multiplesclerosis:current&emerging treatments personalized strategies dr. suhail al-shammri...
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MultipleSclerosis:Current&Emerging Treatments Personalized Strategies
Dr. Suhail Al-ShammriAssociate Professor& Head Division of Neurology, Mubark Al Kabir Hospital
Overview
• The diagnostic criteria of multiple sclerosis( MS)
• Classification of idiopathic inflammatory demyelinating disorders
• Clinical course of MS• Current and emerging MS therapies
Idiopathic CNS Demyelinating Diseases
• Typical CNS demyelinating Diseases:– Radiologically isolated syndrome (RIS)– Clinically isolated syndrome (CIS)– Relapsing –remitting multiple sclerosis (RRMS)– Secondary progressive MS (SPMS)– Primary progressive MS (PPMS)
Atypical CNS Demyelinating Diseases
• Acute disseminated encephalomyelitis (ADEM)
• Acute hemorrhagic leukoencephalitis (AHLE)• Tumefactive MS• Balo’s concentric sclerosis• Marburg
Radiologically Isolated Syndrome (RIS)
– No typical symptoms of CNS demyelination– No formally accepted diagnostic criteria– MRI : Typical MS lesions– CSF abnormalities– Clinical MS Attack:– 35% over 5 years– MRI progression:
• 59-83% in 2 years
– DMT is initiated only in case
of clinical/MRI progressionOkuda DT et al, Neurology2011:76()8, 686-692
Diagnostic Criteria for MS
• An effort to make the diagnostic process more objective• Formal criteria were devised to codify the typical MS
features into indisputable diagnostic criteria• The primary driving force is identification of patients for
research trials. ”a consensus on which patient has MS”• Criteria are designed to be specific• There are patients with MS who do not meet those
criteria• “A patient has MS when an an experienced neurologist
says he or she has MS”
Schumacher Criteria- 1965
• Onset of symptoms between 10 and 50 years• Objective abnormalities on neurologic examination• The signs and symptoms indicate CNS white
matter damage• The lesions are disseminated in space ( 2 or more
separate lesions)• The lesions are disseminated in time (2 attacks at
least 1 month apart)• No better explanation
The Mc Donald Criteria
• ‘the world consists of three types of person: those who have multiple sclerosis; those who do not; and those who might’. Polman CH et al,Ann Neurology, 2001
Episodes from history
Objective clinical signs Additional data needed from MRI or clinical follow up
2 attacks2 attacks1 attack1 attack
Progressive course over 1 year
2 lesions1 lesion2 lesions1 lesion
NoneDISDITBoth DIS&DIT
DIS demonstrated by 2 :1- MRI brain2. MRI cord3. CSF oligoclonal bands
Dissemination in Space
Polman CH et al, Ann Neurol 2011; 69:292–302
Dissemination in Time
Polman CH et al, Ann Neurol 2011; 69:292–302
MRI Brain DIS
MRI Cervical spine: DIS
MRI Brain T2WI
MRI Brain Enhanced T1WI:DIT
CASE
• On 18/3/08 patient complained of ocular pain on moving the left eye with blurred vision.
• 2 days later she developed left frontal headache. • Seen by the ophthalmologist who diagnosed her as
optic neuritis and advised to be on neurobion.• She had several attacks of Rt. Upper limb heaviness
in the last 2 years, each was lasting for a week. • Her cousin has MS .
CASE : Examination
• Her vision was 20/200 in the left eye and 20/40 in the right eye. There was a central scotoma, and red and blue colors were less intense in the left eye.
