1. Etelcalcetide for treating of secondary hyperparathyroidism [ID908]
Slides for public [AIC] [CIC]
Etelcalcetide for treating of secondary hyperparathyroidism [ID908]
1st Committee meeting
8th February 2017
Committee A
Lead team: Justin Daniels, Pam Rees, Ellen Rule
ERG: Southampton Health Technology Assessments Centre (SHTAC)
NICE technical team: Christian Griffiths, Joanna Richardson, Janet Robertson

2. Key issues for consideration
How are patients treated in clinical practice, is NICE guidance on cinacalcet applied?
Which patients would receive this treatment in clinical practice?
Surrogate biochemical outcomes used in the clinical trials of etelcalcetide.
Is the primary outcome of 30% reduction in PTH level and/or a target of 300 pg/ml (or less) appropriate/generalisable to UK clinical practice?
ERG highlighted that the relative efficacy of etelcalcetide and cinacalcet in patients with refractory SHPT unclear.

3. Secondary hyperparathyroidism (SHPT)
SHPT is a serious and common complication in patients with chronic kidney disease (CKD) on haemodialysis
persistent elevations in levels of biochemical markers of mineral metabolism, including parathyroid hormone (PTH), calcium, and phosphate
if inadequately controlled it is associated with vascular calcification and bone disease (increases risk of cardiovascular events, fractures and death) and reduced quality of life
around 9,000 of the 21,000 patients on haemodialysis are estimated to be affected in England
aim of treatment is to maintain parathyroid hormone, calcium and phosphorus levels within acceptable target ranges

4. Treatment pathway – company submission
Treatment initiated in people with uncontrolled PTH (>300 pg/ml))
Current
Anticipated position
PBVD
Etelcalcetide +PBVD
Initial treatment
Cinacalcet + PBVD
Etelcalcetide +PBVD
Refractory SHPT
PBVD
Post medical therapy
Surgery
Key: PBVD, phosphate binders + vitamin D

5. Decision problem Final scope issued by NICE Population
Final scope issued by NICE
Population
People with SHPT with chronic kidney disease, receiving haemodialysis
Intervention
Etelcalcetide
Comparators
For people with refractory SHPT: Cinacalcet

6. Etelcalcetide – description of the technology
Marketing authorisation
Treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) on haemodialysis therapy
Pharmaceutical formulation
2.5 mg, 5 mg, 10 mg solution for injection
(single-use glass vials).
Acquisition cost (excl. VAT) *
XXXXXXXXXXXXXXXXXX.
Method of administration
Administered by bolus injection into the venous line of the dialysis circuit at the end of routine haemodialysis treatment during rinse back or intravenously after rinse back.
Doses
Starting dose is 5 mg 3 times per week during routine haemodialysis sessions. Doses should be titrated up or down so that doses are individualised between 2.5 mg and 15 mg 3 times per week. Treatment is anticipated to be ongoing

7. Patient perspective (British Kidney Association; Kidney Research UK)
Secondary hyperparathyroidism affects both mental and physical health.
Symptoms include bone pain, stomach pain, fatigue, confusion, nausea and depression leading to mobility problems, sleeplessness and reduced quality of life.
Current NHS treatments do not work for some patients.
Drug regimens are burdensome. Surgery carries extra risk and isn’t always successful.
Patients want relief from symptoms, better control of their condition and for different treatment options to be made available.

8. Patient perspective
Patients and carers have indicated that they expect Etelcalcetide to have the following advantages:
Reduction of pain; Increased mobility; Less need for surgery.
Patients dialysing in hospital do not have the worry of taking another oral medication, as for the first time a calcimimetic will be administered through IV, thus reducing the pill burden.
However, people who are on home dialysis are less likely to want to attend hospital 3 times a week to receive this treatment.

9. Equality Issues Raised by the British Kidney Association:
“There are kidney patients who are or may be given current treatments off-label, as they are not on dialysis. They may be post-transplant or pre-dialysis and still have secondary PTH and be symptomatic. We would not wish new guidance to impact on this flexibility. There may also be patients with PTH under 800 who benefit from treatment. New treatments should continue for these patients as well.”

