NATPARA Flashcards
Normal PTH Levels
10-60 pg/mL (normal physiological range)
Normal calcium
8.4-10.6 mg/dL
What is the PDUFA date?
January 24
Positioning
NATPARA is the first and only PTH replacement therapy for hypoparathyroidism that directly treats the condition physiologically giving patients better health today while preventing complications tomorrow
Payer Mix
61% private, 35% public, 4% uninsured (from Vertical Health)
PTH Intestine
PTH stimulates conversion of 25 hydroxy to 1,25 dihydroxy which enhances the absorption of calcium
PTH Kidney
PTH stimulates renal reabsorption of calcium and promotes phosphate excretion.
PTH Bone
PTH stimulates bone resorption which delivers calcium and phosphate into the circulation.
Pharmacokinetics
Peak plasma concentrations Tmax occur within 5 to 30 minutes with a second smaller peak at 1 to 2 hours. Half life was 3.02 and 2.83 hours for the 50 and 100 mcg doses.
Absorption
Absolute bioavailability of 55%.
Distribution
Volume of distribution of 5.35L at steady state.
Metabolized
Clearance is primarily hepatic with a lesser role played by the kidneys.
Excretion
In the liver, most intact PTH is cleaved by cathepsins. In the kidney, most is filtered at the glomerulus.
Tetany
Involuntary contraction of muscle.
Paresthesias
Sensation of tingling, tickling, prickling, pricking, burning.
WW Forecast
$1.3B in 2023
Prevalence
53,000 with 24,500 uncontrolled and 17,500 with an Endo.
Addressable population
53,000 prevalence
24,380 uncontrolled
17,500 seeing an Endo
Specialty Pharmacy
Accredo Express Scripts, CVS Caremark, Walgreens (Diplomat is largest independent)
Number of Endos (SK&A)
5,266 in 2,830 accounts.
3,300 Endo Practices
1,966 Multi-Specialty
REPLACE Number of Patients
124 patients; 84 NATPARA; 40 Placebo
134 patients; 90 NATPARA; 44 Placebo
Hallmarks of the disease
Hypocalcemia, hyperphosphatemia (worsened by active vit D administration) hypercalciuria (worsened by calcium and vit D administration). The 3 H’s.
REPLACE Target Serum Calcium at Optimization
8.0 to 9.0 mg/dL with a minimum of 7.5.
REPLACE List of Secondary Endpoints
Percent change in oral calcium, active vitamin D independence, frequency of hypocalcemia symptoms between wk 16 and 24.
REPLACE Efficacy Serum Calcium Target
> 7.5 mg/dL or baseline and below ULN or 10.6
REPLACE Primary results
55% (46/84) met the primary endpoint vs 3% (1/40) on placebo (in label)
53% (48/90) met the primary endpoint vs 2% (1/44) on placebo.
REPLACE Percent Change in Oral Calcium at Week 24
52% SS reduction vs 7% increase in placebo (not in label)
52% SS reduction vs 6% increase in placebo.
REPLACE patients with symptoms of Hypocalcemia from week 16 to 24
The difference did not reach statistical significance 35% NATPARA vs 38% placebo (not in label)
REPLACE reduction in calcium/phosphate product
SS Mean change decrease from baseline of -5.5 NATPARA vs -0.5 Placebo (not in label)
Baseline NATPARA 39.8 and Placebo 40.8
Week 24 NATPARA 34.8 and Placebo 39.9
REPLACE List of Exploratory Endpoints
Changes in urinary calcium, calcium-phosphate product, bone effects, quality of life.
REPLACE Active Vitamin D Independence
42% (35/84) of patients achieved independence and took <500 mg/day of oral calcium vs 3% (1/40) placebo (on label)
REPLACE Serum Phosphate Results
Serum phosphate levels were significantly decreased from baseline from 4.53mg/dL to 4.03. Placebo was unchanged (off label)
Label: Immunogenicity
Incidence rate of anti-PTH antibodies was 8.6% (3/35) and 5.9% (1/17) in subjects who rec’d subcuateous administration of 50 to 100 mcg NATPARA or placebo once daily for 24 weeks (NEW LABEL)
Label: Immunogenicity across all studies
The immunogenicity incidence rate was 16.1% (14/87). These 14 subjects had low titer anti-bodies and of these, 3 subjects subsequently became antibody negative.
