Industry Update: the Latest Developments in Therapeutic Delivery

Abstract

The time period 6 October 2011 to 5 November 2011 was characterized by a number of major company announcements. Abbott Laboratories, a company that has long prided itself on its diversity, will split into two. The part that will retain the Abbott name will continue this tradition of diversity and the strategy of double-digit growth in earnings per share, albeit, without the pharmaceutical and biopharmaceutical research-based business. This will be spun out as another, yet to be named, publicly traded company. One firm‘s strategic refocusing can, of course, facilitate another‘s strategic development. This is certainly the case in the recent sale by SurModics of its pharmaceutical division to Evonik, where the former‘s decision to concentrate on its device and in vitro diagnostic business opened up an opportunity for the latter to acquire additional formulation, polymer development and manufacturing expertise. Another example of this was Arrowhead‘s purchase of Roche‘s siRNA assets after the Swiss company decided to exit the field. As ever, the article is mainly sourced from company press releases and websites.

Business development

Acquisitions & separations

Abbott Laboratories

On 19 October 2011 Abbott Laboratories (Abbott Park, IL, USA) announced that it will split into two publicly listed companies [101], one specializing in research-based pharmaceuticals and the other in medical products. The medical products company will include its existing device, branded generics, diagnostics and nutritional product portfolio and will retain the name Abbott. Based on current figures, it will have annual revenues of approximately US$22 billion. Its strategy will be to target double-digit growth on earnings per share through geographic expansion into high growth-developing markets.

The pharmaceuticals business, whose name has yet to be made public, will be built around the company‘s work on small-molecule and biological products and include blockbuster drugs, such as Humira^®, Lupron^®, Synagis^® and Kaletra^®. According to 2011 estimates, it will have annual sales of close to US$18 million with future growth fueled by its pipeline in areas such as immunology, multiple sclerosis, chronic kidney disease, Hepatitis C, women‘s health and oncology. Unlike the diversified medical products company, it plans to remain focused on existing developed markets.

It is planned that the separation will occur through a tax-free distribution of publicly traded stock in the new pharmaceutical company to Abbott shareholders. The expected stock distribution ratio is as yet unknown. However, it is anticipated that the two companies will each pay a dividend, which together will equal the Abbott dividend at the time of separation. The company expects to complete the split by the end of 2012, provided it receives final approval from the Abbott Board of Directors and the relevant government authorities. The separation has in general been welcomed by analysts and on news of the planned transaction, shares in Abbott rose on the New York stock exchange [102].

Arrowhead Research Corporation & Roche

Arrowhead Research Corporation (Pasadena, CA, USA) made public on 24 October 2011 that it had acquired RNA therapeutics assets from Roche (Basel, Switzerland) [103]. These assets include Roche Madison Inc (Madison, WI, USA), a research company with state-of-the-art facilities, over 40 employees and a proprietary RNA interference (RNAi) delivery platform called Dynamic PolyConjugates™. This technology is based on nanoparticles of 5–20 nm composed of a membrane-lytic polymer to which siRNA, polyethylene glycol and cell-specific targeting agents can be reversibly attached [104]. The polymer‘s ability to lyse membranes depends on the positive charge on its amine groups and its hydrophobicity. In order to reduce the polymer‘s potential toxicity, its amine groups are masked using proprietary chemistry to produce acid-labile maleamate groups. These break down in the acidic environment of the endosome, unmasking the polymer‘s lytic properties and enabling endosomal breakdown. The siRNA, which is attached to the polymer through a disulphide bond, is then released in the reducing conditions of the cytoplasm. Arrowhead hopes that this technology will offer significant advantages over existing liposomal and lipid nanoparticle delivery systems in terms of reduced particle size, improved tumor penetration and ease of targeting agent addition.

The acquisition also involves a license from Tekmira Pharmaceuticals Corporation (Burnaby, BC, Canada) for proprietary SNALP (stable nucleic acid-lipid particles) RNAi delivery, Roche liposomal nanoparticle technology for RNAi delivery, a license providing access to Alnylam‘s (Cambridge, MA, USA) RNAi intellectual property and canonical siRNA structures and another from the City of Hope (Duarte, CA, USA) allowing the use of Dicer substrate siRNA structures and a third from MDRNA (now Marina Biotech, Bothell, WA, USA) for meroduplex siRNA structures [103].