• RAPD on the left• Left fundus: disc is congested and swollen.• Central Scotoma• Treated with pulse IV methylprednisolone for 3 days
and improved followed by short prednisolone taper
Case 1: Fundoscopy
Case : MRI Brain
Case 2: MRI Spine
Case : CSF Oligoclonal bands
Clinically Isolated Syndrome (CIS)
• Single characteristic clinical attack of CNS demyelination:– Optic neuritis– Acute partial myelitis– Brain stem syndrome– Cortical
•
Clinically Isolated Syndrome (CIS)
• MRI:– Low risk: 1 or no other asymptomatic brain lesion– High risk: 2 or > asymptomatic lesions
• Treatment approved for high risk patients– IFN-B, GA reduces second attack: ARR 15%
Baseline MRI and Risk of CDMS for Monofocal onset CIS (BENEFIT Placebo N=93)
CHAMPS CHAMPS2 ETOMS BENEFIT25
Unifocal/multifocal/No pt
Unifocal/383
Unifocal Unifocal+multifocal/309
Unifocal/487
IFN-B Avonex+Pulse MP
Avonex Rebif Betasron
Dose/ 30µg/im/weekly 30µg/IM/weekly
22µg/SC/Weekly
250µg/SC/EOD
Duration/years 3 5 2 2
Pre-MRI T2 load 2or> 4 or > 2 OR>
%CDMS,P value 35 VS50, p=0.002
36 VS 49,P=0.03
34 VS 45P=0.047
28 VS 45 (69%/85%
+MRI effect Yes Yes, P=0.001
Yes,P=0.001
TOPIC
Primary end point:Conversion to CDMS (as defined by the occurrence of a relapse)
Key inclusion criteria:• Patients 18 to 55 years of age with a first acute/subacute neurologic event consistent with demyelination.• MS symptom onset within 90 days of randomization.• Screening MRI scan with 2 T2 lesions 3 mM diameter that are characteristic of MS.
Screened(N=846)
Placebo(n=197)
Teriflunomide 7 mg (n=205)R Long-Term Extension
Teriflunomide 14 mg(n=216)
108-Week Treatment Phase
Randomizedn=618
Miller A. Plattform presentation ECTRIMS 2013
Primary / Key Secondary Endpoint
Primary Endpoint: Time to Clinically Definite MS
(CDMS)
43%
Safety / Tolerability:Adverse events observed in the trial were consistent with previous clinical trials with Aubagio.
Miller A. Plattform presentation ECTRIMS 2013
21%p=0.43
66
59%p=0.000
8
Gd-enhancing T1 Lesions)
CIS: When To Initiate Therapy?
• Patients with normal MRI or with fewer than 2 – Low risk of developing early clinical attacks– Clinical and MRI monitoring – Without immediately commencing immunotherapy (DMT)
• Those with abnormal MRI with2or> lesions consistent with MS or with evidence of intrathecal synthesis of antibodies should be considered for DMT,
• Patients with atypical clinical or MRI presentation require further diagnostic evaluation.
Relapsing-Remitting MS
• Subacute repeated onset of CNS dysfunction with resolution ( sometimes incomplete , over days to weeks)
• Revised McDonald criteria• MRI: Periventricular, brainstem, juxtacortical
prominent T2, often Gad enhancing lesions, T1 hypointense (black holes)
• Treatment: Interferon-B, Glatiramer acetate, natalizumab, mitoxantrone
Features Consistent With MS
• Relapses and remissions• Age Onset between ages 15 and 50 • Optic neuritis • Lhermitte's sign• Internuclear ophthalmoplegia • Fatigue• Uhthoff's phenomenon
Features Inconsistent With MS
• Steady progression • Onset before age 10 or after age 50 • Cortical deficits such as aphasia, apraxia, alexia,
neglect • Rigidity, sustained dystonia • Convulsions • Early dementia • Deficit developing within minutes
Secondary Progressive MS
• Majority of RRMS many years following onset• Progressive impairment (spastic gait
disturbance) between or in absence of attacks• No clear effect of DMT without ongoing attacks
or inflammation• Role of DMTs in SPMS patients:
– with ongoing relapses – Substantial ongoing accrual on new MRI
inflammatory lesions
Primary Progressive MS
• Presents with progressive myelopathic gait, cerebellar ataxia or cognitive impairment without clear history of any clinical attacks
• Clinical progression must be for at least 1 year and accompanied by a combinstion of brain&spinal abnormalities and/or CSF anormalities consistent with MS
• Lack of clinical attacks/ relative paucity of MRI lesions
• No approved DMTs
Multiple Sclerosis (MS)
