In prior columns, we have discussed novel therapeutics, identification of unmet needs, partnering and funding, and other topics related to product development. We have explored various ways in which entrepreneurs have partnered products for development, and have discussed a consistent message of “beginning with the end in mind.” Many times investment in a new venture starts with a specific technology. Other times the physician-entrepreneur may only have a concept to address a need that has yet to be reduced to practice or aligned with any one specific technology. If integrated with appropriate support and a funding source, this can be a very focused manner of product development, in that the need can be defined and the target product profile outlined, so that the best approach can be followed. In this installment, we will discuss how the identification of a clinical need by an entrepreneur led to partnering on the early concept and execution on development of this novel product. This may potentially assist clinicians, as well as researchers in designing optimized clinical trials.
The Clinical Need
Dry-eye disease is enigmatic, both from the perspective of its pathophysiology and from that of its treatment. It is loosely defined as a dysfunction of the tear film, yet this dysfunction can be the end result of numerous causes: insufficient aqueous tear production following autoimmune damage to the lacrimal and accessory glands; meibomian gland dysfunction causing accelerated evaporation of aqueous tears due to lack of the protective lipid layer; or mucin changes brought on by age, endocrine dysfunction or inflammatory processes. The profound effect of environmental and behavioral circumstances that lead to a constantly variable presentation of signs and symptoms contributes further complexity. The final piece that stumps researchers and clinicians is the seeming disassociation of signs and symptoms: Some patients have terrible discomfort without much signs of damage; others have blatant keratitis—yet without a complaint. The logical outcome of this plurality is that pathology-based subgroups of dry eye exist, and a further tailoring of treatments specifically focused on a pathological subgroup should greatly improve our treatment of this disease.
All these complexities have contributed to the well-known difficulty of establishing efficacy of dry-eye treatments. The success of Restasis (cyclosporine emulsion 0.05%), with close to $1 billion sales worldwide, is testament to the marketability and unmet need that draw startups and venture capital to the world of dry eye. Yet even the Restasis label targets a subgroup of patients for whom the drug may “increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.” This subgroup-specific labeling highlights the need for selecting the proper treatment that is most appropriate for the patient. Consequently, researchers have to be able to design proper studies to select the right subgroup for evaluating novel therapies.
None of the various tools available to diagnose dry eye provides the whole picture. Some of the most commonly used are the Schirmer’s test, which measures aqueous tear production; tear-film breakup time, which determines how quickly the tear film evaporates; and fluorescein or lissamine green staining, which visualize the endgame of epithelial damage. Symptoms of the disorder are variable, but quantitative assessments typically employ questionnaires such as the Ocular Surface Disease Index (OSDI) or other symptomatology scales.
Many drugs for dry eye are indeed progressing to Phase III trials and beyond. If and when these come to fruition, the result will be a polypharmacy of treatment choices. It will be up to physicians to decide which treatment best suits their patients. Potential approvals will allow for additional anti-inflammatory agents such as lifitegrast (Shire); mucogenics (e.g., MIM-D3: Mimetogen) that target evaporative dry eye; multifunctional approaches such as anti-oxidant/anti-inflammatory (SKQ1: Mitotech); improved barrier-function molecules, such as modified hyaluronic acid to increase mucoadhesion, optimize wetting, prolong protection and stabilize tears, as well as combating inflammation and providing a bandage effect to promote healing. It is even more likely that patients will receive multiple therapies that target various aspects of their disease. While refined clinical assessment will help define patients, there is a need for additional diagnostics to complement the clinical assessment.