The purchase adds to the Arrowhead‘s existing expertise in RNA delivery, which is being developed in its Calando and Leonardo subsidiaries. Under the terms of the agreement, Roche gains a minority stake in Arrowhead as well as rights to negotiate for certain future products, milestone payments and royalties on sales [103].

SurModics & Evonik

SurModics Inc (Eden Praire, MN, USA) released a press statement on 1 November 2011 making public that it had agreed to sell its pharmaceutical business to Evonik Industries AG (Essen, Germany) [105] for US$30 million in cash. The sale involves all products and services of SurModics Pharmaceuticals, including its parenteral dosage technology platforms, bioresorbable lactide-glycolide polymers business and the company‘s cGMP development and manufacturing facility in Birmingham (AL, USA). With the sale, SurModics hopes to return to profitability in the long-term by focusing on its medical device and in vitro diagnostics business.

The acquisition follows Evonik‘s recent purchase of Boehringer-Ingelheim‘s biodegradable polymer business and strengths its capability in formulation science significantly [106]. SurModics Pharmaceuticals employs around 80 formulation scientists with expertise in the development and scale up of sustained-release depot injections. It had revenues of US$15 million in 2010 including those from its Lakeshore Biomaterial™ business, which designs and manufactures biodegradable polymers.

Licensing agreements & collaborations

Zosano & Asahi Kasei

Zosano Pharma, Inc. (Fremont, CA, USA) and Asahi Kasei Pharma (AKP) (Tokyo, Japan) announced on 10 October 2011 that they had entered into a long-term strategic collaboration for the development, commercialization and supply of a weekly transdermal patch formulation of Teribone™ (teriparatide acetate) [107]. Teribone contains human parathyroid hormone (PTH 1–34) and is for the treatment of osteoporosis patients with a high risk of fracture. It is currently formulated as a subcutaneous injection.

The transdermal patch product uses Zosano‘s patented titanium microprojection technology (known as ZP Patch Technology) to administer human parathyroid hormone through the skin into the epidermal layers [108]. It is hoped that the transdermal formulation will allow differentiation of Teribone from other parathyroid-hormone products on the market, as it will allow weekly administration of the peptide by the patient using a pain-free method and the product can be stored at room temperature.

The agreement was originally signed in February this year, but was not disclosed until the subcutaneous injection form of Teribone was approved in Japan, which occurred on 26 September 2011. Under its terms, AKP will be responsible for clinical and regulatory development and commercialization activities. In return, it will have exclusive rights to develop and commercialize the transdermal-patch formulation of Teribone in Japan, Korea, China and Taiwan. AKP has already paid Zosano US$7.5 million in upfront payments. In addition, Zosano is entitled to over US$25 million in milestone payments related to development, regulatory and launch activities. The US company will also receive revenue-based royalties on sales of the patch in the Asian territories, plus be reimbursed for all development and manufacturing costs. AKP hopes to initiate clinical trials of the patch in 2012.

Hovione & Bend

On 19 October 2011 Hovione (Loures, Portugal) and Bend Research Inc. (Bend, OR, USA) made public that they had agreed a nonexclusive, co-operation [109]. The agreement will bring benefits to customers of both companies with Bend Research clients having access to Hovione‘s commercial-scale pharmaceutical manufacturing facilities and Hovione clients being able to avail of Bend‘s oral drug delivery, formulation and engineering expertise including its proprietary drug-delivery technologies. The collaboration is designed to accelerate the development of oral products by leveraging both Bend and Hovione‘s skills at the development/clinical manufacture and commercial scale, respectively, and enabling seamless transfer of products from pilot to production scale.

The collaboration also builds on the two companies‘ expertise in specialist areas such as engineered particles for inhaled delivery.

Silence & Mirna

Silence Therapeutics plc (London, UK) and Mirna Therapeutics Inc (Austin, TX, USA) have entered into an agreement to assess the suitability of Silence‘s AtuPLEX™ and DBTC technologies to deliver Mirna‘s microRNA compounds [110]. Silence‘s delivery systems are based on siRNA–lipoplex systems containing proprietary lipid components. On combination with siRNA, these lipids form nanoparticles consisting of cationic, fusogenic and polyethylene glycol (PEG)ylated lipids. The AtuPlex nanoplexes deliver siRNA to the endothelial cells of vascular tissue in various organs, while the DBTC technology targets the siRNA to hepatocytes and the hepatic vascular system of the liver parenchyma [111].

