Listing Yorvipath: why a third PBAC submission must succeed
Bottom line. Palopegteriparatide (Yorvipath) is the first medicine that physiologically replaces the missing hormone in chronic hypoparathyroidism, and its TGA approval in February 2025 was world-leading. Two PBAC rejections later — March and July 2025 — Australians remain tethered to a regimen that controls a blood test but slowly damages their kidneys. The case for PBS listing has not weakened; it has hardened. A third submission, framed around a Managed Access Program with a confidential special price and an Australian outcomes registry, can honour both the PBAC's statutory obligation to value for money and the government's stated commitment to equitable care for rare diseases.
“Australia was first in the world to register Yorvipath after the FDA. It should not be last among comparable countries to fund it."
An approval without access
On 21 February 2025, the Therapeutic Goods Administration registered Yorvipath for the treatment of chronic hypoparathyroidism in adults, following an Orphan Drug designation and a Priority Review pathway. Australia became the first jurisdiction to grant marketing authorisation after the US Food and Drug Administration. The AusPAR was published on 7 August 2025. The clinical community welcomed it. Professor Peter Ebeling AO, Head of the School of Clinical Sciences at Monash Health, observed that conventional calcium and active vitamin D "help to manage the symptoms … but they do not address the underlying deficiency of PTH", and described the resulting unmet need as "urgent".
Reimbursement has not followed. The Pharmaceutical Benefits Advisory Committee considered the sponsor's first submission at its 12–14 March 2025 meeting and did not recommend listing (PBS Medicine Status, Case ID a986; PSD published 18 July 2025). A resubmission was considered at the July 2025 meeting and, according to the PSDs released on 14 November 2025, was again declined. As of April 2026, Yorvipath remains registered on the Australian Register of Therapeutic Goods but absent from the Pharmaceutical Benefits Schedule.
The practical consequence is that roughly 6,400–9,800 Australian adults living with chronic hypoparathyroidism — extrapolating international prevalence of 24–37 per 100,000 to a population of 26.6 million — continue on a seventy-year-old supplementation paradigm that their clinicians know drives renal injury.
Why conventional therapy cannot be "standard care" indefinitely
Parathyroid hormone is the body's master regulator of calcium and phosphate. It tells the distal nephron to reabsorb calcium, the proximal nephron to excrete phosphate, and the kidney to activate vitamin D. None of those signals is restored by swallowing calcium carbonate and calcitriol. The tablets raise serum calcium by brute-force intestinal absorption, then the kidneys, no longer instructed to reabsorb, allow that same calcium to spill into the urine.
The clinical cost of this biochemical workaround is now well-characterised internationally:
Underbjerg and colleagues (J Bone Miner Res 2013, 2015) reported a hazard ratio of 3.67 for renal complications in post-surgical disease and 6.01 for renal insufficiency in non-surgical disease, alongside elevated risks for seizures, cataracts and neuropsychiatric admissions.
Gosmanova and colleagues (Adv Ther 2021), in a US claims cohort of more than 8,000 patients, found a 2.91-fold increased risk of incident chronic kidney disease and accelerated progression to end-stage renal disease.
A Swedish national cohort (Ridder et al, 2022) showed a 4.45-fold risk of CKD and 3–4-fold increased hospitalisation.
An English post-surgical cohort (2025) reported a 2.89-fold all-cause mortality signal.
A Mayo Clinic imaging series found basal ganglia calcification in 25.4% of patients versus 7% of matched controls, associated with cognitive symptoms.
A 2024 systematic review (Büttner et al) covering 23 quality-of-life studies found that 87% showed significant impairment, with SF-36 scores in several domains worse than those reported in adrenal insufficiency.
Behind those hazard ratios are symptoms that clinicians and patients describe in almost identical language across every international survey: fatigue, paraesthesiae, muscle cramps, "brain fog", anxiety and the slow, private exhaustion of monitoring a serum calcium several times a week.
