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Understanding the Process of Clinical Trials presented by Bruce Wentworth at PPMD's 2010 Annual Connect Conference
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Bruce M. Wentworth, PhD PPMD, June 24, 2010, Denver [email protected]
Understanding Clinical Trials:
Information is key to success
The concept of a clinical trial is simple…
Preclinical testing
Phase 1
Phase 2
Phase 3
Develop understanding of drug mechanism, potential for efficacy, dose, and evidence for toxicity
Demonstration of safety
Determine appropriate dose and gain evidence for efficacy The hypothesis generating phase
Confirmatory studies
Demonstrate how drug is to be employed
Seek Approval
Center for Study of Drug Development, Tufts University, 2006
However, the reality is often very complex ...
12.4 Years
85% 45% 70% ph1 to ph2 to ph3 to ph 2 ph3 approval
1.3 yrs
Post-Approval Studies Discovery
Preclinical Research
Preclinical Development
Pivotal Trials
Clinical Research
4.3 yrs 6.8 yrs Lengthy
Costly
w/o failures $170M w/ failures $560M w/ failures $1.2B (11.5% Discount Rate)
Risky 30.2% clinical success rate
very low preclinical
success rate
Success is rare!
regulatory review
*Recent Biotechnology industry metrics, small molecule drug metrics are similar
Phase II is the drug killer
66% of drugs entering phase II fail prior to phase III
Paul, SM et al Nature Reviews Drug Discovery, March 2010
ZAP
Why is this process so costly?
Can we “de-risk” it through better informed choices?
The problem is …. We don’t know enough!
Consider Pompe Disease
Cause GAA (acid maltase) gene mutation; null or ↓activity
Inheritance autosomal recessive
Prevalence ~ 1/40,000
Disease phenotype glycogen accumulation disruption of cellular architecture muscle wasting and weakness, hypotonia
Clinical Presentation “floppy baby” considerable variability often misdiagnosed adults
Treatment Approaches ERT, palliative care, diet & exercise
Emerging Strategies 2 gen. ERT, etc.
Infantile Pompe Is a Fatal Disease
Age (months) 0 6 12 18 24 30 36 42 48 54 60
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 S
urvi
val
Genzyme study (n=163), Kishnani et al J Ped 2006
Survival at 12 mos.: 26% Survival at 24 mos.: 9% Survival at 36 mos.: 7%
~ 1.54 x 106 possible variants
Alglucosidase Alfa (GAA) Molecular Complexity
P
10 10 5 11 4 7 10 significant glycan structures / site
1 2 3 4 5 6 7
rhGAA Glycans Vary With Source
some M6P little terminal mannose more sialic acid
most M6P most terminal mannose not sialylated
more M6P; GlcNac capped more terminal mannose
less sialic acid
HP-GAA
1 2 3 4 5 6 7
P P
P P
P P P
P
tgGAA
CHO- rhGAA
P
P P
6neo/6neo Pompe mouse model: the tool of choice in selecting rhGAA
6neo/6neo mouse; Nina Raben, NIH
Mice lack enzyme activity and accumulate glycogen similar to the human form of Pompe disease
Onset of clinical phenotype at 6-8 months of age
Human Pompe; 30-60% Tissue Glycogen KO Mouse; 5-10% Tissue Glycogen
• 4 weekly doses; 3 mo old mice • GAA enzyme activity
McVie-Wylie et al, Mol Gen Met, 2008
Activity of GAA in Skeletal Muscle: tgGAA > CHO-GAA ~ HPGAA
20 mg/kg 60 mg/kg 100 mg/kg
Comparison of tgGAA, CHO GAA, and HP-GAA in KO Mice
Quadriceps
0 100 200 300 400 500 600
Pre-dose Vehicle tgGAA CHO-GAA HP-GAA GA
A ac
tivity
(nm
ol/h
r/mg)
Heart
0 50
100 150 200 250 300
Pre-dose Vehicle tgGAA CHO-GAA HP-GAA
GA
A ac
tivity
(nm
ol/h
r/mg)
Clearance of Glycogen by rhGAAs
• 4 weekly doses; 3 mo old mice • MetaMorph glycogen content
McVie-Wylie et al, Mol Gen Met, 2008
20 mg/kg 60 mg/kg 100 mg/kg
Quadriceps
0 1 2 3 4 5 6 7 8
Pre-dose Vehicle tgGAA CHO-GAA HP-GAA
% g
lyco
gen
* *
*
Heart
0 2 4 6 8
10 12 14 16
Pre-dose Vehicle tgGAA CHO-GAA HP-GAA
% g
lyco
gen *
* *
* *
*