• Multiple Sclerosis is the commonest disabling neurological condition to afflict young adults
• MS is an autoimmune disease triggered by environmental agents acting in a genetically susceptible people
• Auto-aggresive autoimmune attack on the myelin sheath and other components of CNS
• Current&emerging DMTs are based in the above paradigm
• Is MS a primary neurodegenerative disease
MS: Pathology
MS: Pathology
Demographic Characteristics of Multiple
Sclerosis in Kuwait
Mean Curre
nt age
Mean age at p
rese
ntation
Mean duration of D
isease
0
5
10
15
20
25
30
35
Years
SD±5.4
SD±9.3
Total recruited patients in study: 195
Gender Distribution N(M/F): 195(76/119)
Cross sectional or retrospectively included patients:134
Newly diagnosed drug naïve patient:65
SD±10.3
Clinical Characteristics of Multiple Sclerosis in Kuwaiti Population
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%20.50%
11.70%9.40% 8.60% 7.30%
2.10% 1.50% 1.20% 0.60%
Presenting symptoms
PRESENTING SYMPTOMS IN MS Total %
SENSORY LOSS IN LIMBS 30.7
VISUAL LOSS 15.9
MOTOR WEAKNESS 14.2
DIPLOPIA 6.8
GAIT DISTURBANCE 4.8
INCOORDINATION 2.9
SENSORY LOSS-FACE 2.8
LHERMITTE’S 1.8
VERTIGO 1.7
BLADDER SYMPTOMS 1
AUTE TRANSVERSE MYELOPATHY 0.7
PAIN 0.5
OTHERS 2.5
POLYSYMPTOMATIC 13.7
Medication details in studied Kuwaiti MS patients
Rebif(n=94)
Avonex(n
=30)
Betafero
n(n=6)
Copaxone(n=17)
Tysabry(
n=19)
Mito
zantro
me(n=1)
Rituxim
ab(n=1)
Iv Ig
G(n=2)
Plasma E
xchan
ge(n=1)
Geliniya
(n=5)0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
48.90%
15.40%
3.10%8.70% 9.70%
0.50% 0.50% 1.00% 0.50% 2.60%
MS Therapy: Deciding on which Medication
• Determine Therapeutic Goals– To reduce clinical relapse– To reduce accumulation of new MRI lesions– new T2 lesions– Gadolinium-enhancing lesions– black holes– Brain and spinal cord atrophy
• Reduce short-term relapse related disability
How To Determine of The Goals are Met?
• Compare with baseline relapse rate– Recall bias– Regression to the mean
• Assessment of improvement or stability in neurological impairment– Assess functional ambulatory limitation
• May indicate progression
• MRI ongoing/new inflammatory activity– Serial MRI to assess radiologic stability, worsening or
improvement- q12-24 month except
How To Determine of The Goals are Met?
• If goals of DMT or symptomatic treatment are being met no change in DMT unless problems with medication tolerability
• A detailed evaluation of common and idiopathic side effects will be required– Switching of medication based on adherence and
tolerability ma be needed
What if Goals are not being Met
• If pre-therapy relapse rate is not improved– A therapeutic switch may be indicated
• Relapse rate is incomplete indicator of ongoing inflammatory disease activity
– Cranial and spinal MRI• May show therapy resistant inflammatory disease• Guide switch to a more potent anti-inflammatory
medication• Clinical attack or definitive worsening disability is may
lacking
Case 2
• Mr. A.M.J is a 33 years old Kuwaiti male, diagnosed to have MS in 2008.
• In Jan 2008, he developed diplopia, followed by paresthesia in feet, ascending to abdomen, chest and forearms.
• These symptoms persisted • By June 2008, he was ataxic and on a wheel chair, when he
sought medical advice• MRI was consistent with MS• Marked imrovement was noted in sensory symptoms after
pulse steroids.
Case 2
• His symptoms showed a rapid progression, by Sept 2008, he had optic neuritis, sphincteric disturbance, and positive Lhermitte’s sign.
• In Oct 2008, he started to take Rebif.• His disease remained stable, with no new
relapses and no new lesions on MRI till 2011.• In April 2011, he went for CCSVI treatment and
discontinued Rebif without our knowledge or advice.
CASE 1
• Lhermitte’s sign was positive• Cranial nerves were normal• No motor weakness• Mild sensory deficit for light touch and vibration
on left side• Plantars were flexor bilaterally• Romberg’s sign was mildly positive• Moderate left sided dysmetria, with tandem
ataxia• EDSS :2; AI :1.
