In the previous column, we discussed some points related to the development of the Target Product Profile, specifically those related to retina product development. This month, we’ll continue that theme and look at a few areas that factor into the TPP for drugs designed for selected anterior segment indications. We can’t cover all areas related to anterior segment in this brief piece, but we’ll highlight a few pearls for new physician entrepreneurs to consider when thinking about the selection of a drug’s indication.
Generally, when starting a development program, it’s good to create at least two TPPs and compare them directly against profiles of the existing market leaders. One is a TPP with ideal criteria, and the second is the minimum acceptable profile, in which some elements may not be the best, but are still enough to support development and commercial feasibility. For example, the target may be once-daily dosing, but the minimally-acceptable dosing regimen may be twice daily. Similar thought processes can be used for the drug’s indication, patient population, dosing frequency and duration, container closure and storage conditions (i.e., Will this product be stored at room temperature, or is cold-chain refrigeration— in which the different steps of the supply chain each involve refrigeration—acceptable?), clinical data for the package insert, and safety. Remember that for a topical ocular product, the comfort of the eye-drop formulation upon instillation may be a key aspect of the safety profile, as well. Products have battled in the marketplace based on patient comfort, but in the current reimbursement environment you have to consider if comfort alone would drive coverage by payers v. the standard of care.
When a new drug has a mechanism of action that can be applicable to multiple disease indications, or has various mechanisms of action, the selection of the lead indication(s) will drive the development program, the positioning and value proposition for the fundraising plan and its presentation. Is the plan to study one indication only, or to raise funds for multiple studies to be run either in parallel or sequence, across multiple indications, which may both build additional value and provide additional “shots on goal”? In our experience in talking with entrepreneurs, it’s not always clear to them which indication to lead with, particularly since a product may have applications across multiple indications, each of which have defined clinical-regulatory pathways and unmet needs in the market that can potentially be addressed.
For example, with an anti-inflammatory drug, one has several major indications to consider. This is a general, high-level framework to use when considering them for such a situation:
• Dry eye. Currently, this is certainly the largest market for front-of-the-eye drugs. The success of Restasis and the introduction of Xiidra in 2016 have built considerable awareness of dry-eye disease in the general public, and of the value of dry-eye products in the world of pharmaceuticals and start-up companies. There’s a very large opportunity for new products, especially if they feature different mechanisms of action that address alternative areas of the inflammation cascade and wound-healing response, and/or consist of therapies such as anti-apoptotics, anti-oxidants, secretagogues, mucogenics, mucomimetics, novel lipids, hormonal therapies and polymers. When developing a dry-eye product, it’s important to consider mitigating clinical development risk. This includes targeting the proper subgroup of dry-eye disease, using validated endpoints and controlling environmental factors either through design or a clinical-controlled model approach. For example, there is a seasonal impact on disease signs and symptoms, and this may influence the timing of trials and introduce the need to build in tight control of operations and standardization across sites to maintain timelines and data precision.
Many dry-eye products are unpreserved, which raises different manufacturing considerations that impact time and cost for clinical supplies via utilizing blow fill seal manufacturing of unit-dose vials, alternative formulation technologies or container-closure approaches. These need to be considered early on.
• Blepharitis. One of the most common reasons for office visits is inflammation and discomfort of the eyelids. Interestingly, which side of the gray line of the lid margin you look at has large implications in terms of the actual disease to target and clinical-regulatory pathway to follow. When focusing on treating the posterior portion of the lid margin, the meibomian glands, the ultimate clinical endpoints are signs and symptoms similar to dry eye. Especially helpful for early studies, our group has focused on the imaging and categorization of different characteristics of the glands to help with patient selection, and on the evaluation of gland modulation. When moving to the anterior side of the lid margin, the signs and symptoms of blepharitis become redness and edema of the lid margins, discomfort and lid debris. For blepharitis, the current regulatory requirement is total clearing of these signs and symptoms. On a regulatory note, therapies in clinical trials must show superiority to lid scrubs, which are currently considered standard-of-care. Blepharitis is a large unmet need, and generally speaking, appears to be driven by an inflammatory process. When the first product—which may be a steroid—with a specific label for blepharitis gains approval, this should lay the groundwork for the evaluation of other agents and attract more interest in developing drugs for this indication. As with most product development programs, precise, validated clinical scales and standardized assessments across investigators in a multicenter trial will be two of the keys to success.
• Postoperative inflammation. Evaluating anterior chamber cells and flare, and pain following cataract or refractive surgery, has been a standard clinical-regulatory endpoint/pathway for the development of anti-inflammatories such as steroids and NSAIDs. This well-established clinical-regulatory pathway (acute studies which focus on primary endpoints for the weeks after surgery), has been used for products like difluprednate, ketorolac, bromfenac, nepafanac, loteprednol and others. However, one has to balance the clinical unmet need in this area with the usefulness of the development pathway. Steroids and NSAIDs are standard in postop use, and have a high hurdle for showing superiority. But thanks to superior dosing regimens and/or sustained-release approaches, a higher percentage of patients with clearing, or speed to clearing, or a higher reduction in inflammation and pain—though relatively high hurdles—are areas that can be explored. In general, the studies are placebo-controlled. Naturally, the pharmacokinetics of the drug and formulation need to support penetration of the anterior chamber when compared to the ocular surface indications.