"We are not treating hypoparathyroidism. We are chemically compensating for it, and the kidneys pay the invoice."
What palopegteriparatide actually does
Yorvipath is a prodrug. PTH(1–34) — the same active peptide as teriparatide — is transiently conjugated via a proprietary TransCon linker to an inert branched methoxy-polyethylene glycol carrier. After a once-daily subcutaneous injection, the linker autocleaves at physiological pH and temperature, releasing unmodified PTH(1–34) slowly enough to give an effective half-life of about 60 hours. The result is the first PTH replacement therapy that keeps active hormone within the physiological range for the full 24-hour dosing interval.
That continuous exposure is the whole clinical point. Short-acting teriparatide (multiple daily injections) and rhPTH(1–84) (Natpar; once daily, 3-hour half-life) produced peaks and troughs that normalised serum calcium but left 24-hour urinary calcium elevated — so nephrocalcinosis risk persisted. Continuous PTH exposure restores tubular reabsorption across the day. With Natpar now permanently withdrawn by Takeda (announced 4 October 2022, supply wound down by the end of 2024 due to unresolved manufacturing problems), palopegteriparatide is the only long-acting PTH replacement available anywhere in the world.
The pivotal evidence is the PaTHway trial (NCT04701203; Khan et al, J Bone Miner Res 2023;38(1):14–25), a double-blind, placebo-controlled Phase 3 study in 84 adults, 85% post-surgical, randomised 3:1. At Week 26:
79% (48/61) of palopegteriparatide patients vs 5% (1/21) of placebo patients met the composite primary endpoint of normocalcaemia, independence from active vitamin D and calcium ≤600 mg/day, and no dose increase in the last four weeks (p<0.0001).
93% (57/61) achieved full independence from conventional therapy.
Mean 24-hour urinary calcium normalised.
SF-36v2 Physical Functioning improved significantly (p=0.0347), and the Hypoparathyroidism Patient Experience Scale improved across all four pre-specified domains (p between 0.004 and 0.007).
The durability of that response has since been demonstrated out to three years in the open-label extension (Clarke et al, J Clin Endocrinol Metab 2025;110(4):951–960; ENDO 2025 OR10-05 pooled analysis): at Week 156, 96% remained independent of conventional therapy, 88% were normocalcaemic, and mean estimated glomerular filtration rate had risen by 8.8 mL/min/1.73 m² from baseline (p<0.0001). In participants who began with an eGFR below 60 mL/min/1.73 m², the mean gain was 14.0 mL/min/1.73 m². No cases of nephrolithiasis occurred on palopegteriparatide through Week 104.
Safety is reassuring for a chronic therapy. The most frequent adverse events in PaTHway were injection-site reactions (21.6%), headache (18.7%) and paraesthesia (13.7%); 89% of participants remained in the trial at three years; and, unlike Natpara, Yorvipath carries no boxed warning in the United States. The osteosarcoma signal from rat carcinogenicity remains a class precaution but has not been observed in human data to date.
Addressing the PBAC's specific concerns
The PBAC's concerns in March and July 2025, as reflected in the public commentary and the published PSDs, cluster around four issues. Each deserves a disciplined, evidence-based response rather than a rhetorical one.
Concern 1 — the incremental cost-effectiveness ratio is too high. This is, in substance, a question about price and about the modelled benefits that price must offset. The sponsor has already offered a price reduction and simplified the anniversary-price structure. A third submission should go further: a confidential Special Pricing Arrangement that brings the effective ex-manufacturer price into the range PBAC has indicated it would accept for an orphan-disease therapy of this clinical effect size, and a Risk-Sharing Arrangement with hard expenditure caps and 100% sponsor rebate beyond those caps. This is the combination that converted onasemnogene abeparvovec (Zolgensma) from a July 2021 rejection to a March 2022 recommendation, and that has underpinned successive ivacaftor listings.
