Identifying and Filling the Unmet Need

The holy grail in pharmaceuticals is finding an unmet need for a particular medical problem. Pharma devotes endless rounds of market research, advisory boards, workshops and customer calls to this search, devoting development resources, marketing efforts and scientifi c discovery to products that hope to find a place amongst what may already be a crowded market. Is an unmet need a cure for a hard-to-treat disease? A reduction in symptoms? An increase in quality of life? For the entrepreneur who has identified an unmet need and has a novel concept, it is critical to refine the pitch to drill down on the need gap within current therapies, and what it will take to move the needle to adopt a new therapy. In this installment of the column, we will touch on some aspects of the early process of defining and addressing an unmet need for the new entrepreneur.

Defining the Target

Real success in meeting an unmet need relies on understanding the target disease; its underlying etiologies and subgroups; which clinically relevant change can be measured in controlled trials; and how the basic attributes of a molecule address those aspects. This all ties into building the target product profile (TPP) that we have discussed as an underlying theme across many of our prior columns, and defining how the TPP truly addresses an unmet need. The product needs to own a particular differentiated space that truly capitalizes on the attributes of a molecule. Questions that should be addressed early during planning are: What can this molecule actually do? Where can it best serve a true purpose? Which patient population will find this most useful? How do we ensure the final product design has the appropriate attributes to remain commercially viable?

With reduced R&D spending and a need to boost productivity in finding new products, pharma increasingly relies on new concepts from entrepreneurs who are on the front lines of identifying unmet clinical needs. How will the demand for new products to treat unmet medical needs be met? The answer lies in R&D models that leverage the expertise and capabilities of various stakeholders. The new face of pharmaceutical R&D is marked by open innovation, academic-industry partnerships, and the transformation from FIPCos (fully integrated pharmaceutical companies), which take drug candidates from laboratory bench to market, to FIPNets (fully integrated pharmaceutical networks), which encompass all the major stakeholders in drug development. Stakeholders include large and small pharmaceutical fi rms, academic research centers, patient groups, public-private-partnerships and contract research organizations. In the new model, all stakeholders have a place at the table and share in the rewards of innovation. Early interactions with potential pharma partners will help define key attributes of the TPP that will drive value inflection.

A Real-World Target

One such area of an unmet need that has recently drawn interest from several companies is persistent corneal epithelial defect. PCED occurs when the process of epithelial healing and defect closure is delayed, leading to corneal epithelial defects that can result in ulceration, infection, scarring, perforation and loss of vision. PCED can result from injury, such as chemical or blast trauma, ocular surgery, infections (herpes) or diseases of the eye (including underlying conditions such as severe dry-eye disease and diabetes). It is estimated that DED and diabetes are responsible for more than 50 percent of PCED cases.Buchholz P, Steeds CS, Stern LS, Wiederkehr DP, Doyle JJ, Katz LM, Figueiredo FC. Utility assessment to measure the impact of dry eye disease. Ocular Surface 2006;4:155-161. Diabetes contributes to systemic impaired tissue repair, and the corneal surface is not spared. For health-care practitioners, managing patients with epithelial defects due to diabetic corneal disease and DED is diffi cult, time-consuming, and cost- and resource-intensive. Patients must make repeated offi ce visits for treatment for often lingering disease. Similarly, the impact of moderate to severe dry-eye disease is comparable in scope to conditions such as dialysis and severe angina, and is associated with signifi cant discomfort, role limitations, low vitality and poor general health.,Mertzanis P, Abetz L, Rajagopalan K, Espindle D, Chalmers R, Snyder C, Caffery B, Edrington T, Simpson T, Nelson JD, Begley C. The relative burden of dry eye in patients’ lives: Comparisons to a U.S. normative sample. Invest Ophthalmol Vis Sci 2005;46:46-50. The burden of dry-eye disease alone for the U.S. health-care system is estimated to be more than $3.8 billion and, factoring in diminished productivity, may reach $55 billion for the United States overall.Yu J, Asche CV, Fairchild CJ. The economic burden of dry eye disease in the United States: A decision tree analysis. Cornea 2011;30:379-387.

