comorbidities from drug related adverse events

Distinguishing comorbidities from drug-related adverse events in MS clinical trials

Gavin Giovannoni

Barts and The London School of Medicine and Dentistry

Disclosures

Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Professor Giovannoni would like to acknowledge and thank Abbvie, Biogen-Idec, Genzyme, Merck-Serono, Novartis and several colleagues for making available data slides on alemtuzumab, cladribine, daclizumab, fingolimod and natalizumab for this presentation.

Adverse events

Poor Health

Health MS

Disease-modifying & Symptomatic Therapies

Co-morbidities

?

Defining the task

Data sources

1. Registers (not optimised for pharmacovigilance) 2. National & Regional electronic medical records

a) Scandinavia (Denmark & Sweden) b) HMOs (Kaiser / Vas) c) Hospital Episode Statistics & THIN or GP Database (UK)

3. Spontaneous reporting – yellow carding

Adverse events: fingolimod 0.5 mg compared with placebo

Study : FREEDOMS (D2301) Fingolimod 0.5 mg (N=425) Placebo (N=418)

Lymphopenia

Hepatic enzyme increased

Gamma-glutamyltransferase increased

Tinea versicolor

Vision blurred

Migraine

Alanine aminotransferase increased

Back pain

Bronchitis

Relative risk with 95% CI

Hypertension

Overall AEs

Diarrhea

Dyspnea

Urinary tract infection

Micturition urgency

Musculoskeletal stiffness

Somnolence

Leukopenia

0.016 0.125 1 8 64 512 0.002

Higher with Fingolimod Higher with Placebo

Presentation FDA-Advisory Committee Meeting June 10, 2010; Collins AW et al. Multiple Sclerosis October 2010; 16 : S295 (Poster 843)

Adverse events: fingolimod 0.5 mg compared with IFNβ-1a IM

Study: TRANSFORMS (D2302) Fingolimod 0.5 mg (N=429) IFNβ-1a IM (interferon beta-1a intramuscular) (N=431)

Relative risk with 95% CI

Gamma-glutamyl transferase increased

Hepatic enzyme increased

Alanine aminotransferase increased

Hypertension

Bronchitis

Depression

Arthralgia

Myalgia

Pyrexia

Infusion-related reaction

Influenza-like illness

Chills

Overall AEs

0.004 0.016 0.063 1 4 0.250 16 64 256

Higher with Fingolimod Higher with IFNβ-1a IM

Presentation FDA-Advisory Committee Meeting June 10, 2010

Defining comorbidity

The term "comorbid" has three definitions:

1. to indicate a medical condition existing simultaneously but independently with another condition in a patient . (this is the older and more "correct" definition)

2. to indicate a medical condition in a patient that causes, is caused by, or is otherwise related to another condition in the same patient. (this is a newer, nonstandard definition and less well-accepted)

3. to indicate two or more medical conditions existing simultaneously regardless of their causal relationship.

Poor Health Health

Is premature ageing a comorbidity?

MS-related MS-specific

Possibly MS-related

non-specific

Treatment-related non-specific

Treatment-related specific

At risk High Risk RIS CIS MS

In utero Childhood Adolescence / early adulthood Adulthood

MS ENDOPHENOTYPE

Ageing

Co-morbidties

Non MS-related

Is premature ageing a comorbidity?

MS-related MS-specific

Possibly MS-related

non-specific

Treatment-related non-specific

Treatment-related specific

At risk High Risk RIS CIS MS

In utero Childhood Adolescence / early adulthood Adulthood

MS ENDOPHENOTYPE

Ageing

Co-morbidties

Non MS-related

Seizures (fampridine)

Fractures Osteopenia (steroids)

Small vessel disease HTension (fingolimod)

PML, opportunistic infections Immunosuppression (natalizumab,

fingolimod, DMF, etc.)

Fatigue Flu-like symptoms

(Interferon-beta)

Age-related cognitive impairment CNS anti-cholinergic drugs

Adverse events Co-morbidities

?

Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.

PML complicating treatment with natalizumab and IFNb-1a for MS

“There are known knowns; there are things we know that we know. There are known unknowns; that is to say, there are things that we now know we don't know. But there are also unknown unknowns – there are things we do not know we don't know.”

United States Secretary of Defense, Donald Rumsfeld

Rumsfeldometer

1. Known-knowns - there are things we know that we know

2. Unknown-knowns - these are the things we know will occur

3. Known-unknowns - there are things that we now know we don't know

4. Unknown-unknowns - there are things we do not know we don't know

MITOXANTRONE

Mistry et al. Engl J Med. 2005 Apr 14;352(15):1529-38.

