Industry Update: the Latest Developments in Therapeutic Delivery

Abstract

The present industry update covers the period 6–15 January 2012, with information sourced from company press releases, regulatory and patent agencies, as well as the scientific literature. Despite the preceding holiday break, a number of new announcements were made and there is an ever-increasing desire to formulate molecules with difficult properties, such as complex small molecules, macromolecules and biologics in particular, for product life cycle management where reformulations are a proven strategy and novel drug–device combinations are applied; Kedem with Gleevec^® and ForesightVision4 with Lucentis^® are recent examples. For many conventional pharmaceutical therapies, the efficacy may be improved and the side effects reduced if the therapy is administered continuously (although potentially variable rate), rather than through conventional burst-release techniques. BioDelivery Sciences with polymer film technology and Abbott‘s drug-eluting bioresorbable therapy Esprit™ are proof points for this trend. Additional drivers include the desire to eliminate or minimize the danger of needlestick injuries, increase patient compliance by simplified or reduced stigma delivery methods and reduced health care costs. The mirconeedle or needle-free approaches of Clearside Biomedical, Bioject and the development of nanoparticle-based formulations – ‘smart‘ nanoparticles – structures used in drug- or gene-delivery systems show progress from various research laboratories. Finally, multiple clinical trials as conducted by Alnylam and partners were reported and increase confidence in the formulation of novel siRNA drugs.

Business development

Business restructuring

Bioject

Bioject Medical Technologies (Tualatin, OR, USA) has hired a financial adviser to assist the company in evaluating new strategic options, including the sale of the company. Its shareholders may not gain much from any sale that could take place, “given the liquidation preferences of the preferred shareholders”[1]. Bioject developed a jet-injection drug-delivery process that forces medication at high speed through a tiny orifice held against the skin, creating a fine stream of high-pressure fluid that penetrates the skin and leaves medication in the tissue underneath it. Some industry observers predicting tremendous growth for the needle-free drug-delivery device market as caregivers seek to reduce needle-stick injuries. Nevertheless, Bioject reduced staff in early November, even as it announced that third-quarter revenue had doubled and generated a small profit from short-term gains, in part due to a big Merck Serono order during the previous quarter. Bioject is also moving unto the vaccine market, however, regulators hesitate to approve injections not given by already approved techniques. With Bioject‘s focus on developing mutually beneficial agreements with leading pharmaceutical, biotechnology and veterinary companies, this is a challenge to be addressed.

Kedem Pharmaceuticals, Inc.

Kedem Pharmaceuticals, Inc., a Canadian pharmaceutical company, has moved its headquarters to Mesa (AZ, USA) and plans to open a laboratory in Scottsdale due to the region‘s biotech industry already forming a new hub. Kedem develops new delivery methods for existing drugs already approved by the US FDA. According to the company, its proprietary technology addresses orodispersable version of both generic and brand products and may apply to more than 40 drugs that can benefit from this route. Furthermore, it announced on 12 January 2012 that it has begun to work on a new formulation of Gleevec^®, an anticancer drug originally created by Novartis [2]. Kedem‘s drug will be a sublingual formulation, which means it would be placed under the tongue to be delivered directly into the bloodstream while avoiding the stomach and liver. Gleevec is an important anticancer drug for the treatment of several blood-related cancers in both children and adults. The sublingual formulation with taste-masking features makes the drug more acceptable and pleasant in taste for children with chronic dosage requirements. The company is also working on a sublingual formulation of a drug called X-Excite (PDE5 inhibitor for erectile dysfunction) from Pfizer Inc [2]. Kedem‘s sublingual formulation will begin clinical trials as soon as data on dosage stability and disintegration studies are completed. Kedem is also working on a sublingual formulation for propanolol to treat cardiovascular and anxiety attacks. The company has signed a contract with Corealis Pharma, Inc., (Laval, Quebec, Canada), which will produce the sublingual propanolol drug that will be used in Phase I clinical trials.

Financing

Clearside Biomedical

Ophthalmic startup Clearside Biomedical (Atlanta, GA, USA) and Hatteras Venture Partners (Durham, NC, USA) announced on 6 January 2012 that they had launched the company with a US$4,000,000 Series A venture financing to fund the initial development of Clearside Biomedical‘s ocular microinjection platform and initial clinical testing of Clearside Biomedical‘s lead product for macular edema and retinal vein occlusion [3]. The technology originally developed by researchers at the Georgia Institute of Technology (Atlanta, GA, USA) and Emory University (Atlanta, GA, USA) provides Clearside Biomedical with a proprietary ocular microinjection platform that has been designed to nonsurgically deliver drugs to an area of the eye referred to as the supra-choroidal space, which allows a novel way of dosing therapeutics to the tissues of the posterior segment of the eye and retina by using hollow microneedles [3]. In the case of successful clinical trials it could provide an improved method for treating diseases that affect the back of the eye, including age-related macular degeneration (AMD). Between two and three million eye injections are made each year, many of them to treat AMD. The researchers believe that the microneedle-based technique could be useful for treating AMD and glaucoma, as well as other ocular conditions related to diabetes.

Licensing & collaboration agreements

Alnylam & Arrowhead

In an ongoing business development news story, as featured in the last edition of the Industry News, Alnylam Pharmaceuticals, Inc., (Boston, MA, USA) a RNAi therapeutics company, and Arrowhead Research Corporation (Pasadena, CA, USA), a nanomedicine company with development programs in RNAi and obesity, announced in early January that they have entered into a collaboration and joint licensing agreement [4]. Alnylam considers Arrowhead‘s dynamic polyconjugate technology as a promising emerging delivery approach, with the potential to complement their existing delivery platform that currently includes lipid nanoparticles (LNP) and siRNA conjugates. Alnylam has granted Arrowhead a license under its intellectual property that enables the discovery, development and commercialization of an RNAi therapeutic targeting the hepatitis B virus and is eligible to receive from Arrowhead milestone payments and royalties on sales of product resulting from the license. In addition, Alnylam has received a license from Arrowhead to utilize their dynamic polyconjugate delivery technology for an RNAi therapeutic product [5]. Alnylam expects to deploy this technology for an undisclosed target in its ‘Alnylam 5×15‘ pipeline, which is focused on genetically defined targets and diseases [6]. Arrowhead is eligible to receive milestone payments and royalties from Alnylam on sales of product resulting from the license.

Anylam, in general, reported that the last 12 months were a period of clinical accomplishments for its pipeline efforts and appears to be more confident to harness the RNAi pathway for new medicines. Amongst other objectives they target accelerating clinical development of their Alnylam-transthyretin (ALN-TTR) Program, which targets the TTR gene for the treatment of TTR-mediated amyloidosis. The drug is comprised of an siRNA formulated in a proprietary second-generation LNP. The company recently filed a clinical trial application for ALN-TTR02 to conduct a Phase I trial in the UK as a randomized, single-blind, single-ascending dose study. Alnylam also plans to advance ALN-TTRsc, which utilizes a GalNAc-conjugate delivery approach and subcutaneous dose administration. Preclinical studies have shown that once-weekly dosing with ALN–TTRsc enables robust and sustained silencing of TTR over a multiweek period. Alnylam plans to file an investigational new drug application for ALN-TTRsc in the second half of 2012, with data expected in the first half of 2013. Finally, the company intends to complete its ongoing ALN-TTR01 Phase I study in the first quarter of 2012 and report final data in the first half of 2012. Previously, Alnylam reported positive preliminary results from the study, showing that ALN-TTR01 treatment was generally safe and well tolerated and resulted in a statistically significant lowering of TTR serum levels in TTR-mediated amyloidosis patients. ALN-TTR01 is comprised of an siRNA formulated in a first-generation LNP.

DSM

DSM, a global leader in biomedical materials sciences, announced on 12 January 2012 that it is contributing proprietary knowledge in the preparation of tailored amino acid-based polymers and offering use of processing facilities that will produce an innovative step change in the sustained delivery of drug molecules [7]. The PANOPTES EU-funded consortium‘s goal is to research and develop novel drug-delivery technology for the posterior eye segment. This partnership, which brings together academic experts from the University of Durham (UK), Radboud University Nijmegen (Netherlands), University of Helsinki (Finland), Complutense University of Madrid (Spain) and Eberhard Karls University Tübingen (Germany) will also contribute to further validate the innovative properties of DSM‘s polyesteramide biomaterials as a superior drug-delivery technology.

Development & manufacturing agreements

Genentech & ForSight Vision4

On 13 January 2012, Genentech reported to have overcome an initial hurtle in its push to develop a sustained-delivery version of Lucentis^® (ranibizumab); an anti-VEGF-A targeted drug and the company‘s blockbuster for AMD. The California biotechnology company, Roche‘s US unit, said it has made its first milestone payment to the startup ForSight Vision4 (Woodcliff Lake, NJ, USA) as part of its development program and will submit an investigational new drug on clinical testing of Lucentis combined with the ForSight device. Genentech acquired the exclusive global rights to both develop and commercialize ForSight Vision4‘s implantable refillable drug-port delivery ocular device along with targeted eye therapies. Lucentis is FDA-approved since 2006 to treat two eye conditions through monthly eye injections: neovascular (wet) AMD and macular edema after retinal vein occlusion. Patients with either can lose their vision or go blind. Genentech‘s proposed drug–device combination is a ‘refillable drug-port delivery system‘ that would release Lucentis over weeks and months. Genentech has been fiercely protective of Lucentis^®. Earlier this month, it partly settled a patent dispute with Regeneron Pharmaceutical (Tarrytown, NY, USA), which recently launched the new injectable eye drug Eylea^®, the first competitor for Lucentis. As part of the deal, Regeneron will give Genentech a $60-million milestone payment once Eylea sales reach $400 million and pay royalties when sales surpass that number up to $3 billion.

BioDelivery Sciences International

BioDelivery (Raleigh, NC, USA) announced on 9 January 2012 that it will receive $30 million up front from Endo for the Phase III buccal-mucosa chronic pain treatment and will pay up to $180 million in a milestone-based licensing and development agreement for one of the drug developer‘s pain treatments [8]. The drug, BEMA Buprenorphine, uses BioDelivery‘s BEMA drug-delivery technology, which utilizes a small piece of polymer film that is applied to the inner lining of the cheek and later dissolves. BioDelivery is responsible for the clinical development of the treatment, and Endo is taking charge of submitting the application for FDA approval and working with regulators, according to the companies‘ release. Endo is also in charge of manufacturing and marketing the drug globally.

IntelGenx

Already announced in December 2011 but getting more attention in early January 2012, IntelGenx, a drug-delivery company (Saint Laurent, Quebec) agreed to a co-development and commercialization agreement with Par Pharmaceutical (Pittsburgh, PA, USA) for a new product using one of IntelGenx‘s proprietary oral drug-delivery platforms [9]. The product in question has not been disclosed; however, IntelGenx‘s three technology platforms have been designed to address the challenges commonly encountered in oral drug delivery, such as first-pass metabolism, gastrointestinal side effects or incomplete absorption of the drug in the GI tract. The technologies are broadly applicable and have the ability to improve the performance of a wide variety of existing pharmaceutical compounds.

Regulatory news & approvals

Product approvals

Carticept Medical, Inc.

Carticept (Alpharetta, GA, USA) announced on 16 January 2012 that it will launch its new ultrasound-guided, computer-controlled drug-delivery system for joint pain medications sometime during its fiscal 2012 first quarter, fueled by a new, $10 million round of Series C financing cash [10]. Carticept, which was founded in 2005, raised its new financing from existing investors Domain Associates, New Enterprise Associates and SonoSite and, including the new funding, has raised $53 million to date. The Alpharetta, Georgia-based company gained 510[k] (premarket notification) clearance from the FDA in October 2011 for its product formally known as the Navigator™ DS. The company is targeting patients who suffer from joint pain caused by cartilage damage, osteoarthritis or other factors, for which local injections of corticosteroids and other pain-dulling treatments help. The Navigator DS uses ultrasound to guide where a clinician places the needle before making the injection, and then the system records the treatment data. That information is then transferred to an electronic record-management system to update a patient‘s file. Having such a system is intended to reduce human error in delivering an injection and also automates the preparation of a given dose [11].

Pacira Pharmaceuticals, Inc.

Pacira Pharmaceuticals, Inc., (Parsippany, NJ, USA) on 9 January 2012 provided updated timing for its commercial launch of EXPAREL^® (bupivacaine liposome injectable suspension), a non-opioid analgesic that was approved by the FDA in October 2011 for administration into the surgical site to produce postsurgical analgesia [12]. Pacira has continued to execute its precommercial launch strategy focused on the broad hospital market and has undertaken initiatives to expand and enhance its ability to efficiently manufacture commercial quantities of EXPAREL. EXPAREL is an innovative product that combines bupivacaine with DepoFoam^®, a proven product-delivery technology that delivers medication over a desired time period. It represents the first and only multivesicular liposome local anesthetic that can be utilized in the peri- or post-surgical setting in the same fashion as current local anesthetics. By utilizing the DepoFoam platform, a single dose of EXPAREL delivers bupivacaine for an extended period of time, providing analgesia with reduced opioid requirements for up to 72 h.

Recall

Ikaria INOmax DS drug-delivery system: Class I recall: erratic nitric oxide readings

In early January 2012, the FDA notified healthcare professionals of a Class I recall of the Ikaria INOmax DS drug-delivery system [13]. Erratic nitric oxide monitoring readings were being caused by fretting corrosion at the electrical contact interface of certain metals. INOMAX is a vasodilator, which, in conjunction with ventilatory support and other appropriate agents, is the only FDA-approved drug indicated for the treatment of term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation [14].

Clinical trials

Abbott

Abbot initiated a clinical trial to study drug-eluting bioresorbable therapy for the treatment of blockages in the superficial femoral arteries and iliac arteries that have resulted in claudication (leg pain upon walking) [15]. It is the first-of-its-kind endovascular trial of the investigational Esprit™ therapy that builds upon Abbott‘s extensive experience with drug-eluting bioresorbable treatments for coronary artery disease. Claudication is the most common symptom in patients with peripheral artery disease, and is associated with diminished physical activity and poor quality of life for patients. The Esprit™ drug-eluting bioresorbable vascular scaffold is designed specifically for use in peripheral arteries and is made of polylactide, the same proven biocompatible material used in the company‘s Absorb™ drug-eluting bioresorbable vascular scaffold for coronary artery disease. Absorb is authorized for sale in Europe and is investigational in the USA. Esprit is designed to restore blood flow by opening a blocked vessel and providing support until it is healed. Once the vessel can remain open without the extra support, the scaffold is designed to dissolve, leaving the vessel free of a permanent metallic implant. Because a permanent implant is not left behind, clinical outcomes may be improved and options for retreatment of the vessel preserved.

Civitas Therapeutics, Inc.

Civitas (Chelsea, MA, USA) is a privately held pharmaceutical company developing transformative therapeutics using the ARCUS™ respiratory delivery platform and it announced on 6 January 2012, positive topline results from a Phase I clinical trial for CVT-301, an inhaled formulation of L-dopa for the rapid relief from motor fluctuations associated with Parkinson‘s disease [16]. This Phase I study in healthy volunteers evaluated the safety, tolerability and L-dopa pharmacokinetic profile across a range of doses of CVT-301 delivered using Civitas‘ proprietary, simple, handheld breath-actuated inhaler. By delivering L-dopa through the pulmonary route, CVT-301 is being evaluated as an intermittent adjunct therapy with the potential to produce rapid, consistent and durable relief from debilitating motor fluctuations associated with Parkinson‘s disease.

Financial & competing interests disclosure

OC Steinbach is an employee of Royal Philips Electronics North America Corporation. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.