12.01.073

Module	Clinical Criteria for Approval
PA	Initial Evaluation Target Agent(s) will be approved when ALL of the following are met: 1. The patient has a diagnosis of hypoparathyroidism AND 2. The patient does NOT have acute post-surgical hypoparathyroidism AND 3. The patient does NOT have pseudohypoparathyroidism AND 4. The patient does NOT have hypoparathyroidism caused by calcium-sensing receptor (CaSR) mutations AND 5. If the patient has an FDA labeled indication, then ONE of the following: A. The patient’s age is within FDA labeling for the requested indication for the requested agent OR B. There is support for using the requested agent for the patient’s age for the requested indication AND 6. The patient has baseline (prior to therapy with the requested agent) albumin-corrected serum calcium of at least 7.8 mg/dL using calcium and active vitamin D treatment AND 7. The patient has baseline (prior to therapy with the requested agent) vitamin D levels above the lower limit of normal AND 8. The patient has tried and had an inadequate response to maximally tolerated calcium AND vitamin D supplements (e.g., calcitriol, ergocalciferol, cholecalciferol) AND 9. The patient will continue calcium and vitamin D supplementation while titrating to an appropriate dose of the requested agent AND 10. The patient will NOT be using the requested agent in combination with any bisphosphonate (e.g., alendronate, ibandronate, risedronate), denosumab, estrogen, raloxifene, and Sensipar (cinacalcet) for the requested indication AND 11. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., endocrinologist, nephrologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND 12. The patient does NOT have any FDA labeled contraindications to the requested agent Length of Approval: 6 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. Renewal Evaluation Target Agent(s) will be approved when ALL of the following are met: 1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND 2. The patient has an albumin-corrected total serum calcium concentration between 8.3 to 10.6 mg/dL AND 3. The patient has had clinical benefit with the requested agent AND 4. The patient will NOT be using the requested agent in combination with bisphosphonates (e.g., alendronate, ibandronate, risedronate), denosumab, estrogen, raloxifene, and Sensipar (cinacalcet) for the requested indication AND 5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., endocrinologist, nephrologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND 6. The patient does NOT have any FDA labeled contraindications to the requested agent Length of Approval: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Module

Clinical Criteria for Approval

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has a diagnosis of hypoparathyroidism AND

2. The patient does NOT have acute post-surgical hypoparathyroidism AND

3. The patient does NOT have pseudohypoparathyroidism AND

4. The patient does NOT have hypoparathyroidism caused by calcium-sensing receptor (CaSR) mutations AND

5. If the patient has an FDA labeled indication, then ONE of the following:

A. The patient’s age is within FDA labeling for the requested indication for the requested agent OR

B. There is support for using the requested agent for the patient’s age for the requested indication AND

6. The patient has baseline (prior to therapy with the requested agent) albumin-corrected serum calcium of at least 7.8 mg/dL using calcium and active vitamin D treatment AND

7. The patient has baseline (prior to therapy with the requested agent) vitamin D levels above the lower limit of normal AND

8. The patient has tried and had an inadequate response to maximally tolerated calcium AND vitamin D supplements (e.g., calcitriol, ergocalciferol, cholecalciferol) AND

9. The patient will continue calcium and vitamin D supplementation while titrating to an appropriate dose of the requested agent AND

10. The patient will NOT be using the requested agent in combination with any bisphosphonate (e.g., alendronate, ibandronate, risedronate), denosumab, estrogen, raloxifene, and Sensipar (cinacalcet) for the requested indication AND

11. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., endocrinologist, nephrologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND

12. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 6 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND

2. The patient has an albumin-corrected total serum calcium concentration between 8.3 to 10.6 mg/dL AND

3. The patient has had clinical benefit with the requested agent AND

4. The patient will NOT be using the requested agent in combination with bisphosphonates (e.g., alendronate, ibandronate, risedronate), denosumab, estrogen, raloxifene, and Sensipar (cinacalcet) for the requested indication AND

5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., endocrinologist, nephrologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND

6. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Module	Ops Set Up	Validation Options	Other Explanation
PA	Validation: Apply Baseline and go to Validation Options	Age Verification

