How expert centres can contribute to real-world evaluation of drugs for rare disease

Case study – The National Alkaptonuria Centre

Professor Lakshminarayan RanganathClinical Director of the National Alkaptonuria Centre

Sir

Archibald

Garrod

1857-1936Gregor Johann

Mendel (1822 – 1884)

MALEYLACETOACETATE

HOMOGENTISATE

p-HYROXYPHENYLPYRUVATE

TYROSINE

PHENYLALANINE

FUMARYLACETOACETATE

FUMARATE ACETOACETATE

Tyrosine pathway

Homogentisate

dioxygenaseAKU

Food (Dietary protein – 80-100 g/day)

• Deficiency of HGD

• Accumulation of HGA

• Polymerisation to black pigment – ochronosis

• Autosomal recessive

• 1 in 250,000

• Slovakia, DomincanRepublic, Jordan

AKU: a Rare disease

AKU: a multisystem disease

• Dark urine

• External ochronosis

• Renal/Prostate stones

• Cardiac valve damage

• Fractures

• Ruptures

• Arthritis (Joint/Spine)

Adapted from Stanbury, Wyngaarden, & Frederichson Metabolic Basis of Inherited Disease

CONNECTIVE TISSUE MACROMOLECULES

PHYSICALBONDING CHEMICAL

BONDING

Homogentisic acid 1,2 dioxygenase (HGD) deficiencyBLOCK IN ALKAPTONURIA

DIETARY PROTEIN

MALEYLACETOACETATE

TYROSINE

HOMOGENTISIC ACID

100g of protein = 4g of Phenylalanine/3g of Tyrosine

OHHO

CH2COOH CH

2COOH

=oo=

n

2 (0)HGA

POLYPHENOLOXIDASE(CU++)

POLYMER(Ochronotic

Pigment)

CH2COOH

=oo=

BENZOQUINONE ACETIC ACID

(0)HGA

POLYPHENOLOXIDASE(CU++)

Ochronosis

Lack of disease modifying therapies for AKU

Nitisinone: Action

MALEYLACETOACETATE

HOMOGENTISATE

p-HYROXYPHENYLPYRUVATE

TYROSINE

PHENYLALANINE

FUMARYLACETOACETATE

FUMARATE ACETOACETATE

Homogentisate

dioxygenaseAKU

4-hydroxyphenylpyruvate

dioxygenaseNitisinone

Funarylacetoacetate

hydrolaseHT-1

Nitisinone: Use in AKU

• Lindstedt pioneered use of nitisinone in HT 1

• Inhibits phydroxyphenylpyruvatedioxygenase

Nitisinone

Leptospermone

The Robert Gregory National

Alkaptonuria Centre (Jan 2013)April 2012

NHS England

designated

Royal Liverpool

University Hospital

to be the National

centre for AKU

National Alkaptonuria Centre (NAC)

One-Stop annual service model

Monthly clinics

Large MDT

Baseline visits: 4 days

FU annual visits: 3 days

UK Dept of Health funded

Freely available nitisinone

ITT Long term study model

Clarify Natural History

Efficacy and Safety

Developing nitisinone for AKU

• License nitisinone for AKU• Clinical trials• FP7

• Off-label use• Centre• NHS Highly

Specialised Services

• Raised HGA in AKU

• Dose of HGA determines amount of

ochronosis

• Nitisinone decreases HGA

• Nitisinone in mice prevents ochronosis if

started early

• Nitisinone in mice arrests progression of

ochronosis if started later

2013-1415

Plan of NAC Service

2012

NAC (5 years)2012-20171 - 6 visits so farNitisinone

2012-1322

2014-156

Pre NACMean FU:

36.3 months(2009-2011)

One visit onlyAssessment

No Nitisinone

2009-1117 = 12

2015-167

2016-177

Annual review model: Using Nitisinone carefully in the NAC

• Baseline: 24h urine; 2 fasting blood tests (pre- and post nitisinone)

• 2 mg alternate days for 3 months (blood/24h urine test)

• From 3 months onwards 2 mg daily (6 months: blood/24h urine test)

• Efficacy Metabolic; Clinical

• Safety Metabolic; Ocular; Skin; LFT/eGFR

n = 11 n = 11 n = 11 n = 11 n = 11 n = 11 n = 11

V4 V3 V2 V1

V0

V0

SAME GROUP

VAR GROUP

V4 V3 V2 V1

PRE-NITISINONE POST-NITISINONE

Mean age 47.7±4.4 years

n = 20 n = 47 n = 40 n = 36 n = 34 n = 22 n = 14Mean 47.8±3.1 47.3±2.3 48.3±2.3 48.7±2.6 47.3±3.4 47.3±3.4 47.3±3.4Age years

V5 V6

V5 V6

Cumulative safety54 received nitisinone 2mg (4 self-paid)

• 4 deceased

• 4 on hold

• 1 intermittent dose

Adverse Effects reported:

Haematuria (2); Itch (2);

Rash (2); Odour (1);

Eye keratopathy* (5: 3 due to tyrosine);

Conjunctival injection (2); Thyroid excess (1);

GI bleed (2); Memory (2);

Abnormal LFT (1); ?Dermatomyositis (1);

Acute Haemolysis on ARF (1)

1a 1b

1c1d

MALEYLACETOACETATE

HOMOGENTISATE

p-HYROXYPHENYLPYRUVATE

TYROSINE

PHENYLALANINE

FUMARYLACETOACETATE

FUMARATE ACETOACETATE

Nitisinone

Aim of

Service Evaluation

Is there alteration in metabolicoutcomes in AKU post-nitisinone?

