TransCon PTH: New hope for patients with Hypoparathyroidism (HP)

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TransCon PTH: New hope for patients with Hypoparathyroidism (HP)

TransCon PTH: New hope for patients with Hypoparathyroidism (HP). Hypoparathyroidism (HP) is a rare endocrine disorder that seriously affects the lives of patients.

Hypoparathyroidism (HP) is a rare endocrine disorder that seriously affects the lives of patients. In the United States, Europe, Japan and Korea, HP affects approximately 200,000 patients. Conventional treatment cannot completely control the disease and may lead to the risk of kidney disease.

Compared with conventional treatment, PTH replacement therapy does not cause hypercalcemia, kidney stones and nephrocalcinosis. Currently, the only PTH replacement therapy approved for marketing is Takeda Natpara. TransCon PTH has better efficacy than Natpara, and it is expected to reach years in the future. Sales of 1 billion U.S. dollars.

Introduction to HP Diseases

Hypoparathyroidism (HP) is a rare endocrine disorder characterized by insufficient levels of parathyroid hormone (PTH), which leads to a decrease in blood calcium and an increase in blood phosphorus. In the United States, Europe, Japan, and South Korea, HP affects approximately 200,000 patients.

Most of HP patients are caused by parathyroid gland damage or accidental removal during thyroid surgery. Short-term symptoms include weakness, severe muscle cramps (hand and foot twitches), abnormal sensations such as tingling, burning and numbness (paresthesia), memory loss, decreased judgment, and headaches. Long-term will increase the risk of major complications, such as extra-skeletal calcium deposits in the brain, eye lens and kidneys (which can lead to impaired renal function), and at the same time lead to a decline in the quality of life of patients.

So far, HP is still one of the few hormone deficiency diseases that cannot be treated by supplementing the missing hormones. Conventional treatments supplemented with active vitamin D analogs and calcium can not completely control the disease and may lead to the risk of kidney disease.

Current status of HP treatment

HP conventional treatment

The conventional long-term treatment of HP is oral calcium, active vitamin D or its analogues, and ordinary vitamin D. The treatment principle is to increase intestinal calcium absorption through large doses of calcium and active vitamin D or its analogs, thereby correcting hypocalcemia caused by decreased intestinal calcium absorption and increased renal calcium excretion rate.

Treatment goals: (1) Relieve the symptoms of hypocalcemia; (2) For HP patients, maintain fasting blood calcium at a low or slightly lower than normal value, and maintain it above 2.0 mmol/L as much as possible; (3) Maintain blood phosphorus at a normal value or slightly higher; (4) Avoid or reduce the occurrence of high urine calcium; (5) Maintain calcium and phosphorus product below 55 mg2/d12 or 4.4 mmol2/L2; (6) Prevent abnormalities in soft tissues such as kidneys Local calcification, such as kidney stones or nephrocalcinosis.

The most commonly used calcium agent is calcium carbonate. Calcium citrate can also be selected. Other types of calcium agents include calcium glucuronate, calcium gluconate and calcium lactate. The calcium content is relatively low (6.6% and 9%, respectively). And 3%), generally not commonly used in the treatment of HP. Add 500-1000mg of elemental calcium each time, 2-3 times/d.

Active vitamin D or its analogues: The active metabolite of vitamin D is calcitriol, which has the physiological effect of promoting intestinal calcium absorption and bone turnover. Because PTH stimulates the synthesis of 250HD-1α-hydroxylase, the lack or effect of PTH Obstacles will lead to vitamin D activation obstacles, so the combination of active vitamin D and calcium is an important means to treat HP. Alfacalcidol, fluoroosteol and dihydrotachysterol are active vitamin D analogs and can be used as substitutes for calcitriol.

If active vitamin D or its analogues are not available, or cannot afford the cost, consider replacing it with cheaper ordinary vitamin D, but a toxic dose is required to achieve the therapeutic effect.

