Now and Beyond in the Treatment and Management of AA Amyloidosis

1
Now and Beyond in the Treatment and Management of
AA Amyloidosis

• Helen Lachmann, MD
• National Amyloidosis Centre
• Royal Free and University College Medical School
• London, United Kingdom

2
AA Amyloidosis

• 18 of systemic amyloidosis
• Complication of sustained inflammation
• Diagnosis on the basis of
• Definitive immunohistochemistry and/or
• Characteristic SAP scan appearances and exclusion
  of plasma cell dyscrasia and hereditary
  amyloidosis
• Predominant renal disease
• 57 nephrotic
• 66 ? CrCL
• 10 end stage renal failure (ESRF)
• Further 20 develop ESRF (median 6yrs)

SAP serum amyloid P Data from National
Amyloidosis Centre (NAC) database
3
Objective of Current Treatment Reduction of the
Circulating Fibril Precursor

• Rate of turnover gt that of deposition

Treatment success depends on identification of
underlying inflammatory disease and effective
long-term suppression
Gillmore JD, et al. Lancet. 200135824-29.
4
Underlying Inflammatory Disease in a Cohort of
350 Patients With AA Amyloidosis
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19
10
14
8
4
2
3
6
Data from NAC database.
5
Treatment Regimens in AA Amyloidosis
Whatever it takes to control the acute phase
response

• Inflammatory arthritides
• Disease modifying anti-rheumatic drugs
• Alkylating agents
• Anti-tumor necrosis factor (TNF) therapies
  other biological agents
• Chronic sepsis
• Antibiotics
• Surgery
• Periodic fevers
• FMF colchicine
• TRAPS anti-TNF therapies, corticosteroids
• Muckle-Wells syndrome anti-IL1 therapies

• Crohns disease
• Corticosteriods
• Anti-TNF therapies
• Surgery
• Castlemans disease
• Surgery
• Anti-IL6 therapies

FMF familial Mediterranean fever TRAPSTNF
receptor associated periodic syndrome
Gillmore JD, et al. Lancet. 200135824-29.
6
Relationship Between Median SAA Concentration and
Change in Amyloid Load and Survival Among 195
Patients
Plt0.0001
Median SAAmg/L
Regression
Stable
Progression
Data from NAC database.
7
Changes in Renal Function Over Time
A Amyloid regression
B Amyloid stable
C Amyloid progression
Serum Creatinine
24-hour Protein Leak
Patients with amyloid regression were
significantly less likely to develop
deteriorating renal function and more likely to
have a diminution of their proteinuria than
patients with stable or progressive amyloid
deposits.
Data from NAC database.
8
Blood Pressure Control

• Strong clinical suggestion that hypertension is a
  powerful contributor to renal decline
• No published data but suggest
• BP control similar to diabetic nephropathy
• If no CI, favour ACE inhibitors or ARBs
• Long-term control is vital

CI contraindications ARBs angiotensin
receptor blockers
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Nephrotic Syndrome

• Oedema
• Diuretics/low Na diet/TEDS
• Intravenous albumin
• Measures to reduce GFR often ? ESRF
• Infective risks
• Potentiated by drug therapy
• Thromboembolic risks
• Often anticoagulate as normal, BUT
• Risk of GI bleeding, especially if large amyloid
  load
• Splenomegaly ? thrombocytopenia
• Hyperlipidaemia
• No evidence-based data, but seems wise to treat

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Management of Orthostatic Hypotension

• Nonpharmacologic
• Support stockings and abdominal binders
• Avoidance of
• Large meals
• Sudden changes in posture
• Excessive physical activity
• Dietary fibre/enemas to avoid straining

Mathias CJ. Annu Rev Med. 199950317-336.
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Pharmacologic Management of Orthostatic
Hypotension

• Mineralocorticoids
• Na retention/expand plasma volume
• Fludrocortisone
• Nandrolone
• Alpha-adrenergic agonists
• ? Cardiac output by ?myocardial contractility and
  heart rate, also ? peripheral vasoconstriction
• Midodrine
• Inotropes
• Alpha/beta-adrenergic agonist
• Ephedrine
• Vasopressors
• ? H2O reabsorption ? volume expansion
• Desmopressin

