What Makes Biological Treatment Strategies and Tissue Engineering for DDD Interesting to Industry?

20 What Makes Biological Treatment Strategies and Tissue Engineering for DDD Interesting to Industry?

Hassan Serhan, Elliott A. Gruskin, and William C. Horton

Abstract

Although traditional therapies of decompression and reconstruction have improved countless lives, they primarily address end-stage disease and do not address the underlying patho-physiology or halt the progression of degenerative disc disease (DDD). Dissatisfaction with mechanical solutions, coupled with large-scale global opportunity, creates an environment where the medical device and pharmaceutical industries are looking to bring forward solutions that are biologically targeted and are relevant more broadly across the continuum of care. Open innovation models are taking root in the medical industry and create opportunities for start-ups to participate in the earliest stages of product development. By this approach, new technologies can be fostered with large company involvement, but remain with the passionate inventors during the early stages of development. However, it must be recognized that to attract the investment of larger device companies, new spine technology developers must factor in a few key areas that are not normally the domain of the small-scale academic labs or enterprises. These include, but are not limited to a clear understanding of the unmet clinical need including the financial or “Triple Aim” aspect on a global basis, the intellectual property that can be protected, the positioning of the new approach relative to the current standard of care, the scalability of the technology with respect to global commercialization, the quality and discriminating capacity of the preclinical data, a progressive risk management strategy for each stage of development, the regulatory pathway from a global vantage point, and the clinical evidence plan.

Keywords: biological repair of degenerative disc, degenerative disc disease (DDD), early intervention DDD, open innovation, Triple Aim

20.1 Introduction

Although traditional therapies of decompression and reconstruction have improved countless lives, these primarily mechanical solutions incompletely address the underlying pathophysiology, and primarily address end-stage disease with little application for either prevention or early intervention. Degenerative disc disease (DDD) particularly impacts the cervical and lumbar spine, accounting for the greatest burden of disability globally, where solutions offer an enormous opportunity for impacting health across large populations and markets globally.¹^,²^,³ In general, this dissatisfaction with primarily mechanical solutions, coupled with large-scale opportunity, creates an environment where the medical device and pharmaceutical industries are looking to bring forward solutions that are biologically targeted, are relevant more broadly across the continuum of care, and potentially can alter the natural history of this complex disease.

The sources of axial low back pain (LBP) are many including but not limited to soft tissues, neurological, articular, and discogenic. Multiple skeletal abnormalities including compression fractures, spondylosis, spondylolysis, spondylolisthesis, or tumor also are frequently involved. Of all these pathologies, the disc is felt to be the most common link underlying axial and neurological disease, and thus DDD is of great interest as an innovation target. The clinical features of many cases of LBP with DDD are inadequately explained by anatomical abnormalities alone, and the poor sensitivity and specificity of magnetic resonance imaging (MRI) testifies to this problem.⁴^,⁵

A pathophysiological mechanism that may include one or a combination of mechanical and biochemical factors is an alternative explanation that is accompanied by less paradox than a purely structural and mechanical paradigm.⁶^,⁷^,⁸^,⁹ Consequently, developing new technologies to treat these spine disorders requires a much deeper understanding of the pathobiology and a broad range of research and development (R&D) competencies that blur the traditional boundaries between device, biological, and pharma enterprises. To address these challenges, industry is more and more turning to multidisciplinary teams, and an open innovation model wherein technologies at various stages of development can be fostered in a risk-adjusted, milestone-based process. A spine company’s R&D pipeline can be a mosaic of internal R&D projects, in-licensed technologies, and collaborations with external academic labs or biotech companies, both established and start-up ventures. Successful execution of an open innovation R&D model depends on the ability to identify sound opportunities for investment, assemble the right multifunctional team with appropriate capabilities, and appropriate strategies to sequentially derisk the effort.

