1

Effects of IPLEX in Myotonic Dystrophy Type 1 (DM1)

Muscle Study Group Annual Meeting9/16/2008,

Beaver Hollow, NY

Richard T. Moxley, III, MD

2

University of Rochester Medical Center Principal investigator: Richard Moxley, III, MD Co-investigators: Charles Thornton, MD, Chad Heatwole, MD, Rabi

Tawil, MD, Eric Logigian, MD, Stephen Welle, PhD Biostatistician : Michael McDermott, PhD Clinical Evaluator: Shree Pandya, MS, PT and Katy Eichinger, PT Study coordinators: Jim Hilbert, MS, Christine Quinn, MS and Alexis

Smirnow Data management: Bill Martens. Research administration: Nancy Merriman and Tracy Forester Research assistants: Roxanne Cannarozzo and Karen Berk. Neuro-Ophthalmology: Deborah Friedman, MD

University of Texas Health Science Center, San Antonio. Independent Medical Monitor: Carlayne Jackson, MD

Acknowledgements

3

Acknowledgements

NIH Wellstone Muscular Dystrophy Cooperative Research Center (MDCRC) staff, leaders, and members of the DSMB.

4

Muscle Wasting in DM1 Proposed causes:

Insulin resistance, gonadal insufficiency, decreased growth hormone release.

Unsuccessful trials of insulin, testosterone, and recombinant human growth

factor (rhGH).

Promising results of rhIGF-1 (recombinant human insulin like growth factor) (Vlachopapadopoulou, 1995),

Improved insulin action, decreased body fat, increased plasma testosterone (n=7),

But, clinically significant side effects and short half-life.

5

Insulin Like Growth Factor 1 (IGF-1)

Family of 6 binding proteins (BPs): At least 5 of 6 BP’s form binary complex with

IGF-1. Ternary complex comprised of IGF-1, IGFBP-3,

and an acid-labile subunit (ALS).

95% of circulating IGF-1 is bound to ternary complex.

Small fraction of IGF-1 is unbound or “free” in circulation.

6

IGF Schematic: figure from Denley at el. (2005).

7

Background: IPLEX

IPLEX (Insmed, Inc) is rhIGF-1 complexed to rhIGF-BP3 Longer half-life and better safety profile compared to

rhIGF-1.

IPLEX has been well-tolerated and effective in: Severe primary IGF-1 deficiency, HIV associated adipose redistribution syndrome

(HARS), Severe insulin resistance, Insulin dependent type-II diabetics, Elderly women with hip fractures.

8

Innovative Approach

Preparation of IGF-1 that may bypass insulin resistance and other anabolic defects that hamper muscle loss in DM1.

9

Study Design

Primary Aim: To determine safety and feasibility of daily SC injection of IPLEX as treatment for muscle wasting and weakness in DM1.

Subjects: 15 DM1 patients (21-60 yrs of age) each for initial “Dose Escalation” trial.

10

0 8 2416 28 40

WEEKS

2 4 6 181210 14 20 22

Design for 24 week Dose Escalation Trial of IPLEX

IPLEX 0.5 mg/kg

IPLEX 1.0 mg/kg

IPLEX 1.0 mg/kg

Off study drug

IPLEX 2.0 mg/kg

11

Cohort of Patients Cohort 1: Completed pilot study (n=6).

8 weeks of 0.5 mg/kg/day and 16 weeks of 1.0 mg/kg/day of IPLEX.

DSMB requested that we obtain data on the relationship between blood levels of IGF-I (at 0.5 mg/kg/day and 1.0 mg/kg/day) and any adverse events before moving to a 3-step dose escalation.

Cohort 2: Completed dose escalation of 0.5, 1.0, 2.0 mg/kg/day (8 weeks each) of IPLEX (n=9).

12

Outcome Measures

Primary: Safety and tolerability.

Secondary: clinical laboratory data, lean body mass and fat mass (DEXA), muscle strength (QMA and MMT), myotonia (grip and electrically evoked), IGF-1, IGF-2, and IGF-BP3 levels, gastrointestinal and

cognitive measurements.

13

Timeline 2003-2005

Completed start-up procedures, manual, etc.

2005-2007 Enrolled patients.

September 2007 Presented at the 6th International Myotonic Dystrophy

Consortium (IDMC) Meeting; Presented preliminary data on the first 6 patients.

April 2008 Completed all treatment and post-treatment visits.

14

Results

Adverse Events and safety profile.

Total and free IGF values.

Muscle mass as measured by DEXA.

15

Adverse Events (AE)

1 serious AE (SAE) occurred in the off-drug phase: deemed unrelated (gallbladder removed).

No SAEs related to study drug.

1 moderate, possibly related AE: papilledema and intracranial hypertension that

resolved without sequelae.

