Understanding Clinical Trials: Information is key to success Bruce M. Wentworth, PhD PPMD, June 24, 2010, Denver bruce.wentworth@genzyme.com
The concept of a clinical trial is simple‌
Preclinical testing
Develop understanding of drug mechanism, potential for efficacy, dose, and evidence for toxicity Phase 1
Demonstration of safety
The hypothesis generating phase
Phase 2
Demonstrate how drug is to be employed
Determine appropriate dose and gain evidence for efficacy Phase 3
Confirmatory studies
Seek Approval
However, the reality is often very complex ... Discovery
Lengthy
Clinical Research
Preclinical Development
Preclinical Research
Pivotal Trials
regulatory review
6.8 yrs
4.3 yrs
Post-Approval Studies
1.3 yrs
12.4
Years
w/o failures $170M
Costly
Risky
w/ failures w/ failures
$560M $1.2B
(11.5% Discount Rate)
very low preclinical success rate
30.2% clinical success rate 85% ph1 to ph 2
45% ph2 to ph3
70% ph3 to approval
Success is rare! *Recent Biotechnology industry metrics, small molecule drug metrics are similar
Center for Study of Drug Development, Tufts University, 2006
Phase II is the drug killer  66% of drugs entering phase II fail prior to phase III ZAP
Paul, SM et al Nature Reviews Drug Discovery, March 2010
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 1.0 0.9
Survival at 12 mos.: Survival at 24 mos.: Survival at 36 mos.:
0.8
Surviva l
0.7
26% 9% 7%
0.6 0.5 0.4 0.3 0.2 0.1
0.0 0
6
12
18
24
30
36
Age (months) Genzyme study (n=163), Kishnani et al J Ped 2006
42
48
54
60
Alglucosidase Alfa (GAA) Molecular Complexity P
significant glycan structures / site
1
2
3
4
5
6
7
10
10
5
11
4
7
10
~ 1.54 x 106 possible variants
rhGAA Glycans Vary With Source some M6P P
little terminal mannose
CHO- rhGAA
more sialic acid more M6P; GlcNac capped
P
P
tgGAA
more terminal mannose less sialic acid P P
P
P
P
P
P
most M6P
P
HP-GAA 1
2
3
4
5
6
7
most terminal mannose not sialylated
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
KO Mouse; 5-10% Tissue Glycogen
Human Pompe; 30-60% Tissue Glycogen
Comparison of tgGAA, CHO GAA, and HP-GAA in KO Mice McVie-Wylie et al, Mol Gen Met, 2008
• 4 weekly doses; 3 mo old mice • GAA enzyme activity
300 250 200
20 mg/kg 60 mg/kg 100 mg/kg
150 100 50 0
Pre-dose
Vehicle
tgGAA
CHO-GAA HP-GAA
Quadriceps 600
GAA activity (nmol/hr/mg)
GAA activity (nmol/hr/mg)
Heart
500 400 300 200 100 0
Pre-dose
Vehicle
tgGAA
CHO-GAA HP-GAA
Activity of GAA in Skeletal Muscle: tgGAA > CHO-GAA ~ HPGAA
Clearance of Glycogen by rhGAAs McVie-Wylie et al, Mol Gen Met, 2008
Heart
• 4 weekly doses; 3 mo old mice • MetaMorph glycogen content
16 12
* *
*
10 8
*
6 2
20 mg/kg 60 mg/kg 100 mg/kg
*
*
4
*
0
Pre-dose
Vehicle
tgGAA
CHO-GAA HP-GAA
Quadriceps 8 7
% glycogen
% glycogen
14
6 5
*
4
*
3 2 1 0
Pre-dose
Vehicle
tgGAA
CHO-GAA HP-GAA
“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
Clinical Trial Results in Pompe Infants: confirmation of CHO-GAA selection AGLU01602 (n=18) < 6 months at ERT
AGLU01702 (n=21) 6-36 months at ERT
Start May 2003
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
94%
81%
Measurable Motor Gains
61%
62%
Alive at End of Trial (June 2006)
13 of 18
15 of 21
Parameter
(decrease in LV mass index)
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? Age at Onset of Symptoms Infants
Adults
1 year
Infantile-onset Late-onset
Main Type of Tissue Involved Cardiac and Muscle
Muscle
Amount of Residual GAA Activity (fibroblasts) 40% Minimal/No activity
Measurable activity
MRI reveals loss of muscle in late onset Pompe Early
Late
Intermediate
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
Its difficult to rescue something that is not there Pichiecchio et al Neuromuscular disorders, 2004 Note: This study not connected with the LOTS trial
rhGAA for Late Onset Pompe Disease 8 year old+ ambulatory patients
Mean change in distance walked (m)
• A “modest” positive effect
Mean change in % of predicted FVC
rhGAA demonstrated value in the treatment of late-onset patients: • Improved & maintained walking distance and breathing function Van der Ploeg, AT et al NEJM April 2010
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? Muscle is lost and replaced by fatty infiltration Right Thigh
Hip region
Knee region
Marden et al Skeletal Radiology 2005
gluteus maximus
The 6MWT test records the state of muscle function in DMD patients as a function of time
But, results 6 Min Walk Distance (m)
interpretation may require the “complete data picture” in myopathies where muscle has been lost.
Age (y)
McDonald et al Muscle & Nerve 2010
Why use the 6MWT in Pompe and other diseases?
ď&#x201A;§â&#x20AC;ŻAnswer: 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