Module

Ops Set Up

Validation Options

Other Explanation

Validation: Apply Baseline and go to Validation Options

Age Verification

Module	Clinical Criteria for Approval
Universal QL	Quantity limit for the Target Agent(s) will be approved when ONE of the following is met: 1. The requested quantity (dose) does NOT exceed the program quantity limit OR 2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following: A. BOTH of the following: 1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND 2. There is support for therapy with a higher dose for the requested indication OR B. BOTH of the following: 1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND 2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR C. BOTH of the following: A. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND B. There is support for therapy with a higher dose for the requested indication Length of Approval: up to 12 months

Module

Clinical Criteria for Approval

Universal QL

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR

2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:

A. BOTH of the following:

1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND

2. There is support for therapy with a higher dose for the requested indication OR

B. BOTH of the following:

1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND

2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR

C. BOTH of the following:

A. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND

B. There is support for therapy with a higher dose for the requested indication

Length of Approval: up to 12 months

Module	Ops Set Up	Validation Options	Other Explanation
Universal QL	Validation: Apply Baseline and go to Validation Options

Module

Ops Set Up

Validation Options

Other Explanation

Universal QL

Validation: Apply Baseline and go to Validation Options

CLINICAL RATIONALE

Hypoparathyroidism

Hypoparathyroidism is a rare condition where the parathyroid glands do not produce enough hormone, affecting calcium and phosphorus levels in the blood. This can lead to symptoms like muscle weakness, cramps, nervousness, headaches, and muscle spasms. It is often caused by damage or removal of the glands during surgery, autoimmune disorders, or genetic factors. There are approximately 70,000 to 90,000 people with hypoparathyroidism in the United States affecting males and females equally of any age. Parathyroid hormone (PTH), along with vitamin D and calcitonin, regulates calcium levels in the body and bone growth. Hypoparathyroidism can result from the removal or damage to the parathyroid glands, congenital issues, or underlying disorders. It often occurs due to surgical removal of parathyroid tissue for conditions like hyperparathyroidism. Surgery for thyroid cancer or goiter can also lead to hypoparathyroidism by damaging the glands' blood supply or accidental removal during the procedure. This post-surgical condition can be transient or permanent, with cases appearing shortly after surgery or years later.(3)

Activating mutations of the CASR gene can cause autosomal dominant hypocalcemia type 1, leading to hypoparathyroidism by suppressing parathyroid hormone secretion. Symptoms are often mild and may not require treatment unless they worsen. In addition to low blood calcium levels, high urinary calcium levels result from the same gene's role in kidney calcium excretion.(3)

Pseudohypoparathyroidism is a rare disorder where the body resists parathyroid hormone, unlike hypoparathyroidism. Individuals produce enough hormone but can't use it properly. The condition is often hereditary.(3)

In addition to a calcium rich diet, current guidelines recommend conventional therapy of calcium supplementation and active vitamin D analogue therapy. Doses of vitamin D analogues should be given to achieve a 25‐hydroxyvitamin D level in the normal reference range. Additionally, they are titrated to obtain serum calcium levels in the lower half or slightly below the reference interval. The main supplemental form of vitamin D used for individuals with hypoparathyroidism is calcitriol, however, others may be used such as ergocalciferol or cholecalciferol. Ergocalciferol and cholecalciferol have a longer duration of action than calcitriol or alpha calcidol because the former two forms of vitamin D are stored in the body for long times. Long-term therapy with vitamin D and its analogues and metabolites (like calcitriol) carries a risk of serious side effects including calcium deposits accumulating in the kidneys (nephrocalcinosis), the development of kidney stones and, ultimately, improper function of the kidneys if blood tests are not carefully monitored.(3)