Events of special interest: haematology cell counts

*Based on the full study population (placebo n=437; cladribine 3.5 mg/kg n=433; cladribine 5.25 mg/kg n=456) †Based on analysis from a subset of patients (placebo n=79; cladribine 3.5 mg/kg n=81; cladribine 5.25 mg/kg n=80)

1600

1400

1200

1000

800

600

400

200

0

Cell

s/μ

l

BL 12 24 36 48 60 72 84 96 LA

Weeks

CD3 (T cells)†

8

7

6

5

4

3

2

1

0

Cell

s/n

L

BL 12 24 36 48 60 72 84 96 LA

Weeks

Leukocytes*

250

200

150

100

50

0

Ce

lls

/μl

BL 12 24 36 48 60 72 84 96 LA

Weeks

CD19 (B cells)†

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5

0

Cell

s/n

L

BL 12 24 36 48 60 72 84 96 LA

Weeks

Neutrophils*

*Except uterine leiomyoma; †The percentage of patients in one active treatment group is ≥2 x the percentage of patients in the placebo group or vice versa

TEAEs occurring in ≥2% patients* in any treatment group at ≥2 x frequency of another group†

Preferred term, n (%) Placebo (n=435)

Cladribine 3.5 mg/kg (n=430)


Cladribine Overall (n=884)

Lymphopenia 8 (1.8) 93 (21.6) 143 (31.5) 236 (26.7)

Leukopenia 3 (0.7) 24 (5.6) 39 (8.6) 63 (7.1)

Lymphocyte count decreased 0 (0.0) 13 (3.0) 26 (5.7) 39 (4.4)

Neutropenia 2 (0.5) 8 (1.9) 10 (2.2) 18 (2.0)

Vertigo 11 (2.5) 14 (3.3) 23 (5.1) 37 (4.2)

Tinnitus 2 (0.5) 2 (0.5) 10 (2.2) 12 (1.4)

Hypoaesthesia 4 (0.9) 2 (0.5) 9 (2.0) 11 (1.2)

Pyrexia 8 (1.8) 14 (3.3) 18 (4.0) 32 (3.6)

Viral upper respiratory tract infection

5 (1.1) 13 (3.0) 7 (1.5) 20 (2.3)

Herpes zoster 0 (0.0) 8 (1.9) 11 (2.4) 19 (2.1)

Alopecia 5 (1.1) 15 (3.5) 14 (3.1) 29 (3.3)

Rash 5 (1.1) 10 (2.3) 11 (2.4) 21 (2.4)

Dermatitis allergic 3 (0.7) 12 (2.8) 6 (1.3) 18 (2.0)

Contusion 3 (0.7) 6 (1.4) 9 (2.0) 15 (1.7)

Gastritis 9 (2.1) 3 (0.7) 5 (1.1) 8 (0.9)

Uterine leiomyoma 1 (0.2) 5 (1.2) 4 (0.9) 9 (1.0)

Rumsfeldometer





PML in a Patient Treated with Dimethyl Fumarate from a Compounding Pharmacy

Van Oosten et al. NEJM 2013:368(17):1658-9.

This bulletin advises that patients who develop severe, persistent lymphopenia during Fumaderm therapy (around 3% of patients) are at risk of opportunistic infections, and refers to 3 cases of progressive multifocal leukoencephalopathy (PML), 1 case of Kaposi's sarcoma and 1 case of nocardiosis in such patients.

Unknown-known

Alemtuzumab: overview of adverse events

Adverse events Description

Infusion-associated reactions (IARs)1-4

• IARs were common, predominantly mild to moderate, and reduced with steroid pre-treatment

Autoimmune thyroid events1-4

• The majority of first occurring thyroid AEs occurred after Year 1 (12 months after first course), with the highest incidence occurring in Year 3 and declined thereafter1

• Majority of thyroid events responded to conventional treatment

ITP1-4 • ITP has been reported in 1.5% of patients

• With the exception of a fatal index case, all subsequent ITP cases were detected early through the safety monitoring program and responded to treatment

Nephropathy1-5 • Nephropathies are rare (incidence ~0.3%) and occurred within 48 months of the last alemtuzumab treatment course (the recommended monitoring period)

• All cases in the MS clinical program were detected by the safety monitoring program and none resulted in renal failure5

