As a new physician-entrepreneur, you may have an idea for targeting a specific pharmacologic mechanism and are weighing your options regarding which type of lead drug to focus on: You can synthesize a new chemical entity and take advantage of fresh intellectual property on a novel composition of matter; license and repurpose an approved medication; use a known compound available generically; or make use of an existing platform that’s being developed by another company for other, non-ocular indications. Discussions of repurposing are relevant in ophthalmology, due to the diverse disease mechanisms seen in the eye. Furthermore, since most ophthalmic drugs are administered locally, generally speaking, the systemic exposure to these agents is well within the safety margins of the toxicology identified in studies of the drugs’ other indications. This makes repurposing one of these agents an attractive option.
In prior columns, we’ve analyzed examples of some of the options listed above. This month, we’ll look at the case of licensing the ocular rights for a drug in development for non-ocular indications but which isn’t yet FDA-approved for those other indications. Along the way, we’ll also examine some key considerations that we’ve encountered in such cases, and describe a current example of a program currently in development.
Review of Regulations
First, let’s look at a few key regulatory considerations when taking a repurposing approach.
Section 505 of the Food, Drug and Cosmetic Act outlines three types of new drug applications: 1) A New Drug Application that contains full reports of investigations of safety and effectiveness; 2) an application where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference [section 505(b)(2)]; and 3) an application for a generic drug that shows the proposed product is identical to a previously approved product [section 505(j)].
We’ve looked at the 505(b)(2) approach previously, but there are different cases where reference to other regulatory files come into play that are treated differently. A 505(b)(2) application can rely on information from published literature or the FDA’s previous finding of safety and/or effectiveness for an approved product. One key difference to understand when planning a filing strategy is that, according to its purpose, a 505(b)(2) can help avoid duplication of data that already exists but also requires the applicant to provide notice of certain patent information to the NDA holder and patent owner for the product(s) being referenced. Sometimes there’s an option to pursue either a full NDA or 505(b)(2), and there are multiple factors influencing that decision, one of which is the intellectual property disclosure requirement.
How does a 505(b)(2) relate to a product that’s not yet approved but which is being developed for another indication (or a study that’s already been terminated)? An example of this is a situation in which key information is referenced from a publication that the applicant doesn’t own or have right of reference to (right of reference refers to the ability to refer to studies of a drug conducted by someone else). Even though the approach to this situation is clearly outlined in an FDA Guidance Document [FDA Guidance: Applications Covered by Section 505(b)(2)], we raise the point here because we’ve received questions about how to reference information from programs in which an IND was active for a non-ophthalmic indication but the product wasn’t FDA-approved. In this situation, one can’t simply ask the FDA to rely on these other findings of safety and/or efficacy, because that product is not yet approved and hasn’t been fully reviewed and deemed safe. To use that data in a development program for a product not yet approved, you need a right of reference with the other applicant.
Case Example: Okogen
The Okogen experience is a great example of a company leveraging the right-to-reference approach. Okogen has been successful in recognizing and forming a plan around an unmet need (viral conjunctivitis), identifying a drug with a novel approach to a non-ocular indication currently in development, securing funding, and moving a program towards Phase II trials. A large part of its strategy and success in securing funding was leveraging the ability to reference a product from a separate indication in order to reduce the risk involved with pursuing approval of the drug, and to accelerate its advance to a clinical trial.
Okogen was founded by a small team of industry veterans. With firsthand experience in business development at Allergan and Shire, Chief Executive Officer Brian M. Strem saw a large unmet need in viral conjunctivitis, and precedents for deal structures in that arena. The company’s lead drug is based on the active pharmaceutical ingredient ranpirnase, a low-molecular-weight protein extracted from the eggs of Rana pipiens (northern leopard frog). Ranpirnase preferentially enters into the cytoplasm of virally infected cells due to electrostatic interactions, halts protein synthesis by targeted degradation of mammalian tRNA, blocks NFkB (pro-inflammatory) downstream signaling, and induces cellular apoptosis. These mechanisms drive inhibition of viral replication, reduce inflammation and induce virally-infected cell death. This triple mechanism of activity contributes to the ultimate target product profile, reducing viral burden and subsequent length of contagion, and acceleration of sign-and-symptom resolution.