The collaboration involves Silence formulating selected microRNA sequences from Mirna using its delivery systems. The nanoplexes formed will then be assessed in vitro and in vivo by Mirna prior to lead selection. Financial details of the deal were not disclosed [110].

Alnylam & GlaxoSmithKline

Alnylam Pharmaceuticals Inc. (Cambridge, MA, USA) issued a press release on 1 November 2011 announcing that it had signed a collaborative agreement with GlaxoSmithKline (GSK) plc (London, UK) with respect to the application of Alnylam‘s VaxiRNA™ technology to certain GSK vaccine products, including influenza [112]. This RNAi technology is designed to improve viral vaccine production by increasing viral titres in vaccine production systems. It functions by silencing certain genes, which limit or prevent efficient growth of viruses in cell culture and eggs.

As part of the agreement, Alnylam will receive funding, in addition to potential milestone payments. If the technology is successfully applied to commercial production, Alnylam will also receive payments on sales of vaccine products. Initially, work will focus on the production of influenza vaccine in cell culture; however, GSK has an option to assess VaxiRNA with two additional vaccines.

Regulatory news & approvals

Product approvals & rejections

Combivent^® Respimat^®

On 7 Oct 2011 the US FDA-approved Combivent^® Respimat^® from Boehringer-Ingelheim (Ingelheim, Germany) [113,114]. Combivent Respimat contains the antimuscarinic, ipratropium bromide and the β2 adrenergic agonist, albuterol sulfate in an oral inhalation spray containing no chlorofluorocarbons. It is indicated for patients with chronic obstructive pulmonary disease on a regular aerosol bronchodilator who continue to have evidence of bronchospasm and who require a second bronchodilator. It is set to replace the existing Combivent inhaler, which contains ozone-depleting chlorofluorocarbons and will be on the market by July 2012 [114]. The Respimat inhaler produces an aerosol cloud from a metered volume of drug solution by mechanical energy only.

Glybera^®

At its October meeting, the Committee for Advanced Therapies (CAT) of the European Medicines Agency re-examined its initial negative opinion on Glybera (Alpogene tiparvovec) from Amsterdam Molecular Therapies BV (Amsterdam, The Netherlands) [115]. Glybera is intended for the treatment of lipoprotein lipase deficiency, a rare genetic disease, in adults showing high levels of chylomicrons in the blood or with a history of acute pancreatitis. It was designated as an orphan drug in 2004. The product contains the healthy lipoprotein lipase gene packaged in a delivery vector derived from adeno-associated virus, serotype 1. This vector targets muscle cells, which is the tissue most involved in lipoprotein lipase production. The product is administered as a one-off series of intramuscular injections into the leg muscles [116].

Following its re-analysis of the data and on the advice of the Scientific Advisory Group, the CAT recommended the approval of Glybera for use under exceptional circumstances and proposed restricting the therapy to adult patients with familial lipoprotein lipase deficiency, who had suffered at least one acute attack of pancreatitis despite dietary controls on the amount of fat ingested. The therapy would be further limited to patients with detectable levels of lipoprotein lipase [115]. In addition, post-marketing studies would be required to provide follow-up on efficacy, side effects and risk management. However, the Committee for Medicinal Products for Human Use, which is responsible for issuing the overall recommendation for marketing authorization, disagreed with the CAT‘s proposal and maintained its previous negative opinion on Glybera due to questions over the treatment‘s efficacy [117].

