In previous columns, we’ve explored the importance of an early consideration of the Target Product Profile, or the key areas of the ultimate label/package insert, such as the indication, dosage and administration, and safety. This month, using a retina drug development program as an example, we’ll examine a few kinds of specific inputs for the TPP that bear consideration.

It’s critical to address the potential impact TPP decisions will have on the main elements of the drug development program. The TPP may also have implications for product differentiation, which will impact future managed-care reimbursement. While certainly not an exhaustive discussion, we’ll highlight some key issues encountered by our clients, particularly early-stage, new entrepreneurs.

One consideration that inevitably arises when contemplating a strategy for the development of a product with the potential to treat various types of neurodegenerative disease is whether or not to pursue an orphan-drug indication. The focus of such an indication could potentially be an inherited retinal disease like retinitis pigmentosa, Stargardt’s, Leber congenital amaurosis, etc., or another, more prevalent ocular disease such as dry age-related macular degeneration or glaucoma-related neurodegeneration. While the focus of this column isn’t to advise you on which indication you should pursue, we will target a few key considerations, such as:

• pathophysiology;
• patient subgroups;
• recruitment potential;
• clinical endpoints; and
• pricing.

All of these factor into the creation of the model for the financing pitch and will influence your overall likelihood of success.

We’ve seen situations in which the new entrepreneur creates an initial business plan based on the assumption that a trial in an orphan indication will have a “lower bar” to clear, and therefore will be quicker and have a good chance of requiring only a single trial. In most cases, however, for an orphan indication, the FDA still requires two well-controlled trials with robust endpoints shown to be correlated with visual function.

 Match the program to the indication with the highest chance for success based on the therapy’s mechanism, balanced with a financial outcome that investors will embrace as the best return on their investment. You may determine that the best route will be to pursue an orphan indication, and take advantage of reduced filing fees, added exclusivity and tax credits, with a pricing model consistent with the orphan drug’s lower number of patients.

A key consideration when evaluating a potential orphan indication is the recruitment of the appropriate patient population. With multiple clinical trials targeting inherited retinal diseases (many of which involve gene therapy), you need to be able to realistically assess the viability of a clinical trial, the possible need for treatment-naïve patients for the protocol and the speed of patient enrollment. Multiple clinical programs may be competing for the same limited patient base depending on the timing of specific trials. Another aspect to consider is how the landscape for the chosen orphan may look in the future should other products launch before yours; this will have an impact on the reimbursement for the use of your drug and your investors’ returns.

For example, since diseases like dry AMD and Stargardt’s progress slowly, generally you may be looking at an 18 to 24 month follow-up. Filling a larger study in Stargardt’s may be challenging and will need to be focused on the key clinical centers (generally large institutions and universities) versus a standard dry AMD geographic atrophy trial that can tap into a broader base of investigative sites. Also, note that the recruitment process and patient demographics will impact the approach to a specific project. For instance, a Stargardt’s study for an orphan designation would involve enrollment of pediatric patients, while a dry AMD/GA study would involve the recruitment of elderly individuals.

A three-line change in ETDRS visual acuity has long remained a regulatory standard for assessing efficacy; however, visual acuity assessment is problematic in the context of severe vision impairment. With many inherited retinal diseases, vision is so poor that patients can’t read an eye chart, and as a result, alternative functional endpoints are required. Recognizing this, the NEI/FDA Endpoints Workshop (November 2016) acknowledged the importance of using visual mobility courses as clinical trial endpoints in retinal diseases associated with severe vision loss which were less amenable to standard three-line changes in visual acuity. Our group at Ora has developed standardized multicenter mobility courses that target specific retinal diseases and various levels of central acuity and peripheral vision (i.e., visual field). The diseases targeted include inherited retinal conditions like RP, Stargardt’s and LCA, as well as—potentially—dry AMD. Ultimately, these courses are designed to facilitate the development process and bring new pharmaceutical products and devices to patients with these debilitating conditions.  Other visual function endpoints, such as dark adaptation, may also be important in understanding functional improvements from therapy in earlier stages of dry AMD.

One of the holy grails of drug research is certainly dry AMD, particularly the prevention of progression in its earlier stages. For a given treatment program, you must be able to choose the ideal stage of disease and balance that with the length of the trial and the ability to detect a change in a relevant endpoint. Geographic atrophy is a popular regulatory endpoint because there’s currently a clear definition for an endpoint based on the expansion of GA area versus other potential study designs for earlier disease. However GA’s use is potentially complicated by the fact that researchers will be studying patients who may be too late in the disease process for an intervention to have a significant positive impact. In contrast, the endpoints for early-stage AMD may require a longer trial with a less-well-defined regulatory endpoint. You also need to consider your ability to select the precise subgroup of patients expected to progress the quickest, and sensitive visual function endpoints beyond visual acuity.

Early interaction with the FDA is encouraged so that the ultimate plan to win approval can be outlined for your investors. For the first-time entrepreneur, it’s important to remember that FDA “acceptance” of a Phase II trial isn’t equivalent to the FDA accepting a plan and endpoints that may ultimately support submission and review of the NDA/Biologic License Application. Ensure that the product positioning is precise in your investor presentations.