One of the most interesting and challenging tasks facing a spine company is determining the value and risks associated with specific opportunities. Evaluating the potential of a disc regeneration technology start-up depends a lot on the value proposition of the treatment. A traditional spinal implant technology, leveraging more familiar and less costly development and regulatory pathways, will have a far different evaluation than a high-risk biological compound company. What evaluations boil down to is the risk involved in the investment as well as the return. Risk can be hard to evaluate because there are so many factors that come into play with biological compounds. For example, investing in a new small molecule or protein to treat DDD may require extensive studies to determine the compounds, their stability, reproducibility, preclinical dose findings, animal safety and efficacy studies, and Phase I to III clinical evaluation. Smaller companies may have difficulty taking on this type of expensive and long-term development.¹⁰ Additionally, reimbursement, intellectual properties, and cost are major concerns with new procedures or treatment pathways and will require a huge investment in longitudinal follow-up and evidence generation. The value proposition, risks, ability to execute, and return on investment are some of the main things industry typically seeks to consider when evaluating internal programs or a start-up with a potential biological solution for DDD. Additionally, when looking at a biological technology, companies will also look closely not only at the technology but also the expertise and breadth of knowledge embodied in the concept. Regenerative or tissue engineering solutions become more attractive when being proposed by a group with deep scientific and development expertise, and a proven track record of successful execution.

20.2 Pathophysiology and Targets for Intervention

Confirming that the biological solution targets a critical pathway of clinical significance is extremely important. There is a strong theoretic basis to support the concept that the clinical features of many patients with lumbar disc conditions may be explained by inflammation caused by biochemical factors alone or mechanical factors, or combined chemical/mechanical factors rather than mechanical factors alone. One such example includes inflammation of neural elements caused by the chemical components of the inter-vertebral disc (IVD). The recent demonstration of immuno-histopathological evidence of an immunocompetent cellular response at the epidural interface of lumbar herniated nucleus pulposus (HNPs) supports the concept of the immunogenic capacity of the nucleus pulposus (NP).¹¹^,¹² The identification of high levels of an inflammatory enzyme, phospholipase A2, in lumbar herniated and degenerative discs supports the hypothesis of direct inflammogenic capability of lumbar discs, separate from immunological mechanism.¹³ When a biological solution targets a well-established cellular or molecular mechanism, there will be higher levels of corporate interest in investing in the development work.

Although disc regeneration and repair are attractive concepts, the disc has proven to be a harsh and complex environment, and regenerative attempts carry the risk of rebuilding the very “factory” of biochemical pain factors. The lack of understanding of the pain generators in early disc degeneration “black disc” is one of the biggest challenges in determining the best course of treatment and the optimal solutions. There is much that remains to be learned regarding the molecular basis of pain in the setting of degenerative changes within the disc, and then linking those insights to therapies. Addressing the gaps in our understanding of why most degenerative discs are painless while a few are associated with disabling back pain is a challenge. Solutions with well-developed molecular characterization are of great interest to industry when evaluating biologics for DDD. Our growing understanding of the molecular mechanisms behind IVD homeostasis and the molecular events leading to disc degeneration is one example of how basic research may lead to potential new biological therapies for this difficult clinical problem.

Another challenge is the lack of good large-animal models of spontaneous disc degeneration that might mimic the human situation. Most of the animal degenerative disc models are induced by stabbing the disc and creating an “acute herniation” that leads to degenerative changes. As we know acute sharp trauma is not the common cause of the black disc degeneration or herniation. Companies look carefully at the preclinical models that have been well validated and used to characterize a potential biologic to assess potential safety and efficacy.

Another challenge is the unique biomechanical environment of the human spine, given our upright posture. Hence, companies often pilot human clinical trials to explore the effects of a proposed treatment such as the reimplantation of autologous disc cells and/or the use of recombinant growth factors as potential treatment modalities for symptomatic disc degeneration.¹⁴^,¹⁵^,¹⁶ These human data will be of great interest to industry; however, without double-blinded, randomized clinical studies, or other high-quality human data the results of such pilot studies will be cautiously interpreted.

Because current diagnostics (MRI, discography, etc.) for DDD have challenges with both sensitivity and specificity¹⁷^,¹⁸^,¹⁹

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