PTH replacement therapy

Despite the use of high-dose calcium and active vitamin D, the blood calcium of some HP patients still cannot be raised to the target level, and long-term use of high-dose calcium and active vitamin D may cause high urine calcium, kidney stones, and nephrocalcin. Precipitation and ectopic calcification. In addition, treatment with calcium and vitamin D cannot solve the problem of decreased bone turnover due to PTH deficiency. The obvious advantage of using PTH replacement therapy is that PTH corrects hypocalcemia while significantly reducing urinary calcium levels. Therefore, compared with conventional treatment, PTH replacement therapy does not cause hyperurinary calcium, kidney stones and nephrocalcinosis. . And it can correct abnormal bone metabolism that cannot be corrected by conventional treatment

riparatide chemical structure

Among endocrine diseases caused by hormone deficiency, HP is the last disease to be treated with hormone replacement therapy. It was not until 1996 that Winer et al. first reported the use of recombinant human parathyroid hormone 1-34 fragment (rhPTH1—34) to treat HP. Research result. Currently in clinical studies, there are two types of PTH and its analogs used for HP treatment: rhPTH1-34 (Teriparatide) and rhPTH1-84 (Natpara). The latter was approved by the FDA in January 2015 for the treatment of HP. Natpara (Parathyroid Hormone) is a human-derived recombinant parathyroid hormone polypeptide containing 84 amino acid sequences. Clinical trials have shown that 42% of the participants in the Natpara treatment group have reduced the dose of calcium supplements and the active form of vitamin D. To the normal blood calcium level, and the proportion of the placebo treatment group was 3%.

Natpara was approved by the FDA in January 2015. Natpara has a black box warning and is experiencing storms such as recalls and production suspensions. Even so, Natpara’s sales in 2020 will still be 126 million US dollars.

TransCon PTH

TransCon PTH is a sustained-release long-acting prodrug of parathyroid hormone (PTH[1-34]), developed by Ascendis Pharma, a NASDAQ-listed company located in Denmark. It is developed using TransCon technology and aims to Restore PTH to physiological levels within 24 hours, normalize blood and urine calcium levels, serum phosphate levels, and bone turnover to solve the short-term symptoms and long-term complications of the disease.

In April 2020, Ascendis Pharma announced the positive top-line results of the four-week fixed-dose double-blind part of the PaTH Forward global phase II clinical trial of TransCon-PTH. This trial evaluates the safety, tolerability and efficacy of TransCon-PTH in the treatment of adult patients with hypoparathyroidism (hypoparathyroidism, HP).

In the PaTH Forward trial, TransCon-PTH reached the primary endpoint. Compared with the standard treatment regimen (active calcium + vitamin D), 4 weeks of TransCon-PTH treatment eliminated standard care in up to 82% of patients.

TransCon-PTH clinical data graph

PaTH Forward OLE MeanSerum Calcium and Mean 24-Hour Urine Calcium

PaTH Forward OLE %Change in Mean P1NP and CTx

On May 10, 2021, Ascendis Pharma announced the 58-week follow-up open label extension (OLE) data of the Phase II clinical trial (PaTH Forward) of its long-acting parathyroid hormone TransCon PTH for the treatment of hypoparathyroidism (HP), and the results Excellent, the main contents are as follows:

a) As of May 7, 58 of the 59 subjects in the phase II clinical trial are still participating in the follow-up open label extension (OLE) trial;

b) The curative effect of continuous receiving TransCon PTH treatment:

91% of the subjects did not receive standard care, that is, they did not supplement with active vitamin D (calcitriol or fluorocalcitriol) or calcium supplements of less than 600mg per day;
Urinary calcium level is maintained in the normal range and shows a trend of continuous decrease;
Bone markers tend to be moderately normal;
The quality of life benefit measured by SF-36 was maintained within the normal range.

c) TransCon PTH was safely tolerated at all doses: no serious adverse events related to treatment occurred, and no treatment-induced adverse events (TEAE) resulted in discontinuation events; the safety indicators of the OLE trial were the same as before. In view of the excellent efficacy and safety of TransCon PTH, industry experts predict that TransCon PTH can even completely replace the current standard treatment regimen of active vitamin D and calcium supplements in the treatment of different degrees of parathyroid hormone depression, and restore normal blood calcium. , Urine calcium, blood phosphorus levels and normal bone transformation.

In addition, Ascendis has applied for TransCon PTH global patents. Among them, the Chinese patent is currently in the substantive examination stage. If approved, the patent right will expire in 2037.

At present, TransCon PTH has carried out phase III clinical trials for the treatment of PH in the United States and Europe. Weisheng Pharmaceutical has the rights and interests of TransConPTH in Greater China. It submitted an import registration application for TransCon PTH to CDE in March 2021, May 12, 2021. , Ascendis announced that it has submitted a Phase III clinical trial notice (CTN) for the treatment of hypoparathyroidism (HP) under its long-acting parathyroid hormone TransCon PTH to PMDA, the Japanese drug administration department.

The existing clinical data of TransCon PTH has shown extraordinary efficacy and safety, and it is expected to achieve simultaneous listing in the United States, the European Union, China, Japan and other countries or regions in the near future, bringing new hope to HP patients.

(source:internet, reference only)

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