16

Adverse Events 103 mild AEs:

42% (n=44/105) were not related, 45% (n=47/105) were possibly related, 13% (n=14/105) were probably related.

14 AEs probably related to study drug: 2 AEs of light headedness, 3 AEs of hypoglycemia, 9 injection site reactions (n=8 patients).

17

Safety Profile

Of the 9 injection site reactions, 7 occurred at first dose (0.5 mg/kg/day); 2 occurred at second dose (1.0 mg/kg/day); 0 occurred at third dose (either 1.0 or 2.0

mg/kg/day).

Laboratory and imaging results indicated IPLEX was safe and well tolerated.

18

0

100

200

300

400

500

600

Base 8 wks 16 wks 24 wks 24wks post 4 post 16

To

tal I

GF

-1 (

ng

/mL

)Fig 1: Mean total IGF-I levels analyzed. Mean normative range indicated as dashed line; 100 – 308ng/mL (Esoterix).

Total IGF-1 values

0.5 mg/kg 1.0 mg/kg 1.0 mg/kg 2.0 mg/kg

n=15

n=15n=15 n=5 n=9

n=15 n=15

19

0

1

2

3

4

5

6

Base 8 wks 16 wks 24 wks 24wks post 4 post 16

Fre

e IG

F-1

(n

g/m

L)

Fig 2: Mean free IGF-I levels analyzed to date. Mean normative range indicated as dashed line; 0.65 – 5.2ng/mL (Juul et al., 1997).

Free IGF-1 values

0.5 mg/kg 1.0 mg/kg 1.0 mg/kg 2.0 mg/kg

n=15

n=15 n=15 n=5 n=9

n=15 n=15

20

Lean Muscle Mass: Cohort 1

718 712

-219

1123 *

1363 *

-500

0

500

1000

1500

2000

Lean Mass (g)

Fig 3: Change in mean lean muscle mass (g) compared to baseline and measured by Dual Energy X-ray Absorptiometry (DEXA) (n=6). * p<0.05

On IPLEX

Off IPLEX

8 wks Post 16 wks

16 wks 24 wks Post 4 wks

21

1882 *

879

12801240

2275 *

0

500

1000

1500

2000

2500

3000

8 wks 16 wks 24 wks Post 4wks

Post 16wks

Lean Mass (g)

On IPLEX

Off IPLEX

Lean Muscle Mass: Cohort 2 Fig 4: Change in mean lean muscle mass (g) compared to baseline and measured by Dual Energy X-ray Absorptiometry (DEXA) (n=9). * p<0.05

22

Summary IPLEX was safe and well-tolerated in DM1

(n=15 patients).

Encouraging trends in a variety of endpoint measures, including patient reported outcomes.

23

A Catalyst For Future Study

These initial pilot studies have led to a multi-center collaborative study using methods established by our NIH Wellstone MDCRC dose escalation trial.

24

Phase II Trial

Led by Insmed, Inc, with funding through Insmed and Muscular Dystrophy Association (MDA) Translational Research Corporate Grant.

12 sites participating in the randomized, placebo-controlled, double-blind clinical study of IPLEX in ~70 DM1 patients.

25

0 8 2416

WEEKS

4 12 20

IPLEX 1.0 mg/kg/day

or placebo

Study DesignEndpoints:

Endurance Ambulation Cognitive function Insulin resistance Cholesterol and

triglycerides Muscle function and

strength Pain Gastrointestinal

function Quality of life

26

Progress and Collaborations

Current Phase II trial is beyond the scope of traditional Wellstone funding.

NIH Wellstone MDCRC funding has nurtured collaboration between industry, patient advocacy groups, and medical centers.

What other studies can develop?

27

Future Questions

What measures of IGF-1 and/or related proteins best indicate a therapeutic response?

Additional measures may include other IGF BPs, sex steroid BP, growth hormone, and other pituitary-hypothalamic axis hormones.

What are the best endpoint measures in our optimal dose treatment trial?

28

Extra slides, drafts

29

Lean Muscle Mass (Cohort 1)

44.5 44.946.9

44.543.8 43.5

30

35

40

45

50

Baseline 8 wks 16 wks 24 wks Post 4wks

Post 16wks

Lean Mass (kg)

Fig 2: Mean lean muscle mass (kg) as measured by Dual Energy X-ray Absorptiometry (DEXA) (n=5 for week 24; n=6 all other weeks).

On IPLEX

Off IPLEX

30

Lean Muscle Mass (change each visit)

Post 4 wks

24 wks (2.0)

24 wks8 wks

Post 16 wks

16 wks

-1500

-1000

-500

0

500

1000

1500

Lean Mass (g)

Fig 2: Mean lean muscle mass (kg) as measured by Dual Energy X-ray Absorptiometry (DEXA) (n=5 for week 24; n=6 all other weeks).

On IPLEX

Off IPLEX