REPLACE How was the titration done?
A pre-specified algorithm vs a flexible one that was used in RACE.
REPLACE Treatment Phase
24 wk treatment with a 12 wk titration phase and 12 wk maintenance phase where Natpara could be reduced but not increased.
Label Adverse Reactions
Paraesthesia (31% vs 25%), hypocalcemia (27% vs 23%), headache (25% vs 23%), hypercalcemia (19% vs 3%), nausea (18% vs 18%).
Phase 1 Phosphate Excretion
24 hour urinary phosphate excretion was increased by 51% (50 mcg) and 60% (100 mcg).
REPLACE Duration
24 weeks treatment and 4 weeks follow up.
REPLACE Vitamin D Reduction at 24 weeks
78% reduction in the NATPARA group vs 30% placebo. Not in the label.
REPLACE Discontinuation
6 (6.6%) on Natpara 7 (15.9%) on placebo.
REPLACE Compliance
Compliance of 80% or higher in 98% of Natpara patients and 96% of placebo. (This meant that 98% of pts administered over 80% of the prescribed dose as measured by returned supplies)
REPLACE Dose Distribution
56% on 100 mcg, 26% on 75mcg, 18% on 50 mcg.
Edited post FDA
REPLACE Baseline Urinary Calcium
Mean urinary calcium exceeded 300 mg/24 hr in both groups. 361 mg/24 hr Natpara and 338 placebo.
Mean urinary calcium exceeded 300 mg/24 hr in both groups. 354 mg/24 hr Natpara and 345 placebo.
REPLACE Bone Data
Bone turnover markers were in the lower part of normal range and increased BMD at baseline confirmed the presence of adynamic bone disease. After 24 wks of treatment there was a marked increase in all bone turnover markers and a mean decrease in BMD in the hip which was not significant at the lumbar spine and the distal third of the radius. There was no increase in BTM markers and a slight increase in BMD in the placebo group.
REPLACE Bone Marker Results
Increased CTX a resorption marker and BSAP a formation marker.
RACE Study Design
12 month open label study extension study
REPLACE Serious Adverse Events SAEs
SAEs were balanced with 7 events in 5(6%) NATPARA patients and 3 events in 2(5%)on placebo.
NATPARA included: back pain, cerebrovascular accident, diarrhea, diverticulitis, erysipelas, hypercalcemia, vomiting.
REPLACE Hypercalciuria Shifts
At baseline 42 (57%) patients in the NATPARA arm had >300mg/day while at week 24, 25(34%) patients. Placebo went from 16(48%) to 13(39%).
RACE Titration
It was a flexible titration schedule where physicians could increase or decrease the NATPARA dose at any time. Patients were started on the 50 mcg if there serum calcium was less than 9.5. As a result 46/49 started on the 50.
RACE Primary Endpoint
Reduction in oral calcium or an oral calcium dose of 7.5mg/dL or baseline
RACE efficacy outcome measures
> 50% reduction in oral calcium or dose 50% reduction in oral active vitamin D or calcitriol dose baseline and <ULN
RACE sources
Of the 49 patients, 10 came from REPLACE and 39 came directly from RELAY.
RACE Results
Patients achieved a 60% response at 1 yr.
RACE Open Label Long Term Study Number of Patients
49 patients with 44/49 retained at two years.
53 patients with 51/53 retained at one year.
RACE Calcium/Phosphate product at two years
43 at baseline and 35 at two year (week 104)
RACE Responders based on RACE criteria.
74% (36/49) responders vs 27% (13/49) non-responders (based on the RACE poster at AACE 2014)
RACE Retention at 2 Years
38 of 49 patients completed two years
RACE Serum Phosphate at 2 Years
4.8 at baseline and 4.2 at year two.
RACE Dose Distribution
100 mcg 57%, 75 mcg 15%, 50 mcg 26%, 25 mcg 2%
RELAY Study Design
8 week study with the 25 mcg and 50 mcg doses with 47 patients.
RELAY Study Length and Number of Patients
25 and 50 mcg study for 8 wks and 47 patients.
