Last year, we instituted a quarterly column that addressed some of the considerations of ophthalmic product development: securing the appropriate patents, planning regulatory meetings, calculating business plans to secure financing, and concepts for crafting the Target Product Profile. We invite you to join us as we continue to peel back the curtain to reveal how ophthalmic innovators are identifying and capitalizing on the current trends while advancing novel technologies to treat patients. In this issue, we will explore a couple of key elements around how entrepreneurs with broad platforms may choose to lead with an ocular indication. We will use a current case study of a start-up company that is tying together many of the elements we have been discussing. We feel it provides a great example of using the eye as a proof of concept for an exciting platform delivery technology.

Novel Science for Ocular Indications
As stated with the old proverb that “the eyes are the window to the soul,” innovative science has a habit of flowing through the eye. Pursuing ophthalmic indications can help novel technology platforms “move the ball down the field” for the following reasons.

• Attenuating toxicity and delivery issues. While most therapies in development have been optimized to target their respective receptors, enzyme binding sites and/or substrates, failing to achieve sufficient bioavailability can derail even the most promising clinical candidate. Whether one is trying to treat a disease of the anterior or posterior segment, topical and intravitreal administration typically deliver clinically meaningful dosages of the therapeutic to the tissue where it is supposed to produce a treatment effect. Achieving sufficient bioavailability in the vitreous or retina can be more challenging due to the restricted injection volume, degradative enzymes, and the expedient elimination of small molecules, certainly if one is trying to deliver a drug topically to the back of the eye with sustained release. However, it is possible to optimize formulations or utilize sustained-release implants to deliver clinically significant amounts of therapy to the target tissue in the eye. In the same vein, local ocular dosing dramatically reduces the systemic absorption of therapies compared to other routes of administration, limiting the potential for untoward systemic consequences that can impact your development program. Ergo, there is significant potential to repurpose therapies for ophthalmic indications based on demonstrated clinical efficacy in other indications that show effect with the mechanism of action, but were halted because the active pharmaceutical ingredient did not go or reside where it was supposed to, or faced systemic safety issues.

• Time and cost-to-value inflection. As stated in our previous article, Developing a Business Plan to Secure Funding (September 2013), venture capital firms or pharmaceutical partners may prefer to see data from clinical trials before investing in young companies. Therefore, it can be difficult to raise money around novel technology platforms that are yet to be validated. Luckily, the path to an Investigational New Drug, and ultimately the clinic, can be relatively straightforward (fast and inexpensive) for ophthalmic indications where the intervention is dosed locally.

No Adverse Effect Level (NOAEL) doses that arise from systemic toxicology studies are typically many multiples of the doses tested in Good Laboratory Practice ocular toxicology studies, and of the anticipated clinical dosage. Clean toxicology studies usually translate to IND acceptance, which allows for progress to the clinical proof-of-concept study and for the therapeutic to reach value inflection, increasing the potential for additional external investment. Investment from alternative sources, other than VCs, can be covered by translational science grants, friends and family, strategic partners and angels and should be pursued if the desire or ability to raise venture dollars doesn’t materialize. Strategic partners can become invaluable based on their ability to help shape the Target Product Profile, critical study elements and designs that will help drive decisions within organizations (which may be different across companies) in addition to their stated interest aiding in fundraising/business development. With this in mind, designing creative deal structures by engaging strategic and exit partners as early as possible can help ensure appropriate focus.

Many ophthalmic indications can serve as the lead, as proof-of-concept and to build value for other diseases in the areas of inflammation, allergy (specifically leveraging the unique clinical-regulatory allergen challenge pathway available for the eye), neuroprotection, infection, vascular disease and others.

Pursuing orphan diseases is a strategy to potentially significantly lower the cost of development, while attempting to serve patients who have large unmet needs. EvaluatePharma’s 2013 Orphan Drug Report estimates that pivotal studies cost about $186M per drug (across all pharma) and that huge cost savings are possible by pursing orphan indications, where pivotals cost are between $43 and $85 million if the 50-percent U.S. tax credit available via the Orphan Drug Act is factored into the equation. That said, assets targeting orphan diseases do not usually have an expedited pathway to the clinic and typically still require the standard IND enabling safety studies.

