Gene Therapy Case Studies - ema.europa.eu · Session 4: Gene Therapy - Case Study 1 Author: Gopalan...
Transcript of Gene Therapy Case Studies - ema.europa.eu · Session 4: Gene Therapy - Case Study 1 Author: Gopalan...
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© Crown copyright 2005
Safeguarding public health
Gene TherapyCase Studies
Dr Gopalan Narayanan, MHRACAT-ESGCT WORKSHOP ATMPs: from regulation to reality27th October 2011, Brighton, UK
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Slide 2
27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
DISCLAIMER
The views expressed are mine and not to be taken as representative of MHRA/EMA
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27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
Gene Therapy License Applications
• Experience to date:- Sitimagene ceradenovec (Cerepro) - Contusugene ladenovaec (Advexin) x2- Alipogene tiparvovec (Glybera)
• All products received negative opinion
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27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
Contusugene ladenovaec
• Adenovirus with P53 gene
• Indicated for recurrent/refractory head and neck cancer
• CHMP opinion- Not shown to be beneficial- Insufficient evidence to demonstrate the product was
· Safe· Could be made reliably· Not harmful to the environment
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Slide 5
27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
Cerepro
• Adenovirus with thymidine kindase gene
• Indicated for high-grade glioma
• CHMP/CAT opinion- Not demonstrated to be effective- Increased risk of serious AEs eg, hemiparesis, seizures- Side effects a concern, considering the lack of proved efficacy
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27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
Fictionase deficiency syndrome
• Muscle pain and weakness, lethargy, fatigue
• Debilitating, but near normal life-span
• Prevalence 510/million
• No specific licensed treatment
• NSAIDs used with some success
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27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
Product
• Retrovirus with fictionase gene
• Currently in Phase III with pre-commercial product
• 10% process and product related impurities
• Non-clinical: no oncogenicity seen in immunocompromisedanimals
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Slide 8
27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
Clinical trial
• 40 patients
• Single-arm trial
• Multiple intramuscular injections over 3 days
• Follow-up data up to 1 year for all patients
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Slide 9
27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
End-points
• Fictionase levels in blood
• Gene expression in muscles
• Muscle strength
• 6-minute walking test
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27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
Results
• Doubling of fictionase levels at 3 and 6 months, but decreasing at 12 months
• Gene expression +ve in 50% muscle biopsy samples
• Muscle strength and 6-MWT increased by 25% at 6/12
• Not statistically significant
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Slide 11
27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
Safety
• Infusion reaction in 80% of patients
• Muscle pains with raised CK in 50%
• Joint pains 30%
• Raised LDL-C 20%
• 1 case of anaphylactoid reaction
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Slide 12
27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
Immunogenicity
• Low titre IgG Ab in 90%
• T-cell immunity in 40%
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27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
Aspects to resolve
• Quality comparability issue• Effect of impurities• Tumourigenicity• Limited exposure• Fictionase levels• 25% clinical benefit clinical relevance• Increase in LDL• Anaphylactoid reaction
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Slide 14
27th October 2011Dr Gopalan Narayanan
CAT-ESGT WORKSHOP ATMPs: from regulation to reality
© Crown copyright 2005
Aspects to be further addressed
• Overall impact on patient’s life
• Is readministration possible?
• Effect of immunogenicity
• Long-term safety, including tumour risk
• Plans to demonstrate comparability