10. Clinical trial evidence – etelcalcetide versus placebo
NCT (n=508)
NCT (n=515)
Adults with CKD receiving haemodialysis 3 times per week for ≥ 3 months
Stable calcium (≥ 8.3 mg/dL or mmol/L) and PTH > 400 pg/mL (42.4 pmol/L)
R A N D O M I S E D : 1
IV Etelcalcetide*
IV Placebo*
Treatment for 26 weeks + 30 day follow up period
Primary outcome:
proportion of people with >30% reduction from baseline in PTH levels (assessed during Efficacy Assessment Phase wks 20-27)
Secondary outcomes:
Proportion of people with predialysis PTH ≤ 300 pg/mL in wks 20-27
% change from baseline in predialysis PTH, cCa, cCa x P and P in wks
*Both groups could receive active vitamin D, phosphate binders, and calcium supplements

11. Pooled results for studies 20120229 and 20120230
Placebo
(N = 514)
Etelcalcetide
(N = 509)
Primary outcome
Achievement of a > 30% reduction in mean PTH from baseline during EAP, n (%)
46 (8.9%)
380 (74.7%)
Odds ratioa (95% CI)
31.60 (21.59, 46.25)
P value
<0.001
Secondary outcome
Achievement of mean PTH ≤ 300 pg/mL during EAP, n (%)
25 (4.9%)
262 (51.5%)
27.02 (16.62, 43.93)
<0.001 
CI, confidence interval; EAP, Efficacy Assessment Phase (weeks 20-27); n, number of patients with observed data; P, phosphate; PTH, parathyroid hormone; SE, standard error
a Cochran-Mantel-Haenszel (CMH) stratified odds ratio (etelcalcetide:placebo). P value from CMH test.

12. Kaplan-Meier – time to 1st occurrence of PTH >30% reduction vs baseline
(6-month placebo-controlled pooled dataset – full analysis set)
ID908 Etelcalcetide for treating secondary hyperparathyroidism – premeeting briefing

13. Etelcalcetide vs cinacalcet NCT20120360
Population
Adults with CKD receiving haemodialysis 3 times per week for ≥ 3 months
Stable calcium ≥ 8.3 mg/dL (2.1 mmol/L) and PTH levels of > 500 pg/mL (53 pmol/L)
Primary outcome:
Non-inferiority vs cincalcet for lowering PTH levels by >30% from baseline (assessed during EAP at wks 20-27)
Secondary outcome (sequential test for superiority):
Proportion of people with >50% reduction in PTH,
Proportion of people with >30% reduction in PTH

14. Summary of results NCT20120360 Cinacalcet (N=343) (N=340)
Cinacalcet
(N=343)
(N=340)
Primary Endpoint (Non-inferiority)  
> 30% reduction in mean PTH from baseline (%)
63.9%
77.9%
-10.48% (95% CI, , -3.51)
Key Secondary Endpoints (Superiority) 
> 50% reduction in mean PTH from baseline during EAP, n (%)
40.2%
52.4%
Odds ratio 1.65 (95% CI, 1.21, 2.23),
p-value = 0.001
> 30% reduction in mean PTH from baseline during EAP, n (%)
57.7%
68.2%
Odds ratio 1.59 (95% CI, 1.16, 2.17)
p-value = 0.004
CI, confidence interval; EAP, Efficacy Assessment Phase (weeks 20-27); n, number of patients with observed data; P, phosphate; PTH, parathyroid hormone; SE, standard error

15. Kaplan-Meier – time to 1st occurrence of PTH >30% reduction vs baseline
NCT
Key:
AMG 416, etelcalcetide; PTH, parathyroid hormone

16. Subgroups Pre-specified subgroup analyses
Studies , and
Based on demographics, severity of SHPT and prior use of cinacalcet
Company state that superior efficacy of etelcalcetide over the comparators was consistent across all pre-defined patient subgroups
ERG comments
Agree that there were no significant differences in efficacy between the whole trial populations and the pre-specified subgroups
Caution required as the subgroup analyses were not statistically powered to detect treatment differences

17. Long term efficacy Open-label extension study 20120231 (OLE1)
OLE (n=891) Multicentre single-arm, 52-week extension study to parent studies , , and
Results
>30% reduction from baseline PTH (%, 95%CI)
PTH <300pg/mL
(%, 95%CI)
EAP6
68.1% (64.6% to 71.4%)
55.5% (52.0% to 59.1%)
EAP12
67.5% (63.8%, to71.0%)
56.4% (52.6% to 60.0%)
EAP
67.7% (64.2% to 70.9%)
57.3% (53.8% to 60.7%)
EAP= efficacy assessment phase; IV = intravenous;
Company stated that OLE1 showed continued reductions in PTH, calcium and phosphorus are observed, with long-term treatment
Note: 300 pg/mL is equivalent to 31.8 pmol/L