Indications with High Unmet Need
Programs that focus on an indication with high unmet need may be able to leverage a regulation that provides several incentives for development in indications that have fewer than 200,000 patients in the United States, or affects more than 200,000 patients but are not expected to recover the costs of developing and marketing a treatment drug in the United States (21 USC 360bb). The Orphan designation provides for:

•    Seven years’ marketing exclusivity from the date of marketing approval;
•    Tax credit of up to 50 percent for qualified expenses for clinical research to support approval of an orphan drug;
•    Grants to support clinical development of products for use in rare diseases;
•    Exemption from certain user fees that are normally charged sponsors; and
•    Other special consideration from the Food and Drug Administration for accelerated development, review by the FDA and approval, on a case-by-case basis.

This can have significant implications in some programs where a streamlined clinical program can be used. In ophthalmology, this includes indications such as, but not limited to, posterior uveitis; vernal keratoconjunctivitis; pterygium; ocular melanoma; endothelial dystrophies; inherited retinal diseases (retinitis pigmentosa, Stargardts; Leber’s congenital amaurosis; Leber’s hereditary optic neuropathy), corneal ectasia; and others.

AURA Biosciences
Started in Cambridge in 2009 by CEO Elisabet de los Pinos, PhD, Aura Biosciences is developing its novel tumor-targeting pseudovirion technology discovered at the National Cancer Institute, with the lead indication for ocular melanoma. To date, Aura has been funded mainly through angel funding, including convertible debt instruments as well as government grants.

Pseudovirions are made up of the protein coat of a virus, conferring tumor specificity, but without infectious potential. Aura’s lead drug, AU011, features virion capsules conjugated to a photoreactive dye. The capsule selectively binds to cancer cells, and then the associated photoreactive dye is activated with infrared energy, free radicals are released that efficiently kill the cancer cells without damaging surrounding tissue. Each pseudovirion particle is able to deliver up to 1,000 of the photoreactive dye molecules without compromising its tumor-targeting capabilities, thus serving as an efficient delivery mechanism.

AU011 can be leveraged for indications such as head and neck, lung and prostate cancer. The pseudovirion technology can also be combined with other drug payloads, beyond the photoreactive dye from the ocular project, unlocking the potential of a transformative technology platform. Despite a wide range of uses to address high unmet medical needs and generate value, the company decided to develop its lead product, AU011, in a rare cancer indication (ocular melanoma) to speed the path to clinical proof of concept, and obtain registration in approximately four years. But, this is certainly a strategy that reduces the risk for further development across other indications.

Ocular melanoma is a highly unmet medical need. There are currently no targeted therapies available to treat primary tumors, and all current treatment options like surgery (enucleation) and radiotherapy (plaque radiotherapy) are highly invasive and have major side effects for these patients. There is a high interest in treating smaller tumors with therapies other than surgery and brachytherapy alone. In fact, a trend in diagnosing a greater proportion of small melanomas and a shift toward eye-sparing treatment of smaller tumors was reported from the Collaborative Ocular Melanoma Study (COMS) centers. Aura expects that ocular melanoma will be granted orphan status by the FDA, and if successful, will provide the first tumor-targeted therapy for these patients.

In focusing on optimizing the initial Target Product Profile to make the clinical program as efficient as possible, the program is able to leverage: a) local delivery via intraocular injection, reducing the risk of systemic toxicity; b) direct visualization of the tumor area to monitor efficacy in a short period of time; and c) clear clinical endpoints to evaluate safety. These elements provide a clear path to proof-of-concept for the lead indication in ocular melanoma and opens the future possibility to expand the product to treat other non-ocular cancers. This is a clear example of how a company can be financed through different sources, and focus on building value for its platform, leading with an identified unmet need in the eye.

Mr. Chapin and Mr. Sandwick are with the Corporate Development Group at Ora Inc. Ora provides a comprehensive range of product development services in ophthalmology. Ora is providing clinical-regulatory and development services to Aura Biosciences. They welcome comments or questions related to this or other development topics. Please send correspondence to: