This program ties together several of our prior columns on business models, development and funding. For early-stage physician-entrepreneurs and for pharmaceutical companies looking to efficiently enter the space or spin-out certain assets, it serves as a good example of an efficient virtual model for product development, strategic investment and partnership with a contract research organization, or CRO, and how to approach repurposing known compounds into unmet needs.
Background on Repurposing
Re-purposing is the phrase used to describe drugs that have been used for other indications, and formulating or re-formulating them for another use (in this case ophthalmology), a strategy that is seen frequently across the pharmaceutical industry to elevate the likelihood of success.
There are several advantages to this approach. An active pharmaceutical ingredient (API) has known pharmacology; has been shown to be efficacious in relevant models or diseases outside the eye, validating the mode of activity; has existing toxicology information and known physiochemical parameters; and usually has an active drug master file (DMF) for the API, which can be referenced in the file to the Food and Drug Administration, greatly supporting the Chemistry, Manufacturing and Controls, or CMC program. Generally speaking, available systemic toxicology information does not have to be repeated as long as: a) there is an appropriate bridge of potential systemic bioavailability of the drug from the topical ocular dose to doses used in prior systemic toxicology data; and b) an appropriate “no observed adverse effect level,” or NOAEL, was identified in the systemic studies.
For example, if you calculate the theoretical systemic exposure, assuming 100 percent of the entire topical dose is absorbed and becomes systemically bioavailable, and that amount is still significantly (e.g., 10 times) less than the systemic NOAEL level (adjusted for weight), then generally speaking the existing systemic information would cover that for ocular use. The preclinical safety program can then focus on ocular toxicology (with ocular dosing). The FDA’s typical requirement for ocular toxicology, two species, may also many times be reduced to a single species, if the API has already been approved in the United States for other uses at a relevant and supportive dose. Of course, this should always be confirmed via an early pre-IND communication with FDA.
The re-purposing approach generally leverages a type of new drug application (NDA) called 505(b)(2), in which one or more investigations that the applicant relies on was not conducted by the applicant, and there is not a right obtained from the original applicant (21 U.S.C. 355(b)(2)). Types of information that can be leveraged in a 505(b)(2) include published literature and the FDA’s prior findings of safety and efficacy.
In cases of the re-purposing of active ingredients, it is important to point out the approach to protecting the products with patents. One can approach patent protection with: a) method of use if use in the eye is non-obvious; b) formulation patents created by inventive steps around specific formulations for optimizing efficacy with concentration range, dwell time/duration of action, penetration, comfort and safety; c) manufacturing process (e.g., novel crystalline forms); and d) delivery technology leveraging novel platforms for sustained release.
Repurposing in Action
Aciex was funded by three top health-care venture capital firms (Bay City Capital, New Enterprise Associates and Healthcare Ventures), Ora Investment Group and a subsequent strategic investment by Akorn. Ora provided turnkey CRO development services at reduced fees and also made further investment through its financing arm, a creative mechanism some CROs are using. But in our case at Ora, this effort is differentiated by being focused in the area of expertise and broad operational capability within ophthalmology.
Aciex remained a virtual organization, which is commonplace now among start-ups looking to be capital-efficient and leverage outside expertise, with no more than two employees at a given time. Engaging a CRO at this level of partnership aligns the parties and enables the rapid allocation of resources internally within the organization as needed to meet the ever-changing plans typically seen in a pharma start-up. This enables the partnership at the strategic level to focus on the common objective rather than a fee-for-service, vendor-type relationship, and in this case resulted in a high amount of work performed, and additional work as needed, within budget.
The deal demonstrates also the still unmet needs in some key front-of-eye areas. Ophthalmology has seen a dramatic increase in the number of products in development, for example, in the high-profile and large dry-eye market. Yet opportunities remain for differentiated products in indications such as allergy and postoperative inflammation, where there are established and efficient development pathways.
The lead product announced in this deal is an ocular formulation of the well-known allergy drug cetirizine, the main ingredient in the systemic allergy medication Zyrtec, now an over-the-counter product. While systemic cetirizine is approved for relief of nasal and ocular symptoms, controlled studies have shown that topical treatment has a greater therapeutic effect than systemic administration. Cetirizine has potent efficacy for rhinitis, and has a very safe systemic profile, well-known to both ophthalmologists and non-eye-care professionals, including primary-care physicians, allergists and pediatricians, who drive more than half of the prescriptions of ocular allergy drugs. This product will provide ophthalmologists another option for treating patients with allergies in an area where a percentage of patients remain non-responsive to the leading antihistamine products. The cetirizine data also demonstrated higher level of efficacy in patients with more severe and widespread level of allergic signs and symptoms, including those with lid swelling.
The second re-purposed product is a formulation of fluticasone for post-surgical inflammation. Steroids and NSAIDs have been the mainstay treatment for treating inflammation after surgery, and while there has been work across the field on development of soft-steroids, the opportunity for a more potent steroid, with more complete anti-inflammatory effects, and possible once-daily dosing, is still available. Fluticasone has been known under the names Flonase and Flovent for many years, and is a more potent steroid at the glucocorticoid receptor compared with dexamethasone, prednisolone and difluprednate.
The Aciex portfolio also included an exciting program investigating a new chemical entity. Syk-kinase has a key role in the degranulation of mast cells, and inhibition has potent effects in reducing the release of pro-inflammatory mediators from the mast cell, with proven efficacy in systemic disease, in addition to broad anti-inflammatory effects. Syk-kinase inhibition has potential to thus impact both acute phase reaction via mast cell stabilization, and have ongoing anti-inflammatory activity in allergy and other inflammatory indications. Recent advancements in the design of the conjunctival allergen challenge (CAC) model enables more sensitive assessment of specific anti-inflammatory effects (late phase), versus antihistaminic effects (early phase). An estimated 30 to 40 percent of ocular allergy patients report not being sufficiently treated with current antihistamines with complete relief of symptoms, and still have redness and persistent late-phase allergy or allergic inflammation.
The signing of the agreement for Nicox to aquire Aciex is an example of a strategic exit for a company that was spun-out as re-purposed concepts, funded early on by investment from the CRO and VCs, entry of another strategic pharma investor, and ultimate acquisition by a strategic partner looking to advance its future commercial presence in the space.
Mr. Chapin is senior vice president of the Corporate Development Group at Ora Inc. Ora provides a comprehensive range of product development, clinical-regulatory and product consulting for developers, due diligence support for investors and buyers, clinical trial services, and asset and business partnering and commercialization support in ophthalmology. We welcome comments or questions related to this or other development topics. Please send correspondence to email@example.com.