatide is better than placebo and no less than cinacalcet
.
However, unlike cinacalcet, etecartide is a peptide drug.
It is administered by intravenous injection three times a week (cinacalcet is taken orally twice a day).
The number of times of administration of etecartide is small, and patients comply with it.
It has good properties, is not easy to relapse, and has good clinical application prospects
.

03

03

market expectation

market expectation

As the first approved oral calcimimetic, Cinacalcet was first approved for marketing in the United States in March 2004 under the trade name Sensipar; in December of the same year, it was approved for marketing in Europe under the trade name Mimpara
.
In 2014, Cinacalcet entered the Chinese market under the trade name: Gaiping
.
In the "National Basic Medical Insurance, Work Injury Insurance and Maternity Insurance Drug Catalog (2020)", Cinacalcet is included as a calcium homeostasis drug, which is suitable for hemodialysis and secondary hyperparathyroidism.
Patient [6]
.

In 2015, Cinacalcet's sales exceeded US$1 billion
.
In 2018, Cinacassie sales peaked, creating sales of 1.
774 billion U.
S.
dollars
.
However, in the past two years, due to the expiration of patents and the approval of competing products, Cinacalcet's sales have fallen off a cliff
.

After its launch in 2017, Etecartide's sales have risen year by year.
In 2020, sales will reach 716 million U.
S.
dollars.
It is expected to become a blockbuster product with sales exceeding one billion U.
S.
dollars
.

Evocalcet was approved in Japan in March 2018 for the treatment of secondary hyperparathyroidism in maintenance dialysis patients.
The drug is currently in the phase III clinical stage in China
.

Parathyroid gland is an essential gland for human life.
SHPT is a common and serious decompensation disease in chronic kidney disease patients undergoing dialysis treatment.
It is one of the important manifestations of mineral metabolism disorders and is also an end-stage maintenance of chronic kidney disease.
One of the most important and serious complications of dialysis patients during dialysis
.

The results of the 2012 Chinese epidemiological survey showed that the number of patients with end-stage renal disease in China is about 2 million, the dialysis rate is less than 20%, and the conversion rate of SHPT in patients with mineral and bone metabolism disorders (CKD-MBD) is close to 50%.

.
The dialysis rate in developed countries (the United States, Europe, Japan) is 90%
.

Based on this, it can be predicted that the number of SHPT in China in the future will release a larger room for growth as the diagnosis, detection, and treatment of chronic kidney disease improve
.

reference:

1.
Retrieved May 18, 2021, from http:// Hyperparthyroidism: Pathogenesis, Diagnosis, Preventive and Therapeutic Strategies.
Reviews in Endocrine and Metabolic Disorders.
04 April 2017.

3.
Ivanovski O, Nikolov IG, Joki N, et al.
The calcimimetic R-568 retards uremia-enhanced vascular calcification and atherosclerosis in apolipoprotein E deficient (apoE-/-)mice[J].
Atherosclerosis.

4.
Etecaxetide: a new drug for the treatment of secondary hyperparathyroidism in chronic kidney disease[J].
Drug Evaluation Research, 2017.

5.
Etelcalcetide Lowers PTH in Patients on Dialysis.
Medscape.
January 13, 2017.

6.
National Medical Insurance Bureau, Ministry of Human Resources and Social Security.
Notice on Printing and Distributing the "National Basic Medical Insurance, Work Injury Insurance and Maternity Insurance Drug Catalog (2020)".
Medical Insurance Fa [2020] No.
53, 2021-01-12.