Amgen's Next-Generation Calcimimetic Etelcalcetide Nears Approval in China for SHPT Treatment

Recently, as announced on the official website of the CDE, the marketing application for Amgen's new drug, etelcalcetide hydrochloride injection (etelcalcetide, trade name Parsabiv), has been accepted by the CDE.^【1】The drug was approved in the United States in 2017 for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) receiving hemodialysis.

Before learning about this medication, let us first understand why patients with kidney disease develop SHPT.

SHPT is one of the common complications in patients with chronic kidney disease (CKD) that severely affect patient prognosis and quality of life.^【2】. When renal function declines, factors such as reduced active vitamin D, hyperphosphatemia, and hypocalcemia stimulate the parathyroid glands, causing hyperplasia and hypertrophy and leading to excessive secretion of parathyroid hormone (PTH). Increased PTH secretion can further disrupt calcium and phosphate metabolism, resulting in osteitis fibrosa and mixed bone disease, which manifest as bone and muscle pain, muscle weakness, and fractures. Patients with severe SHPT may experience pruritus, hypercalcemia, cardiovascular disease, muscle necrosis, neuropsychiatric disturbances, and even death.

The treatment of SHPT can initially involve pharmacological control of hyperphosphatemia and maintenance of serum calcium levels within the target range. If parathyroid hormone (PTH) levels still fail to reach the target, medications such as active vitamin D and calcimimetics may be employed.

Currently, three calcimimetics have been approved for marketing worldwide: cinacalcet, etelcalcetide, and evocalcet. Cinacalcet is currently the only calcimimetic available in the Chinese market.

01

Mechanisms of Action of Three Calcimimetics

Calcimimetics are allosteric agonists that act on the calcium-sensing receptor (CaSR). By binding to CaSR in organ tissues, they increase the receptor's sensitivity to calcium ions, thereby activating CaSR to exert corresponding pharmacological effects.

Cinacalcet, on the one hand, inhibits PTH synthesis by modulating the calcium-sensing receptors in the parathyroid glands to increase their sensitivity to extracellular calcium ions. On the other hand, it upregulates the transcription and translation of parathyroid calcium-sensing receptor mRNA and vitamin D receptor mRNA, thereby suppressing PTH synthesis.^【3】。

The mechanism of action of etelcalcetide is similar to that of cinacalcet. Its terminal cysteine residue directly forms a disulfide bond with the cysteine at position 482 on the calcium-sensing receptor, inducing allosteric activation of the receptor and thereby reducing the concentrations of parathyroid hormone (PTH) and calcium ions in the circulating blood. Etelcalcetide is a long-acting formulation.^【4】。

Evocalcet is currently the latest calcimimetic agent. Its pharmacological action is similar to that of cinacalcet, and it was developed to reduce gastrointestinal adverse reactions. Currently, research on evocalcet remains limited, and further studies are still anticipated.

02

# Clinical Efficacy of Etelcalcetide

Etelcalcetide vs Placebo^【5】

The approval of etelcalcetib was primarily based on a Phase 3 randomized controlled trial enrolling 1,023 patients with moderate to severe secondary hyperparathyroidism (SHPT). The mean age of the participants was 58.2 years, with males accounting for 60.4%. Following dialysis, subjects were randomized to receive etelcalcetib (n = 503) or placebo (n = 513) once weekly. The starting dose of etelcalcetib was 5 mg, with dose escalations of 2.5 mg at weeks 5, 9, 13, and 17 based on PTH and serum calcium levels (maximum dose: 15 mg). Serum calcium and phosphorus levels were monitored once weekly, and PTH levels were assessed every two weeks. The primary endpoint was a ≥30% reduction in PTH levels from baseline during weeks 20–27.

Results showed that the proportion of patients achieving the primary endpoint was significantly higher in the etelcalcetide group than in the placebo group (74.0% vs. 8.3%; P < 0.001; 95% CI: 65.7%). The most common adverse event was hypocalcemia requiring calcium supplementation, calcium-containing phosphate binders, or active vitamin D analogs.

