Industry Update: the Latest Developments in Therapeutic Delivery

Abstract

This month‘s article covers the time period 16 January–15 February 2012 and features a number of important developments in the business and regulatory fields. Cytomedix took another step forward in its strategy to become a broad-based regenerative medicine company, when it completed its acquisition of Aldagen, Inc. Patheon added to its technology offering and services with a tie-up with the South American soft-gel capsule specialists, Procaps. Smaller companies, such as Arrogene Nanotechnology and Nanologica, also had something to celebrate when they received capital and EU funding, respectively. On the regulatory front, the US FDA issued a long-awaited draft guidance on biosimilars, while the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a guideline on factoring genetic variations into the drug-development process. Last but not least, Bydureon^®, the sustained-release formulation of the glucagon-like peptide agonist, exenatide, finally obtained FDA approval at the third attempt. As ever, the article is mainly sourced from company press releases and websites.

Business development

Acquisitions & mergers

Cytomedix & Aldagen

On 8 February 2012 Cytomedix, Inc. (MD, USA) announced that it had completed its takeover of Aldagen, Inc. (NC, USA) [201]. The acquisition will give the developer of regenerative cell therapies access to Aldagen‘s bright cell (‘ALDH^br‘) technology. This technology involves a patent-protected bone marrow fractionation process, which identifies and isolates cells expressing high levels of the enzyme aldehyde dehydrogenase (ALDH). ALDH converts vitamin A into retinoic acids, which, in turn, regulate genes that affect the differentiation of blood, neural, endothelial and other types of stem and progenitor cells [202]. Cells containing high levels of ALDH can therefore promote the regeneration of cells and tissues, including the development of new blood vessels. This technology has the advantage that it does not require cell expansion such as other stem cell therapies do. It therefore has the potential to be cheaper and enable faster patient treatment (typical turnaround time is 36 h from receipt of the patient‘s bone marrow) compared with others. Three products based on the ALDH^br technology are currently in clinical development.

The acquisition is part of Cytomedix‘ strategy to move away from its former focus on wound healing, and become a broad-based regenerative medicine company. Its technologies now cover autologous stem cells, platelet-derived signal molecules and plasma scaffolds. As part of the acquisition agreement, Cytomedix issued preferred shares valued at US$16 million to Aldagen shareholders. The stockholders will receive further common stock if Aldagen achieves pre-agreed clinical milestones associated with a Phase II trial of one of its clinical candidates in post-acute ischemic stroke. The transaction also involved the purchase of $5 million of Cytomedix common stock by certain Aldagen investors in a private placement. As a result of the deal Aldagen becomes a wholly owned subsidiary of Cytomedix, and will retain its existing manufacturing and product-development facilities [201].

Valeant & Eyetech

Valeant Pharmaceuticals International, Inc. (Ontario, Canada) made public on 13 February 2012 that it had agreed to purchase Eyetech, Inc. (FL, USA) [203]. The Florida-based company is a privately owned ophthalmic company that markets Macugen^® in the USA. Macugen contains pegaptanib sodium, an anti-VEGF inhibitor approved for the treatment of wet age-related macular degeneration. The company was acquired for an upfront payment and potential future milestones, which total significantly less than twice the value of the current sales, and will add value to the existing Valeant ophthalmic franchise.

Licensing agreements & collaborations

Patheon & Procaps

Patheon, Inc. (NC, USA) and Procaps SA (Barranquilla, Columbia) signed an agreement on 19 January 2012 that will result in Patheon being able to offer Procaps‘s prescription soft-gel product development and manufacturing services [204] to clients in Europe, America and Asia. Procaps has GMP, ISO9000 and 14000 certified manufacturing facilities throughout Latin America and has the capacity to manufacture up to 9 billion capsules per year. The exclusive agreement is part of Patheon‘s strategy to strengthen its core operations and product offerings.

Novartis & GenVec

On 27 January 2012 GenVec, Inc. (MD, USA) issued a press statement that it had extended its existing collaboration and license agreement with Novartis (Basel, Switzerland) on the development of treatments for hearing loss and balance disorders [205]. The collaboration involves use of GenVec‘s adenovector technology to deliver an atonal gene (Atoh1) to stimulate the formation of new sensory hair cells in the inner ear and, hence, restore hearing and balance [206]. Under the terms of the original global licensing agreement Novartis purchased $2 million of GenVec common stock and GenVec was entitled to receive up to $213.6 million in the form of upfront ($5 million) and milestone payments plus royalties on future sales if certain clinical, regulatory and sales targets were met. The agreement also included funding for research into other adenoviral vectors for the delivery of genes in hearing loss [207]. As a result of the extension, Novartis will fund research on the project through to January 2013 [205].

