New breakthroughs in science, such as gene and cell therapies, give medical researchers potential new pathways to develop treatments for diseases for unmet medical needs. One of those diseases is Duchenne muscular dystrophy (DMD), a genetic disease in which patients lack the protein dystrophin, which is critical for stabilizing muscle cell membranes. Without a functional dystrophin protein, muscle cells are susceptible to damage and progressively die. Patients experience progressive muscle weakness starting at an early age, loss of ambulation typically in the first decade of life, and eventual respiratory and cardiac failure. 

Currently, there are no effective treatments for DMD.  But one cell therapy company, Capricor Therapeutics, based in Beverly Hills, Calif., is trying to change that.  Capricor, launched in 2005, is developing CAP-1002, an off-the-shelf cardiac cell therapy that is currently in clinical development for the treatment of DMD.

Leading Capricor’s research is co-founder and CEO Linda Marban, who combines her background in cardiac research with her business experience to lead the company’s research and commercialization efforts for its novel therapies. From 2003 to 2009, Marban was with Excigen, Inc., a biotechnology start-up company. She began her career in academic science, first at the Cleveland Clinic Foundation working on the biophysical properties of cardiac muscle. Marbán earned a Ph.D. from Case Western Reserve University in cardiac physiology.

As part of a new cell therapy industry series, WuXi AppTec Communications spoke with Marban about how Capricor’s cell therapy can be utilized to bring new therapies to patients and specifically the company’s efforts to use cell therapy to find an effective treatment for DMD disease.

WuXi: What cell therapies is your company developing and what diseases do they target?

Linda Marban: Capricor Therapeutics is a clinical-stage biotechnology company focused on the discovery, development and commercialization of first-in-class biological therapeutics for the treatment of rare disorders. Capricor’s lead candidate, CAP-1002, is an allogeneic cell therapy meaning that it is manufactured from donor heart tissue and then stored until needed for use. CAP-1002 consists of allogeneic cardiosphere-derived cells, or CDCs, a unique population of cells that contains cardiac progenitor cells.

CAP-1002 is currently in clinical development for the treatment of Duchenne muscular dystrophy, a devastating genetic disorder that causes muscle degeneration and leads to death, generally before the age of 30, most commonly from heart failure. It occurs in one in every 3,600 live male births across all races, cultures and countries. Duchenne muscular dystrophy afflicts approximately 15,000 boys and young men in the US and 200,000 around the world. Treatment options are limited, and there is no cure.

Capricor has the only therapy to-date that has shown improvement in scarring or fibrosis in the heart as well as cardiac function in later stage patients with Duchenne muscular dystrophy. As a result, CAP-1002 could be important in counteracting the worsening of the heart associated with Duchenne. CAP-1002 has also been shown to exert potent immunomodulatory activity, meaning it regulates the immune system’s activity to encourage cellular regeneration. CDCs have been the subject of over 100 peer-reviewed scientific publications and have been administered to approximately 140 human subjects across several clinical trials.

WuXi: Describe your current work with your cell therapy.

Linda Marban: Our first clinical trial, HOPE-Duchenne, found that boys and young men in advanced stages of Duchenne muscular dystrophy experienced significant and sustained improvements in cardiac structure and function, as well as skeletal muscle function, following a single intracoronary treatment with CAP-1002. Capricor is now enrolling a Phase II clinical trial of CAP-1002, called HOPE-2. It is a randomized, double-blind, placebo-controlled clinical trial of intravenous CAP-1002 in boys and young men in advanced stages of Duchenne muscular dystrophy. In order to evaluate CAP-1002’s potential for sustained clinical improvements over time, the HOPE-2 Trial will test the safety and efficacy of repeat intravenous doses given at three-month intervals. For HOPE-2, the primary efficacy endpoint will be the relative change in patients’ abilities to perform manual tasks that relate to activities of daily living and are important to their quality of life. These abilities will be measured through a validated test for skeletal muscle function in Duchenne muscular dystrophy, the Performance of the Upper Limb (PUL) test. HOPE-2 will focus on the mid-level dimension of the PUL – or the ability to use muscles from the elbow to the fingers, which are essential for operating wheelchairs and performing other daily functions.

WuXi: How will cell therapies evolve over the next 10 years?

Linda Marban: In our area, our pre-clinical studies are increasingly finding that the extracellular vesicles, or exosomes, secreted by cardiosphere derived cells (CDCs), are the active component in our cell therapy, CAP-1002. Exosomes are nano-sized, membrane-enclosed vesicles, or bubbles, that are secreted by cells and contain bioactive molecules, including proteins, RNAs and microRNAs. They serve as messengers to regulate the functions of neighboring cells. For instance, we have found that the exosomes were effective in increasing exercise capabilities and muscle activity in a mouse model of Duchenne muscular dystrophy. We also found that the exosomes secreted by the CDCs reduced muscle fibrosis, which causes a loss of muscle function in Duchenne patients, and the proliferation of activated T cells, which help govern the body’s immune response, in the Duchenne mouse model.

WuXi: What is the future for exosomes?

