Long-term results are in, and Ascendis Pharma can make the case that its Transcon PTH could become a new treatment for adults with hypoparathyroidism. The pressure is now on the Danish group to move quickly to take advantage of a fortuitous window of opportunity.
This is because the previous hormone-replacement therapy for the disease, Takeda’s Natpara, an injectable parathyroid hormone (PTH), was pulled from the US market last year owing to manufacturing contamination. Ascendis will hope that a regulatory following wind allows it to begin a US pivotal trial immediately, something that would help back its $8bn market cap.
To be fair, this valuation also factors in a more advanced growth hormone project, which scored an important pivotal trial win last year. The Transcon PTH result thus adds to the evidence backing Ascendis’s technology, which lies behind both assets.
The logic behind Transcon PTH is the clever delivery of a long-acting prodrug of PTH, which hypoparathyroidism patients produce in insufficient amounts. This aims to overcome Natpara’s problem – variable PTH levels; Natpara was also associated with calcium imbalances, and carried a black box warning for osteosarcoma.
Ascendis had earlier reported positive data from the controlled portion of Transcon PTH’s phase II trial, and with the longer-term results it has moved to amend its US IND to allow phase III to begin as soon as possible.
|Summary of Ascendis's phase II study of Transcon PTH|
|Transcon PTH (3 doses)||Placebo|
|Subjects evaluable at 4wk||44||13**|
|Met composite measure* at 4wk (primary endpoint)||50%||15%|
|Transcon PTH (3 doses)||Placebo then Transcon PTH|
|Subjects evaluable at 6mth||39||10|
|Met composite measure* at 6mth||74%||60%|
|Note: *normalised serum & urine-excreted calcium, coming off vitamin D, reducing calcium intake to ≤1,000mg/day; **2 patients excluded because they had received <0.25µg bid of calcitriol. Source: Ascendis presentations.|
The latest results relate to the open-label six-month extension of the mid-stage study. The extension had been opened for all 59 participants across the various dose and control arms, and 58 elected to take part; the subject who declined did so “for reasons unrelated to safety or efficacy of” Transcon PTH.
After the four-week controlled phase 50% of 44 subjects across three doses had met the primary endpoint, seeing normalised serum and urine-excreted calcium, coming off vitamin D, and reducing calcium intake to 1,000mg/day or less. In comparison 15% of 13 placebo recipients met this endpoint.
With time the data have only got better – at least if you ignore several additional missing patients. 49 subjects, across all four cohorts, have available data at six months, and 71% met the composite primary efficacy measure at this later time point.
Ascendis said three subjects’ urine samples had not been prepared properly, and another two had not been received by the laboratory. The remaining four omitted subjects were excluded because of missing a day 169-210 urine sampling window; all four were in fact off vitamin D and were on ≤500mg of calcium supplements, Ascendis said, and three of them had normalised serum and urine calcium.
The open-label extension data support the planned pivotal study, which will have a six-month primary endpoint. This composite measure will differ slightly from phase II, comprising only serum calcium normalisation, plus vitamin D independence and ≤600mg calcium supplementation.
Urinary calcium normalisation will be a secondary measure in phase III. The plan is to randomise 57 subjects to the middle phase II dose of Transcon PTH (18µg/day), and 19 to placebo.
On an analyst call today Ascendis said that, depending on various assumptions, 45 of the 49 evaluable phase II subjects would have met the phase III endpoint. The planned study is “extremely well powered for success”, it stated.
EvaluatePharma sellside consensus sees Transcon PTH generating $847m of 2026 sales. Though this lags the $1.4bn expected of Transcon Growth Hormone, the forecast and the new data show that Ascendis is not a one-trick pony.