Despite major advances in medical care over the past few decades, there are still a number of acute diseases for which there is substantial room for improvement in patient outcomes. For many of these conditions, the chances for positive outcomes are limited by the inability to deliver sufficiently high and sustained drug concentrations to the injury site without causing side effects in other parts of the body.
Edge’s current product development strategy involves identifying hospital-based products for acute, life-threatening neurological conditions where limited or no current therapies exist. The company’s two novel product candidates have the potential to target multiple indications associated with brain hemorrhage. Edge is also leveraging the Precisa™ development program to address other therapeutic areas.
Precisa is Edge’s proprietary, programmable, biodegradable polymer-based development platform. It allows Edge to create polymer-based therapeutics capable of delivery directly to the site of injury to potentially avoid serious systemic side effects often associated with oral or intravenous delivery. Precisa enables high and sustained drug exposure with only a single dose at the initial time of procedural or surgical intervention.
We use Precisa to design our product candidates based on specific physical and chemical properties (size, shape, surface area) that allow for one-time administration at or near the targeted injured organ, vessel or cell. The diagram below depicts the specific form of Precisa microparticles containing nimodipine (EG-1962) that are approximately 70 microns in diameter, which is small enough to allow easy administration through a brain catheter, yet large enough to prevent macrophages from carrying the microparticles away from the site of injury.
Precisa is programmed with a specific blend of polymers in order to obtain the desired release profile of the selected therapeutic. This is accomplished by immersing the specified therapeutic in a matrix of clinically validated, biodegradable and biocompatible polymers. The foundation of Precisa are polymers such as poly (DL-Lactic-co-glycolide), or PLGA, the polymer in dissolvable sutures that has been used since the 1970s. PLGA is biodegradable, has minimal toxicity in humans, even when used intracranially, and is one of the few matrix delivery systems where drug release can be sustained over weeks.
Upon administration, the therapeutic that is on the surface of the microparticle immediately releases to provide high initial concentrations of the therapeutic. Subsequently, the therapeutic begins to diffuse through the polymer-based matrix and the polymer breaks down into lactic acid, a compound naturally found in the body, in order to deliver the therapeutic with the desired release profile.
Once Edge has identified an unmet clinical condition and several therapeutics that may have activity against this condition, we engineer multiple types of polymer-based formulations and systematically vary physical and chemical properties, such as polymer size, surface properties, dose level and release profile, using an established process. We program Precisa to achieve an initial and sustained release rate with effective targeting (based on form) for a particular administration given the organ or tissue target. We believe that this development platform allows us to advance a new product candidate from concept to preclinical testing in an expedited manner.
Edge can use the Precisa development platform to incorporate therapeutics with a wide range of physicochemical properties such as small molecules and proteins. We have demonstrated in preclinical studies that nimodipine, an L-type calcium channel blocker, manufactured into a polymer-based microparticle, provided differentiated pharmacokinetics. We are also using our Precisa development platform to develop EG-1964, which contains aprotinin, an FDA-approved pancreatic trypsin inhibitor.
Edge’s lead product candidate, EG-1962, is currently being investigated in the pivotal Phase 3 NEWTON 2 clinical study comparing the efficacy and safety of EG-1962 administered through an external ventricular drain (EVD) compared to oral nimodipine in adults who suffer an aneurysmal subarachnoid hemorrhage (aSAH) resulting from a ruptured brain aneurysm. To learn more about the Phase 3 NEWTON 2 study, please go to the clinicaltrials.gov website using the identifier NCT02790632. If positive, Edge believes data from the NEWTON 2 study will support a marketing application for the approval of EG-1962.
Nimodipine, delivered via oral or intravenous routes of administration, is currently the standard of care for the management of aSAH. Nimodipine is believed to work by modifying several pathways that otherwise contribute to unfavorable outcomes. Current treatment guidelines recommend that within 96 hours after aneurysm rupture, all aSAH patients receive nimodipine delivered orally or, in some countries, intravenously every four hours over a 21-day period. However, the ability to dose oral or intravenous nimodipine at appropriate therapeutic levels is limited by serious side effects, primarily hypotension, which can exacerbate the complications of aSAH.
Developed using Edge’s Precisa™ development platform, EG-1962 has the potential to improve patient outcomes by delivering a high concentration of nimodipine directly to the brain as a single dose with sustained drug exposure over a 21-day period, while potentially avoiding the dose-limiting side effects associated with currently available formulations of nimodipine. The U.S. Food and Drug Administration granted orphan drug designation and Fast Track designation to EG-1962 for the treatment of subarachnoid hemorrhage. The European Commission granted orphan drug designation to EG-1962 for treatment of aneurysmal subarachnoid hemorrhage.
The North American NEWTON study, a Phase 1/2 multicenter, randomized, controlled, open-label, dose-escalation clinical study, compared the safety, tolerability and pharmacokinetics of EG-1962 delivered via an EVD versus oral nimodipine in 72 patients with aSAH in six dose cohorts.
Ninety-day outcome data from the North American NEWTON study demonstrated that EG-1962 met the primary and secondary endpoints of safety, tolerability, defining the maximum tolerated dose (MTD) and pharmacokinetics. The data showed that the principal exploratory efficacy endpoint from the 90-day follow up demonstrated that 60 percent patients treated with EG-1962 experienced a favorable clinical outcome (a score of six- to-eight on the extended Glasgow Outcome Scale, or GOSE) versus only 28 percent of patients treated with oral nimodipine. Of the patients treated with EG-1962, 29 percent achieved the highest clinical outcome score (GOSE = eight, Upper Good Recovery) at 90 days post treatment, versus only six percent of patients treated with oral nimodipine.