Linda Marban: We are pleased to see that the power of these nanometer size microvesicles are beginning to be recognized by the academic as well as the biotech communities. Essentially exosomes are being developed by us and others for three basic purposes. They are being developed as a measurement or diagnostic tool whereby you obtain blood samples, isolate the exosomes and refine the understanding of the disease process. Second, they are being developed as a therapeutic, which is one of the strategies we are pursuing with CAP-2003, our exosome-based therapy. The idea is that one can harness the power of the cell without using the fragile cells themselves. This is the type of exosome found in CAP-2003. It brings all the promise of the cells without having to deal with the challenges of a living product. To that end, CAP-2003 is being investigated in multiple pre-clinical indications, including our recent collaboration with the U.S. Army Institute of Surgical Research (USAISR) to determine if CAP-2003 can help in trauma related injuries that might occur on a battlefield where there is severe inflammation after an injury. We have entered into a co-operative research and development agreement with the USAISR, which will conduct studies using our CAP-2003 product. Lastly, exosomes may be used as delivery vehicles for proteins, genes and almost anything that can be packaged into the exosome with instructions for delivery. We are actively working on the premise that exosomes can be a delivery vehicle for gene and other therapies.

WuXi: What regulatory challenges do you face?

Linda Marban: As a company focused on rare and orphan diseases, Capricor actually has some regulatory advantages. We have secured FDA designations that would expedite the development and review of a marketing application for CAP-1002 and give Capricor a competitive advantage. These include Orphan Drug Designation, which gives the company seven-year market exclusivity upon approval of CAP-1002; Rare Pediatric Disease Designation, which means that if CAP-1002 is approved first for use in Duchenne muscular dystrophy, the company can secure a priority review voucher to fast-track a potential future therapy. Or we can sell the voucher to another company; and RMAT designation, which makes therapies eligible for the same actions to expedite the development and review of a marketing application that are available to drugs that receive breakthrough therapy designation – including increased meeting opportunities, early interactions to discuss any potential surrogate or intermediate endpoints and the potential to support accelerated approval. The RMAT designation is an expedited program established under the 21st Century Cures Act to foster the development and approval of regenerative medicine products intended for the treatment of serious and life-threatening diseases and conditions.

WuXi: What are some of the major challenges in bringing cell therapies to patients? Is manufacturing the most difficult hurdle?

Linda Marban: Manufacturing is a challenge, especially finding space for manufacturing in a highly urbanized area, like Los Angeles County, where Capricor is located, because property values are high and research space is limited. We are focused on scaling up our cell manufacturing processes which will help enable us to take our novel cell therapy, CAP-1002, to market by ensuring we can manufacture adequate supplies to meet commercial Duchenne muscular dystrophy demand. We have entered into agreements with national organ procurement organizations to provide the donated cardiac tissue needed to help ensure we can meet demand for the therapies we are developing.

WuXi: Is gene editing the key technology in cell therapies?

Linda Marban: Not for Capricor’s cell therapy, CAP-1002. We have conducted a preclinical clinical study that assessed the biological mechanisms of action of paracrine factors and extracellular vesicles, also known as exosomes, secreted by cardiosphere derived cells (CDCs), the active component of Capricor’s novel cell therapy, CAP-1002. We found the exosomes were responsible for CAP-1002’s immunomodulatory effects. We are developing these proprietary extracellular vesicles as another therapy, CAP-2003, which we believe has the potential to be used in gene editing and in the delivery of gene therapies to cells.

WuXi: How would you compare cell therapies to gene therapies? And what benefit do you believe Capricor’s cell therapy will have for patients?

Linda Marban: While gene therapy involves the transfer of genetic material, which can potentially correct a genetic disorder, cell therapy involves the transfer of cells that can provide therapeutic benefit to a patient. In the case of our cell therapy, CAP-1002, we believe it can be complementary to the gene therapies currently being investigated to treat Duchenne muscular dystrophy. CAP-1002 has been shown in preclinical and clinical studies to help preserve and strengthen skeletal and cardiac muscle function in patients in the advanced stages of Duchenne muscular dystrophy, a fatal genetic disease.  Gene therapies in development may be poised to change the course of Duchenne muscular dystrophy for patients, but there are still many unanswered questions about the ability of gene therapies to be effective in older patients with more advanced disease states, whether re-dosing can occur, the possibility of immune complications especially in older patients and the ability to manufacture adequate amounts for all the patients who need it.

Preliminary clinical data suggests that gene therapy can address the underlying genetic cause of Duchenne muscular dystrophy – mutations in the dystrophin gene that result in the absence or near-absence of dystrophin protein that is needed to keep muscle cells intact. Capricor’s cell therapy can potentially complement this therapy by mitigating inflammation and improving the bioenergetics of the cells, which would reduce the inflammatory processes that are present throughout the duration of the disease. Pre-clinical and clinical studies have already shown CAP-1002 to be strongly immunomodulatory, meaning it regulates the immune system to allow healthy muscle to form, and anti-fibrotic, so that it reduces the scarring that occurs in Duchenne muscular dystrophy. As a result, CAP-1002 may be well positioned to provide additional treatment benefit for patients in the advanced stages of Duchenne, where fibrosis may reduce the potential effectiveness of the gene therapy.