Exparel™

It was good news for Pacira Pharmaceuticals Inc. (Parsippany, NJ, USA) when on 28 October 2011, the FDA approved its liposomal formulation of bupivacaine, Exparel. The product is indicated for single dose infiltration into surgical sites to produce post-operative analgesia [118]. The product is a preservative-free formulation of the local anaesthetic at a concentration of 13.3 mg in multi-vesicular liposomes. It is based on the company‘s DepoFoam^® technology [119]. This technology consists of spherical, lipid-based particles, which in the case of Exparel have a median size of 24–31 µm. The lipid particles have numerous, non-concentric, internal aqueous chambers in which the drug is entrapped. The drug is released from the DepoFoam particles over time due to erosion and/or reorganization of the lipid membranes. Clinical efficacy of Exparel was demonstrated in a number of clinical studies, in which it was shown to produce postsurgical analgesia for up to 72 h following a single-dose local administration at the surgical site [120]. According to data quoted on the Pacira website the annual US market opportunity for this product could be as high as US$39 million [120].

Clinical trials

Halozyme

Halozyme Therapeutics Inc. (San Diego, CA, USA) issued two press releases on 27 October 2011 [121,122] providing updates on Phase I studies involving its recombinant human hyaluronidase technology, which breaks down hyaluron in the extracellular matrix and therefore has the potential to speed and improve the delivery of drugs.

The first press release concerned data from a Phase Ib trial of patients with Type 1 diabetes who receive their insulin via a pump [121]. The study involved administering 150 units (approximately 1.3 µg) of recombinant human hyaluronidase (rHuPH20) prior to initiating three days of NovoLog^® insulin aspart pump infusion therapy. The study had a randomized, double-blind, crossover design and its aim was to determine insulin pharmacokinetics, glucodynamics and the safety and tolerability of rHuPH20. The data showed that pre-administration of rHuPH20 resulted in less variable insulin absorption over the infusion period compared with NovoLog alone and glucose control following meals was improved. rHuPH20 pre-administration also accelerated insulin absorption by 57% (p<0.0001) and decreased its duration of action by 27 min (p<0.0001).

The second press release related to two Phase I dose-finding studies of its PEGylated recombinant human hyaluronidase product (PEGPH20) [122]. The results of these trials were presented at the 2011 European Organisation for Research and Treatment of Cancer–National Cancer Institute–American Society of Clinical Oncology Annual Meeting on ‘Molecular Markers in Cancer‘, which took place in Brussels (Belgium) between 27–29 October 2011. The presentation, which was held on the first day of the conference, focused on translational biomarker and pharmacodynamic results from the two Phase I studies in patients with advanced solid tumors that had been previously unresponsive to treatment. It was hoped that by conducting tumor imaging and biopsies. both pre- and post-administration in these trials to obtain evidence that PEGPH20 can break down the protective layers of hyaluron found in many tumors, thus, improving blood circulation and potentially allowing greater drug access to the cancerous site.

Study 101 investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of PEGPH20 as a single agent and Study 102 investigated multiple-dosing of PEGPH20 in combination with dexamethasone. The pharmacodynamics of PEGPH20 were evaluated by measuring the concentration of circulating hyaluronan catabolites. As expected from the proposed mechanism of action of PEGPH20, the level of these breakdown products in plasma increased in a dose-dependent manner after PEGPH20 administration.

Tumor imaging from sub-groups of patients showed that that the treatment restored tumor perfusion and decreased tumor metabolic activity.

Histochemical analysis of pre- and post-treatment tumor biopsies further confirmed PEGPH20‘s ability to break down hyaluron with samples from two patients with colorectal cancer showing reduced staining for this natural polymer after one cycle of treatment. This would suggest that PEGPH20 could potentially act as an adjunct in the treatment of cancers, such as pancreatic and colorectal, which are known to accumulate hyaluron.

Santaris

On 5 November 2011, Santaris Pharma A/S (Hoersholm, Denmark) presented Phase IIa clinical data on its product, Miravirsen, for the treatment of Hepatitis C infection at the American Association for the Study of Liver Diseases Liver Meeting in San Francisco, (CA, USA) [123]. Miravirsen inhibits miR-122, a microRNA required for the accumulation of the virus. It has been developed using Santaris locked nucleic acid chemistry, which enables oligonucleotide drugs to be produced that are smaller and have higher affinity for RNA than those made using earlier antisense technologies [124].

The company reported that Miravirsen given as a 4-week monotherapy resulted in a mean reduction of 2–3 logs from baseline in Hepatitis C virus RNA (log10 IU/ml) levels. This reduction was maintained for more than 4 weeks after therapy completion and was dose dependent. Four out of the nine patients treated with the highest dose of Miravirsen (7 mg/kg) had undetectable levels of Hepatitis C virus RNA during the study. In addition, the study showed that the drug is well tolerated [123].