Infections1-4 • Infections with alemtuzumab were predominantly mild to moderate and responded to conventional treatment

• Lymphocyte counts did not correlate with occurrence of infection

1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380(9856):1829-39;

4. Fox E et al. AAN 2013, S41.001; 5. Wynn D et al. ECTRIMS 2013. P597.

Anti-natalizumab Antibodies

Number of Patients at Risk

Placebo

Antibody Negative

Transiently Positive

Persistently Positive

315

568

20

37

296

550

19

32

283

538

18

26

264

526

16

25

248

506

16

24

240

487

16

22

229

480

15

22

216

470

14

19

208

460

14

16

200

449

14

15

Weeks

0.0

0.1

0.2

0.3

0.4

0.5

0 12 24 36 48 60 72 84 96 108 120

29%

Placebo

17%

Antibody Negative

17%

Transiently Antibody Positive

34%Persistently Antibody Positive

Cu

mu

lati

ve

Pro

po

rtio

n o

f P

ati

en

ts

wit

h S

us

tain

ed

Dis

ab

ilit

y

Pro

gre

ss

ion

(E

DS

S) *,†

*p ≤0.05 vs. antibody-negative patients†p=0.66 vs. placebo

Number of Patients at Risk

Placebo

Antibody Negative

Transiently Positive

Persistently Positive

315

568

20

37

296

550

19

32

283

538

18

26

264

526

16

25

248

506

16

24

240

487

16

22

229

480

15

22

216

470

14

19

208

460

14

16

200

449

14

15

Weeks

0.0

0.1

0.2

0.3

0.4

0.5

0 12 24 36 48 60 72 84 96 108 120

29%

Placebo

17%

Antibody Negative

17%

Transiently Antibody Positive

34%Persistently Antibody Positive

Cu

mu

lati

ve

Pro

po

rtio

n o

f P

ati

en

ts

wit

h S

us

tain

ed

Dis

ab

ilit

y

Pro

gre

ss

ion

(E

DS

S) *,†

*p ≤0.05 vs. antibody-negative patients†p=0.66 vs. placebo

0.73

0.220.16

0.48*

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Ad

jus

ted

An

nu

ali

ze

d R

ela

pse

Ra

te (

95

% C

I)

Placebo

(n=315)

Antibody Negative

(n=568)

Transiently

Antibody Positive

( n=20)

Persistently

Antibody Positive

(n=37)

*p=0.009 vs. antibody-negative patients

0.73

0.220.16

0.48*

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Ad

jus

ted

An

nu

ali

ze

d R

ela

pse

Ra

te (

95

% C

I)

Placebo

(n=315)

Antibody Negative

(n=568)

Transiently

Antibody Positive

( n=20)

Persistently

Antibody Positive

(n=37)

*p=0.009 vs. antibody-negative patients

Calabresi et al, Neurol 2007

Impact of anti-natalizumab antibodies on . . . . .

Annualized relapse rate Progressive disability

Natalizumab infusion reactions

• Acute hypersensitivity reactions are well-recognized

• Generalized urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, dyspnea, chest pain

• Onset generally during or within 1 hour of second infusion

• Incidence ~4%

• severe anaphylactic/anaphylactoid reactions <1%

• Most reactions are associated with anti-natalizumab antibodies

• Treatment:

• immediate and permanent cessation of natalizumab

• antihistamines

Rudick et al, NEJM 2006

Rumsfeldometer





0.33

0.14 0.15

Cladribine

Placebo (n=437)

Cladribine 3.5 mg/kg

(n=433)

An

nu

alis

ed

re

lap

se r

ate

(9

5%

CI)

ITT, intent-to-treat population

0.40

0.30

0.20

0.10

0.00


(n=456)

54.5% reduction vs placebo

p<0.001

57.6% reduction vs placebo

p<0.001

AEs of special interest: malignancies

The standardised incidence ratio (SIR) matched for country/gender/age1 was 0.99 (95% CI: 0.25, 2.70)

Reliable risk estimate is not possible in a 2 year clinical trial setting for events:

With a long latency

With a low incidence

Further characterization of this potential risk

CLARITY extension study

Post-marketing surveillance (PASS)

Preferred term, n (%) patients

Placebo (n=435)



(n=454)

Cladribine overall

(n=884)

During study

Malignant melanoma 0 0.2 (1) 0 0.1 (1)

Ovarian cancer 0 0.2 (1) 0 0.1 (1)

Pancreatic carcinoma, metastatic 0 0.2 (1) 0 0.1 (1)