Mathias CJ. Annu Rev Med. 199950317-336.
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Adrenal Insufficiency

• Reported in up to 40 of some series
• Gunduz Ren Fail. 2001 Largely
• Malik Ann Clin Biochem. 1995 AA amyloidosis
• Harvey Nephrol Dial Transplant. 1995 with
• el-Reshaid. Ren Fail. 1994 advanced/end-stage
• Danby Q J Med. 1990 renal failure
• Arik Nephron. 1990
• Short ACTH test normal or equivocal in 200
  patients seen at NAC
• Only abnormalities found in patients on
  haemodialysis with symptomatic hypotension
• Assessment of adrenal function in critical
  illness/hypoalbuminaemia is difficult
• ? short ACTH test is not the best screen
• Free cortisol would be better, but not routinely
  available

Hamrahian AH, et al. N Engl J Med.
20043501629-1638.
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Dialysis

• UK figures
• 11.5 annual mortality, median survival 55 mo.
• cf 16 annual mortality for all UK HD patients
• Historically, reports of increased mortality are
  associated with
• Sepsis
• Poor access
• Cardiovascular disease in rheumatoid patients
• Concerns regarding sepsis on PD
• Again not confirmed by publications or UK data

Date from NAC database. Moroni G, et al. Clin
Nephrol. 19923881-85. Martinez-Vea A, et al.
Am J Nephrol. 199010(4)283-289.
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Renal Transplantation

• 24 Patients
• 27 grafts
• 3 primary nonfunction (2 patients died)
• 1 graft lost due to biopsy-proven AA
• 6 patients died, 3 probably due to amyloidosis

National Standards
Patient Survival 1 year 92 5 years
92 10 years 91
Graft Survival 1 year 89 5 years 89 10
years 80 Median follow-up 98 mo.
RTx Pts 1 year 88 95 5 years 69 83 10
years 44 58
Data from NAC database.
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Problems With Current Treatments

• Patient frailty late diagnosis
• Too sick to treat
• Unlikely to survive long enough to benefit
• Precursor production cannot be controlled
• Refractory underlying disease
• Circulating precursors are produced ubiquitously
• Nature of precursor is unclear failure of
  amyloid typing

Lachmann HJ, et al. Nephron Clin Pract.
200394c85-88.
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Potential Therapeutic Strategies
Native protein
Amyloid deposits
Reversion to native fold

Fibrillogenesis

• Stabilise precursor proteins
• Inhibit GAG binding
• ß sheet breakers

• Immunotherapy
• Destabilise by SAP depletion

Reduce supply of amyloid precursor protein
Lachmann HJ, et al. Nephron Clin Pract.
200394c85-88.
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Inhibition of GAG binding1,3-propanedisulfonate,
Fibrillex? (NC-503)

• First of new class (anti-amyloid agents)
• Orally administered capsules readily soluble in
  water
• Food significantly alters the pharmacokinetics
• Minimal drug-drug interactions expected
• Since eliminated/secreted by the kidney, dose is
  dependent on renal function

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Rheumatic diseases, Familial Mediterranean Fever,
infectious diseases, inflammatory bowel diseases
Current Treatment Targets
Inflammation
liver
? SAA (serum amyloid A precursor protein)
amyloid deposits
AA protein GAGs (HSPG) ( complement (C1)
serum amyloid P)

• Polymerization into aggregates
• Protected from proteolysis

Kidney Spleen GI tract Liver Heart
Damage to
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• Results from Protocol CL-503004
• A 2 Year Phase II/III Clinical Trial
• NC-503 vs Placebo
• in AA Amyloidosis Patients

Neurochem International Limited (Neurochem Inc.).
Press release 18 April and June 5 2005.
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Study Design

• Pivotal, phase II/III study
• Multicenter (27 sites 13 countries), randomized
  (11), double-blind, placebo-controlled,
  parallel-design
• 400, 800, 1200 mg BID, depending on renal
  function (all doses aim to provide same
  therapeutic blood level)

Placebo
NC-503
NC-503 (400, 800, 1200 mg BID)
24 months
24 months
Double Blind (Protocol CL-503004)
Open Label Extension (Protocol CL-503009)
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Inclusion Criteria