Case 1: MRI Cervical spineTWI
Case 2• In August 2011 he reported dizziness, ataxia and diplopia • He was treated with pulse steroids with marked recovery.• He was clinically stable, and was advised to restart Rebif.• In Jan 2012, EDSS:1, AI:0.• MRI in June 2012 showed new cerebellar lesions, with no
enhancement. • In Oct 2012, he came in with a mild relapse and was treated with
pulse steroids.• An MRI in Dec 2012 showed worsening lesion load, and he was
advised to start Tysabri after JCV serology.• He started Tysabri in Dec 2012, and till 5 months post Tysabri ,
there were no active lesions.
Case 2
• In Sept 2013, patient came with another severe relapse , with homonymous hemianopia, sphincteric problems, gait ataxia, and sensory disturbance.
• Treated with pulse steroids with partial improvement in urinary symptoms and ataxia, but not in visual symptoms.
Case 2: MRI Brain 2
Case 2: MRI Cervical spine 2
Case 2
• MRI showed marked worsening, with tumefactive enhancing lesions
• A CSF study was done, which was normal, negative for JCV.
• Considering this as a failure of Tysabri, it is planned to treat him with Rituximab
Is Clinical Worsening due to Attack related Disease or Progression?
• If it is due to non-inflammatory MS progressive disease– Neurodegenerative MS– ?subclinical ( and sub-radiologic) inflammation
unresponsive to current DMTs– Switching to alternative MS therapy is futile
• Escalating therapy If clinical impairment is strongly associated with ongoing relapses or marked new inflammatory MRI activity
Existing & Emerging MS therapies
Modified from P. Vermersch
Phase I
Phase II
Phase III
MarketedInterferons
Antiproliferativeagents
Cytolytic mAbs
Symptomatic TxVaccine, tolerization
Lymphocyte trafficking
Immune regulation
Other
Idebenone
BIIB033
Fingolimod
Firategrast
SiponimodONO-4641
CS-0777
ELND-002
Tysabri
Daclizumab
LaquinimodBG12
NI-0801
AZD5904
GRC4039
CCX-140
AIN457
Cladribine
Nerispirdine Ofatumumab
Belimumab
Ampyra
Ocrelizumab
Sativex
Alemtuzumab
Copaxone
IPX-056 RPI-78M
LY-2127399
Novantrone
Rebif Betaferon
Pixantrone
Peg IFNb(BIIB017)
ATX-MS-1467
PI2301
RTL1000
Copaxone generics x2
Azathioprine
Teriflunomide
LV Copaxone
Avonex
= Oral administration
= Injectable
ExtaviaPonesimod
IFNβ-1b SC qod
GA SC qd
IFNβ-1a IM qwk
MitoxIV q 90 d
wks
IFNβ-1a SC tiw
NatalizumabIV q 4 wks
Fingolimod 0.5 mg gd
TeriflunPO qd
LaquinPO
DaclizumabSC
BG-12PO bid
Alemtuz IV
The Changing Landscape of MS Disease Modifying Treatment Of Approved and Emerging Therapies
19901992
19941996
19982000
20022004
20062008
20102012
2014
How are MS medication is selected?
• Injectable interferon-β and glatiramer acetate remain the first line DMT for many clinicians– Their side effects are manageable with minimum
of serious side effects• First line DMTs are effective in reducing clinical
attacks and new MRI lesions
Injectable therapiesOral therapies
Consider side effectsBG 12
FingolimodTerflunomide
Natalizumab
GlatiramerInterferon β
Relapsing inflammatory MS clinical course
First lineFirst line?
Severe relapsing inflammatory MS/JCV negative
Inadequate response/inj intolerance
Inadequate response/oral intolerance
Parallel switch
Inadequate response/JCV negative
Drawback of injectable Medication
• Interferon-β– “Flue-like illness” often transient– Liver enzyme monitoring– Rarely depression
• Glatiramer acetate– Flushing, eosinophilia, rare allergic reaction,
injection-site reactions (skin liopatrophy)– Conbination therapy+interferon-β1a IM/weekly and
glatiramer acetate does not appear to be significantly more efficacious than monotherapyLublin FD et al, Ann Neurology 2013
BG-12Phase III trials
BG-12
Integrated analysis• Compared with PBO, BG-12 240 mg BID and TID
significantly reduced ARR, risk of relapse, adjusted ARR requiring steroids, disability progression, and MRI outcomes.