Concern 2 — surrogate endpoints do not reliably predict final outcomes. In almost every disease, that caution is reasonable. In chronic hypoparathyroidism it is over-applied. The surrogate in question — 24-hour urinary calcium and eGFR — is the mechanism of harm in this disease, not a distant biomarker. Five independent long-term cohorts (Underbjerg Denmark, Gosmanova US, Ridder Sweden, Vadiveloo Scotland, the 2025 English cohort) consistently link hypercalciuria and low eGFR in this population to incident CKD, dialysis and mortality. PaTHway's three-year data show eGFR rising by 8.8 mL/min/1.73 m² — with the largest gains in those with the worst baseline kidney function. Demanding a 20-year randomised comparison against a regimen that its own prescribers acknowledge is nephrotoxic is ethically untenable and epidemiologically unnecessary. A Managed Access Program that collects Australian registry outcomes over three to five years offers a proportionate compromise.
Concern 3 — the modelled time horizon is uncertain. The sponsor proposed 51 years; the PBAC preferred 30. The honest answer is that neither is perfect, but 30 years systematically devalues a lifelong replacement therapy in a disease whose renal complications accrue in the second and third decades of exposure. A disciplined response is not to dig in at 50 years as a base case, but to present 30 years as the base case (accepting PBAC's conservatism) and 50 years as a scenario analysis with explicit discounting, half-cycle correction, and sensitivity testing on the renal-event hazard. The ICER at both horizons, coupled with the Special Pricing Arrangement, should be transparent to the Economics Sub-Committee.
Concern 4 — Australian epidemiological data are limited. This is true, and it is also circular: no national registry exists because no listed therapy has incentivised clinicians to enrol patients. The solution is an Australian Hypoparathyroidism Registry, co-funded by the sponsor and the Commonwealth under a Deed of Agreement (analogous to the Australian Cystic Fibrosis Data Registry), with participation as a condition of subsidy. Within three years such a registry would deliver the prevalence, utilisation, eGFR trajectories and hospitalisation data that PBAC has correctly asked for — and would allow the economic model to be re-run on Australian evidence at the next review.
A proposed Managed Access Program
Drawing on Australian precedents — nusinersen for SMA, ivacaftor for CF, and onasemnogene abeparvovec — a workable Managed Access Program for Yorvipath would have four pillars.
First, a narrow, clinically defensible initiation population: adults with chronic hypoparathyroidism of at least 12 months' duration (aligned with the 2025 ESE guideline redefinition and endorsed by the Endocrine Society of Australia) who are inadequately controlled on optimised conventional therapy. "Inadequately controlled" should be explicit: 24-hour urinary calcium above 7.5 mmol, or eGFR below 60 mL/min/1.73 m², or nephrocalcinosis or nephrolithiasis on imaging, or recurrent symptomatic hypocalcaemia requiring hospital presentation, or an inability to achieve albumin-corrected serum calcium in the normal range despite ≥2,000 mg/day elemental calcium plus active vitamin D. Initiation restricted to consultant endocrinologists; Section 100 (Highly Specialised Drugs) Authority Required (Written).
Second, explicit stopping rules: treatment response to be reviewed at 26 weeks, with continuation contingent on a clinically meaningful reduction in oral calcium requirement (≥50%), discontinuation of active vitamin D, or normalisation of 24-hour urinary calcium. Non-responders to be weaned per protocol. The government does not pay for what does not work.
Third, a confidential Special Pricing Arrangement and Risk-Sharing Arrangement: an effective price consistent with PBAC's willingness-to-pay for a rare-disease disease-modifying therapy; a fixed expenditure cap set on a transparent eligible-population estimate (approximately 400–800 patients initiated in years one to three, based on the inadequately controlled subset of ~6,400–9,800 Australians with chronic disease); a 100% sponsor rebate beyond the cap; and performance-based rebates should registry data fail to demonstrate the expected renal protection over three years.