• ? 18 years of age
• Positive biopsy (immunohistochemistry) for AA
  amyloidosis
• Proteinuria ? 1 g/day OR CrCl ? 60 ml/min
• CrCl ? 20 ml/min AND serum creatinine ? 3 mg/dl
• No other potential causes of renal diseases
• Stable cytotoxic agent/colchicine therapy for 3
  mths prior to screening
• Stable ACE inhibitor therapy for 3 mths prior to
  screening

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Primary EndpointComposite assessment of Renal
Function at end of study vs baseline

• Improved
• ? 50 increase in CrCl
• No other parameter in the worse category

• Worse
• ? 50 reduction in CrCl
• ? 100 increase in SCr
• progression to dialysis/ESRF
• death

• Stable
• None of the milestones met

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Patient Disposition
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Underlying Diseases
Patients could count in more than one category.
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DemographicsClinical profile of AA patient at
baseline
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Primary EndpointRelative Risk (Cox regression
analysis)
Favors NC-503
Favors Placebo
Doubling SCr
50 decrease CrCl
ESRD/Dialysis
All cause mortality
First worse event
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Summary of Secondary Efficacy Endpointsmeasuring
worse parameters
NC-503
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Slope of Creatinine Clearance(based on 24 hr
urine collection)
Months in study
NC-503 - 10.9 49.7 ml/min/1.73 m2/yr
CrCl (mL/min/1.73 m2)
Placebo - 15.6 37.5 ml/min/1.73 m2/yr
After 2 years ? 9.4 mL/min/1.73 m2, p0.025
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Summary of Results

• The primary endpoint shows a trend in favor of
  NC-503
• 13.4 fewer worse patients on NC-503 as
  compared to Placebo (p-value 0.063)
  (RR reduced by 33)
• NC-503 reduces the risk of any event of renal
  decline or death by 42 (p-value 0.025)
  (95 CI 0.366-0.934)
• Secondary Endpoints
• All renal parameters measuring decline are in
  favor of NC-503 (e.g. slope of CrCl (p0.025),
  time to 50 reduction in CrCl (p0.029)
• NC-503 delays the time to renal decline events

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Clinical Adverse Event ExperienceSummary
NC-503
Placebo
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Summary

• AA amyloidosis is a complication of chronic
  inflammation
• Clinical manifestations are predominantly renal
• Median survival is 20 yrs, although renal
  failure supervenes in 1/3 of patients
• AA amyloidosis is a potentially reversible
  disease
• Reduction in the supply of fibril precursor, SAA,
  significantly improves outcome
• Current management centres on
• Defining the aetiology of the underlying
  inflammation
• Sustained complete normalisation of the
  inflammatory response
• Control of blood pressure and renal replacement
  therapy if necessary
• New treatments on the horizon

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Acknowledgements
At RFUCMS David Booth

Dorothea Gopaul Alison Bybee

Philip Hawkins Ruth Gallimore

Jayshree Joshi Janet Gilbertson

Sheril Madhoo Julian
Gillmore
Mark Pepys
Hugh Goodman
Dorota
Rowczenio MRC and NHS research and
development funds
Neurochem Study CL-503004 Hédi Ben Maïz,
Tunisia Merrill D. Benson, U.S. Irena
Butrimieme, Lithuania Laura M. Dember, U.S.
Haner Direskeneli, Turkey Angela Dispenzieri,
U.S. Anna Filipowicz-Sosnowska, Poland Peter D.
Gorevic, U.S. Ahmet Gul, Turkey Eric Hachulla,
France Philip Hawkins, UK Bouke P.C. Hazenberg,
Netherlands Partial support from an Orphan
Products Development Grant (FD-R-002007) All the
physicians who have diagnosed and cared for
these patients
John A. Hunter, UK Kalevi Kaarela, Finland Olga
Lesnyak, Russia Avi Livneh, Israel Giampaolo
Merlini, Italy Jose Muñoz Gomez, Spain Huri
Ozdogan, Turkey E.I. Nasonov, Russia Xavier
Puechal, France Xavier Tena Marsa, Spain J.
Valverde Garcia, Spain Itzhak Rosner, Israel
Piotr Wiland, Poland