How expert centres can contribute to real- world evaluation of drugs for rare disease Case study – The National Alkaptonuria Centre Professor Lakshminarayan Ranganath Clinical Director of the National Alkaptonuria Centre Sir Archibald Garrod 1857-1936 Gregor Johann Mendel (1822 – 1884)
41
Embed
How expert centres can contribute to real- world ... · Eye Pigment R Eye Nasal PHOTO L Eye Nasal PHOTO R Eye Temporal PHOT L EyeTemporal PHOTO Ear Pigment RIGHT ear PHOTO LEFT ear
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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
• 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