Industry Update: The latest developments in therapeutic delivery

Business development

Acquisitions & mergers

Neostem & Amorcyte

On 14 July 2011 NeoStem, Inc. (New York, NY, USA) made public that it had agreed to merge with Amorcyte, Inc. (Allendale, NJ, USA) [1]. Both of these companies are involved in the development of cell-based therapies, while Neostem also offers contract manufacturing of such products through its recently acquired subsidiary, Progenitor Cell Therapy, LLC (Allendale, NJ, USA) [2]. Certain terms of the agreement are subject to the achievement of goals relating to the development of Amorcyte’s lead product candidate, AMR-001. This is a treatment for acute myocardial infarction, which is about to enter a Phase II study. It is an autologous, bone marrow-derived, cell-based product, enriched with CD34⁺CXCR4⁺ cells. It appears to limit heart muscle damage following infarction by increasing microvascular blood flow in the myocardium via neoangiogenesis [3].

The agreement results in the issuing of an aggregate of 6,821,283 shares of NeoStem common stock, together with the purchase of an aggregate of 1,881,008 NeoStem shares. An additional 4,092,768 shares of NeoStem stock will be issued upon achievement of specified AMR-001-related milestones. Amorcyte shareholders will receive additional benefits upon commercialization of the product [1].

Licensing & collaboration agreements

Sanofi & Audion Therapeutics

Sanofi (Paris, France) released a press statement on 16 June 2011 announcing a 2-year research collaboration with Audion Therapeutics (Amsterdam, The Netherlands) [4]. The latter company is focused on the development of drugs and delivery systems to treat hearing loss through regeneration of sensory hair cells in the inner ear, which is a major cause of hearing loss [5]. The collaboration concerns the optimization of small molecules for the treatment of deafness and is based on technology developed at and licensed by Audion from the Massachusetts Eye and Ear Infirmary (Boston, MA, USA). It will leverage Sanofi’s expertise in optimizing and developing small molecules and Audion’s discovery platform and in-depth knowledge of inner ear physiology. As a result of the agreement, Sanofi has an option to license technology rights from Audion based on the research conducted under the collaboration [4].

Cambrex & Tillotts

On 6 July 2011 the Cambrex Corporation (East Rutherford, NJ, USA) and Tillotts Pharma AG (Rheinfelden, Switzerland) made public that they had signed a Development and Commercialization Agreement for a proprietary mesalamine-based (5-aminosalicylic acid, [5-ASA]) technology for use in the treatment of Inflammatory Bowel Disease (IBD) [6]. Tillotts already have two products in their portfolio for treatment of conditions of the large bowel namely Asacol^® and Colpermin^®.

Under the terms of the agreement, Tillotts receives worldwide exclusive rights to develop and commercialize drug products based on the proprietary 5-ASA-based technology in exchange for developmental, regulatory and intellectual property milestone payments plus royalties [6]. The 5-ASA technology was originally developed by PLx Pharma, Inc. (Houston, TX, USA) and is outlicensed to Cambrex. PLx Pharma has developed, PLxGuard™ technology, which consists of well-known non-steroidal anti-inflammatories (NSAID) formulated in a phospholipid envelope to reduce the gastric-irritant side effects of this class of compounds [7]. It is based on research carried out by the company’s scientific founder, Lenard Lichtenberger, which showed that NSAID binding to phosphatidycholine in the stomach lining compromised its barrier function. The company has a number of products in clinical development based on the PLxGuard™ technology including Zavryl™ (ibuprofen 400 mg) and PL3100 Naproxen (250 mg) both for the treatment of arthritis.

Zogenix & Durect

The 12th of July 2011 brought the announcement that Zogenix (San Diego, CA, USA) had signed a licensing and development agreement with the Durect Corporation (Cupertino, CA, USA) to develop and commercialize a proprietary long-acting injectable formulation of the anti-psychotic risperidone [8]. The drug is currently approved for the treatment of both schizophrenia and bipolar I disorder in adults and children over the age of 13 years. If successful, the product, named Relday™, will actively compete with Johnson & Johnson’s Risperdal^® Consta^®, which had global net sales of US$1.5 billion in 2010. However, it will differ from the currently marketed product in that it will be administered once monthly (Risperda Consta is injected twice monthly) and will be delivered using Zogenix’s DosePro^® needle-free, injection system.

Relday will be based on Durect’s SABER™ technology, which consists of a high-viscosity component, such as sucrose acetate isobutyrate (SAIB), biocompatible excipients and other additives [9]. Following injection, the excipients diffuse away, leaving a viscous depot that controls the release of entrapped actives. Depending on the formulation, the SABER system can sustain delivery for a period ranging from 1 day to 3 months.

The financial terms of the agreement include Zogenix making an upfront payment of $2.25 million to Durect, with the latter company being eligible for up to an additional $103 million in future clinical, regulatory and commercial milestone payments [8]. Zogenix has exclusive global rights to commercialize Relday and will pay Durect a royalty on product sales. Zogenix plans to initiate clinical trials in early 2012.

Catalent & Sanwa Kagaku Kenkyusho

Catalent Pharma Solutions (Somerset, NJ, USA) and Sanwa Kagaku Kenkyusho Co., Ltd (Higashi-ku, Nagoya, Japan) announced on 14 July 2011 that they had entered into an exclusive agreement that will allow Catalent to market Sanwa’s OSDrC^® tableting technology in all regions outside of Japan, Korea, China (Hong Kong) and Taiwan [10].

This technology is a core tabletting technology that enables the manufacture of single- or multi-core tablets, with a variety of core numbers, shapes, sizes and placement within the tablet [11–12]. It consists of a one-step dry-coating procedure that employs a rotary tabletting machine with 54 variable double punches, whose position is controlled by an innovative cam design and three feeders. The core tablet is held in place by the lower outer punch until immediately before the final compression, thus, removing the risk of misalignment. It can be used to produce pulsatile, multi-core, delayed release and dividable tablets containing separate cores. It can also be employed to manufacture direct-compression orally dissolving tablets and enables the production of tablets containing pellets and cores of poorly compressible materials. The appearance, shape and coating thickness and core position is controlled by the selection of the double-punch variations. The technology has already been scaled to produce 100,000 tablets per hour. The agreement will enable Catalent to broaden its client offering. Customer product development trials are planned for January 2012 [10].

Regulatory news & approvals

Product launches

Nometex™

At the 2011 meeting of the American Society of Clinical Oncology (3–7 July 2011, Chicago, IL, USA) Neurowave Medical Technologies™ (NMT) (Chicago, IL, USA) presented Nometex™, a new transdermal neuromodulation device to treat patients with acute and delayed chemotherapy-induced nausea and vomiting (CINV) [13]. The device is the first to be approved by the US FDA for this indication and was launched by the company earlier this month. It employs NMT’s proprietary neuromodulation technology to stimulate the median nerve on the underside of the wrist. This results in neural modulation via the vagus nerve, which restores the normal gastric rhythm [14]. The device can be used to treat breakthrough, or refractory CINV or provide prophylaxis. A clinical study in patients being treated for gynecological cancers showed that use of the device resulted in a significant reduction in the severity of nausea over days 2–4 [13]. The first model Nometex N2C provides up to 150 h of therapy, which is sufficient to help most patients through two cycles of chemotherapy and the associated CINV episodes. The company is planning to expand its commercial operations as a result of the launch of the product.

Product approvals

Lupron Depot^®

On 20 June 2011 Abbott Laboratories (Abbott Park, Il, USA) announced that the FDA had approved a new 45 mg formulation of Lupron Depot^® (leuprolide acetate for depot suspension) that enables delivery of the peptide over a 6-month period [15]. This product is already on the market in a variety of strengths and treatment durations (7.5 mg for 1 month, 22.5 mg for 3 months and 30 mg for 4 months). The injection is indicated for the palliative treatment of advanced prostate cancer. Approval was based on data from a 48-week, open-label study involving 151 patients with prostate cancer. This study, in which patients received a total of two injections, 24 weeks apart, showed that the 45 mg formulation resulted in sustained suppression of testestorone levels over the entire treatment period. The 45 mg formulation is expected to be available in late June.

Buccolam^®

At its July meeting the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency recommended that ViroPharma’s (Exton, PA, USA) Buccolam^® (midazolam oromucosal solution) receive market authorization for the treatment of prolonged, acute, convulsive seizures in patients from 3 months to 18 years of age [16]. This recommendation is the first that the CHMP has made for a pediatric-use marketing authorization. Buccolam is a pre-measured, age-specific dose formulation for buccal delivery. Four clinical studies have shown that the buccal formulation is either comparable or superior, in terms of both effectiveness and speed of onset of action, to rectally administered diazepam, the current standard treatment.

Lazanda^®

Archimedes Pharma Ltd (Reading, UK) and its subsidiary, Archimedes Pharma US, Inc. (Bedminster, NJ, USA), received good news on 30th June 2011 when the FDA approved Lazanda^® (fentanyl) nasal spray [17]. This product is approved for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. The product is already approved in the EU and is marketed under the trade name, PecFent^®. It is based on the company’s PecSys^® pectin-based system [18].

Clinical trials

LCP-Tacro™

On 21 June LifeCycle Pharma A/S (Hørsholm, Denmark) made public that their lead product, LCP-Tacro™, dosed once daily had successfully met the primary efficacy end point of non-inferiority compared to the currently marketed product, Prograf^® (Astellas Pharma, Inc, Tokyo, Japan) dosed twice daily in a Phase III trial [19]. The Phase III open-label conversion (switch) study involved 326 stable kidney transplant recipients. The composite primary end point for efficacy included Biopsy-Proven Acute Rejection (BPAR; microscopic evidence of rejection), graft loss (return to dialysis or need for re-transplant), death and loss to follow-up. The primary analysis (local pathology for BPAR) showed a treatment failure rate at month 12 for the composite end point of 2.5% (four total treatment failures) for both LCP-Tacro and Prograf. In the secondary analyses (central blinded pathology for BPAR) the treatment failure rate during the study and follow-up, for the composite end point was 2.5% for LCP-Tacro and 4.9% for Prograf. As measured by the central-blinded pathologist, the rates of BPAR alone were 0.6% for LCP-Tacro and 3.1% for Prograf (p = 0.214). Both LCP-Tacro and Prograf demonstrated similar safety and tolerability profiles. More LCP-Tacro patients discontinued the study than those administered Prograf. However, the reasons for discontinuation were various and could not be attributed to particular causes.

LCP-Tacro was developed using LifeCycle Pharma’s MeltDose^® technology. The MeltDose technology is based on a patented ‘Controlled Agglomeration’ process that involves incorporating poorly soluble compounds into a molten vehicle. The vehicle is then sprayed on to an inert particulate carrier using fluidized bed equipment. This results in the drug being loaded in an amorphous or in a nano-crystalline state form. The size of the spray-dried particles is then increased in a controlled manner to enable tabletting [20]. On average LCP-Tacro patients in the study required a daily dose that was 20% lower than patients receiving Prograf, demonstrating the ability of the formulation to improve the absorption of tacrolimus [19].

PF329

PharmacoFore, Inc. (San Carlos, CA, USA) announced on 23 June 2011 that positive results had been achieved in a Phase I human proof-of-concept (hPOC) study of its hydromorphone (HM) Bio-Activated Molecular Delivery™ (Bio-MD™) candidate, PF329 [21]. PF329 has been designed using the firm’s Bio-MD technology. This technology results in the release of opioid drugs only when they are orally ingested, hence, limiting the potential for abuse. This is due to the drugs only being activated in the GI tract. Activation in the systemic circulation does not occur, thus, removing the potential for ‘highs’ to be obtained by injection or inhalation [22].

The Phase I study was a single-center, dose-escalation and fixed-dose crossover, cohort study to determine the safety and pharmacokinetics of PF329. It involved 51 healthy volunteers who received oral doses of PF329 in solution ranging from 1–48 mg, and 12 who received immediate-release HM in approximately molar-equivalent doses. The study demonstrated that the formulation is safe and releases HM in a dose-proportional manner and that delivery is efficient. Time to maximal plasma concentration of HM following administration of PF329 was approximately 2 h, slower than immediate release HM but more rapid than the published data for the commercial, once-daily HM product, Exalgo^®. By delivering PF329 in solution in this study, PharmacoFore demonstrated that the extended release profile is intrinsic to the molecule. It is estimated that abuse costs the US government approximately $468 billion annually [21].

