Understanding the Process of Clinical Trials

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