• Allergy. Don’t forget allergy. Dominated by topical antihistamines, and now with generic and over-the-counter ketotifen available (it’s currently the only long-acting antihistamine available OTC) and once-a-day products, the focus here is on novel mechanisms. There’s still a large unmet need in a large proportion of patients with ocular allergy, with 30 to 40 percent of patients suffering from persistent allergic inflammation and showing an incomplete response to antihistamines. Steroids, of course, are still reserved for acute therapy in severe patients and cases non-responsive to antihistamines, due to their well-established side effects. There is opportunity, however, for the development of novel anti-inflammatories and agents with non-steroid mechanisms. A key attribute of allergy programs is the very rapid, precise and reproducible clinical trials utilizing the conjunctival allergen challenge (CAC) model that is validated and acceptable for use in both Phase II and Phase III U.S. trials, as well as trials in Japan, the second-largest market for allergy therapies. The CAC’s precision for positive proof of concept and dose ranging, reproducibility, and then speed through Phase III is unique and attractive and several companies with novel anti-inflammatories have chosen to go after allergy as a lead, or at least as a parallel program to complement their clinical data set. Of note, the above CAC model is also ideal for rapid proof-of-concept testing to demonstrate effects on ocular surface inflammation and dose ranging, whether or not the goal is allergic conjunctivitis.
More severe chronic allergic diseases such as atopic keratoconjunctivitis and vernal keratoconjunctivitis can also be considered lead indications for targeted therapeutics. However, as they are orphan indications, they’re more difficult to recruit for.
• Uveitis. Anterior uveitis is another of the more mainstream anterior segment inflammatory conditions worth considering. As there are multiple subgroups within this disease that can be targeted with specific anti-inflammatories, and generally due to the overall market size, we don’t see many programs leading with anterior uveitis with broad anti-inflammatory products unless there is a specific mechanistic story that fits best for uveitis compared to the other main indications. But we mention it here to round out the list of key inflammatory indications for consideration.
The topic of class labeling is reserved for another discussion, but suffice it to say that there are opportunities for class labeling, and this requires showing efficacy across multiple indications, and is usually part of a life-cycle plan.
A Case Study
The ophthalmic program that pharmaceutical company ReGenTree is pursuing with Thymosin Beta 4 (Tβ4) serves as a good case study and example of a business structure for funding between a U.S. firm and an ex-U.S company that has a strategic interest in the product. RegeneRx (Rockville, Md.) had been developing its Tβ4 platform across indications in the eye, as well as systemic indications. Tβ4, a naturally occurring peptide, enhances wound healing and tissue remodeling by increasing cell migration, cell-to-cell and cell-to-matrix contacts, and antioxidant activity, and by reducing apoptosis and inflammation via downregulation of chemokines and cytokines. With these broad activities, Tβ4 has many potential applications.
After performing compassionate-use and investigator-led proof-of-concept evaluations in neurotrophic keratitis, RegeneRx chose to pursue dry eye as well. Neurotrophic keratitis would be a parallel program; NK is an orphan indication with a lower number of patients, but there are advantages to orphan indication status, and the pathology fits with the wound-healing properties of Tβ4. This approach potentially provides multiple ‘shots on goal,’ and demonstrates Tβ4’s breadth of applications.
In 2015, RegeneRx partnered with the Korean clinical-stage development company GtreeBNT (Gtree) and formed the joint-venture ReGenTree, as a vehicle for funding and conducting the ophthalmic program in the United States. After reviewing more than 50 candidates in the early stage of human trials, Gtree concluded that a dry-eye indication would be the best fit for it because it determined that it could cover the investment of time and money required to develop an NDA in the United States. This led to Gtree reaching out to RegeneRx. Gtree also agreed to this deal given its strategic interest in eventually marketing a novel treatment globally, and its ability to attract funds from Korean-based venture capital firms for the funding of ReGenTree. The funding has financed Phase III studies, and Gtree plans to partner this product with a global pharmaceutical company for U.S./global rights.
Won Yang, president and CEO of GTree, explains the thought process behind the partnership. “We selected dry eye based on the total market potential for that indication,” he says. “However, strategically, since wound healing is related directly to the primary mode of activity, we supported funding of a parallel program in neurotrophic keratitis. This structure leveraged GTree’s access to investors in Korea, to identify and invest in a novel treatment from the U.S. that can also be eventually brought to the Korean market.”
While this is not intended to be an exhaustive review, we hope we’ve elucidated the thought process involved when considering a drug’s indications for the anterior segment and ocular surface. Specifically, when a drug has anti-inflammatory activity, the key is to be able to select from a range of ocular indications. The crucial factors in the selection of the lead indication(s) are: the specific molecular pathways targeted; formulation and manufacturing considerations; pharmacokinetics appropriate for the lead indication; and how different it is from the current standard of care for that indication. Examining the target profile (both the ideal and the minimal acceptable targets) and predicting how the product will differentiate itself from the competition will help drive its positioning in the minds of clinicians and payers, the plans for development and funding, and the designs of future studies.
Mr. Chapin is senior vice president of corporate development at Ora, and Mr. Ousler is vice president of dry eye. 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 firstname.lastname@example.org or email@example.com or visit www.oraclinical.com.