The Approach
TeaRx, is a biomarker panel originally conceived by an entrepreneurial researcher, Eran Eilat. Dr. Eliat recognized that dry eye is a multifactorial disease that has been difficult to study and whose proper subgroups are difficult to define. His concept was to create a diagnostic that would address these issues, and that would be useful to clinicians, pharmaceutical companies developing new products and researchers conducting clinical research. He approached a life sciences investment group in Israel, BioLight, with his idea to look at dry eye through a different lens (or rather multiple lenses), creating an objective, multi-parameter kit for a multifactorial disease. BioLight is focused on investing in various unique ophthalmology products. Without being tied to any specific test method, they embarked on the journey together, creating DiagnosTear. BioLight is implementing a unique business model that combines novel ophthalmic technologies to narrow in on ophthalmic conditions from various angles, affording a synergy in economies of scale and knowledge that is in line with the entrepreneur’s vision. They first identified the key elements of dry eye and of the tear film, and potential markers that can be measured. They identified key constituents in the tear film (e.g., lysozyme, lactoferrin, proteins and others) that have been well-researched and connected to dry eye of various forms, and can potentially highlight important indicators of the health of the tear film and ocular surface. They developed technology for easy, rapid test strips that semi-quantitatively measure the levels of the four different markers in one test strip.
Says Suzana Nahum Zilberberg, BioLight CEO: “The clinical need for a better protocol of treatment for dry-eye patients is clear and growing. The multi-parameter approach that was presented by Dr. Eilat was clearly in line with our approach of targeting ophthalmic needs from multiple angles, which made us invest in the concept in a very early stage. In a relatively short timeframe we have developed a pool of biomarkers related to dry-eye patient populations that have the potential to provide solutions not only for better diagnostics but also for a better treatment.”
First Clinical Trial
The first prospective study of approximately 200 subjects has been completed in the United States implementing the DiagnosTear panel in suspected dry-eye and normal subjects. Widely used tests for dry eye (Schirmer’s, TFBUT), as well as staining of corneal and conjunctival epithelial cell damage and patient questionnaires, were compared with the TeaRx diagnostic parameters. There were positive statistical correlations between these widely used benchmark tests and the TeaRx diagnostic parameters tests. The positive correlations identified between certain TeaRx diagnostic parameters and subjective testing standards that are widely used today indicate a unique ability for improving the dry-eye syndrome diagnosis by objective quantification of measures over subjective evaluation. This is a major advancement in the proper diagnosis of dry eye and has potential to provide physicians with an efficient approach to selecting treatments for individual patients. These results led to a further study and advancement of the regulatory program of TeaRx towards commercial development.
The goals and vision for this particular diagnostic are to have TeaRx generate three revenue streams, leveraging the unmet need in the field:
• as a leading point-of-care solution that will assist ophthalmologists to better diagnose and treat dry-eye patients;
• as a companion diagnostic product to assist in introducing personalized treatment to the market (by better defining endpoints for clinical development, increasing efficacy by targeting the specific responder sub-population, supporting the reimbursement process and providing a cost-effective solution); and
• a valuable research and clinical trials tool.
This model also highlights that diagnostics can generate revenue not only by being sold to clinicians, but by following a path of licensing for incorporation into pharmaceutical trials.
In early development of diagnostics for dry eye, other tests have become available; however, these all measure a single marker. The advantage of the TeaRx system is that different measured parameters could enable identifying specific dry-eye subgroups characterized in aqueous tear deficiency such as inflammation, evaporative dry eye and others. In-office data from this panel of compounds informs the physician on how to treat the patient, the ultimate goal of any diagnostic.
The recognition that we need to understand and categorize our patients to the upcoming drugs has opened the market for precise diagnostics. Opportunities have arisen for pharma, physicians and entrepreneurs to bring their ideas forward. The bundling of various parameters that together define the diagnosis of dry eye, as performed by DiagnosTear, is an elegant example of an unmet need leading to translational science, and evolving into a marketable idea.
Mr. Chapin is senior vice president of the Corporate Development Group, Mr. Ousler is vice president of Dry Eye, and Ms. Smith is a senior medical writer at Ora Inc. Ora provides a comprehensive range of product development, clinical-regulatory and product consulting for developers, investors and buyers; clinical trial services and regulatory submissions; and asset and business partnering support in ophthalmology. We welcome comments or questions related to this or other development topics. Please send correspondence to mchapin@oraclinical.com.
