Stem Cell Therapy for Heart Failure? Ixmyelocel-T to Prevent CV Events

Heart failure affects more than 23 million people worldwide and is associated with significant complications that relate to the disease. Mortality, morbidity, and health care expenditures are increased particularly among those aged ≥65 years. Current medications on the market have been successful at reducing heart failure-related mortality, however, hospitalizations are stagnantly high and readmission rates are increasing. The current approach to this problem is using a holistic approach to every comorbidity the patient may have or will develop.¹

Dilated cardiomyopathy is a form of heart failure and is one of the most common causes of the disease itself and is the most frequent cause of heart transplantation. This form of heart failure can be associated with both systolic and diastolic complications.² Remodeling of the heart may provide a way to treat dilated cardiomyopathy without the need for heart transplantation, or at least delaying the procedure.

Quality of Life, Advanced Disease State

Quality of life and NYHA functional class have been shown to be inversely proportional. A study revealed quality of life significantly decreased as NYHA functional class increased, showing a linear trend, P < .0001. The peak oxygen uptake and the 6-minute walk test were 2 other tests that had shown relation as well.³ Current standard of treatment leaves very few options when medications are maxed out and the patient is still having symptoms and/or hospital visits. These non-medication approaches include implantable cardioverter defibrillator, revascularization, heart transplant or palliative care. ⁴

Why Use Stem Cells?

Before I delve into the clinical trial, I believe it’s important to know more about the stem cell therapy and its justification in use, in this case, for heart failure. It has been seen that monocytes and lymphocytes are involved in the process of tissue repair. The proliferation of cells lead to accumulation and increasingly produce cytokines and growth factors. Clonogenic and self-renewing capacities allow cells to differentiate into whichever tissue is surrounding it, known as plasticity. Plasticity can be the ability to repair, in this case, vascular tissue. ⁵

What Is Ixmyelocel-T?

Manufacturing of ixmyelocel-T is a unique method called the Aastrom process, which significantly amplifies the number of CD90 mesenchymal stromal cells and M2 macrophages while maintaining many of the mononuclear cells from the original bone marrow sample. Typically, a large number of bone marrow cells are needed to notice improvement that is significant enough to produce angiogenesis. The ixmyelocel-T product is a result of amplifying important repair cells extracted from bone marrow with only 60 mL of the bone marrow from the patient.⁶

Preclinical Studies

Macrophages, specifically M2 macrophages, have anti-inflammatory and remodeling actions. The macrophages found in ixmyelocel-T show an expression mainly of M2 markers. However, rather than secreting the active heterodimer IL-12 p70 (which have pro-inflammatory functions), ixmyelocel-T macrophages release a comparable amount less than a typical M1 or M2 macrophage. In fact, ixmyelocel-T had shown to secrete elevated levels of IL-10 (anti-inflammatory functions) at a significant level. ⁷ Finally, with phagocytic properties, these cells could act to remove necrotic tissue and apoptotic cells in diseased or damaged tissues, such as those in dilated cardiomyopathy.⁸ Actions of these cells have warranted justification in studying ixmyelocel-T for tissue regeneration and repair.

In a rat model, an incision was given to the hind-limb along the femoral artery of rats. After intramuscular injections in the ischemic limb, ixmyelocel-T had shown to secrete pro-angiogenic cytokines to allow repair. Nitric oxide, a regulator of blood flow and a proliferation enhancer, was also shown to have increased levels in the rats treated with ixmyelocel-T. Along with NO promotion, ixmyelocel-T has the ability to reduce inflammation and apoptosis in endothelial cells.⁹