Bend Research & Eli Lilly

Bend Research (OR, USA) announced on 8 February 2012 that it had signed an agreement with Eli Lilly and Company (IN, USA), which will give Lilly access to Bend‘s spray-dried dispersion technology for improving the solubility and bioavailability of poorly water-soluble compounds [208]. As a result of this agreement, Lilly will also obtain broad rights to use Bend‘s other drug-delivery technologies. This agreement is in addition to an existing one under which Bend provides formulation, development, analytical, engineering and manufacturing services to Lilly in support of its preclinical and clinical development programs. The spray-dried dispersion technology is thought to improve the solubility of compounds by converting and stabilizing them in the amorphous form, and also due to the fact that the spray-dried particles disperse to form various species including nanocolliods in the range of 20–300 nm on dispersal in aqueous media [1].

Financing & grants

WestPark Capital & Arrogene NanoTechnology

On 13 February 2012 the investment bank, WestPark Capital, Inc. (CA, USA) issued a press statement on the second closing of a private placement for Arrogene NanoTechnology Inc. (CA, USA) [209]. The first closing in January raised $500,000, while the second generated in excess of $600,000. The proceeds will be used for working capital and Arrowgene‘s research and development programs, which are based on a new family of Polycefin™ nanobiopolymers. These biopolymers when conjugated to chemotherapeutic drugs can target tumors and deliver drugs into tumor cells [210]. Polycefin has been shown in preclinical studies to cross the blood–brain barrier. Therefore, the delivery platform has potential applications in the diagnosis and therapy of primary brain tumors and secondary metastases caused by cancers such as lung and breast.

Nanologica

Nanologica AB (Stockholm, Sweden) announced on 15 February 2012 that it will play a vital role in the 4-year ORCHID project, which is partially funded through the EU Seventh Framework Programme [211]. The $10 million ORCHID project, which is led by GlaxoSmithKline, involves a number of academic, industrial and not-for-profit partners, in a collaboration focused on the discovery and development of treatments for multiple drug-resistant TB. The Swedish company‘s silica-based mesoporous carrier materials and expertise will be used to improve the water solubility of actives against TB from GlaxoSmithKline and other project partners [212].

Regulatory news & approvals

Product approvals

Bydureon™

Amylin Pharmaceuticals, Inc. (CA, USA) and Alkermes plc (Dublin, Ireland) made public on 27 January 2012 that Amylin had received US FDA approval for Bydureon, its sustained-release exenatide formulation for subcutaneous injection [213,214]. Exenatide is a glucagon-like agonist that is indicated as an adjunct to diet and exercise to improve glycemic control in adults with Type 2 diabetes mellitus in multiple clinical settings. Bydureon is based on Alkermes Medisorb^® technology in which the peptide is entrapped in biodegradable microparticles formed from 50:50 poly(D,L-lactide-co-glycolide) polymer [215]. The product is administered once weekly and represents an improvement in patient convenience compared with the currently marketed exenatide product, Byetta^®, which must be injected twice daily.

Approval signals the end of a long, uphill struggle to get the product on the US market. Amylin had previously received two complete response letters from the FDA with respect to this product, the second of which included a request for a detailed study to assess the effect of higher than typical exposures to exenatide on cardiac ventricular depolarization and repolarization (QT interval) and, hence, the potential for such exposures to result in cardiac arrhythmias [216]. The product has been approved in Europe since June 2011 [217].

Prometra^®

It was good news for Medasys, Inc. (NJ, USA) on 13 February 2012 when the FDA approved its Prometra^® programmable implantable drug pump [218]. It is the first non-peristaltic programmable implantable pump that has received FDA approval for the intraspinal delivery of Infumorph^® (preservative-free morphine sulfate sterile solution) for the management of pain. The pump demonstrated a 97% clinical accuracy in the delivery of the physician-programmed dose in a clinical trial, which is the highest labeled accuracy available for this type of pump.

Regulatory

European Medicines Agency guidance on factoring genetic variations into drug development

The Committee for Medicinal Products for Human Use of the EMA adopted on 19 January 2012 a guideline that describes how drug developers can factor genetic variations into the drug-development process [219]. It addresses a number of issues including at what stage(s) in clinical development the pharmacogenetic-related pharmacokinetic studies should be performed, and recommendations/requirements with respect to studies investigating the effects of polymorphisms affecting drug absorption, distribution, metabolism and excretion. The guideline will come into effect on 1 August 2012.

