Transcript Committee papers Clinical slides

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
1
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.
2
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
3
Treatment pathway – company
submission
Treatment initiated in people with uncontrolled PTH (>300 pg/ml))
Current
Initial treatment
Anticipated position
PBVD
Etelcalcetide
+PBVD
Cinacalcet +
PBVD
Etelcalcetide
+PBVD
Refractory SHPT
PBVD
Post medical
therapy
Surgery
Key: PBVD, phosphate binders + vitamin D
4
Decision problem
Final scope issued by NICE
Population
People with SHPT with chronic kidney disease, receiving
haemodialysis
Intervention
Etelcalcetide
Comparators Established clinical practice without calcimimetic (dietary
modification to restrict phosphate, phosphate binders,
analogues of vitamin D)
For people with refractory SHPT: Cinacalcet
5
Etelcalcetide – description of the
technology
Marketing
authorisation
Pharmaceutical
formulation
Acquisition cost
(excl. VAT) *
Method of
administration
Doses
Treatment of secondary hyperparathyroidism (SHPT)
in adult patients with chronic kidney disease (CKD)
on haemodialysis therapy
2.5 mg, 5 mg, 10 mg solution for injection
(single-use glass vials).
XXXXXXXXXXXXXXXXXX.
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.
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
6
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.
7
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.
8
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.”
9
Clinical trial evidence – etelcalcetide
versus placebo
NCT20120229 (n=508)
NCT20120230 (n=515)
Adults with CKD receiving haemodialysis 3 times per week for ≥ 3 months
Stable calcium (≥ 8.3 mg/dL or 2.075 mmol/L) and PTH > 400 pg/mL (42.4 pmol/L)
R A N D O M I S E D
IV Etelcalcetide*
1:1
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 20-27.
*Both groups could receive active vitamin D, phosphate binders, and calcium supplements 10
Pooled results for studies 20120229
and 20120230
Pooled
Placebo (N = 514) Etelcalcetide (N = 509)
Primary outcome
Achievement of a > 30% reduction
in mean PTH from baseline during
EAP, n (%)
Odds ratioa (95% CI)
P value
Secondary outcome
Achievement of mean PTH ≤
300 pg/mL during EAP, n (%)
Odds ratioa (95% CI)
P value
46 (8.9%)
380 (74.7%)
31.60 (21.59, 46.25)
<0.001
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.
11
Kaplan-Meier – time to 1st occurrence
of PTH >30% reduction vs baseline
(6-month placebo-controlled pooled dataset – full analysis
set)
12
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
13
Summary of results NCT20120360
Cinacalcet
(N=343)
Etelcalcetide
(N=340)
63.9%
77.9%
Primary Endpoint (Non-inferiority)
> 30% reduction in mean PTH from
baseline (%)
Stratified treatment difference
-10.48% (95% CI, -17.45, -3.51)
Key Secondary Endpoints (Superiority)
> 50% reduction in mean PTH from
baseline during EAP, n (%)
> 30% 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
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
14
Kaplan-Meier – time to 1st occurrence
of PTH >30% reduction vs baseline
NCT20120360
Key:
AMG 416, etelcalcetide; PTH, parathyroid hormone
15
Subgroups
• Pre-specified subgroup analyses
• Studies 20120229, 20120230 and 20120360
– 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
16
Long term efficacy Open-label
extension study 20120231 (OLE1)
OLE1 20120231 (n=891) Multicentre single-arm, 52-week extension study to
parent studies 20120229, 20120230, and 20120359
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
17
Health-related quality of life
• Collected as part of study 20120360 (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
18
Adverse events in etelcalcetide RCTs
• fdfd
Total placebo-controlled
studies
Placebo
Etelcalcetide
(n=513)
(n=503)
All treatment
emergent 410 (79.9) 461 (91.7)
AEs –n (%)
SAEs –n (%) 149 (29.0) 130 (25.8)
AEs leading
to drug
13 (2.5)
9 (1.8)
withdrawal –n
(%)
Fatal AEs –n
15 (2.9)
11 (2.2)
(%)
Study 20120360
Cinacalcet Etelcalcetide
(n=341)
(n=338)
307 (90.0) 314 (92.9)
93 (27.3)
85 (25.1)
16 (4.7)
19 (5.6)
6 (1.8)
9 (2.7)
AEs=adverse events; SAE=serious adverse events
XXXXXXXXXXXXXXXXXXXXXXXXXXXX
19
Adverse events
(≥ 5% of etelcalcetide group and ≥ 1% difference from
placebo/cinacalcet)
Total placebo-controlled studies
Preferred term
Blood calcium
decreased
(asymptomatic)a
Muscle spasms
Diarrhoea
Nausea
Vomiting
Headache
Hypocalcaemia
(symptomatic)b
Hypotension
Study 20120360
Placebo, % Etelcalcetide % Cinacalcet, % Etelcalcetide
(N = 513)
(N = 503)
(N = 341)
% (N = 338)
10.1
63.8
59.8
68.9
6.6
8.6
6.2
5.1
6.0
0.2
5.1
11.5
10.7
10.7
8.9
7.6
7.0
6.0
5.9
10.3
22.6
13.8
7.0
2.3
2.9
6.5
6.2
18.3
13.3
6.5
5.0
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)
20
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
21
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 –
63.6 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)
22
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.
23