RELAY Results
At week 8, 4/23 (18%) in the 25 mcg and 6/24 (25%) in the 50 mcg groups met the primary composite endpoint.
REPEAT Overview
24 week open label extension study in Hungary with 24 patients
PARADOX Top Physical Symptoms
Fatigue, muscle pain/cramping, paresthesia, tetany, joint/bone pain.
PARADOX Symptom Types
Physical, Emotional, Cognitive
PARADOX Co-morbid Conditions
Heart arrhythmia, kidney stones, bone abnormalities.
PARADOX Number of Symptoms
71% experienced greater than 10 symptoms, 19% between 4 to 10.
PARADOX Co-Morbid Conditions
Heart arrhythmias, kidney stones, bone abnormalites.
PARADOX Emotional Symptoms
Anxiety, sadness, sensitive, misunderstood, hyperirritability.
PARADOX Cognitive Symptoms
Brain fog, focus, forgetfulness, sleep disturbance.
PARADOX Mood Disorder Medications
Over 1/3 of patients were taking antidepressants, antianxiety or medications to improve concentration.
Exclusivity for Biologics
U.S. Exclusivity 12 yrs post approval
Diuretics
Diuretics, such as hydrochlorothiazide .
Medication Guide: Symptoms of hypercalcemia
Tell your doctor right away about any of these symptoms of high blood calcium: Nausea and vomiting, Loss of appetite, Being very thirsty, Passing urine often,Constipation or belly pain, Weak muscles, Muscle and joint aches, Being confused, Feeling tired or having no energy
Distribution Vendors
Vetter cartridge, Haselmeier pen, Duoject mixing device, Sharp packaging, ICS 3PL.
Rolcaltrol dose
0.25 and 0.50 mcg
Label: Refrigeration Temperature
Refrigerate at 36 to 46°F (2-8°C). Do not freeze.
Label: Osteosarcoma
Prescribe NATPARA only to patients who cannot be well-controlled on calcium and active Vitamin D. Avoid use of NATPARA in patients who are at increased baseline risk for osteosarcoma.
Label: Adverse reactions (highlights section)
The most common adverse reactions associated with NATPARA and occurring in greater than 15% of individuals were: paresthesia, hypocalcemia, headache, hypercalcemia, nausea and hypoesthesia.
Label: Warnings and Precautions (risks)
Prescribe NATPARA only to patients who cannot be well-controlled on calcium and active vitamin D. Severe hypercalcemia during initiation monitor serum calcium when starting or adjusting dose. Severe hypocalcemia can occur with interruption or discontinuation. Digoxin toxicity is increased with hypercalcemia.
Label: Injection Site reactions
Injection site reactions have been reported in the placebo-controlled study in 10.0% (9/90) in the Natpara-treated patients and in 15.9% (7/44) in the placebo group.
Label: Dosing Guidelines
The dose of NATPARA should be individualized based on total serum calcium and 24 hour urinary excretion. The optimal dose is the minimum dose required to prevent both hypocalcemia and hypercalciuria.
Label: Needle
31 gauge 8 mm BD needle
Label: Titration
Based on calcemic response, NATPARA can be titrated at approx 2 to 4 week intervals upward to doses of 75 mcg and then 100.
Label: Indication Statement
NATPARA is a parathyroid hormone indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathryoidism.
Label: monitoring to assess safety
When initiating or changing dose, serum calcium levels should be measured within 7 days
What fragment is teriparatide?
N-terminal fragment
Label: Drug interactions
Digoxin: Monitor serum calcium more frequently when using NATPARA in patients receiving digoxin.
Label: Injection Volume
71.4 micro liters mL per dose
What PTH is Radius developing?
PTHrP or PTH-related Protein
What strain of rats was used in the teriparatide rat study?
Fischer 344 rats were tested at all dose levels 5,30,75 mcg/kg. A more recent study in Japan itch Sprague-Dawley strain of rats also described a dose- and time- dependent induction of osteosarcoma following treatment for 2 years. However lower doses were evaluated 1.5, 4.5, 13.6, mcg/kg. these authors identified a 4.5 dose as non-carcinogenic. A 5mcg dose resulted in a 5-7 incidence (Vahle et al, 2002)
NATPARA rat study
A Fischer 344 rat study also suggested osteosarcoma but unlike teriparatide an increase in osteosarcoma was not observed at the lowest dose. (NOEL)
What are the terminal regions for 1-84
N-terminal (teriparatide) and C-terminal.