Fourth, the Australian Hypoparathyroidism Registry described above, with pre-specified endpoints mirroring the PaTHway outcomes: serum and 24-hour urinary calcium, phosphate, eGFR, hospitalisations, patient-reported outcomes using the validated HPES and SF-36v2, and adverse events. Data governance through the Endocrine Society of Australia or an equivalent professional custodian; public reporting annually.
"This is not a request to suspend PBAC's rigour. It is a request to deploy the instruments — Managed Access, Risk-Sharing, Special Pricing — that the PBAC has built precisely for this class of decision."
The international context Australia should heed
Every comparator system to which Australia routinely benchmarks is further down the reimbursement pathway than we are.
Germany launched Yorvipath on 31 January 2024 and received a G-BA decision on 20 June 2024 granting orphan-drug "additional benefit" status.
France HAS issued a favourable SMR on 11 September 2024, restricted to patients inadequately controlled on conventional therapy — the very population this article proposes.
United Kingdom MHRA approved on 24 April 2024; NICE is completing its technology appraisal (ID6380), with the draft guidance under consultation and the final determination expected in 2026.
Canada CDA-AMC reimbursement review is open.
Japan launched on 6 November 2025, with NHI listing in October 2025 and an explicit home-nursing support model through Teijin Pharma.
United States has approximately 5,300 patients on therapy as of Q4 2025 with ~70% commercial insurance approval within 8 weeks, notwithstanding a list price of roughly US$285,000 per year.
Australia's TGA was faster than any of these agencies. Our HTA process is now the slowest of the comparator set. That is not a failure of the PBAC's statutory mandate; it is a mismatch between a process designed for statins and a therapy that only ~6,400–9,800 Australians will ever need.
The "whole-of-government" economic case
The PBAC's preferred viewpoint is the direct health-system perspective. That is a legitimate but incomplete lens for this disease. Chronic kidney disease cost the Australian health system approximately $1.9 billion in 2020–21 (AIHW). Dialysis costs about $85,000–$100,000 per patient per year in metropolitan areas, and up to $120,000 per year in remote settings once transport and infrastructure are included. Over 15,000 Australians currently receive dialysis, and rural households face mean out-of-pocket CKD costs of about $1,266 per quarter.
If a Managed Access Program restricted to the inadequately controlled cohort delayed dialysis by five years in even a small fraction of that cohort, the arithmetic is no longer ambiguous. A Productivity Commission–style whole-of-government view — which the Department of Health, Disability and Ageing can legitimately model even where PBAC's base case does not — is that every year of kidney function preserved is a year of workforce participation preserved, a year of Disability Support Pension deferred, and a year of out-of-pocket financial toxicity avoided.
Equity, rurality and the rare-disease action plan
The National Strategic Action Plan for Rare Diseases, released on 26 February 2020 with Rare Voices Australia's leadership, rests on three pillars: awareness and education, care and support, and research and data. A decision to fund Yorvipath through a registry-linked Managed Access Program advances all three simultaneously. A decision to continue with no subsidy retreats from the second and postpones the third.
The equity argument has a specific Australian dimension. Patients in regional and remote areas bear the heaviest share of the supplementation burden — more frequent pathology, more emergency presentations for hypocalcaemia, higher dialysis costs when renal disease eventually arrives. A once-daily subcutaneous injection delivered through a pre-filled pen, supported (as in Japan) by a home-nursing initiation model, is better suited to rural and remote Australia than lifelong multi-times-daily tablets with monthly bloods.
A respectful call to action
The PBAC's two previous decisions were not unreasonable. They were responses to the evidence and price on the day. The clinical evidence has since strengthened: three-year durability, sustained eGFR gains, no nephrolithiasis, and a confirmed safety profile without a boxed warning. The international reference set has moved. Natpar has gone. The sponsor has signalled willingness to negotiate price and structure.