“Mother of all experiments” conclusion
All 3 drug candidates “worked”, but,
The drug that got to the heart the best was not the drug that cleared glycogen the best
Clearance of skeletal muscle glycogen:
CHO rhGAA > HP-GAA > tgGAA
Parameter AGLU01602 (n=18) < 6 months at ERT
Start May 2003
AGLU01702 (n=21) 6-36 months at ERT
Start March 2003
Alive 72% at 36 months age ↓risk of death by 95%
71% at study end ↓risk of death by 58%
Alive without Invasive Ventilator Support
49% at 36 months age ↓risk of inv. vent. by 91%
44% at study end ↓risk of inv. vent. by 58%
Reversal of Cardiomyopathy
(decrease in LV mass index) 94% 81%
Measurable Motor Gains 61% 62%
Alive at End of Trial (June 2006)
13 of 18 15 of 21
Clinical Trial Results in Pompe Infants: confirmation of CHO-GAA selection
Kishnani et al, Neurology, 2007, BMRA Group
Conclusion: Mechanisms matter in selecting rhGAA for treatment of Pompe disease
We needed to understand the differences in activity of the 3 sources of rhGAA
• Before clinical development !
What about late onset Pompe patients?
40%
Infants Adults 1 year
Minimal/No activity Measurable activity
Cardiac and Muscle Muscle
Infantile-onset Late-onset
Age at Onset of Symptoms
Main Type of Tissue Involved
Amount of Residual GAA Activity (fibroblasts)
MRI reveals loss of muscle in late onset Pompe
57 yo F Onset @ 50 yo FN stage 8
39 yo F Onset @ 26 yo FN stage 4
57 yo F Onset @ 37 Fn stage 8
Early Intermediate Late
Pichiecchio et al Neuromuscular disorders, 2004 Note: This study not connected with the LOTS trial
Its difficult to rescue something that is not there
rhGAA for Late Onset Pompe Disease
8 year old+ ambulatory patients
• A “modest” positive effect
Mean change in distance walked (m)
Mean change in % of predicted FVC
Van der Ploeg, AT et al NEJM April 2010
rhGAA demonstrated value in the treatment of late-onset patients: • Improved & maintained walking distance and breathing function
A possible explanation for the modest response of GAA in the late onset patients
Patients present late in disease progression after damage has been done
• So, they should be treated earlier, as soon as the disease is diagnosed, to prevent further damage
The 6MWT may be a challenging assessment in patients with significant muscle loss
• This could have implications for other myopathies
What about DMD?
Marden et al Skeletal Radiology 2005
Right Thigh
Hip region
Knee region
Muscle is lost and replaced by fatty infiltration
gluteus maximus
The 6MWT test records the state of muscle function in DMD patients as a function of time
6 M
in W
alk
Dis
tanc
e (m
)
Age (y)
But, results interpretation may require the “complete data picture” in myopathies where muscle has been lost.
McDonald et al Muscle & Nerve 2010
Why use the 6MWT in Pompe and other diseases?
Answer: Time
Declining ambulatory function is an important functional characteristic of Pompe and other myopathies
The 6MWT is a validated test accepted by regulatory authorities
Time spent developing new functional assays with uncertain outcome can also be spent in the clinic testing the drug in question
Take home message: learn as much as possible before clinical trial
The attrition rate for drug candidates during clinical development is high.
The successful approval of Myozyme depended upon understanding • the complexity of biochemical mechanisms, and, • the molecular and functional basis for efficacy
Sole reliance on the 6MWT may present challenges in chronic myopathies where muscle is lost
Acknowledgements
Genzyme • Alan Smith • John McPherson • Robert Mattaliano • Mike O’Callaghan • Seng Cheng • Allison McVie-Wylie • William Abernathy • Gavin Malenfant • The many members
of the Pompe team
Colleagues at PTC
Parent Project Muscular Dystrophy