PTH replacement therapy, according to current guidelines, should be considered in patients who are not adequately controlled on conventional therapy. Inadequate control is considered to be defined when any one of the following are present despite maximal effort with conventional therapy: symptomatic hypocalcemia, hyperphosphatemia, renal insufficiency, hypercalciuria, or poor quality of life. Individuals with poor compliance, malabsorption, or who are intolerant of large doses of calcium and active vitamin D may also benefit from PTH therapy. Individuals requiring high doses of conventional therapy, such as calcium supplement of > 2 mg/day, or active vitamin D > 2 mcg/day, may also benefit from PTH therapy. Medical management options are limited but may be useful in particular situations. Oral or intravenous bisphosphonates, denosumab, estrogen, and raloxifene should not be routinely used in patients with chronic HypoPT because these antiresorptive agents will cause the already-present low bone turnover to worsen. Cinacalcet should never be used as this prevents residual PTH secretion by the remaining parathyroid glands if present. Thiazide-type diuretics may be used to reduce urinary calcium excretion and prevent hypercalciuria and kidney stones. Individuals with poor compliance, malabsorption or who are intolerant of large doses of calcium and active vitamin D may also benefit from PTH therapy.(4)

Guidelines further recommend the following:(4)

Avoid hyperphosphatemia. Panel members prescribe calcium supplements with meals to serve as phosphate binders, implement a low phosphate diet in adults and judiciously use active vitamin D analogue therapy. Hyperphosphatemia may be associated with an increased incidence of ectopic calcification; however, currently there is no evidence of this in HypoPT.
Treat to normalize plasma magnesium levels. Magnesium supplements can be used as tolerated by the patient.
Consider treating hypercalciuria with thiazide diuretics in conjunction with a low sodium diet with careful monitoring of serum magnesium, potassium, and renal function.

Efficacy

At physiological conditions, palopegteriparatide releases PTH(1-34) to maintain a continuous systemic exposure. Endogenous PTH maintains extracellular calcium and phosphate homeostasis by increasing serum calcium and decreasing serum phosphate. These effects are mediated by stimulating bone turnover to mobilize calcium and phosphate from bone, promoting renal calcium reabsorption and phosphate excretion, and facilitating active vitamin D synthesis, in turn increasing intestinal absorption of calcium and phosphate. Similar to endogenous PTH, PTH(1-34) released from palopegteriparatide exerts these effects through its main receptor, parathyroid hormone 1 receptor (PTH1R), which is highly expressed on osteoblasts, osteocytes, renal tubular cells, and in several other tissues.(1)

Study 1 was conducted in 82 subjects with hypoparathyroidism. Prior to randomization, all subjects underwent an approximate 4-week screening period in which calcium and active vitamin D supplements were adjusted to achieve an albumin-corrected serum calcium concentration between 7.8 and 10.6 mg/dL, a magnesium concentration greater than or equal to 1.3 mg/dL and below the upper limit of the reference range, and a 25(OH) vitamin D concentration between 20 to 80 ng/mL.(1) During the double-blind period, subjects were randomized to either Yorvipath (N = 61) or placebo (N= 21), at a starting dose of 18 mcg/day, co-administered with conventional therapy (calcium and active vitamin D). Randomization was stratified by etiology of hypoparathyroidism (postsurgical vs. all other causes). Study drug and conventional therapy were subsequently titrated according to the albumin-corrected serum calcium levels. The mean age at enrollment was 49 years (range: 19 to 78 years), 78% were female, and 93% were Caucasian. Eighty-five percent (85%) of subjects had hypoparathyroidism acquired from neck surgery. Of the subjects with other etiologies of hypoparathyroidism, 7 (8.5%) subjects had idiopathic disease, 2 had autoimmune polyglandular syndrome type 1 (APS-1), 1 had autosomal dominant hypocalcemia type 1 (ADH1, CaSR mutation), 1 had DiGeorge Syndrome, and 1 had hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome (GATA3 mutation). At baseline, the median duration of hypoparathyroidism was 8.5 years (range 1 to 56 years). Baseline mean albumin-corrected serum calcium was 8.8 mg/dL and 8.6 mg/dL and mean 24-hour urine calcium was 392 mg/day and 329 mg/day for Yorvipath and placebo, respectively. The mean baseline dose of elemental calcium was 1839 mg/day, and the mean baseline doses of active vitamin D were 0.75 mcg/day in calcitriol-treated subjects (n=70), and 2.3 mcg/day in alfacalcidol-treated subjects (n=12).(1)

Efficacy was assessed based on the proportion of subjects who achieved all of the following at Week 26:(1)