A third submission, built around a Managed Access Program with a confidential Special Pricing Arrangement, a Risk-Sharing Arrangement with expenditure caps, narrow initiation criteria aligned with the 2025 ESE guideline, explicit stopping rules, and a sponsor-funded Australian Hypoparathyroidism Registry, resolves every substantive concern the PBAC has raised. It does so while honouring both the Committee's statutory obligation to value for money and the Commonwealth's stated commitment — through the National Strategic Action Plan for Rare Diseases — to equitable access for people with rare conditions.
To the PBAC: a third consideration, framed this way, is warranted. To the Department of Health, Disability and Ageing: the Deed of Agreement and registry infrastructure are within existing administrative reach. To the Endocrine Society of Australia, the Australian and New Zealand Bone and Mineral Society, the Royal Australasian College of Physicians, Hypopara Australia, the Australian Thyroid Foundation and Rare Voices Australia: a coordinated clinician and consumer comment process at the next PBAC consultation window will matter. To Australian adults living with chronic hypoparathyroidism: your voices, submitted through the PBAC consumer-comments portal, are the single most under-used lever in this process.
Australia was first in the world to register Yorvipath after the FDA. It should not become a cautionary tale about what happens when regulatory leadership and reimbursement follow-through part ways.
Key references
Khan AA, Rubin MR, Schwarz P, et al. Efficacy and safety of parathyroid hormone replacement with TransCon PTH in hypoparathyroidism: 26-week results from the Phase 3 PaTHway trial. J Bone Miner Res 2023;38(1):14–25. https://doi.org/10.1002/jbmr.4726
Clarke BL, Khan AA, Rubin MR, et al. Efficacy and safety of TransCon PTH in adults with hypoparathyroidism: 52-week results from the Phase 3 PaTHway trial. J Clin Endocrinol Metab 2025;110(4):951–960. https://doi.org/10.1210/clinem/dgae693
Rejnmark L, Gosmanova EO, Khan AA, et al. Palopegteriparatide treatment improves renal function in adults with chronic hypoparathyroidism: 1-year results from the Phase 3 PaTHway trial. Adv Ther 2024;41(6):2500–2518.
Khan AA, Clarke BL, Rubin MR, et al. OR10-05: Efficacy and safety of palopegteriparatide in adults with hypoparathyroidism — 3-year results. J Endocr Soc 2025;9(Suppl 1):bvaf149.560.
Bollerslev J, Rejnmark L, Marcocci C, et al. Revised ESE Clinical Practice Guideline: Treatment of Chronic Hypoparathyroidism in Adults. Eur J Endocrinol 2025;193(5):G83–G112 (endorsed by the Endocrine Society of Australia).
TGA AusPAR: Yorvipath (palopegteriparatide). https://www.tga.gov.au/resources/auspar/yorvipath
PBS Medicine Status, palopegteriparatide (Case ID a986). https://www.pbs.gov.au/medicinestatus/document/1310.html
Gosmanova EO, Chen K, Rejnmark L, et al. Risk of chronic kidney disease and estimated glomerular filtration rate decline in patients with chronic hypoparathyroidism. Adv Ther 2021. https://pubmed.ncbi.nlm.nih.gov/33687651/
Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Postsurgical hypoparathyroidism: risk of complications. J Bone Miner Res 2013 and 2015. https://doi.org/10.1002/jbmr.1979 and https://doi.org/10.1002/jbmr.2501
National Strategic Action Plan for Rare Diseases (Rare Voices Australia, 2020). https://rarevoices.org.au/
Specialised Therapeutics announcement of TGA registration, 21 February 2025. https://stabiopharma.com/first-and-only-treatment-for-chronic-hypoparathyroidism-approved-in-australia/
Takeda announcement of Natpar/Natpara global discontinuation, 4 October 2022.
The author is a clinical psychologist in Perth. He has no financial relationship with Ascendis Pharma, Specialised Therapeutics or any entity with a commercial interest in Yorvipath. This piece is a citizen-clinician brief, not a formal sponsor submission; it is written to inform public and professional discussion ahead of the PBAC's next consideration of palopegteriparatide and to support coordinated consumer and clinician comment.