During post-study surveillance

Choriocarcinoma 0 0 0.2 (1) 0.1 (1)

1International Agency for Research on Cancer database (1998–2002) and the Globocan 2002 database

Cancer risk not increased from cladribine in relapsing MS

Pakpoor et al. Submitted 2015

Forest plot of malignancy rates in treatment groups from phase III trials with a placebo group

Forest plot of malignancy rates in placebo groups of phase III trials

Cancer risk not increased from cladribine in relapsing MS

Pakpoor et al. Submitted 2015

Forest plot of malignancy rates in treatment groups of all phase III trials

Rumsfeldometer





Rheumatoid arthritis

Reduced efficacy due to IFNbeta NAbs – systematic review

Farrell & Giovannoni, Multiple Sclerosis 2007; 13: 567-577.

Epoetin-induced PRCA

Eckardt & Casadevall Nephrol Dial Transplant 2003;18:865-869.

1999 2000 2001 2002 2003J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J

1997 1998J F M A M J J A S O N D J F M A M J J A S O N D

t Epo-refractory anemia (diagnosis)

l Pure Red Cell Aplasia (diagnosis)

Epoetin alfa SC Eprex

Epoetin alfa IV Eprex

Darbepoetin

Epoetin beta SC NeoRecormon

Since Dec 93

Since Feb 93

Since Dec 95

NABs: Endocrine vs. Paracrine vs. Autocrine

Effects of NABs

• Common side effects

• No flu-like side effects

• No lymphopaenia

• No abnormal LFTs

• Skin reactions?

• Loss of efficacy

• Rare immune effects

• Antiviral?

• Anti-tumour?

• Autoimmunity?

• Bone metabolism?

• Other?

Mechanisms of interferon-b effects on bone homeostasis

Abraham et al. Biochem Pharmacol. 2009 Jun 15;77(12):1757-62.

Osteopaenia / Osteoporosis?

Derry et al Nature Reviews Immunology 7, 715-725 (September 2007)

Neonatal Fc receptor

Tumours

Infection

Pharmacovigilance

Unknown-knowns

Known-unknowns

Unknown-unknowns

Known-knowns

Take special care with Interferon-beta-1b: If you might have a disorder of the immune system in which abnormal proteins are found in the blood (monoclonal gammopathy), you must check this with your doctor before you use interferon beta-1b. Patients who have the rare condition known as monoclonal gammopathy may develop problems with their small blood vessels (capillaries) leading to shock (collapse) which can be fatal, when they use medicines like interferon-beta-1b. See also 4. Possible side effects.

Oral fingolimod or intramuscular interferon for relapsing MS

Cohen et al. N Engl J Med. 2010 Feb 4;362(5):402-15.

Thrombotic Microangiopathy Associated with Interferon Beta

Hunt et al. N Engl J Med. 2014 Mar 27;370(13):1270-1.

Rumsfeldometer





5. Unclassifiable

REBOUND AFTER NATALIZUMAB WITHDRAWAL

Rigau et al. Neurology. 2012 Nov 27;79(22):2214-6.

Co-morbidity classification

Known Knowns

Unknown Knowns

Known Unknowns

Unknown Unknowns

Unclassifiable

Mode of Action 1. On-target 2. Off-target 3. Specific 4. Non-specific 5. Interaction with

MS-relate comorbidities and/or human biology

6. Withdrawal

Type 1. Treated individual 2. Teratogenic 3. Congenital

(transplacental)

Frequency: common, uncommon, very uncommon, rare (pharmacovigilance) Comparator: placebo, active, population Analogy: other diseases Systems biology: ageing Integrate data sources: big data project

Inflammation as a Cardiovascular Risk Factor

Willerson & Ridker. Circulation 2004:109[suppl II]:II-2–II-10.

Defining the problem

Poor Health Health

1. the state of being free from illness or injury;

2. a person’s mental or physical condition;

3. used to express friendly feelings towards one’s companions before drinking.

Source: Oxford English Dictionary

Health [noun]

“Health is a state of complete physical, mental and social well-being, and not merely the absence of disease or infirmity.”

World Health Organisation

“Health is more than the opposite of disease.” David Seedhouse, New Philosopher 2015;7:97-99

comorbidities from drug related adverse events

Healthcare

fingolimod higher

msrelated msspecific

drugrelated adverse

placebo n

transforms d2302 fingolimod

freedoms d2301 fingolimod

risk high risk ris cis

placebo study