18. Health-related quality of life
Collected as part of study (etelcalcetide vs cinacalcet)
Measured using KDQOL-36 (has 5 sub-scales ….
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX performed)
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
The company did not use these results in the economic base case analysis and no HRQoL benefit is assumed for calcimimetic treatment in the base case (although a scenario analyses explored this)
ERG agrees that XXXXXXXXXXXXXXX HRQoL scores from the KDQOL-36 results, the company’s approach was reasonable
ID908 Etelcalcetide for treating secondary hyperparathyroidism – premeeting briefing

19. Adverse events in etelcalcetide RCTs
fdfd
Total placebo-controlled studies
Study
Placebo
(n=513)
Etelcalcetide
(n=503)
Cinacalcet
(n=341)
(n=338)
All treatment emergent AEs –n (%)
410 (79.9)
461 (91.7)
307 (90.0)
314 (92.9)
SAEs –n (%)
149 (29.0)
130 (25.8)
93 (27.3)
85 (25.1)
AEs leading to drug withdrawal –n (%)
13 (2.5)
9 (1.8)
16 (4.7)
19 (5.6)
Fatal AEs –n (%)
15 (2.9)
11 (2.2)
6 (1.8)
9 (2.7)
AEs=adverse events; SAE=serious adverse events
XXXXXXXXXXXXXXXXXXXXXXXXXXXX
ID908 Etelcalcetide for treating secondary hyperparathyroidism – premeeting briefing

20. Total placebo-controlled studies
Adverse events (≥ 5% of etelcalcetide group and ≥ 1% difference from placebo/cinacalcet)
Total placebo-controlled studies
Study
Preferred term
Placebo, %
(N = 513)
Etelcalcetide % (N = 503)
Cinacalcet, %
(N = 341)
Etelcalcetide % (N = 338)
Blood calcium decreased (asymptomatic)a
10.1
63.8
59.8
68.9
Muscle spasms
6.6
11.5
5.9
6.5
Diarrhoea
8.6
10.7
10.3
6.2
Nausea
22.6
18.3
Vomiting
5.1
8.9
13.8
13.3
Headache
6.0
7.6
7.0
Hypocalcaemia (symptomatic)b
0.2
2.3
5.0
Hypotension
2.9
6.8
AE, adverse event
a asymptomatic reduction in serum corrected calcium below 7.5 mg/dL (1.875 mmol/L) or asymptomatic reduction in serum corrected calcium between 7.5 and < 8.3 mg/dL (1.875 to <2.075 mmol/L) requiring medical management or deemed clinically significant by the investigator
b symptomatic reduction in serum corrected calcium < 8.3 mg/dL (2.075 mmol/L)

21. ERG comments clinical effectiveness (1)
Good quality trials although unclear if double-blinding was preserved, some results not ITT (risk of attrition bias)
People included in trials were generally representative of those seen in practice in the UK
Submission may not provide evidence about the efficacy of etelcalcetide vs cinacalcet in refractory SHPT population
Trial included broad population of patients with SHPT, rather than those with refractory SHPT
Trials did not measure the longer-term clinically relevant outcomes specified in the scope

22. ERG comments clinical effectiveness (2)
Drug doses in the trials titrated to a PTH target of <300 pg/mL (31.8 pmol/L)
ERG suggest that in practice 130 – 600 pg/mL (13.8 – pmol/L) would be acceptable depending on Ca and P parameters
Target used in trials did not include a lower range cut-off, therefore some at risk of PTH over-suppression (could impact longer term outcomes and cost effectiveness)

23. Key issues for consideration
How are patients treated in clinical practice, is NICE guidance on cinacalcet applied?
Which patients would receive this treatment in clinical practice?
Surrogate biochemical outcomes used in the clinical trials of etelcalcetide.
Is the primary outcome of 30% reduction in PTH level and/or a target of 300 pg/ml (or less) appropriate/generalisable to UK clinical practice?
ERG highlighted that the relative efficacy of etelcalcetide and cinacalcet in patients with refractory SHPT unclear.