Eculizumab in aHUS

Elaine Majerus, MD PhD

February 21, 2009

Disclosures

• Uncompensated consultant for Alexion in the development of this trial.

Case Presentation

• 28 y/o WF w/ a h/o migraines, anxiety, and lower back pain who presented 1/8/09 to OSH ER with complaints of nausea, vomiting, and abdominal pain for 1 week. Was in usual state of health until Thanksgiving when she developed URI symptoms. PMD gave Biaxcin. Symptoms resolved but then developed

Case cont.

• Sore throat and ear pain. Given Aleve by her physician. Re-presented to PMD one prior to admission with N/V and abd pain and was send to ED with abnormal UA.

• Meds: Lexapro 20 QD, OCP, Colace prn.• All: PCN; Cleocin, rash.• PMHx: C-sxn• FHx: F with HTN, GF with DM• SHx: works as an OT. Married with 3 y/o

daughter. Denies A/T/D.

Case cont.

PE: T=37.3 P=78 BP=176/90

WD/WN WF anxious, NAD.

Skin: petechiae on face and chest.

Lungs: CTA CV: RRR

Abd: soft, mild RLQ tenderness, +BS

Ext: edema in UE and LE

Labs

• OSH: Hb 9.1/78 Plt 96 WBC 13.4• BUN101; Cr8; K4.5.• UA with 5-10 granulocytic casts, 3+

protein, 3+ blood.• Renal US with increased echogenicity

c/w chronic renal disease.• ANA -; ASO titer -; anti-GBM -.• 24 hour urine protein 5.3.

Labs cont.

• 1/11. WBC 7.3 Hb 5.6 Plt 67 LDH 1500; Hapto undetectable. 1-2 schistocytes per HPF.

Diagnosis

• Started on plasma exchange for ? Of thrombotic microangiopathy.

• ADAMTS13 sent and Nl.• Plt bounced around to as low as 40,000.• Receive packed RBCs.• No response to plasma exchange after 10

days.• Dialyzed for volume overload and remained

on HD.

Atypical Hemolytic Uremic Syndrome (aHUS)

• Non-diarrheal, not Shiga toxin related.• Sporadic or familial.• Warwicker et al. in 1998 identified an

association in three families with aHUS with the Regulators of Complement Activation gene cluster on 1q32.

• Genes for Factor H, MCP, and DAF are located there.

Mutations have been found in five complement factors:

• Mutations in Factor B and C3 have also been identified.

• Inhibitory antibodies directed against Factor H have also been found associated with atypical HUS

Diagnosis with HUS

• Genetic screening identifies mutations but is expensive (and slow with sendout).

• Assessment of protein levels can be helpful using antigenic assays or flow cytometry.

• Normal C3 levels do not rule out a mutation.• C3, C4, and factor B levels are usually

normal.

Inactivation

+ Factor I

Binding

MCP MCP

C3bC3b iC3b C3f

Inactivation

+ Factor I

Binding

MCPC4d

MCP

C4b C4cC4b

Cofactor ActivityCofactor Activity

Factor H Factor H

Factor I

I + + I

Complement regulators in aHUSComplement regulators in aHUSProtein Synthesized Function

(C3b)Mutation

(%)

FHFH LiverLiver CofactorCofactor 20 to 3020 to 30

MCP MCP (CD46)(CD46)

CellsCells CofactorCofactor 10 to 2010 to 20

FIFI LiverLiver ProteaseProtease 5 to 155 to 15

Factor H mutationsFactor H mutations

19 20

1 - 4

Cofactor Site

s s

922delC*

R317W

(1446-1450) del5bp

W486X*

W546X*

D519N

D524V

C1610ins AT*

IVS12+5G>T

A240GM138I

W145X*

Fact

or I

mod

ule

CD5 do

mai

n

LDLr

mod

ule

LDLr

mod

ule

Serin

e pr

otea

se d

omai

n

G271D

Factor I MutationsFactor I Mutations

in aHUSin aHUS

MCP mutations in aHUS MCP mutations in aHUS

Factor B

• A family was recently identified with gain of function mutations in Factor B.

• Leads to enhanced formation of the C3bBb convertase.

• Increased resistance to inactivation by complement regulators.

Inheritance

• Heterozygous expression leads to disease.

• Homozygotes are also seen with MCP mutations.

• Presentation usually occurs by 30 years of age. Most present in childhood.

• Penetrance is about 50%. Most “sporadic cases” have an unaffected parent with the disease-causing mutation.

• Other genetic or environmental factors involved.

• Disease is recurrent and leads to loss of renal function.

Treatment

• Plasma exchange.

• No prospective randomized controlled trials.

• Overall mortality decreased from 50% to 25% with the introduction of plasma infusion or exchange.

Renal Transplantation

• Transplant in those with MCP mutations has been successful since it is a membrane protein.

• Those with Factor H mutations should not be transplanted since Factor H is made in the liver and the kidney is still susceptible to damage. (80% chance of recurrence.)

• Factor I mutations are thought to have a similar risk of recurrence.

• Potential donors who are family members should be screened for the MCP mutation since the penetrance is incomplete.

aHUS Conclusions

• Inciting event such as bacterial or viral infection or pregnancy.

• Robust complement activity leads to endothelial and renal damage.

• Fibrin-rich thrombi develop.

• If aHUS is an activated complement syndrome, could decreasing complement activity help?

• Eculizumab is an antibody directed against C5 of the terminal complement cascade.

• Effective for PNH.

Investigator-initiated Trial

• Submitted to Alexion in 2/08 using eculizumab for aHUS and following platelet, Haptoglobin, and LDH for response.

• With low patient numbers, a company-sponsored international trial was best option.

• Abstracts at ASH 12/08.

Poster Session

Disorders of Platelet Number or Function Poster II

Successful Treatment of Atypical Hemolytic Uremic Syndrome with the Complement Inhibitor Eculizumab.

Jens Nuernberger1,*, Oliver Witzke1,*, Russell P. Rother, PhD2,*, Thomas Philipp1,*, Udo Vester1,*, Hideo Baba1,*, Lothar Bernd Zimmerhackl3,* and Andreas Kribben1,*

1 Department of Nephrology, University Duisburg-Essen, Essen, Germany, 2 Research, Alexion Pharmaceuticals, Cheshire, CT, USA, 3 Department of Pediatrics, Innsbruck Medical University, Innsbruck, Austria

Disorders of Red Cell Regulation and Production

Efficacy of Eculizumab in a Plasmatherapy-Dependent Patient with Atypical Hemolytic Uremic Syndrome with C3 Mutation Following Plasmatherapy Withdrawal

Valerie Chatelet, MD1,*, Veronique Fremeaux-Bacchi, MD, PhD2,*,Maxence Ficheux, MD1,*, Thierry Lobbedez, MD1,* and Bruno Hurault-Deligny, MD1,*

1 Nephrology Department, CHU Clemenceau, Caen, France,2 Immunology Department, HEGP, Paris, France

Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract 2294© 2008 American Society of Hematology

ADAMTS13 <5% Cr, microM 119 +/- 14 SEM

ADAMTS13 >5% 206 +/- 58

P=0.042

Conclusions

• Great job of screening and recognizing these patient.

• If idiopathic thrombotic microangiopathy and nl ADAMTS13, think aHUS.

• Inclusion criteria will be basically this.

Thank You

• Luke

• Jeevan

• John Atkinson