乌鸦传媒

SEATTLE -- Nearly all patients with chronic hypoparathyroidism were able to remain off conventional therapy with active vitamin D and calcium long-term after treatment with an investigational prodrug, according to the phase II PaTH Forward.

A total of 93% (53 of 57) of patients treated with palopegteriparatide (TransCon PTH), which releases a sustained flow of parathyroid hormone (PTH), were off conventional therapy through week 110, said Mishaela R. Rubin, MD, of Columbia University in New York City.

This meant patients were not taking active vitamin D and were on 600 mg/day or less of elemental calcium, which is "considered a dietary supplemental dose, whereas higher than that would be considered a therapeutic dose," she said during a presentation at the American Association of Clinical Endocrinology (AACE) annual meeting.

A total of 77% (44 of 57) of patients were completely off of calcium supplementation and active vitamin D by week 110.

"These [findings] really establish the durability of the efficacy out to 2 years of keeping patients off of conventional therapy," Rubin added.

After being granted orphan designation for palopegteriparatide, developer Ascendis Pharma applied to the FDA for new drug approval in August 2022 based on these phase II data, along with findings from the phase III PaTHway trial.

released by the company from the 84-patient randomized phase III trial showed that palopegteriparatide achieved the primary composite endpoint of normalized serum calcium and independence from active vitamin D and calcium supplements in 78.7% of patients, compared with 4.8% in the control group (P<0.0001). Quality of life also improved significantly.

But after being granted priority review by the FDA, the agency declined to approve the drug in a complete response letter issued last week that cited manufacturing concerns.

"The FDA did not express concern about the clinical data submitted as part of the NDA package and no new preclinical studies, or phase 3 clinical trials to evaluate safety or efficacy, were requested in the letter," the developer said . "Ascendis will request a with the FDA as soon as possible to agree on the best path forward."

If approved, palopegteriparatide would be the first hormone replacement therapy targeting the underlying cause of hypoparathyroidism.

In the phase II trial, serum calcium levels remained steady in the normal range from week 26 through the end of the trial, ending at 8.6 mg/dL at week 110. Average 24-hour urine calcium dropped from a baseline level of 428 mg/24-hr to within the normal range at week 26 (173 mg/24-hr) and held steady thereafter through week 110 (167 mg/24-hr).

"The continuous 24-hour-a-day exposure of the renal tubule to PTH most likely promoted the renal reabsorption of calcium, and thus allowed for this reduction in urine calcium levels," she pointed out. "This is a really important outcome, because we know high urine calcium in these patients sets them at risk for going on to develop nephrocalcinosis, nephrolithiasis, and ultimately chronic kidney disease."

When it came to markers of skeletal dynamics, procollagen type 1 N-terminal propeptide (P1NP) peaked at 26 weeks and then trended downward through week 110. Likewise, C-terminal telopeptide of type 1 collagen (CTx) peaked at week 12 and tapered off through week 110. The most rapid decrease in both markers was seen between weeks 26 and 58, with a slow but steady decline thereafter. This is consistent with the levels equilibrating to a new steady state, Rubin pointed out, saying these final levels are those seen in euthyroid patients.

"You see this robust increase in the bone turnover marker," Rubin noted. "It's almost as though the bone is waking up, if you will. We believe that this is consistent with calcium being mobilized from the skeleton and going into the circulation."

At week 110, balance appeared to be reached, she said. "It's not the low levels they had at baseline; it's not the high levels they had at the peak, but the levels are now approximately age- and sex-matched control levels."

Throughout the trial, bone mineral density Z-scores trended downwards. Measured by dual-energy x-ray absorptiometry (DXA), this was true at the lumbar spine L1-L4 (1.6 at baseline vs 0.7 at week 110), femoral neck (1.0 vs 0.3), total hip (1.0 vs 0.4), and distal one-third radius (0.4 vs 0.2).

The treatment was generally safe and well-tolerated, with the majority of treatment-emergent adverse events graded as 1 (59.3%) or 2 (28.8%) unrelated to the study drug, with no serious treatment-related adverse events. The most common adverse events were hypercalcemia, headache, and paresthesias.

Treatment consisted of one of three fixed doses of palopegteriparatide -- 15, 18, or 21 μg/day once daily -- given via subcutaneous injection. One group got placebo for comparison during a double-blind phase in the first 4 weeks and then were transitioned to the study drug for the open-label extension. The drug is designed to provide a stable flow of PTH levels within the physiological range for 24 hours.

During the open-label extension period, palopegteriparatide and conventional therapy were titrated to maintain normocalcemia. Dose of the investigational drug ranged from 6 to 60 μg/day. This phase is slated to run a total of 214 weeks.

Typical of a hypoparathyroidism population, most participants were female (81%) and white (92%), and had their condition for an average of 12 years. The majority acquired hypoparathyroidism from neck surgery (80%), followed by idiopathic disease (19%) or autoimmune disease (2%). At baseline, patients were taking an average of 1,888 mg of calcium, 0.79 μg of calcitriol, and 2.38 μg of alfacalcidol.

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