Ranpirnase was initially developed as an intravenous anti-cancer drug, Onconase, and, as such, its preclinical safety fully supported clinical trials in cancer patients through Phase III. Unfortunately, it missed the primary efficacy endpoint in the second of the global Phase IIIb trials in patients with unresectable malignant mesothelioma, and the oncology program was discontinued. Alfacell, the sponsor of those studies, was restructured into Tamir Biotechnology. Prior to restructuring, scientists had identified the broad-spectrum antiviral potential of ranpirnase and the new management team at Tamir is leading the effort to develop ranpirnase as the first approved antiviral for human papillomavirus genital warts.
The company had demonstrated efficacy in preclinical models against a wide range of viruses, including adenovirus. Okogen identified the opportunity for repurposing it, and licensed the ocular use for ranpirnase, effectively using existing IP for methods for treating viral infections. As part of that arrangement, Tamir has granted Okogen full rights of reference to existing data and regulatory filings, including preclinical studies, as well as the safety data collected from all clinical studies completed with the IV drug. The existing information on genotoxicity and toxicology following systemic administration was used to support the assertion of a reasonable safety margin based on absorption from ocular dosing. With the additional toxicology work, per Good Laboratory Practices, done by Okogen for ocular dosing, the ocular studies then completed the package as a basis for initiating the Phase II trial.
Another question that comes up is whether or not non-GLP systemic studies from the reference program can be used. In order for prior work to be useful, and to definitely avoid the need to repeat studies, those systemic studies need to have been conducted as per GLP regulations, unless there’s a specific justification to deviate from GLP. (Cost savings isn’t an acceptable justification for the FDA.) Make sure to verify that GLP was observed in the studies if you’re considering referencing other work.
For a new drug, the FDA usually requires ocular toxicology from two species. In the context of repurposing a drug, however, the question of whether the agency will accept the IND with ocular toxicology from just one species depends on the situation. Unless there’s a specific justification, if the reference drug isn’t yet approved for other purposes, then you will most likely need two species for GLP ocular toxicology. So, it’s best to plan for the use of two species until the FDA confirms otherwise.
As we’ve discussed in previous columns, there’s a benefit to having an early pre-IND meeting with the FDA in order to help refine budgets for the IND-enabling work. Typically, it’s most useful to include in the pre-IND package a description of the intended final formulation and a justification of how you plan to bridge the ocular use to the already completed toxicology safety data derived from systemic dosing. The latter may require some preliminary, possibly non-GLP, data on systemic absorption following ocular dosing. Having such data ensures that the FDA has enough information to provide you with complete responses and guidance that can help you plan and budget your remaining IND-enabling activities.
In the case of Okogen, in addition to safety information, since ranpirnase had previously been in clinical trials under an IND, significant chemistry, manufacturing and control information was also available for use, including the other company’s analytical methods, manufacturing process and specifications. Further, as new inventions are generated, Okogen is building its own, wholly-owned IP portfolio, providing multiple layers of patent protection.
In our ongoing survey of business issues and case studies within the industry, the case of Okogen demonstrates the successful referencing of a drug from a previously failed systemic program. Because it was able to structure and execute a license for the drug and relevant data package for repurposing, it realized significant cost savings in its development program, and with Okogen’s recent $10 million financing round, the company’s able to deploy funds and rapidly move toward a Phase II trial.
Ultimately, it’s important to understand the best way to reference prior data, whether it’s from an existing approved drug (with or without right to reference), a primary peer-reviewed publication, or from another ongoing development program. Early interaction with the FDA can help clarify the proper path to approval and confirm which parts of a development program you can avoid.
Mr. Chapin is senior vice president of corporate development at Ora Inc. The author welcomes your comments and questions regarding product development. Send correspondence to firstname.lastname@example.org or visit www.oraclinical.com.