Issue:May 2013

EXECUTIVE INTERVIEW - SNBL, Ltd.: Innovation in Drug Delivery Enabled Through a Unique Business Model

Drug development companies are abuzz regarding alternative routes of delivery. Current buzzwords, such as buccal, nasal, parenteral, and pulmonary are stirrin the nest, and for good reason. It is difficult to read an article about the biopharmaceutical industry without being reminded of the massive paradigm shift currently in midstride. Within this shift, the necessity of easy-to-use and effective self-dosing medications is underscored and at this juncture, these buzzwords are seen as imperative solutions. Healthcare costs as a whole are rising. Hospital-only administered treatments are becoming more expensive and burdensome on an already strained system, and demand for therapeutically relevant medications for diseases with high unmet needs (as opposed to incrementally better me-toos) continues to grow. Pharma and biotech companies are falling behind; R&D budgets of the 90s for a single project are rare, cut-and-run decisions are being made sooner in early development than ever before. Hospitals, pharma, and biotech alike need to save money, as does the consumer during this economic depression, and the consumer has grown aware of power in demanding more affordable price points. The immense in-flux of patent expiries and the subsequent market flood of generics have only further highlighted the “price gouging” of the biopharmaceutical industry to consumers. Unfortunately, many have too little understanding of the need for companies to regain the amount spent in upfront R&D, a hard feat without considerable marketshare and blockbuster status. In response, pharma and biotech are searching for de-risking partnerships and cost-minimizing development options. Thus is the dilemma of the aforementioned buzzwords, and creators of said drug delivery platforms are providing previously underappreciated solutions through innovative science, novel business models, and advantageous partnerships. Drug Development & Delivery recently interviewed Dr. Shunji Haruta, founder of NDS (Nasal Delivery Systems) Division and Executive Officer, SNBL, Ltd. to discuss how NDS Division and its powder nasal delivery platform, µco System, fit into this new paradigm.

Q: For our readers who are not yet familiar with your technology, can you briefly describe the µco System?

A: The µco System is a nasal drug delivery platform stemming from two breakthroughs. The first breakthrough is our muco-adhesive carrier technology. The carrier technology lays the groundwork for API effectiveness. Holding the API on the nasal mucosa for an extended period of time, the carrier allows for absorption into the blood stream. Our carrier consists of GRAS excipients and is virtually inactive and non-absorbable. Natural mucocilliary clearance eventually removes the carrier from the nasal cavity and is then moved through the GI tract and cleared from the body.

The second breakthrough technology of the µco System is our line of in-house designed nasal delivery devices, Fit-lizer. We have designed both single- and multiple-use devices, which achieve 100% delivery of the formulation into the nasal cavity with every use; usability studies have confirmed this delivery across a variety of patient actuation pressures. We wanted a user-friendly, simple, and effective delivery device and we have been able to achieve that.

Q: You are the inventor of the µco System; tell us about why you chose to pursue powder delivery instead of the popular liquid and gel route?

A: The nasal cavity is an opportune drug delivery route because of its rich vascular capillary bed situated directly beneath the surface, but it was frustrating to see nasal medications consistently fail in effectiveness. Biology shows the nasal cavity is ideal for many types of therapies, but it is clear to anyone who has ever used a traditional liquid nasal product that the medication is not staying in the nasal cavity. Liquids simply run too quickly. Without time to absorb nasally into the blood stream, minimal effect is seen and by looking at PK profiles of liquid nasal medications, you typically see a double-peak; initially for absorption through the nasal mucosa and the second through the GI tract. This is why I chose to begin looking at mucoadhesive carriers for increased nasal absorption. There had to be a better way, and muco-adhesive carriers were the logical next step.

Q: Is it uncommon that a delivery technology offers both a carrier and device? Why did SNBL develop both? Why not just the carrier?

A: We saw the problem with nasal delivery as two-fold: medications that run out of the nasal cavity after delivery and poor delivery of the formulation. If we developed a fantastic, enabling carrier, we knew it could only be as good as the device used to deliver it. The majority of nasal delivery devices deliver inconsistently and/or less than 70% of the formulation into the nasal cavity. That results in inconsistent absorption (efficacy) and is costly to both the pharma company and the patient. On top of that, devices seem to become more and more complicated; some devices can only be used by certain patient populations and not by others. We wanted to design a universal device with simple operation and complete delivery that can be used by virtually any adult; we have been able to do just that. I am very proud we have two technologies that complement one another so well.

Q: You founded NDS Division in SNBL, Ltd., a CRO. It is unusual for a CRO business to develop a drug delivery platform? Why did SNBL make the commitment to the µco System?

A: As a CRO, SNBL has done copious amounts of testing throughout its now 55 years. We began to recognize that the industry standard models for nasal delivery were not producing predictive results. Preclinical testing is to prove safety before entering volunteers, but for pharma and biotech companies that are investing limited R&D dollars, the preclinical results are too often misleading in terms of PK.