• Demonstrated consistent benefits on clinical efficacy across prespecified subgroups of RRMS pts with varied baseline demographics and disease characteristics
• Overall incidence of AEs, SAEs, and discontinuations due to AES similar across tx groups; flushing and GI events most common AEs
Nrf2
- Detox Enzymes- Antioxidant Enzymes- NADPH Generating Enzymes- GSH Biosynthesis Enzymes- Chaperones- Ubiquitination/Proteasome
Cell and Tissue Protection
NFkB
- Proinflammatory cytokines- Leukocyte adhesion molecules
- Lymphocyte activation
Inflammation, Tissue Damage
Nrf2 Pathway May Induce a Cytoprotective Response and Inhibit NFkB Mediated Inflammation
BG-12
DEFINE Trial BG12 240mg bid vs tid: Primary endpoint - Relapses
p<0.0001
p<0.000141.3%
52.7%
DEFINE: MRI
p<0.0001
85%p<0.0001
90%
PlaceboBG12 bidBG12 tid
BG-12 (dimethyl fumarate, DMF): CONFIRM — Annualized Relapse Rate
Daclizumab
• Anti-CD25 mAb
Daclizumab
• Effects similar in patients with highly active MS compared with pts with less aggressive disease prior to tx initiation
• Treatment resulted in significant increase in number of pts who were disease- activity free following 1 year of tx in SELECT trial
• Patients had reductions in % change in volume of T1-hypointense and T2-hyperintense lesions over 52 wks of treatment vs increases in PBO group
S1P receptor modulators/ agonists• In phase 2b study, ponesimod significantly reduced inflammatory MRI
activity at all doses tested, with a significant dose response; lower ARR also observed with ponesimod compared with PBO, and was generally well tolerated
• Primary endpoint met in phase 2 DreaMS trial: ONO-4641 demonstrated significant efficacy on all key MRI measures of disease activity at all 3 doses compared with PBO, and was generally
• well tolerated Compared with PBO, reduction in mean CUAL observed as early as
• month 1 for siponimod 0.25 mg/day and 2.0 mg/day, and in all doses at month 2 in phase 2 BOLD trial; effect maintained at each month up to month 6; similar pattern for new/enlarging T2 lesions for all siponimod doses at month 2 and maintained at each month up to month 613
Glatiramer acetate
• Compared with PBO, GA 40 mg SC TIW significantly reduced:
• ARR by 34.4.% (P < .0001) Cumulative # GdE lesions by 44.8% (P < .0001) Cumulative # new/enlarging T2 lesions by 34.7%
• (P < .0001) Safety profile consistent with GA 20 mg/day SC
Teriflunomide
Pyrimidine Synthesis Inhibitor (anti-
metabolite)
Teriflunomide
• Compared with PBO, 7 mg/day and 14 mg/day teriflunomide significantly reduced ARR by 22.3% and 36.3%, respectively (P = .0183 and P = .0001, respectively)
• Compared with PBO, 14 mg/day teriflunomide significantly reduced 12-wk CDP (HR = .685; P = .0442)
• Both teriflunomide doses generally well tolerated; safety profile consistent with prior studies
• Update from TEMSO trial Mean reductions in lymphocyte and neutrophil observed in TEMSO were small in magnitude and were reversible after treatment discontinuation or on treatment in some cases; no other clinically significant complications to blood cytopenias reported
a)Adjusted for Expanded Disability Status Scale (EDSS) score strata at baseline and takes duration of treatment into account .ARR, annualised relapse rate; RRR, relative risk reduction
0.369
0.370
0.539
0 0.1 0.2 0.3 0.4 0.5 0.6
14 mg
7 mg
Placebo
Teri
flu
no
mid
e
Adjusteda annualized relapse rate
RRR: 31.2% p=0.0002
RRR: 31.5% p=0.0005
TEMSO: Relapse Rate
279290285
363365358
306309302
Number at riskPlacebo7 mg teriflunomide14 mg teriflunomide