FDA biosimilar guidelines

On 9 February 2012, the FDA issued three guidance reports on the development of biosimilar biotechnology products to inform companies of the agency‘s interpretation of the Biologics Price Competition and Innovation Act of 2009 [220], and the issues that sponsors must address to demonstrate biosimilarity. The Act created an abbreviated licensing pathway for biological products that was shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product, and opened the door for the approval and launch of biosimilar biologics in the USA. The three documents, one dealing with quality topics, the second covering scientific considerations and the third containing questions and answers regarding implementation of the Act, are currently in draft form.

Clinical trials

IMA910

Immatics Biotechnologies GmbH (Tuebingen, Germany) presented positive Phase II data on its therapeutic cancer vaccine, IMA910, in patients with advanced colorectal cancer at a poster session at the Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology (ASCO) in San Francisco, CA, USA, on 24 January 2012 [221]. The vaccine consists of 13 tumor-associated peptides (TUMAPs) identified directly from colorectal cancer patients. The study involved 92 patients with advanced/metastatic CRC whose cancer had not progressed after 12 weeks of treatment with oxaliplatin-based chemotherapy. The patients received low dose cyclophosphamide (CY) as an immunomodulator prior to the first injection of IMA910. They then received IMA910 plus GM-CSF with or without an additional immunomodulator, imiquimod, which was topically applied. In total the study participants were vaccinated up to 16-times over 9 months.

The study results showed that the vaccine is well tolerated, with injection site-related side-effects being the most typical adverse effect. With respect to efficacy the data showed that IMA910 is able to elicit relevant immune responses against the TUMAPS in the majority of patients. It also suggested that the clinical outcome of patients with T-cell responses against two or more of the tumor-derived peptides was better than in those who did not experience a multi-T-cell response. In addition, in cases where the vaccine resulted in both CD8⁺ and CD4⁺ multi-T-cell responses, patients did not reach the median survival after more than 28 months of follow-up compared with a 16-month median survival time for patients where there was no multiple T-cell response.

Lixisenatide

On 8 February 2012 Zealand Pharma A/S (Copenhagen, Denmark) and its partner Sanofi (Paris, France) made public that positive top-line results had been achieved in the GetGoal Phase III study [222]. This clinical trial is part of the Phase III program for lixisenatide (Lyxumia^®), a once-daily glucagon-like agonist for the treatment of Type 2 diabetes, which was discovered by Zealand Pharma and licensed to Sanofi. This placebo-controlled trial, involving 484 patients, investigated the efficacy of lixisenatide as an add-on therapy to pioglitazone with or without metformin in Type 2 diabetes. The primary efficacy end point was significantly reduced blood glucose levels (HbA1c) compared with placebo (p < 0.0001). The results showed that HbA1c levels in patients treated with lixisenatide decreased from a mean baseline value of 8.08% to a mean value of 7.06% after 24 weeks of treatment. In comparison, values in the placebo group declined from 8.05 to 7.59%. The study also confirmed the safety of the investigational drug. A regulatory dossier for lixisenatide, which Sanofi will market under the tradename Lyxumia, was submitted to European authorities in November 2011. A US regulatory filing is anticipated in the fourth quarter of 2012. On 9 Feb 2012, 1 day later, the Danish company announced that it will receive a $20 million milestone payment from Sanofi following the completion of the global Phase III program for lixisenatide in Type 2 diabetes [223].

Patents

GeNO

GeNO LLC (FL, USA) announced on 31 January 2012 that the US Patent and Trademark Office had granted it a further patent for its proprietary GeNOSYL™ Nitrosyl nitric oxide generation and delivery technology [224]. This technology functions by passing prediluted NO₂ gas in O₂ or air through a small powder conversion reactor to generate nitric oxide in O₂ or air at the therapeutic dose. The reactor bed is made of ascorbic acid adsorbed on silica particles. The system is currently being assessed in two Phase II trials in pulmonary arterial hypertension and in pulmonary hypertension caused by pulmonary arterial hypertension and secondary to idiopathic pulmonary fibrosis [225]. The patent (US 8083997 [101]), which is the tenth US patent received by the firm, covers the conversion of nitrogen dioxide into nitric oxide using the GeNO cartridge technology.

Financial & competing interests disclosure

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.