Sunovion

Again on 5 Nov 2011, Sunovion Pharmaceuticals Inc. (Marlborough, MA, USA) presented four separate posters at the 2011 annual meeting of the American College of Allergy, Asthma and Immunology in Boston (MA, USA) on a Phase III study of its ciclesonide nasal spray [125]. This is a corticosteriod treatment for allergic rhinitis formulated with a hydrofluoroalkane propellant. The spray is designed to produce a fine dry mist in a volume of 50 µl to reduce the potential for an excess volume of spray to run down the nose or the back of the throat, a problem that can occur with aqueous corticosteroid sprays.

The 26-week, double-blind, randomized study compared 74 with 148 µg doses of ciclesonide nasal aerosol once daily per nostril with placebo in 1111 patients with perennial allergic rhinitis. Statistically significant improvements in nasal symptoms compared with placebo were seen after 6 weeks at both doses. Results from the full 26-week treatment period showed that the nasal spray was well tolerated.

The company was also able to demonstrate improvements in overall rhinoconjunctivitis-related quality of life with the lower dose spray over the first 6 weeks of treatment. This was done using prospectively designed analyses and the Rhinoconjunctivitis Quality of Life Questionnaire with Standard Activities (RQLQ[S]) for patients with a baseline RQLQ[S] score of ≥3.0. The study results are similar to those obtained in a previous trial of patients with seasonal allergic rhinitis.

The New Drug Application for ciclesonide nasal aerosol is currently under review by the FDA. The proposed dose is 74 µg per nostril daily.

Patents

Incept LLC

On 25 October 2011, the US Patent and Trademark Office issued Patent Number 8,044,137 entitled ‘Materials formable in situ within a medical device‘ [1]. The patent is assigned to Incept LLC (Mountain View, CA, USA), a privately held IP holding company with multi-purpose hydrogel technology, which licenses the technology out to start-ups [126,127]. The patent‘s claims concern administering a water soluble polymer precursor solubilized in a flowable aqueous solution into a body cavity. Following administration the polymer precursors undergo covalent bonding to form a solid and nonbiodegradable material having a swellability less than approximately 20% v/v and a Young‘s modulus of at least about 100 kPa. Polymer formation occurs from approximately 30 s to 30 min after initiation of the chemical reaction. One or two polymers with different functional groups can be used. If two polymers are used, then the first polymeric precursor should have a molecular weight of at least approximately 10,000 Da and the second polymeric precursor should have a molecular weight of less than approximately 3000 Da.

The invention has applications for the treatment of abdominal aortic aneurysms, where there is a need for an endograft that fills the space exactly in order to allow blood flow and support the aortic wall without danger of the endograft migrating. It is foreseen that patients would be treated by placing a thin, double-walled balloon across the aneurysm, the inner lumen of which allows blood flow through the endograft. The balloon would then be filled in situ with flowable polymeric precursors that polymerize and harden into a solid material to create an endograft, which is leak-proof, stable and fits the dimensions of the aneurysm exactly.

Dicerna Pharmaceuticals

Dicerna Pharmaceutcals Inc. (Watertown, MA, USA) announced on 5 Nov 2011 that the US Patent and Trademark Office had issued a notice of allowance in the ‘Rossi‘ patent family [128]. This patent family covers the company‘s Dicer substrate RNA therapeutics. Dicer substrate molecules are 25–30 mer double-stranded silencing RNA, which interact with the Dicer enzyme in the RNAi pathway. This interaction makes them more active and gives them a longer duration of action than their 19–23 mer counterparts, which do not bind to this enzyme.

The notice of allowance applies to 148 claims that concern both in vivo therapeutic and in vitro uses of the Dicer substrates for reducing expression regardless of the specific sequence. The company believes that the therapeutic claims granted are the broadest for any RNAi therapy to date. Double-stranded silencing RNA was discovered by John Rossi, Mark Behlke and Dongho Kim at the City of Hope (Duarte, CA, USA) and Integrated DNA Technologies Inc. (Coralville, Iowa, USA). The patent family was licensed to Dicerna in 2007.

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.