242252251
211234227
200224217
160178175
336343329
258266262
40
0
0 36 72 84 96 10848 60
Dis
abili
ty p
rogr
essi
on (%
)
30
24
Week
10
20
12
224238234
Placebo vs 7 mg: HRR 23.7% p=0.0835
Placebo vs 14 mg: HRR 29.8% p=0.0279
27.3%
21.7%20.2%
Placebo7 mg teriflunomide14 mg teriflunomide
TEMSO: EDSS progression (3 month confirmed)
TENERE: Annualized relapse rate
• The ARR in the 14 mg teriflunomide group was not statistically different from the ARR in the Rebif® group
• The estimated ARR was higher in the 7mg treatment group
0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45
Annualized Relapse Rate
Teriflunomide14 mgN=109
Teriflunomide 7 mgN=111
0.216Rebif®N=104
0.259
0.410
Genzyme, Press release, Cambridge, MA – December 20, 2011
FINGOLIMOD
Sphingosine-1-Phosphate (S1P) Receptor Agonist
Fingolimod• Treatment with fingolimod 0.5 mg:
– Significant benefits on relapse-related outcomes within first 3 months and on volume loss over 6 months compared with PBO in FREEDOMS and FREEDOMS II studies; concordant results from 2 large phase 3 trials, along with phase 2 data, allow better definition of expectations regarding time lag between initiation and effects of fingolimod treatment
• Fingolimod treatment initiation effects in pooled population from FREEDOMS, FREEDOMS II (vs PBO), and TRANSFORMS (vs IM IFN à-1a) a transient, mostly asymptomatic decrease in heart rate; symptomatic bradycardia and Mobitz I and 2:1 AVBs were dose-dependent; AVB first occurrences most common <6 h post-dose5
• Analysis of TRANSFORMS trial demonstrated advantage of switching to fingolimod over remaining on IFN à-1a IM with regard to time to relapse in RRMS6
LN
T-cell FTY720-P
Prevents T-cell invasion of central nervous system
S1P receptor
Sphingosine-1-phosphate (S1P) receptor modulator
Internalises S1P1, blocks lymphocyte egress from lymph node (LN) while sparing immune surveillance by peripheral memory T-cells
FTY720 traps circulating lymphocytes in peripheral lymph nodes
Multiple sclerosis
FTY720
Fingolimod: Mechanism of Action
FREEDOMS (Fingolimod) Annualized Relapse Rate
0.160.18
0.40
0.0
0.1
0.2
0.3
0.4
Annu
alis
ed re
laps
e ra
te
Placebo (n = 418)
Fingolimod 0.5 mg(n = 425)
Fingolimod 1.25 mg(n = 429)
-54% vs placebop < 0.001
-60% vs placebop < 0.001
ITT population; negative binomial regression model adjusted for treatment group, country, number of relapses in previous 2 years and baseline Expanded Disability Status Scale (EDSS) as covariates
*Analysis performed using a negative binomial regression model adjusted for treatment group and country**Analysis performed using rank ANCOVA adjusted for treatment group, country and number of lesions at baselineGd+, gadolinium-enhancing; MRI, magnetic resonance imaging
Fingolimod 0.5 mg
(n = 370)
Fingolimod 1.25 mg
(n = 337 )
0
2
4
6
8
10
12
9.8(13.2)
2.5 (7.2)
2.5(5.5)
Placebo (n = 339)
# new/enlarging T2 lesions at month 24 from baseline*
Fingolimod 1.25 mg
(n = 343 )
0
0.2
0.4
0.6
0.8
1
1.2
Mea
n (S
D)
lesi
on n
umbe
r
Placebo (n = 332)
Fingolimod 0.5 mg
(n = 369)
0.2 (1.1)
1.1(2.4)
0.2(0.8)
# T1 Gd+ lesions at month 24**
p < 0.001
p < 0.001
p < 0.001p < 0.001
FREEDOMS (Fingolimod) MRI Lesion Activity
FREEDOMS (Fingolimod) Disability (Disability) Progression
Placebo
Fingolimod 0.5 mg
Fingolimod 1.25 mg
Patie
nts
with
3-m
onth
con
firm
ed E
DSS
pr
ogre
ssio
n (%
)
Days on study
Fingolimod 1.25 mg vs placebo, HR = 0.68, p = 0.012
Fingolimod 0.5 mg vs placebo, HR = 0.70, p = 0.026
0
5
10
15
20
25
30
0 90 180 270 360 450 540 630 720
HR, hazard ratio