Phase 2B trial¹⁰

• Ixmyelocel-T injection vs placebo
• Criteria: NYHA class III or IV, has an ICD, or who are ineligible for revascularization procedures
• Number of patients: 114 were included in modified intention to treat and 109 in per protocol Remained on medications
• Primary endpoint: Composite of the total cardiac events (all-cause deaths, cardiovascular admissions to the hospital or emergency room visits) after a 12 month period Result: Poisson regression ratio was 0.63 (95% CI 0.42-0.97); p-value of 0.0344 The number needed to treat to prevent death was 9, and to prevent cardiovascular events was 11 62% ixmyelocel vs 51% placebo patients had no CV event
• Secondary endpoints All-cause deaths, cardiovascular admissions, and emergency/outpatient visits due to treating acute decompensated coronary heart failure Result using win-ratio: 1.56 (0.87—2.81); p-value: 0.1391 First occurrence of the primary endpoint Result: HR 0.67 (95% CI 0.38-1.19), p-value=0.1667 This score, though non-significant, may possible show significance in a larger trial and should be observed in phase 3. Structural change Result: no difference It should be noted that the ejection fraction did increase 2% at 6 months for ixmyelocel-T group and then flattened out. NYHA symptomatic improvement Increased in both groups, but no significant difference between group Beginning of trial: each arm had 2 patients in NYHA class II, 0 in class I End of trial: each arm had ~50% of patients in either NYHA class I or II

When approaching this trial from a clinical perspective, patients did not seem to increase in quality of life assessments as a result of ixmyelocel-T (aside from NYHA classification adjoined by the possible placebo effect). The trial had met its primary efficacy endpoint, but it is in relation to hospital visits and death. A 12-month follow-up had shown 8 placebo patients died compared to 4 ixmyelocel-T patients, which may show signs of lasting repair in some way. Despite being a large trial in the field of stem cell studies, a larger phase 3 trial will be needed to ensure the primary endpoint is true and possibly show significant improvement of quality of life with a larger group to meet power. If this trend remains the same, insurance companies may encourage patients to receive the injection (depending on cost), even if patients don’t improve their quality of life.

Ixmyelocel-T most likely won’t be stopping at heart failure. Patients who require statins or PCSK-9 inhibitors for hyperlipidemia may be another population to study. Regarding future vascular studies, preclinical data have shown benefit with other atherosclerotic conditions, increasing the possible utility of ixmyelocel-T in treating cardiac related conditions earlier. ¹¹

References

1. Roger VL. Epidemiology of heart failure. Circ Res. 2013;113(6):646-59.

2. Nguyen VQ. Dilated Cardiomyopathy (Medscape Reference: Drugs, Diseases and Procedures) [http://emedicine.medscape.com/article/152696-overview]

3. Juenger J, Schellberg D, Kraemer S, et al. Health related quality of life in patients with congestive heart failure: comparison with other chronic diseases and relation to functional variables. Heart. 2002;87(3):235-41.

4. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-327.

5. Van weel V, Van tongeren RB, Van hinsbergh VW, Van bockel JH, Quax PH. Vascular growth in ischemic limbs: a review of mechanisms and possible therapeutic stimulation. Ann Vasc Surg. 2008;22(4):582-97.

6. Bartel RL, Cramer C, Ledford K, et al. The Aastrom experience. Stem Cell Research & Therapy. 2012;3(4):26.

7. Ledford KJ, Zeigler F, Bartel RL. Ixmyelocel-T, an expanded multicellular therapy, contains a unique population of M2-like macrophages. Stem Cell Res Ther. 2013;4(6):134.

8. Henry TD, Schaer GL, Demaria A, et al. The ixCELL-DCM Trial: Rationale and Design. Cell Transplant. 2016;25(9):1689-1699.

9. Ledford KJ, Murphy N, Zeigler F, Bartel RL, Tubo R. Therapeutic potential of ixmyelocel-T, an expanded autologous multicellular therapy for treatment of ischemic cardiovascular diseases. Stem Cell Res Ther. 2015;6:25.

10. Patel AN, Henry TD, Quyyumi AA, et al. Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial. Lancet. 2016;387(10036):2412-21.

11. Ledford KJ, Murphy N, Zeigler F, Bartel RL. Potential beneficial effects of ixmyelocel-T in the treatment of atherosclerotic diseases. Stem Cell Res Ther. 2013;4(6):135.