Etelcalcetide vs Cinacalcet^【5】

In a study comparing the efficacy of etelcalcetide and cinacalcet, a total of 683 patients with moderate-to-severe secondary hyperparathyroidism (SHPT) were enrolled. The mean age of the subjects was 54.7 years, and 56.2% were male. Patients were randomized to receive etelcalcetide plus placebo (n = 340) or cinacalcet plus placebo (n = 343). The initial dose of etelcalcetide was 5 mg administered three times weekly post-hemodialysis, with dose increments of 2.5 mg or 5 mg permitted based on PTH levels. The initial dose of cinacalcet was 30 mg/day. The primary endpoint was the non-inferiority of etelcalcetide in achieving a ≥30% reduction in PTH levels from baseline during weeks 20 to 27.

The results demonstrated that the efficacy of etelcalcetide was comparable to that of cinacalcet, with the proportion of patients achieving a ≥30% reduction in PTH levels from baseline being 68.2% vs 57.7% (95% CI: -17.5% to -3.5%; non-inferiority P < 0.001). Furthermore, the proportion of patients achieving a ≥50% reduction in PTH levels from baseline was 52.4% in the etelcalcetide group compared with 40.2% in the cinacalcet group, demonstrating superior efficacy for etelcalcetide (P = 0.001; 95% CI: 4.7% to 19.5%).

These findings indicate that the efficacy of etelcalcetide is superior to that of placebo and non-inferior to that of cinacalcet. However, unlike cinacalcet, etelcalcetide is a peptide-based drug administered via intravenous injection three times weekly (whereas cinacalcet is administered orally twice daily). Its less frequent dosing regimen enhances patient adherence, reduces the risk of recurrence, and demonstrates promising potential for clinical application.

03

Market Outlook

Cinacalcet, the first approved oral calcimimetic, was initially approved for marketing in the United States in March 2004 under the trade name Sensipar; it was subsequently approved in Europe in December of the same year under the trade name Mimpara. In 2014, cinacalcet entered the Chinese market under the trade name Gaiping. In the 《National Catalogue of Drugs for Basic Medical Insurance, Work-Related Injury Insurance, and Maternity Insurance (2020 Edition)》, cinacalcet is listed as a Category B calcium homeostasis agent, indicated for hemodialysis patients with secondary hyperparathyroidism.^【6】。

In 2015, cinacalcet sales surpassed $1 billion. In 2018, cinacalcet sales peaked at $1.774 billion. However, over the past two years, due to patent expiration and the approval and commercial launch of competing products, cinacalcet sales have plummeted.

Since its launch in 2017, sales of etelcalcetide have climbed steadily year by year, reaching $716 million in 2020. It is expected to become a blockbuster product with sales exceeding $1 billion.

Evocalcet was approved in Japan in March 2018 for the treatment of secondary hyperparathyroidism in patients on maintenance dialysis, and is currently in Phase III clinical trials in China.

The parathyroid gland is a vital gland essential for human life. Secondary hyperparathyroidism (SHPT) is a common and severe decompensatory disorder among chronic kidney disease patients undergoing dialysis therapy. It is one of the key manifestations of mineral metabolism disorders and also represents one of the most major and severe complications during dialysis in patients with end-stage renal disease on maintenance dialysis.

Results from a 2012 epidemiological survey in China showed that there were approximately 2 million patients with end-stage renal disease (ESRD) in the country, with a dialysis rate of less than 20%, and the prevalence of secondary hyperparathyroidism (SHPT) among patients with chronic kidney disease–mineral and bone disorder (CKD-MBD) approached 50%. In contrast, the dialysis rate in developed countries (the United States, Europe, and Japan) was 90%.

Based on this, it can be projected that the number of SHPT patients in China will show substantial growth potential as the diagnostic, testing, and treatment capabilities for chronic kidney disease continue to improve.

Reference:

1.Retrieved May 18, 2021, from http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=21；

2.Secondary 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. Etelcalcetide: 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 Healthcare Security Administration, Ministry of Human Resources and Social Security. Notice on Printing and Distributing the “National Basic Medical Insurance, Work-Related Injury Insurance and Maternity Insurance Drug Catalogue (2020)”. NHSA [2020] No. 53, 2021-01-12.