Addressing Unmet Needs: Novel Therapies in the Treatment of Adult Hypoparathyroidism

Aliya A. Khan, MD, FRCPC, FACP, FACE, FASBMR, is a clinical professor of medicine at McMaster University in Hamilton, Ontario, Canada, and is the director of the Calcium Disorders Clinic at McMaster University Medical Centre. She is also the director of the fellowship program in metabolic bone disease at McMaster University. Dr Khan’s clinical areas of focus include the diagnosis and management of hypophosphatasia. She led the development of the international standards of care for hypoPT and is currently investigating the use of various PTH molecules in the management of hypoPT in phase 1, phase 2, and phase 3 clinical trials.

HypoPT is notable for being a hormone insufficiency that currently does not have an approved replacement therapy to restore hormone levels at a stable physiologic level. Can you describe the overarching rationale behind the need for therapy beyond that of calcium and vitamin D replacement therapy?

HypoPT is diagnosed in the presence of low serum calcium and low PTH or inappropriately normal PTH in the presence of hypocalcemia. It is associated with reductions in 1,25 dihydroxyvitamin D (1,25(OH)₂D) as well because PTH enhances the conversion of 25-hydroxyvitamin D (25(OH)D) to 1,25(OH)₂D . Therefore, in hypoPT, we actually have a deficiency of 2 hormones: PTH and 1,25(OH)₂D. In hypoPT, we can correct the hypocalcemia by supplementing with calcium, and we can correct the low 1,25(OH)₂D levels by providing active vitamin D. These therapies constitute conventional therapy for hypoPT.

However, if we do not replace PTH, we will not be able to correct the hyperphosphatemia, which results from lack of PTH. Giving active vitamin D enhances the absorption of calcium and phosphate from the bowel and can further elevate serum phosphate. We believe that high phosphate and high calcium phosphate product is associated with ectopic calcification such as intracranial calcification as well as calcification of the lens. Additionally, in the absence of PTH, as we elevate serum calcium, we will increase renal calcium filtered load, and this results in further exacerbation of hypercalciuria, which can increase the risk of nephrocalcinosis, nephrolithiasis, and renal impairment.¹

Therefore, just giving conventional therapy does not address the long-term complications of hypoPT and may, in fact, exacerbate them. In addition, conventional therapy may not effectively normalize serum calcium throughout the day. Patients may experience wide fluctuations in their serum calcium during day-to-day activities and have associated symptoms, including neuromuscular and cognitive changes.² The effects of PTH on the brain are not fully appreciated at this time, and inadequate levels of PTH may also impact cognition, well-being, and overall function.

What are some of the most pressing concerns facing clinicians when prescribing conventional treatments of active vitamin D and calcium for the treatment of hypoPT in adults?

It is important to correct the symptomatic hypocalcemia and also ensure that we are not elevating phosphate further with large doses of active vitamin D. We also need to ensure that urine calcium is not elevated and is in the normal reference range. The large pill burden is a huge practical issue for patients and compliance is not easy; we need to recognize this and try to emphasize compliance. Also, we should emphasize to patients that calcium should be taken with meals, as this enables the calcium to function as a phosphate binder while lowering serum phosphate. These simple strategies can improve patient care and enable us to achieve better biochemical control.

Recombinant PTH therapy is currently a second-line therapy, in part due to its subcutaneous administration route as well as potential concerns related to skeletal osteosarcoma risk, particularly in children. It is available only via the Risk Evaluation and Mitigation Strategy (REMS) program to minimize the potential risk of osteosarcoma.^3,4 Can you discuss the role that recombinant human PTH (rhPTH) therapy plays for patients with chronic hypoPT who cannot maintain stable serum and urinary calcium levels with calcium and vitamin D supplementation?

PTH therapy has been shown to improve QOL, reduce pill burden, and lower serum phosphate levels while maintaining serum calcium in the normal reference range.³ It is indeed a major advance in the treatment of hypoPT. Long-term follow-up studies have not demonstrated an increase in the risk of osteosarcoma,⁵ and it is a valuable and safe treatment option for patients with hypoPT.

Recombinant PTH therapy can cause hypercalcemia, especially in initial phases of initiation during the titration period, in which supplemental calcium and vitamin D are still being given.³ Can you review the monitoring process once recombinant therapy is started?