The incidence of PCED is estimated based on assumptions regarding the likely causes of PCED. Overall, the estimated number of PCEDs per year in the United States is roughly 73,434 to 99,465 cases; and being less than 200,000, PCED is considered an orphan disease.Wirostko, BM, Rafi i MJ, Sullivan DA, Morelli J, Ding J. Novel therapy to treat corneal epithelial defects: A hypothesis with growth hormone. The Ocular Surface, published online March 27, 2015. In press, accepted manuscript. Current treatments for healing PCED are suboptimal, temporizing measures consisting of lubricants, bandages (contact lens, patches and invasive surgical graphs), and endogenous growth factors provided through autologous serum, amniotic membranes and umbilical fluids. These may not heal the corneal defects completely in a timely manner. The therapies produce varied results, can be invasive as well as expensive and are inconvenient for patients. With no existing approved pharmacologic therapy, PCED represents a major unmet medical need with a potential annual market estimated to exceed $500 million. In diabetic corneal epitheliopathy, there is a decrease of corneal sensation due to the diabetic nerve involvement. Hosotani H, Ohashi Y, Yamada M, Tsubota K. Reversal of abnormal corneal epithelial cell morphologic characteristics and reduced corneal sensitivity in diabetic patients by aldose reductase inhibitor, CT-112 Am J Ophthalmol 1995;119:288-294. For those patients with diabetes, it has been hypothesized that the use of aldose-reductase inhibitor can improve the corneal sensation, possibly resulting in improved nerve function and healing of the epithelial defect. In the instance of corneal stem cell defi ciency, limbal transplantation is the fundamental treatment. Therapeutic contact lens and surgical intervention such as tarsorrhaphy have been proven successful as well. Both treatments decrease the necrosis and desquamation of the corneal epithelium by preventing mechanical stress of blinking and accelerating wound healing. The use of large, fluid-ventilated, scleral contact lenses has recently gained popularity in treating severe ocular surface disease, including-dry eye secondary to graft-versushost disease and chemical burns. These lenses have also been used successfully to treat ocular surface disease and ectasia. The PROSE Treatment (Boston Foundation for Sight, Needham, Mass., formerly the Boston Scleral Lens) vaults over the entire cornea and limbus and bathes the cornea in fluid. This device has been used to heal PCED. Rosenthal P, Cotter JM, Baum J. Treatment of persistent corneal epithelial defect with extended wear of a fluid-ventilated gaspermeable scleral contact lens. Am J Ophthalmol 2000;130:33-41.

Amniotic membrane, now available commercially in fresh-frozen (Amnion; Bio-Tissue, Inc., Miami) or freeze-dried (AmbioDry2; IOP Ophthalmics, Costa Mesa, Calif.) forms, can be sewn into place over the PCED. More recently, it has been suggested that the membrane can be glued in place using fi brin glue. Amniotic membrane is also available as a self-retaining device (ProKera; Bio-Tissue) that can be inserted in the offi ce. Autologous serum application has proved to help reconstruct the ocular surface and it has been suggested that serum can provide essential factors to the ocular surface.

Matching a Solution to the Need

There is an unmet need to provide an optimal treatment to treat PCED when examining effi cacy, convenience and cost. While the disease is rare, the consequences are devastating and the burden is on patients, physicians and payors. In a 2011 article, Bennie H. Jeng, MD, professor and chair of the department of ophthalmology and visual sciences at the University of Maryland School of Medicine, said this condition can be recalcitrant to standard treatment modalities, leading to several approaches being investigated. Recognizing that PCED treated earlier in the course of the disease may heal faster, consideration should also be given to prophylactically treating eyes at risk for developing PCED.

Jade Therapeutics is one company that has focused on PCED as a target indication for a recombinant human growth hormone (HGH) product in a novel formulation for one-week delivery. Jade developed its business case leveraging physicians and practitioners for primary research. It specifi cally targeted leaders in ophthalmology and/or non-ophthalmologic wound healing; with academic prominence with respect to corneal and/ or non-ophthalmologic wound healing; and who currently participate in patient care. Physicians identified PCED as one of the indications with a high unmet need that could be satisfied by Jade’s corneal wound-healing agent. While PCED has a broad range of etiologies and diverse healing times, there is a signifi cant desire to decrease healing times across this population of patients, thereby shortening the duration of symptoms.

It was important for Jade’s business model that they recognize that the different subgroups of PCED in their segmentation (neurotrophic, surgical procedures, corneal burns and trauma, and severe dry eye) had different assumptions for the number of weeks of potential therapy that may lead to the target amount of healing (ranging from one to six treatments). This supported a $500 million market estimate. Jade developed its plan for PCED and received orphan status for PCED from the Food and Drug Administration in 2012. This afforded them seven years of exclusivity within the disease, and potential for accelerated approval.

Jade’s PCED program is a relevant example of a company that recognized an unmet need through its interactions with physicians; segmented the unmet need into its relevant etiologies and specifi c treatment paradigms; identified what would move the needle across those subgroups in terms of reducing healing times; and defined its target product profi le for this unmet need.

Mr. Chapin is the senior vice president of corporate development 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. Dr. Rafii is the senior director of corporate development at Ora, and co-founder of Jade Therapeutics. We welcome comments or questions related to this or other development topics. Please send correspondence to mchapin@oraclinical.com.