Nitisinone 2 mg daily oral used off-label

0

10000

20000

30000

40000

50000

60000

Baseline D4 3M 6M V2 V3 V4 V5 V6

uHGA24 umol/day

Urine HGA

0

10

20

30

40

50

60

70

80

90

Baseline D4 3M 6M V2 V3 V4 V5 V6

sHGA umol/L

Serum HGA

95%↓ in NAC

0

200

400

600

800

1000

1200

1400

Baseline D4 3M 6M V2 V3 V4 V5 V6

sTYR umol/L

>10 fold increase in NAC

Serum Tyrosine

Effects of AKU

The NAC GroupIs there alteration in NON-metabolic outcomes in

AKU post-nitisinone?Nitisinone 2 mg daily oral used off-label

Alkaptonuria Severity Score Index (AKUSSI)

AKUSSICLINICAL

JOINTSPINE

ALL

FEATURE TEST FEATURE TEST

Eye Pigment R Eye Nasal PHOTO L Eye Nasal PHOTO

R Eye Temporal PHOTO L EyeTemporal PHOTO

Ear Pigment RIGHT ear PHOTO LEFT ear PHOTO

OCHRONOSIS

Mild (1) Mod (2) Marked (3)

SUPERFICIAL CONJUNCTIVAL PIGMENTATION

Eye scoring

DEEPER SCLERAL PIGMENTATION

Mild (4) Mod (6) Marked (8)

Present (2) Marked (4)

Ear scoring

Data shown

For 2 groups of data

N = 11 – same 11 patients in all visits

N = variable – variable numbers of pairs of data at different visits

Ochronosis data (eye+ear)

ALL AKUSSI data (CLIN+JOINT+SPINE)

ACTUAL SCORES AS BOXPLOTS

RATE OF CHANGE/PATIENT/MONTH AS BOXPLOTS

75th centileMean

Median

90th centile

25th centile

10th centile

B

BB

B B BB

Pre Base Y1 Y2 Y3 Y4 Y5

-5

5

15

25

35

OchronosisSCORES

GROUPN = 11

P<0.002 p<0.06

p<0.004

Base – Pre score

Base - Pre time months

15 - 8

39 months

0.18/month

5y - Base score

5y - Base time

13 - 15

60 months-0.03

Ochronosis ScoresChange per patient per

monthN = 11

B

B B

BB B

P/B B/Y1 B/Y2 B/Y3 B/Y4 B/Y5

-0.25

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

0.15

ALL AKUSSI

Summary of Features

Total 55 (Engl/Scot) 23 Female 52.3+15.8 yrs 32 Male 48.5+14.9 yrs

Asian 17 (Engl/Scot) 6 Female 38.5+13.4 yrs 14 Male 48.4+13.9yrs

Prostate stones 27 (72) 37.5%

Renal stones 22 (ep) 26.4%

Osteopenia 48 (72) 66.7%

Aortic valve disease (Scl/Mild/Mod/Severe) 26/10/2/4 58.3%

Fractures 46 (72)

Ruptures (ligament,tendon,muscle) 45 (72)

Joint replacements (in 26 patients) 92 (72)

FEATURE TEST FEATURE TEST

Eye Pigment R Eye Nasal PHOTO L Eye Nasal PHOTO

R Eye Temporal PHOT L EyeTemporal PHOTO

Ear Pigment RIGHT ear PHOTO LEFT ear PHOTO

Prostate Stones (4 per

episode)

US/HIS

T

Kidney Stones (4 per

episode)

US/HIST

Osteopenia (4) CT-

BMD

Hearing impairment

(4)

HIST

Aortic sclerosis (6), Aortic stenosis (mild, moderate,

severe) (8,10,12)

ECHO

Fracture (8 per #) HISTO

RY

Muscle rupture (8

per rupture)

HISTORY

Ligament rupture (8 per

rupture)

HISTO

RY

Tendon rupture (8

per rupture)

HISTOR

Y

CLINICAL AKUSSI

JOINT AKUSSI TEST

JOINT PAIN score (1 for each large joint area; 14

large joint areas)

HISTORY

Scintigraphic scan joint score (2 for each large

joint; 14 large joints areas)

PET

Number of joint replacements Each joint 4 HISTORY

SPINE AKUSSI TEST

SPINAL PAIN score (2 each for cervical,

thoracic, lumbar, sacroiliac)

HISTORY

Scintigraphic scan spine score (6 areas; 4

point for each area; pubic symphysis,

costochondral, Lumbar, Thoracic, Cervical,

Sacroiliac)