When PTH therapy is started, it is important to monitor patients closely and gradually titrate down the conventional therapy. If there are delays in the downward titration of conventional therapy, it is possible that patients will develop hypercalcemia. When PTH therapy is started, it is reasonable to decrease the active vitamin D by one-third and monitor the serum calcium corrected for albumin every 5 to 7 days. Gradually, the dose of the active vitamin D and calcium is tapered off and the PTH therapy is increased. The half-life of teriparatide PTH 1-34 is approximately 1 hour, and this molecule can be given in doses of 20 ug twice daily. The half-life of rhPTH 1-84 is longer at 3 hours and this is amenable to once daily dosing. However, this molecule has been withdrawn by the FDA due to rubber particles present in the solution. Palopegteriparatide (TransCon PTH) has a half-life of 60 hours and is ideal for daily dosing.³

TransCon PTH is an investigational once-daily, long-acting prodrug of PTH 1-34 designed to restore physiologic levels of PTH for 24 hours each day.  What unmet needs would this investigational drug meet in this adult population with hypoPT?

This molecule can provide circulating PTH levels in the normal reference range throughout the 24-hour time period and can normalize serum calcium while lowering serum phosphate and the 24-hour urine calcium. It allows patients to stop active vitamin D and reduce the calcium supplement to 600 mg or less daily in 93% of patients.⁶ It has also shown dramatic improvements in QOL in the phase 3 study (ClinicalTrials.gov identifier: NCT04701203) completed to date.

Results from 2 trials found that treatment with TransCon PTH resulted in durable response rates in terms of achieving independence from conventional therapy and restoration of bone mineral density. Additional results suggest that QOL, which is notably reduced in chronic hypoPT, is improved along with cognitive function.^6,7 Can you comment on QOL specifically in hypoPT in framework or current therapy?

Patients with hypoPT do have significantly impaired QOL due to multiple factors. The wide fluctuations in serum calcium are disabling in many patients and the neurologic manifestations — with numbness and tingling in the face, hands, and feet — can prevent an individual from engaging in a meaningful work schedule. Depression and anxiety are also more common in these individuals.² Conventional therapy can certainly improve serum calcium but may not be able to eliminate the fluctuations in serum calcium and may not be able to improve QOL. Also, the effects of inadequate PTH levels on neurocognition require further study; however, we have noticed dramatic improvements in well-being, function, and QOL with the implementation of PTH therapy.

This Q&A was edited for clarity and length.

Disclosures

Aliza A. Khan, MD, FRCPC, FACP, FACE, FASBMR, reported affiliations with Alexion Pharmaceuticals, Inc; Amgen, Inc; Amolyt; Ascendis; Chugai; Radius; and Ultragenyx.

References

1. Ketteler M, Chen K, Gosmanova EO, et al. Risk of nephrolithiasis and nephrocalcinosis in patients with chronic hypoparathyroidism: a retrospective cohort study. Adv Ther. 2021;38(4):1946-1957. doi:10.1007/s12325-021-01649-2
 
2. Saponaro F, Alfi G, Cetani F, et al. Serum calcium levels are associated with cognitive function in hypoparathyroidism: a neuropsychological and biochemical study in an Italian cohort of patients with chronic post-surgical hypoparathyroidism. J Endocrinol Invest. 2022;45(10):1909-1918. doi:10.1007/s40618-022-01822-6
 
3. Zavatta G, Clarke BL. Challenges in the management of chronic hypoparathyroidism. Endocr Connect. 2020;9(10):R229-R240. doi:10.1530/EC-20-0366
 
4. Bilezikian JP, Brandi ML, Cusano NE, et al. Management of hypoparathyroidism: present and future. J Clin Endocrinol Metab. 2016;101(6):2313-2324. doi:10.1210/jc.2015-3910
 
5. Gilsenan A, Midkiff K, Harris D, Kellier-Steele N, McSorley D, Andrews EB. Teriparatide did not increase adult osteosarcoma incidence in a 15-year US postmarketing surveillance study. J Bone Miner Res. 2021;36(2):244-251. doi:10.1002/jbmr.4188
 
6. 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. Published online October 21, 2022. doi:10.1002/jbmr.4726
 
7. Khan AA, Rejnmark L, Rubin M, et al. PaTH Forward: a randomized, double-blind, placebo-controlled phase 2 trial of TransCon PTH in adult hypoparathyroidism.J Clin Endocrinol Metab. 2021;107(1):e372-e385. doi:10.1210/clinem/dgab577

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