Albumin-corrected serum calcium in the normal range (8.3 to 10.6 mg/dL)
Independence from conventional therapy (defined as requiring no active vitamin D and ≤600 mg/day of calcium supplementation, including no use of "as needed" (or prn dosing) since Week 22
No increase in the study drug dose since Week 22
No missing active vitamin D and calcium data since Week 22
Study drug dose of 30 mcg or less once daily during the 26-week treatment period

In the Yorvipath group, 68.9% (42/61) of subjects met the efficacy endpoint at Week 26 compared with 4.8% (1/21) of subjects in the placebo group. The treatment difference was 64.2% (95% confidence interval: 49.5%, 78.8%). When compared with placebo at week 26, significantly more patients treated with palopegteriparatide achieved a normal serum calcium level (8.3 to 10.6 mg/dL) without active vitamin D treatment or elemental calcium supplementation exceeding 600 mg/day [68.9% vs 4.8%; difference, 64.2% (95% CI, 49.5% to 78.8%)]. To meet the composite efficacy outcome, in addition to achieving normocalcemia, individuals also must have been independent of conventional treatments and without a dosage adjustment to palopegteriparatide for the last 4 weeks of the study; patients who received more than 30 mcg/day of palopegteriparatide at any time were considered non-responders.(1)

In the open-label extension study, the proportion of patients randomized to palopegteriparatide meeting the composite efficacy endpoint decreased to 39.3% at weeks 52 and 78. When allowing for upward titration of palopegteriparatide, 64% and 66% achieved normocalcemia without conventional treatments at weeks 52 and 78, respectively.(2)

Yorvipath once daily subcutaneous dosage is individualized. The recommended starting dosage is 18 mcg once daily and is titrated in 3 mcg increments or decrements with the goal of maintaining serum calcium within the normal range without the need for active vitamin D (e.g., calcitriol) or therapeutic calcium doses (elemental calcium >600 mg/day). Calcium supplementation sufficient to meet daily dietary requirements may be continued.(1)

Safety

Yorvipath once daily subcutaneous dosage is individualized. Patients should use only one daily Yorvipath injection. Using two Yorvipath injections to achieve the recommended once daily dosage increases the variability of the total delivered dose which could lead to unintended changes in serum calcium levels. The recommended starting dosage is 18 mcg once daily and is titrated in 3 mcg increments or decrements with the goal of maintaining serum calcium within the normal range without the need for active vitamin D (e.g., calcitriol) or therapeutic calcium doses (elemental calcium >600 mg/day). Calcium supplementation sufficient to meet daily dietary requirements may be continued.(1)

Yorvipath is contraindicated in patients with a severe hypersensitivity to palopegteriparatide or any components of Yorvipath.(1)

REFERENCES

Number

Reference

Yorvipath prescribing information. Ascendis Pharma. August 2024.

Yorvipath. Micromedex (electronic version). Merative; 2024. Accessed September 16, 2024. https://www.micromedexsolutions.com

Hypoparathyroidism - symptoms, causes, treatment | NORD. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/hypoparathyroidism/

Khan AA, Guyatt G, Ali DS, et al. Management of hypoparathyroidism. Journal of Bone and Mineral Research. 2020;37(12):2663-2677. doi:10.1002/jbmr.4716.

Final Module	Target Agent GPI	Target Brand Agent(s)	Target Generic Agent(s)	Strength	Targeted MSC	Targeted NDCs When Exclusions Exist	Final Age Limit	Preferred Status	Effective Date

	3090516000D2	Yorvipath	palopegteriparatide pen-inj	168 MCG/0.56ML ; 294 MCG/0.98ML ; 420 MCG/1.4ML	M ; N ; O ; Y

Wildcard	Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	QL Amount	Dose Form	Days Supply	Duration	Targeted NDCs When Exclusions Exist	Age Limit	Effective Date	Term Date

3090516000D220	Yorvipath	palopegteriparatide pen-inj	168 MCG/0.56ML	2	Pens	28	DAYS
3090516000D230	Yorvipath	palopegteriparatide pen-inj	294 MCG/0.98ML	2	Pens	28	DAYS
3090516000D240	Yorvipath	palopegteriparatide pen-inj	420 MCG/1.4ML	2	Pens	28	DAYS