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Friday, May 11, 2012

RENEW Your Optimism For Aastrom

By Jason Napodano, CFA

Phase 2a DCM Study Encourages

On May 10, 2012, Aastrom Bio presented the 12-month follow up results from the phase 2a dilated cardiomyopathy (DCM) study at the Society for Cardiovascular Angiography and Interventions (SCAI) Scientific Sessions. The data presentation, entitled "Safety and Efficacy of Ixmyelocel-T, An Expanded Patient-Specific Mixed Cell Therapy, in Dilated Cardiomyopathy” highlighted injection of Aastrom’s expanded multicellular therapy using J&J’s NOGA/MyoSTAR transendocardial catheter.

…Design Background…

The phase 2a program enrolled 22 patients with ischemic or non-ischemic DCM that had no other options available for revascularization (meaning the next available options are surgical – a heart transplant or LVAD). The study took place at three centers all in the U.S. Patients were randomized 2:1 to receive Ixmylocel-T + standard of care vs. standard of care alone. Below we highlight some of the more important baseline characteristics of these 22 patients:

The primary endpoint of the study was safety, with a planned interim analysis conducted when all subjects completed 6 months. There was also a planned final analysis conducted when all subjects completed 12 months, with control patients being able to crossover to the Ixmyelocel-T group after 6 months.

…Safety Improved…

As noted above, a total of 22 subjects were randomized. One subject in the control with NIDCM withdrew prior to day-1 so was not included in the safety assessment. One subject in the Ixmyelocel-T group with NIDCM discontinued due to heart failure on day 322.

Investigators concluded that transendocardial injection of Ixmyelocel-T was well tolerated in patients with DCM. In fact, management noted that the tolerability of the procedure was significantly better than the previous study (IMPACT-DCM) conducted by Aastrom in which patients received the cells via a minithoracotomy. Adverse events were similar between the Ixmyelocel-T and control group, a clear positive considering the control group underwent no transendocardial injection procedure. We strongly feel that use of the NOGA/MyoSTAR transendocardial catheter is the superior delivery option for cell therapy.

Secondary objectives were included to investigate signs of efficacy, including:
- Major Adverse Cardiovascular Events (MACE) – The key clinical endpoint
- Cardiopulmonary stress and 6-minute walk – Key functional endpoints
- Echo and left-ventricle ejection fraction (LVEF) – Key structural endpoints
- New York Heart Associate (NYHA classification) – Subjective / Quality of Life endpoints

…Proof-Of-Concept Evident…

Proof-of-Concept was clearly evident by analyzing the data. Given the small size of the trial, no results are statistically significant, but the signs point to a reduction in MACE and improvement in quality of life measures with Ixmyelocel-T. Also, similar to the IMPACT-DCM results, the data shows an improved outcome for the IDCM patients far greater than for the NIDCM patients. We believe that efficacy observations related to structural and functional end points including major adverse cardiovascular events (MACE), New York Heart Association (NYHA) functional classification, 6-minute walk distance were consistent with improved function of impaired myocardium.

The key clinical endpoint is MACE. Below (Figure-1) is a graphical representation of the Time to First Occurrence of MACE. The results show an observational benefit in favor of the Ixmyelocel-T group, although not statistically significant due to the small number of patients (n=19) completing the study. The data in Figure-2 shows the clear separation of benefit for patients with IDCM verses NIDCM.

click to enlarge
Additional functional and quality of life benefits also trended in favor of the Ixmyelocel-T group, specifically in patients with IDCM. However, no noticeable benefit in ejection fraction was observed in either group.

…Phase 2b Planned For Mid-2012…

Earlier in the year, Aastrom met with the FDA to outline the design and necessary endpoints for a phase 2b study. Management expects the phase 2b program to begin around the middle of the year 2012. The trial, to be called RENEW, will be a randomized, placebo-controlled program using the NOGA/MyoSTAR transendocardial catheter, seeking to enroll about 100 ischemic DCM patients at around 15 sites all in the U.S. Finding the right sites and investigators for RENEW will be key to its success.

We expect that MACE will be the primary endpoint of the study, with moderate powering (~80%) for significance. Secondary endpoints are expected to include cardio-pulmonary function, exercise capacity, 6-minute walk test, and safety. We view this as a “registration quality” study, as the data should give Aastrom – and potential partners – a clear sign on the profile of Ixmyelocel-T before proceeding into a pivotal phase 3 trial. We expect 12 months to enroll, with data during the first half of 2014. We estimate the trial will cost Aastrom around $5 million ($50k per patient).

…DCM Backgrounder…

DCM is a condition in which the heart becomes weakened and enlarged, and cannot pump blood efficiently. The expansion of the heart and the decreased function results in poor blood circulation and affect the lungs, liver, and other body systems. In patients with DCM, the left or right ventricular systolic pump function of the heart becomes impaired, leading to progressive cardiac enlargement and hypertrophy, a process called remodeling.

There are an estimated 200k to 250k people living (prevalence) in the U.S. with DCM, with roughly 20,000 new cases (incidence) each year. About one in three cases of congestive heart failure (CHF) is due to DCM. The 1-year survival rate for a patient diagnosed with DCM is roughly 75%. The 5-year survival rate drops to only 30% because many patients with DCM go un-diagnosed until the disease has progressed to the most severe stages. As a general rule for idiopathic DCM, after 1-year, 1/3rd of patients exhibit improved cardiac function, 1/3rd have stable cardiac dysfunction, and 1/3rd progress to significant cardiac dysfunction. These 1/3rd that progress to severe cardiac dysfunction will require a heart transplant. We remind investors that the FDA has granted Orphan Drug designation to Aastrom for use of its ixmyelocel-T in patients with DCM.

Standard of care for patients with DCM is often to treat secondary co-morbid conditions such as hypertension or renal failure. As such, patients with DCM are often prescribed angiotensin-converting enzyme (ACE) inhibitors, diuretics, beta-blockers, and sometimes digitalis. Anticoagulants may also be used. Artificial pacemakers and left ventricular assist devices (LVADs) may be used in patients with intra-ventricular conduction delay, and implantable cardioverter-defibrillators in those at risk of arrhythmia. These forms of treatment have been shown to improve symptoms and reduce hospitalization. They can cost upward of $75,000 each, and many patients will require re-implantation or an upgraded or new device in a year.

However, for patients with advanced disease who are refractory to medical therapy, cardiac transplantation is the only option. LVAD are commonly known as a "bridge to transplantation”. The problem however, and the reason this is such as a significant medical problem, is that only about 2,000 heart transplants are done in the U.S. each year. That means of the estimated 150k NYHA Class III or IV patients with dilation, over 95% will never get a transplant. Accordingly, this is why mortality rates start to rise dramatically after a patient has been diagnosed with DCM.