SNBL has some of the world’s most extensive experience working with NHPs and recognized the problem with using rat and dog models: anatomy and physiology are too distinct from that of humans. There is no way to get an accurate and predictive PK from rats and dogs. However, SNBL soon realized that the nasal anatomy of NHPs is comparable to that of humans. So we designed and validated a nasal NHP model, along with an in-house designed nasal testing mechanism, which synchronizes with the breathing cycle and automatically administers upon inhalation. This allows PK testing of nasal drugs on unanesthetized NHPs while maintaining lower stress levels, producing exceptional data and, consequently, fewer animals and decreased cost per study. Simply put, SNBL’s CRO capabilities complemented the development of the µco System. Management saw the potential and made the choice to move forward and support it.

Q: You said that initial development of the µco System was for insulin, but that the course changed after you learned more about its characteristics and capabilities. What pilot program(s) did you run instead? What kind of regulatory hurdles did you encounter?

A: Insulin is a White Whale for many drug delivery systems, so we learned a lot about the capabilities of our carrier by trying to overcome hurdles with insulin. Ultimately, we chose to pursue other paths for proof-of-concept, and we chose granisetron with the µco System (TRG) as our first pilot program. For the treatment of chemotherapy-induced nausea and vomiting (CINV), we have taken TRG through Phase II clinical trials, aiming for a 505(b)(2) approval. Our initial proof-of-concept came in a Phase I study, where we achieved 100% absolute bioavailability against I injection of marketed granisetron. The preclinical data generated using our NHP model, which I previously touched on, proved predictive. Our second pilot program is zolmitriptan with the µco System (TRZ). TRZ, for the treatment of migraine headaches, recently completed a successful Phase I clinical trial, also aiming for a 505(b)(2) approval, with promising results. Cmax was reached by 20 minutes after dosing, and relative bioavailability compared against a marketed tablet was 136%; relative bioavailability to marketed nasal spray was 182%. We have been very happy with the results from our clinical trials, and it has certainly been a learning experience for our small NDS team.

SNBL has GLP preclinical capabilities as well as clinical capabilities, so being able to conduct our preclinical and Phase I work inhouse has been very helpful. But in terms of CMC work, we had never done anything like this previously. That was a challenge, and the NDS team was on a steep learning curve, but we now have a well-equipped lab for delivered-dose testing, particle size measurements, and plume geometry. In addition, we have gained a lot of regulatory know-how having compiled the IND filing inhouse, as well as oversaw the Phase I studies at our clinical facility in Baltimore.

The biggest regulatory hurdle we have come across is the lack of precedent in powder nasal drug delivery. Aiming for a 505(b)(2) approval pathway for powder nasal delivery is something that the Agency had not previously dealt with. It has been a good experience speaking and meeting with the Agency at each step of development, and the Agency has given the NDS team great depth in understanding what is expected from a regulatory standpoint.

Q: NDS offers licensing of the µco System. What is different about partnering with NDS?

A: As stated earlier, our parent company is a CRO, and preclinical services are truly our bread and butter. Licensing of the µco System inherently comes with the knowhow and background of our CRO experience. SNBL is the largest worldwide provider of CRO NHP expertise, and this knowledge is invaluable during the drug development process. Partnership with NDS has a consultancy aspect to it. We are not manufacturers, every partner is not coming from the same mold, and we understand that. Each project and compound has specific needs, and our inhouse capabilities from assay development and validation to tailored study designs and formulation optimization supports these needs. We also have regulatory experience, which means we are able to provide insight regarding strategy.

Q: Overall, what success has the µco System had, and what is your 3-year projection?

A: Thus far, we have licensed the µco System to Pastorus Pharma for use with oxytocin for the treatment of autism. We are also in talks with a number of other companies regarding licensing of the µco System and are very excited about our future working relationships with these companies.

As for our 3-year projection, we realize that it is necessary to always continue improving and innovating. We have confidence in the µco System and are driven to use it for bringing therapeutically relevant and improved treatments to patients; the relief and safe treatment of patients is what NDS and SNBL value most. Making a positive impact in patients’ lives excites us, and we will achieve that by partnering the system for systemic delivery of small molecules and peptides. Following will be the use of the µco System for powder nasal delivery of vaccines, which will be groundbreaking in its own right. Finally, we will be adding to our CRO capabilities through the development of a self-inhalable pulmonary delivery system for NHPs and other species; this system is currently under development, and we are pleased by the progress it is making.

NDS and SNBL are really a prime example of how out-of-the-box business models can be harnessed for mutual benefit. NDS has this very unique technology that could not have been created without SNBL’s expertise and in return, the development NDS spearheaded gave SNBL a one-of-a-kind model and testing mechanism; there are multitudes of mutual benefit. NDS and SNBL have become leaders in nasal drug delivery development and testing, both in their own right, and it is due to the relationship and business model. I am confident that NDS will continue to progress with development and partnering of the µco System, and through this progress will persist in contributing to SNBL’s CRO capabilities. There are always improvements to be made and new discoveries to be had, and the biopharmaceutical industry is constantly changing to adapt to these discoveries. NDS and SNBL are adaptive, innovative players that will contribute to advancements in the industry over the coming years.