PET

ALL AKUSSI

B

B B B B B B

Pre Base Y 1 Y 2 Y 3 Y 4 Y 5

0

20

40

60

80

100

120

140

160

180

ALLAKUSSI SCORES

GROUPN = 11

P<0.002

ALL AKUSSISCORES

Change per patient per

monthN = 11

B

B

B B BB

P/B B/Y1 B/Y2 B/Y3 B/Y4 B/Y5

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Echocardiographic findings

• Left ventricular systolic function was normal, except in the single patient with frequent RVOT VEs

• No significant mitral valve disease was seen

• No aortic root dilatation was seen

• Calcific aortic valve disease was common, despite absence of previous history of VHD

Aortic sclerosis 13 patients (35%)

Definite aortic stenosis 9 patients (24%)

Moderate aortic regurgitation 2 patient

Pettit SJ, Fisher M, Gallagher JA, Ranganath LR

J Inherit Metab Dis. 2011;34:1177-81.

Helliwell TR, Gallagher JA, Ranganath L.

Histopathology. 2008;53:503-12.

Progression of aortic valve disease

Pettit SJ, Fisher M,

Gallagher JA,

Ranganath LR

J Inherit Metab Dis.

2011;34:1177-81.

Correlation between Age and Peak Aortic Velocity (Orginal Cohort)

R2 = 0.62

Current Cohort (Nov 2017)

• Patients with at least 2 evaluable echocardiograms – N = 44

• Peak aortic velocity used as a measure of degree of stenosis

• Progression index calculated according to the formula:

(AoVmax2 – AoVmax1/Days)*100

Progression vs. Regression

REGRESSED Progressed

On 13 25

Not 1 5

Chi Square p = 0.39

Degree of Progression

On Nitisinone – 0.66 (3.64)

Off Nitisinone – 4.51 (3.39)

T-test – p = 0.038

What is Clinical Gait Analysis?

• 60 patients tested since 2013

• 12 are on their 5th repeated GA visit

• Detailed analysis of each individual’s gait

• Focus on cause-effect mechanisms

• Temporal and spatial charts

• Movement Deviation Profile (Barton et al 2015) – REF 2014: 4* Rating

• Detailed summary – GPs/local physiotherapist

2017 Progress Update

0

1

2

3

4

0

1

2

3

4

10 20 30 40 50 60 70 80

MD

Pm

ean

Age (years)

Deviation of AKU gait from normality (Barton et al., 2015)

Controls mean Controls

Controls mean ±SD AKU population

Your results (3 walks)

Conclusion (1)• Use of unlicensed nitisinone well tolerated and safe

• Data suggests ochronosis is slowed if not partially reversed

• Experience suggests clinical outcomes (AKUSSI, all components) are slower in terms of progression after nitisinone

• Aortic stenosis appears to progress slower after nitisinone

• Gait appears to be altered early despite minimal external ochronosis – may indicate ochronosis proceeding at the different rate in loaded osteoarticular tissue

Conclusion (2)

• Insights gained in AKU is also informing of osteoarthritis

• Knowledge of natural history and modification by therapy in younger patients requires a specialised centre approach where long term follow up is possible

USA:

Portland: M Grompe, Ms N Paulk

NIH : W Wintrone, W Gahl

Spain:

Dr Fernandez-Canon (Leon)

Italy:

Annalisa Santucci, L Tinti

Poland: Histology

UK:(Clinical)

Royal Liverpool University Hospital:

Clin Chem:L Ranganath, A Milan, A Hughes, A

Davison, J Devine, J Usher,

NAC Coordination: H Washington, P Drane

Orthopaedics: J Davidson

Rhuematology:A Daroszewska

Cardiology: M Fisher

ENT: M McCormick

Ophthalmology: M Briggs

Radiology: A Dunn

Phyiotherapy: S Taylor, N Loftus

Dietetics: S Judd

Pain relief management: A Jones

Dermatology: L West, G Sharpe

Medical Photography: J Soden

Clinical Gait Analysis: GJ Barton, H Shepherd,

S King

Nuclear Medicine: S Vinjamuri

Nurses: E Luangrath, H Bygott, G Bretland

Patients (and surgeons) providing surgical

samples

Mrs B from Sleaford and other patients

R Gregory N Sireau, Lord Ward-Atherton

Sponsors:

NHS England Highly Specialised Services

European Union

National Lottery UK

University of Liverpool

Royal Liverpool University Hospital

Swedish Orphan

Research team in University of Liverpool:

L Ranganath,

JA Gallagher,

G Bou-Gharios,

J Jarvis,

E Lock,

H Sutherland,

P Wilson,

C Keenan,

J Dillon,

L Taylor,

B Norman,

J Hughes,

M Khedr

AM Taylor

Acknowledgements

AKU Society of the UK

N Sireau

OG Timmis

L Harrison,

C Scott

R Munro

E Whitley

S Roberts

L Powell

Y Ayoob

Thank you for your attention