Hanggi D, Etminan N, Macdonald RL, Steiger HJ. NEWTON – Nimodipine microparticles to Enhance recovery While reducing Toxicity after subarchNoid hemorrhage. Neurocritical Care. Published online: 13 February 2015.
In addition, improved clinical outcome was supported by a reduction in vasospasm, delayed cerebral ischemia, reduced use of rescue therapies, and shorter intensive care and overall hospital lengths of stay. Safety results in the North American NEWTON study showed that no patients experienced EG-1962 related hypotension, compared to 17 percent of patients treated with oral nimodipine.
Edge also intends to expand the population of aSAH patients who may benefit from EG-1962 by exploring alternative routes of administration. In the second half of 2016, Edge plans to initiate a clinical study of EG-1962 dosed by intracisternal delivery in aSAH patients who do not receive an EVD, but remain at risk for delayed neurological complications following surgical repair of a ruptured aneurysm.
Future Product Candidates
We are using our Precisa Platform™ to develop additional product candidates for other acute neurological conditions, including chronic subdural hematoma. In addition, we intend to apply our Precisa development platform to develop treatments for other acute, serious conditions where limited or no current therapies exist by targeting other organs across additional therapeutic targets.
The Zebrafish Centre for Advanced Drug Discovery
The Zebrafish Centre for Advanced Drug Discovery (ZCADD), a unit of St. Michael’s hospital, is one of the most advanced facilities in the world for high throughput drug screening. We have a multi-year research and discovery collaboration with St. Michael’s Hospital, which is affiliated with the University of Toronto, focused on the discovery of new therapeutic approaches to treat various acute neurological conditions. The ZCADD allows for rapid screening of libraries of compounds for therapeutics activity, and could identify lead candidates for our early stage pipeline.
EDGE Therapeutics, Inc. (“EDGE”) is a clinical-stage biotechnology company that discovers, develops and seeks to commercialize novel, hospital-based therapies capable of transforming treatment paradigms in the management of acute, life-threatening critical care conditions. Our initial product candidates target rare, acute, life-threatening neurological and other conditions for which we believe the approved existing therapies, if any, are inadequate. To do this, EDGE conducts clinical studies to assess the safety and efficacy of our investigational medicines, which may allow us to obtain the necessary regulatory approvals and provide patients with broader access to these medicines.
EDGE believes that participating in clinical studies is the best way for patients to access medicines prior to approval. In some circumstances when a clinical study is not possible, the Food and Drug Administration (“FDA”) has provided a method for patients with serious diseases or conditions to seek special access to investigational medicines. This access to investigational medicines is often referred to as expanded access or compassionate use. Because of the type of diseases and medications EDGE studies and the need to focus development efforts on clinical studies that could support regulatory approval, and/or because an FDA approved therapy already exists, EDGE generally will not provide access to its investigational medicines via expanded access or compassionate use. However, EDGE is willing to evaluate requests for such access in the United States from qualified physicians, based on the following factors:
- Whether the disease or condition is serious or life-threatening.
- Whether the indication for which the medication is requested is consistent with and not likely to interfere with EDGE’s overall development plan for the medication.
- Whether there are adequate alternative therapies available.
- Whether the patient either is ineligible for or is unable to participate in a clinical trial for the investigational product.
- Whether there is substantial scientific evidence to support both the safety and the efficacy of a product for the indication requested and sufficient clinical data are available to identify an appropriate dose.
- Whether the potential benefit to the patient justifies the potential risks of the treatment with the investigational medicine and those potential risks are not unreasonable in the context of the disease or condition to be treated.
- Whether allowing expanded access or compassionate use will interfere with the initiation, conduct, or completion of clinical studies that could support marketing approval of the investigational medicine for the disease or condition for which expanded access or compassionate use is sought.
- Whether adequate and appropriate drug supply is available and can be provided in the timeframe required for treatment.
- The qualifications of the physician, including experience with the therapy or expertise with the specific disease or condition, ability to administer the drug and monitor the patient’s safety, and ability to otherwise comply with regulatory requirements and good clinical practices.
- Whether the potential patient and/or his or her guardian is willing and able to provide informed consent and comply with study subject requirements defined by EDGE.
- Such other factors as EDGE may deem appropriate to consider, in its full discretion.
All questions and requests regarding EDGE’s expanded access or compassionate use programs should be submitted to EDGE by email: email@example.com. In the case of requests by treating physicians, the email should contain information sufficient for EDGE to evaluate the request consistent with all the requirements specified in this policy. The requesting physician must agree to obtain appropriate regulatory and ethics committee approvals and to comply with all other safety, monitoring, and patient consent requirements defined by EDGE. Requests for expanded access or compassionate use may only be made by licensed US physicians. EDGE will attempt to respond to requests within 5 business days. EDGE cannot guarantee that the investigational medicine will be available for a particular patient under an expanded access or compassionate use program. If granted, access will be for a designated period of time and then a request must be submitted and reviewed to continue the program.
At any point, EDGE can, in its sole discretion, cease to make expanded access or compassionate use available for any given drug. This policy may change without notice, and is not a guarantee of access to any investigational product.
For further information on available clinical trials and expanded access programs, visit www.clinicaltrials.gov and search for trials where “EDGE” is the sponsor.