Forging the fate of cellular therapies for cardiovascular disease

Short abstract

The field of cell therapy for cardiovascular disease has progressed at an uneven rate and will likely follow the translational paths of other biologic therapies. The field will require novel public-private partnerships to guide it to its ultimate applications.

The long process of developing new therapeutics for cardiovascular disease may often seem like a guideless journey into the unknown. The process begins with definition of an unmet clinical need and is combined with insights into the pathophysiologic nature of disease. Whether the proposed therapy is a device, small molecule or biologic, each requires extensive preclinical and clinical investigation prior to approval. While each new treatment must create its own path to approval, outcomes may be predicted by prior experiences.

The development of cell-based therapies for cardiovascular disease

Cell-based therapies for cardiac and vascular disease have progressed at an uneven pace. High profile publications suggested plasticity and potency of bone marrow-derived cells when delivered into infarcted myocardium and spurred clinical investigation seemingly before the ink dried on the original papers¹. These human studies identified a promise of therapy without harmful effects when data were aggregated². However, these uniformly positive small studies have not been confirmed by larger studies. This has prompted a reexamination of the underlying premise upon which the original studies were based ^3,4.

The path by which cell-based therapeutics is being developed is illuminated by the development of other biologic approaches for cardiovascular disease. The similarities allow for educated guesses as to the outcome of this therapeutic journey. Will cells ever be widely utilized as first line therapy for cardiac and vascular diseases? Which diseases will be the first approved targets for cell-based therapies? How might the development process be improved? I believe the answers to these questions may be informed by the fates of other biologics including antibodies, gene therapy and peptides.

Development and challenges of biologic therapies

Few academic investigators have ready access to drug libraries or medicinal chemists. Yet the production of peptides, antibodies, gene transfer vectors and cells are essential parts of modern laboratories. This results in most academic labs being capable of biologic drug production (at least for preclinical studies) very much unlike the limited capacity to generate novel small molecules. The FDA has been receptive to early clinical testing of biologics often involving the same sites involved in discovery and development. This democratic approach to biologic development allows for an incredibly rich source of discovery but may risk the lack of oversight found in settings of professional drug development. In spite of the capability for early development of biologics, it is my opinion that the ultimate success of new biologic therapies will be dependent upon the experience and capital of the pharmaceutical industry.

Drug development includes multiple decision points involving medical and business decisions. In general non-peptide biologics (cells and gene vectors) require intravenous or intra-arterial delivery, have additional regulatory burdens and complex production and storage. Thus, while academic investigators may favor clinical development, future pharmaceutical partners may feel differently. An example of this is the development of autologous CD34+ cells for myocardial ischemia. In spite of impressive preclinical and Phase 2 data, an ongoing and promising Phase 3 trial (RENEW) was stopped reportedly for business reasons⁵. This decision may have been consistent with the business needs of the sponsor but it ended the promise of a first cardiovascular cell product for an important unmet need. This is an example of the discordance that exists at the interface between academia and industry in the field.

Impact of biologics in cardiovascular medicine

In the 1990’s there was great hope that gene transfer and therapeutic antibodies would revolutionize medicine. Many labs were focused on the use of gene transfer to limit restenosis following angioplasty⁶. These studies furthered our understanding of the role of cellular proliferation and the regulation of the cell cycle which in part contributed to the generation of stent-based antiproliferatives and the revolution of drug eluting stents. The intention of using a genetic approach was replaced by a mechanical and small molecule-based alternative.

So where did gene therapy go? While there remain studies testing the effectiveness of gene transfer for myocardial dysfunction, the field has embraced the power of potent viral vectors to address niche but important disorders such as for Leber’s congential amaurosis that allows for delivery of a potent transgene into an immunoprotected area⁷. Furthermore, hope for genetic therapies for cystic fibrosis have been replaced by small molecule approaches⁸.

Might cell therapy be replaced by the use of paracrine mediators? While the paracrine hypothesis of cell delivery originally focused on secreted proteins, the list of potential mediators is expanding⁹. RNA-based mediators and exosomes are an increasingly exciting source of cellular effects¹⁰. As the effects of cell delivery get parsed to potent individual mediators, the development of these mediators as therapeutics will grow. This will include development of novel small molecules with more defined business plans..

