A Phase 1/2 Study of High-dose Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure

Heart failure (HF) is a disabling chronic disease and the most frequent discharge diagnosis
for hospitalization among older adults.The American Heart Association (AHA) 2006 update on
heart disease reported that 5 million Americans are believed to have symptomatic HF, and
550,000 patients are newly diagnosed each year. The estimated direct and indirect cost of HF
in the United States (U.S.) for 2006 was ~$29.6 billion. Despite the significant resources
expended on the treatment of this disease, outcomes remain poor. The five-year survival for
individuals diagnosed with HF is less than 50%, and in end-stage HF, the one-year survival
may be as low as 25% regardless of medical therapy.

Recent studies suggest that the failing heart is not refractory to treatment, as was
previously believed. For example, the observation that a small percentage of subjects with
left ventricular assist devices can be permanently weaned from their device strongly
suggests that damaged hearts are capable of recovering lost function.

Celladon Corporation (Celladon) is investigating gene transfer as a method to restore
calcium ion (Ca++) cycling in HF patients. The gene therapy vehicle uses a recombinant
adeno-associated viral vector (AAV), which consists of an AAV serotype 1 capsid and contains
the human sarcoplasmic reticulum Ca++ ATPAse (SERCA2a) complementary DNA (cDNA) flanked by
inverted terminal repeats derived from AAV serotype 2 (AAV1/SERCA2a). MYDICAR® refers to
AAV1/SERCA2a drug product intended for administration by percutaneous delivery. Phase 1/2
clinical trials have demonstrated initial safety and evidence of improvement in clinical
outcomes at MYDICAR doses of up to 1 x 10^13 DNase-resistant particles (DRP). The trial
described here is designed to investigate the safety profile and preliminary activity of
MYDICAR at a dose of 2.5 x 10^13 DRP; this dose is 2.5-fold higher than previously
investigated doses.

Inclusion Criteria:

- Unless otherwise specified, screening must be performed within 30 days prior to
enrollment (phase 1) or enrollment/randomization (phase 2) except as noted below.
Subjects must meet the following criteria to be eligible for the study:

1. AAV1 neutralizing antibodies (NAb) negative (titer <1:2 or equivocal) within 60
days prior to screening.

2. Age 18-80 years, inclusive, at the time of signing the first informed consent.

3. Chronic ischemic or non-ischemic cardiomyopathy, except for hypertrophic
cardiomyopathy. Toxic or alcoholic cardiomyopathies are allowed as long as toxin
or alcohol exposure has been eliminated and a sufficient amount of time has
elapsed to rule out spontaneous recovery. Similarly, patients with viral or
peripartum cardiomyopathy will not be enrolled until sufficient time has elapsed
to rule out spontaneous recovery. Subjects with ischemic cardiomyopathy must
have at least 1 major coronary vessel with thrombolysis in myocardial infarction
(TIMI) grade 3 flow. (If a subject has not undergone recent coronary
angiography, TIMI flow may be assessed during the study angiography just prior
to investigational medicinal product [IMP] infusion).

4. Left ventricular ejection fraction ≤35%.

5. Diagnosis of New York Heart Association class III/IV heart failure (HF) for a
minimum of 60 days prior to screening.

6. For phase 2 only, the presence of at least one of the following risk factors:

1. Hospitalization for HF within 6 months of screening, or in lieu of
hospitalization, at least 2 outpatient interventions for the intended
treatment of signs and symptoms of worsening HF (e.g., intravenous [IV]
diuretics, peripheral ultrafiltration).

2. N-terminal prohormone brain natriuretic peptide (NT-proBNP) >1200 pg/mL
within 30 days of screening; if subject is in atrial fibrillation,
NT-proBNP >1600 pg/mL within 30 days of screening.

7. Individualized, maximal, optimized HF therapy consistent with American College
of Cardiology/American Heart Association practice guidelines for the treatment
of chronic heart failure (ACC/AHA HF guidelines) and as updated from time to
time:

1. Medical therapy, as appropriate to the individual subject, including oral
diuretic, angiotensin-converting enzyme (ACE) inhibitor or, if ACE
intolerant, angiotensin-receptor blocker and beta blocker at approved
dosages as labeled in the respective package insert and optimized for the
subject.

- The choice of beta blocker is limited to those approved for HF
(bisoprolol, carvedilol or metoprolol succinate). Metoprolol tartrate
is not approved for HF and is not allowed.

- Unless contraindicated or not tolerated, the addition of an
aldosterone antagonist should be considered in the absence of
hyperkalemia and significant renal dysfunction and according to
evolving standards. However, the final decision is at the discretion
of the investigator.

- Dosing of the above medications must be stable for a minimum of 30
days prior to screening, although up- or down-titration of diuretics,
as medically indicated, is permitted.

- Patients requiring IV diuretics during this period will be required to
undergo an additional 30 day period of stabilization on oral
diuretics.

- Enrollment of any subject with any deviation from these criteria must
be preapproved by the medical monitor.