VGX-3100

Inovio Pharmaceuticals, Inc. (Blue Bell, PA, USA) reported promising results on its VGX-3100 DNA vaccine at the DNA Vaccines 2011 Conference held in San Diego, CA, USA between 12 and 14 July [23]. This vaccine is designed to treat cervical dysplasia and cancer caused by human papillomavirus (HPV) and is delivered by intramuscular electroporation using the company’s CELLECTRA^® electroporation device.

The data relate to a follow-up to a Phase I study. The original trial involved 18 women who had previously been diagnosed with and surgically treated for high-grade cervical intraepithelial neoplasia (CIN 2/3). The regimen for the first trial was three vaccinations with 12 out of the 13 initial responders showing significant T-cell responses nine to 19 months after the initial vaccination. As a result of this data Inovio decided to initiate a follow-up study in which 11 responders and two non-responders from the original trial were inoculated with 6.0 mg vaccine (the highest dose in the first trial). The data collected to date shows that of the eight patients evaluated, seven had T-cell responses for up to over 2 years with one non-responder to the original three injection regimen also showing no immune response after the fourth injection. The company is now planning a Phase II trial that will involve 148 patients at approximately 25 study centers in the US, Korea, South Africa, Australia and Canada.

Patents

EffRx Pharmaceuticals

EffRx Pharmaceuticals SA (Epalinges/Lausanne, Switzerland) released a press statement on 11 July 2011 [24] that the US Patent and Trademark Office (USPTO) had issued US patent 7,964,212 [101] on 21 June 2011. This patent provides additional protection for EffRx’s effervescent formulations of oral bisphosphonates including EX101, its 70-mg alendronate product for the treatment of osteoporosis.

The patent relates to a formulation that delivers bisphosphonates to the stomach in a proprietary buffered solution which protects the stomach and esophagus against from attack from these irritant drugs. The claims relate to the buffering composition and method of manufacture.

Nycomed has licensed EX101 for territories outside the USA, Canada and Japan, and the product has been submitted for regulatory approval in a number of countries.

Bioalliance

On 11 July 2011 Bioalliance Pharma SA (Paris, France) announced that they had been granted a European patent for its Transdrug™ nanotechnology [25]. This technology is based on nanoparticles that deliver anti-cancer agents into resistant tumor cells by overcoming multidrug resistance mechanisms. Multi-drug resistance can occur spontaneously or after the first treatment. The patent covers Livatag^®, its doxorubicin Transdrug product until 2023. This company is currently preparing to take this product into Phase III trials in primary liver cancer, a cancer which is known to become spontaneously chemoresistant.

Proteus

Proteus Biomedical, Inc. (Redwood City, CA, USA) made public on 14 July 2011 that it had been awarded US Patent Number 7,978,064 entitled “Communication System with Partial Power Source,” by the USPTO [26,102]. The patent relates to Proteus ingestible event marker, which is a sensor and communication device that forms the basis of the Proteus Raisin™ System. This system collects and aggregates various behavioral, physiological and therapeutic metrics including medication adherence, heart rate, sleep patterns, physical activity and stress and converts the data into personal health management tools delivered to the mobile devices of consumers and their carers.

The Proteus Ingestible Event Marker (IEM), which is the focus of the issued patent, is a minute micro-fabricated device composed of materials found in the food chain. It is comprised of two materials that when they come in contact with stomach fluids, provide power to the IEM. The IEM varies the current flow between the two materials to generate a digital signal which can be detected. The device can be incorporated into pharmaceutical tablets or capsules to allow real-time detection of dosage form ingestion, thereby helping to measure and improve patient compliance. The IEM’s digital signature can also be used for supply chain and product integrity applications. The device has been validated in numerous preclinical and human clinical studies, including those for the treatment of heart failure, hypertension, mental health, transplantation, diabetes and tuberculosis.

The patent is the 21st US patent obtained by Proteus for this technology. The company plans to launch its first commercial product based on the IEM technology in 2012.