What doses were used in the NATPARA carc study?
Daily subcutaneous injection of 0, 10, 50 and 100 mcg/hg/day for 2 years. Corresponding AUC values averaged 4.6 to 66 times higher than PM women taking the 100 mcg dose. (Label says 3 times to 71)
Primary determinants of osteosarcoma incidence.
Dose and duration of treatment.(Vahle et al 2004)
What is MID in quality of life research?
Minimal importance difference…
Signs
Trousseau sign:
A blood pressure cuff is inflated to a pressure above the patients systolic level
Chvostek’s sign
Shows hyper excitability (tetany) of the facial nerve in Hypocalcemia by stimulation of the facial nerve.
ICD-9 code
252.1
Endocrinologists also titrate…
Testosterone and thyroid hormone also insulin…
OPDP
Office of Prescription Drug Promotion
APLB
Advertising and Promotion Labeling Branch is the OPDP in CBER
Normal 1,25 di Hydroxy vitamin D levels
Females 18-78pg/mL
Males 18-64pg/mL
Hypoparathyroidism is characterized by…
Abnormal mineral homeostasis including hypocalcemia and hyperphosphatemia
ICD 10 Code
E20 Hypoparathyroidism
Normal serum creatinine
0.6 to 1.2 mg/dL
Label: Limitations of use
Because the potential risk of osteosarcoma, NATPARA is recommended only for patients who cannot be well-controlled on calcium and active forms of vitamin D alone.
Label: Black Box
In male and female rats, parathyroid hormone caused an increase in the incidence of osteosarcoma (a malignant bone tumor). The occurance of osteosarcoma was dependent on parathyroid hormone dose and treatment duration.
Label: Black Box Exposure
This effect was observed at parathyroid hormone exposure levels ranging from 3 to 71 times the exposure levels in humans receiving a 100 mcg dose of NATPARA.
Label: Black Box Well-Controlled
Because the potential risk of osteosarcoma, use NATPARA only in patients who cannot be well-controlled on calcium and active forms of vitamin D alone and for whom the potential benefits are considered to outweigh this potential risk.
Label: Before initiating NATPARA (vitamin D)
Ensure 25-hydroxyvitamin D stores are sufficient. If insufficient replace to sufficient levels per standard of care.
Label: Initiating NATPARA
1) 50 mcg; 2) decrease active vitamin D by 50%, 3) maintain oral calcium, 4) measure serum calcium within 3 to 7 days 5) Adjust active vitamin D or oral calcium based on serum calcium value and clinical assessment
Label: Initiating NATPARA Adjustment Table
1) Greater than 9 mg/dL and above the ULN decrease or discontinue active Vitamin D and or oral calcium 2) Greater than 9 mg/dL and below the ULN decrease or discontinue active Vitamin D and decrease oral calcium if active D is discontinued 3) Less than or equal to 9 mg/dL and above the lower limit of normal no change 4) Lower than the lower limit of normal…increase active vitamin D and/or oral calcium.
Label: Adjunct Language
If the drug is used for an indication only in conjunction with a primary mode of therapy (i.e., diet, surgery, behavior changes, or some other drug), a statement that the drug is indicated as an adjunct to that mode of therapy. (CFR Title 21 Sec 201.57 (i) (A)
Label: ETASU
Elements to Assure Safe Use
Label: ETASU Healthcare Providers
Healthcare providers who prescribe NATPARA are specifically certified to: review the PI, the REMS introduction, complete the training module, and knowledge assessment, enroll in the REMS, Review the Patient Brochure with the patient, complete the patient/prescriber acknowledgement form.
Label: ETASU NPS will…
1) Ensure that healthcare providers are certified 2) ensure the certification process can be completed 3) Ensure prescribers are notified when they are certified 4) maintain a validated secure database of prescribers who are certified 5) Provide all the documents 6) Ensure the REMS materials are available on the REMS website
Label: REMS Documents
1) REMS program and introduction 2) Training Module for Prescribers 3) Prescriber Enrollment Form 4) Patient Brochure 5) Patient/Prescriber Acknowledgement Form