2. Resynchronization therapy, if clinically indicated according to ACC/AHA HF
guidelines, must have been initiated at least 6 months prior to screening.

3. If the subject is already participating in a cardiac rehabilitation
program, it should be consistent with the current clinical practice and
guidelines and continue at least through the 12-Month Active Observation
Period. This does not imply that the potential candidate must be enrolled
in a cardiac rehabilitation program at screening or in the future.

8. Implantable cardioverter defibrillator is required and must have been implanted
a minimum of 30 days prior to screening.

9. All male subjects regardless of fertility status or the fertility status of
their partner must agree to use a condom and spermicide during any sexual
relations for 6 months following IMP administration to protect their partner
from potential viral shedding.

10. All subjects regardless of fertility status or the fertility status of their
partner must agree to have any male partner use a condom and spermicide during
any sexual relations for 6 months following IMP administration to protect their
partner from potential viral shedding.

11. All subjects capable of procreation with their partners must agree to use
adequate contraception for 6 months following IMP administration to avoid
pregnancy (defined as oral or injectable contraceptives, intrauterine devices,
surgical sterilization in addition to/or a combination of a condom and
spermicide).

12. Agree to not donate sperm or oocytes for 6 months following IMP administration.

13. Ability to sign Informed Consent Form and Release of Medical Information Form.

Exclusion Criteria:

- Subjects meeting any of the following criteria will be excluded from the study:

1. De novo diagnosis of heart failure.

2. Any IV therapy with positive inotropes, vasodilators or diuretics within 30 days
prior to screening or enrollment.

3. Restrictive cardiomyopathy, obstructive cardiomyopathy, acute myocarditis,
pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected
thyroid disease or discrete left ventricular aneurysm.

4. Cardiac surgery, percutaneous coronary intervention, valvuloplasty or valve
replacement within 30 days prior to screening.

5. Myocardial infarction (e.g., ST elevation myocardial infarction [STEMI] or large
non-STEMI) within 90 days prior to screening. Large non-STEMI shall be defined
>3x the upper limit of normal (ULN) for creatinine kinase test or >5x ULN for
troponin.

6. Prior heart transplantation, left ventricular reduction surgery (LVRS),
cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support
Device), mechanical circulatory support device (MCSD) or cardiac shunt.

7. Likely to receive cardiac resynchronization therapy, cardiomyoplasty, LVRS,
conventional revascularization procedure or valvular repair in the 6 months
following treatment.

8. Likely need for an immediate heart transplant or MCSD implant due to hemodynamic
instability.

9. Prior coronary artery bypass graft(s) is not necessarily exclusionary. A
potential candidate should be reviewed on a case-by-case basis by the treating
interventionist, taking into account the dominance of the system, the
accessibility of the graft(s) orifice, and the contribution of the graft
vessel(s) and native coronary arteries to viable myocardial perfusion. The case
and tentative infusion strategy must be discussed with the medical or safety
officer prior to enrollment of the subject into the study.

10. Known hypersensitivity to radiopaque agents used for angiography; history of or
likely need for, high dose corticosteroid pretreatment prior to contrast
angiography.

11. Significant, in the opinion of the investigator, left main or ostial right
coronary luminal stenosis.

12. Liver function tests (alanine aminotransferase, aspartate aminotransferase,
alkaline phosphatase) >3x ULN, total bilirubin >2x ULN or known intrinsic liver
disease (e.g., cirrhosis, chronic hepatitis B or hepatitis C virus infection).

13. Current or likely need for hemodialysis within 12 months following enrollment or
current glomerular filtration rate (GFR) ≤20 mL/minute/1.73 m^2 estimated by
Modification of Diet in Renal Disease (MDRD) formula for calculating the GFR
MDRD calculation.

14. Bleeding diathesis or thrombocytopenia defined as platelet count <75,000
platelets/μL.

15. Anemia defined as hemoglobin <9 g/dL.

16. Diagnosis of, or treatment for, any cancer within the last 5 years except for
basal cell carcinoma or carcinomas in situ where surgical excision was
considered curative. (Past medical history of cancer is not exclusionary as long
as the subject has been disease free for at least 5 years since the time of
diagnosis and treatment).

17. Previous participation in a study of gene transfer; however, if the study was
unblinded or documentation otherwise exists that the subject was randomized to
the placebo control group and did not receive active gene transfer agent, the
subject may be considered for this study.

18. Receiving investigational intervention or participating in another clinical
study within 30 days or within 5 half-lives of the drug prior to screening.
Exception may be made if the individual is enrolled in a non-therapeutic
observational study (registry) or the observational portion of a therapeutic
study where the sponsoring authority authorizes enrollment.

19. Pregnancy or lactation.

20. Recent history of psychiatric disease (including drug or alcohol abuse) that is
likely to impair subject's ability to comply with protocol-mandated procedures,
in the opinion of the investigator.

21. Other concurrent medical condition(s) that, while not explicitly excluded by the
protocol, could jeopardize the safety of the patient or objectives of the study.