We’ve seen cases in which a company will pursue both the mainstream and the orphan indications in parallel, with a plan to focus on a single lead for subsequent studies. Certainly, this requires two pricing and commercial models. Particularly in the situation in which a product is repurposed from an existing marketed drug, the threat of competitors simply compounding it needs to be considered versus your production of a high-priced orphan drug.

Another example is anti-neovascular and/or anti-inflammatory agents. From a mechanistic perspective, these drugs can be applied to various retinal diseases, such as wet AMD, diabetic macular edema, diabetic retinopathy, macular edema associated with CRVO/BRVO and, if it’s an anti-inflammatory drug, perhaps posterior uveitis. Wet AMD may be the entrepreneur’s first choice, based on the large markets of leading products like aflibercept, ranibizumab and bevacizumab. On the flip side, these other anti-VEGF drugs have generated such great outcomes it may appear that the bar has been set too high.

For example, looking at the current anti-VEGF market and the clinical hurdles to overcome, it may make more sense to lead with diabetic eye disease. According to the American Diabetes Association, about 29.1 million Americans (9.3 percent of the total population) have either type 1 or type 2 diabetes, with an estimated growth of about 1.4 million every year. Of this population, it was reported that about 28.5 percent had cases of diabetic retinopathy (4.2 million) and about 3.8 percent were diagnosed with DME (770,000).

For any of the above conditions, another key consideration for refining the TPP and pitch to investors is determining whether the treatment is intended to be primary or adjunctive. The bar is high for being approved as a primary therapy, and would require clinical trials showing non-inferiority or superiority to the standard of care represented by the approved agents ranibuzimab and aflibercept, with the margin of noninferiority to ranibizumab being a three- to four-letter difference at nine months for wet AMD.

Alternatively, one can explore adjunctive therapy, combining the novel approach with the standard-of-care and comparing that combination to the results of the standard-of-care alone (dosed according to its label). Since this decision relates to the design (and ultimately time and cost) of the Phase I and Phase II trials to get to a point where the program sees an increase in value to investors and partners, you have to ask: Should the focus be on newly diagnosed patients naïve to treatment, or patients who are sub-responders to existing therapy? Keep in mind complete non-responders are hard to come by, so the key will be defining the sub-responder in the inclusion/exclusion criteria, and understanding how that choice will influence recruitment. Current anti-VEGFs achieve a three-line gain in visual acuity in approximately one-third of patients. There’s still room for an adjunctive therapy to possibly provide greater efficacy, or a primary therapy that uses something other than an intravitreal injection as its route of administration.

The goal is to obtain proof-of-concept, and have that data support a plan for the intended dosing and use of the drug to drive further investment. A Phase I study in retina is generally done in patients with the target disease, and can also incorporate some efficacy measures in the form of either visual function (e.g., ETDRS visual acuity) or ocular structure (e.g., optical coherence tomography) endpoints. With a focus on early OCT findings, you can sometimes obtain an earlier proof-of-concept than you can by using a visual acuity endpoint. The drug’s mechanism of action also plays a key role in establishing expectations for a particular approach to reduce the edema seen with OCT, and/or drive VA changes. While either visual function or OCT improvement is an acceptable approach to establish proof-of-concept, properly setting expectations with investors and partners will help drive decision-making going into any subsequent Phase II trial. Initial trials (adjunctive or primary) may involve patients with poor VA potential, but can still be important if they demonstrate efficacy using OCT. Such results will still carry significant weight with physicians and investors as a reason to believe.
It’s important to remember to balance the impact of study design with the toxicology requirements for opening the IND to conduct the trials. If dosing is monthly and the intended follow-up is six months, for example, one needs to plan for a chronic ocular toxicology study for the IND, as opposed to a situation in which the trial is first focusing on acute dose and follow-up. Ultimately, what is the true differentiation in the TPP: dosing frequency; efficacy or both? Going after a sustained-release delivery route will impact the length of the required ocular toxicology, so if sustained release is driving the TPP, then extra time and cost will be needed for the IND. Again, it’s not a matter of a right or a wrong approach, but rather ensuring that the entrepreneur considers the way in which these factors impact feasibility, time, cost, likelihood of success and, ultimately, create optimal value.

Recognize that the FDA is willing to meet with companies early in the process to discuss requirements. For the company that hasn’t visited the ophthalmic division at the FDA, it may be refreshing to learn that the agency is open to discussing multiple potential indications for a single product at the pre-IND meeting, and such a meeting can be critical for gathering the input necessary for selecting the lead indication for use in your business plan.

For the first-time physician entrepreneur, developing the right financing plan relies on a well-thought-out TPP. To this end, this discussion isn’t an exhaustive review, but instead highlights a few areas for consideration, and shows that there are multiple approaches to TPP design that promote value for investors and partners.

Mr. Chapin is senior vice president of corporate development at Ora, and Mr. Diaz is an associate in corporate development. Ora provides a comprehensive range of development, clinical-regulatory and consulting services for developers, investors and buyers; preclinical and turnkey clinical trial services; assistance with regulatory submissions; and the integration of business development and fundraising support in ophthalmology. The authors welcome your comments or questions regarding product development. Please send correspondence to or visit