The use of antibodies in cardiology may be similarly viewed. While Digibind remains available for use in digitalis poisoning, it is expensive and many cardiologists might never use it¹¹. Similarly, abciximab (Fab fragments to GPIIb/IIIA) use in acute coronary syndromes has been replaced by small molecule drugs. The ultimate use of antibodies to PCSK9 for statin-resistant hyperlipidemia remains uncertain. Antibodies have limited use to cardiologists and may be replaced by small molecules as they become available.

While peptide therapeutics share some of the features of antibodies and gene vectors, they may be less costly to produce, have greater stability and have alternative routes of administration including subcutaneous. Yet even with these advantages, the widespread use of peptide therapeutics has not been adopted. As an example, the original enthusiasm for natrecor (b-type natriuretic peptide) in acute heart failure waned following larger scale trials¹².

The lessons for cell-based therapies from other biologics

So how does the history of biologics inform the future for cell-based therapeutics? The process to clinical utility for cell-based therapeutics will be long and indirect. The time frame should be considered to be multiple decades and not years. The eventual targets will not likely be those currently studied. Anyone considering the indirect nature or evolving targets for cell therapy as failures is missing the inherent nature of drug development.

There will be important and meaningful impact of cell-based therapies. Like other biologics, this impact may include improving our knowledge base that will facilitate the development of small molecules (or peptides) that may have business (and perhaps scientific) advantages over cells. Almost certainly there will be subsets of cardiovascular disease that provide unique and specific targets for cell-based therapeutics. Early clinical trials in cardiac anthracycline toxicity or hypoplastic left heart syndrome are such examples (clinicaltrials.gov).

Cell-based therapeutics will likely evolve into standard of care through combinations with drugs or as part of complex tissue engineering approaches. Much like stents provide a platform to deliver potent antiproliferatives, scaffolds will provide infrastructure to deliver and retain cells. The involvement of bioengineers and surgeons is critically important to the success of the field.

Forging a public-private partnership to support the development of cell-based therapies

The biomedical enterprise funded by the NIH will continue to provide the basic and early translational science that supports the development of novel cell-based therapies. This is the fertile soil in which our future success will grow. Much like ongoing federal support for gene therapy (e.g. Gene Therapy Resource Program), ongoing support for cell-based therapies has been critically important. An example of such support is the Cardiovascular Cell Therapy Research Network (CCTRN)¹³. The NHLBI-sponsored CCTRN has focused on early stage multicenter trials of cell delivery. The CCTRN has provided trial design, cell production, core labs and data analysis for academic-initiated studies of cell delivery. However the predicted future state includes more than just cell delivery and is inclusive of tissue engineering and development of potent small molecule mediators of tissue repair. This future will require more significant and enduring support.

To support this future state, the CCTRN model should be expanded in a way to support and align the transition of cell-based therapies from academic labs to industry. The needs of academic investigators are capital and expertise to drive forward the most promising projects. These needs include cell production, clinical trial design and endpoint assessment as well as regulatory support. The needs of industry are access to valuable and rigorously de-risked projects to move forward to larger scale trials and approval. This de-risking would allow for clarity of future clinical trials and associated business models.

I would propose a public private partnership whereby translational funds from the NIH (such as clinical trial networks) could be combined with funding from a suitably interested pharmaceutical consortium to support a steady and reliable platform composed of seasoned clinical trialists, core laboratories, cell manufacturing facilities, and accomplished analysts. Each partner would share rights with the inventors and the industry partners would have priority to licensing the properties that proceed through this process. This program would provide robust and rigorous support through the transition from academia to pharma with value for both.

Conclusion

The history of cell-based therapies for cardiovascular disease is not a simple one. It is cluttered with stops and starts and evolving futures. Yet, the power of the underlying science is overwhelming and steady hands are necessary to lead us to its ultimate clinical utility. The proposed public-private partnership would allow for two steady hands to guide this field forward.