Industry Update: the Latest Developments in Therapeutic Delivery

Abstract

This article covers the period between 1–31 May 2013. During this period, Takeda bolstered its presence in the field of vaccines with the acquisition of the viral vaccine manufacturer, Inviragen, while Valeant dramatically expanded its eye healthcare offering with the purchase of Bausch & Lomb. Product choice for those suffering from growth hormone deficiency in the EU looks set to increase as the Committee for Medicinal Products for Human Use of the European Medicines Agency has given the green light to Biopartners GmbH microparticulate-based, once weekly, subcutaneous injection of recombinant somatotropin. If given approval by the EU commission (anticipated middle of Q3 2013), the product will be the only sustained release growth hormone injection on the European market. As ever, the Industry Update is based mainly on information from press releases and company websites.

Business development

Mergers & acquisitions

Takeda & Inviragen

The 7 May 2013 brought the news that the Takeda Pharmaceutical Company Limited (Osaka, Japan) through its subsidiary, Takeda America Holdings, Inc., will acquire the vaccine developer, Inviragen, Inc. (CO, USA) for an upfront payment of US$35 million, and future payments of up to $215 million based on clinical development and the achievement of key commercial milestones [101]. Inviragen is a privately held biopharmaceutical company developing vaccines for the prevention of diseases, such as dengue and hand, foot and mouth disease [102]. The company‘s lead candidate, DENVax, a four-strain, recombinant viral vaccine against Dengue, is currently in Phase II clinical trials, while its vaccine candidate for hand, foot and mouth disease has successfully completed Phase I. The company is also developing a viral vaccine against Japanese encephalitis and one for the Chikungunya virus, which, like Dengue, is mosquito-borne. Infection with this virus results in a number of symptoms including joint pain that, in some patients, can persist for years.

The purchase of Inviragen will bolster Takeda‘s presence in the field of viral vaccines and complements its 2012 acquisition of LigoCyte Pharmaceuticals, which added a norovirus vaccine, a preclinical vaccine pipeline and proprietary virus-like particle vaccine technology to its portfolio [103].

Valeant & Bausch & Lomb

On 27 May 2013 Valeant Pharmaceuticals International Inc (Laval, Canada) and Bausch & Lomb Holdings Inc (NY, USA) signed an agreement under the terms of which Valeant will acquire Bausch & Lomb and its portfolio of eye healthcare products for $8.7 billion in cash [104]. Of this sum $4.5 billion will be paid to Bausch & Lomb‘s current owners, an investor group led by Warburg Pincus and approximately $4.2 billion will be used to repay Bausch & Lomb‘s outstanding debt. The transaction will be financed with debt and approximately $1.5–2.0 billion of new capital.

Valeant will integrate its ophthalmology products [105], which include Visudyne^® (verteporfin for injection), a light-activated drug used in photodynamic therapy for indications such as subfoveal choroidal neovascularization, into Bausch & Lomb. Bausch & Lomb, whose products include well-known prescription brands, generics and over-the-counter products, contact lenses, intraocular lenses and surgical equipment [106], will retain its name and become a division of Valeant. Together the two companies‘ eyecare franchise is expected to capture net revenues of more than $3.5 billion in 2013. The Canadian company expects to make annual cost savings of $800 million by end 2014. By taking over Bausch & Lomb, Valeant hopes to gain a larger share of the growing eye healthcare market, which is fuelled by an aging population, a higher incidence of diabetes and the growth of emerging markets.

Licensing agreements & collaborations

Ambrx & Bristol-Myers Squibb

Ambrx Inc (CA, USA) released a press statement on 3 May 2013 that it would collaborate with Bristol-Myers Squibb (BMS) (NY, USA) to discover and develop novel antibody–drug conjugates using Ambrx‘s proprietary protein medicinal chemistry technology [107]. This technology involves the insertion of novel amino acids with the appropriate functional groups into the structure of a protein or antibody to enable the site-specific conjugation of a small molecule or polymer [108]. The conjugates can be developed and optimized rapidly using proprietary recombinant DNA-based processes.

This is the third agreement that the San Diego-based company has signed with BMS, the other two produced two therapeutic candidates that are currently being developed by BMS. One is a FGF-21 derivative for the potential treatment of Type 2 diabetes, while the second is a Relaxin hormone derivative, which will be evaluated for its safety and efficacy in heart failure [107,108].

Under the terms of the deal, Ambrx will receive an initial $15 million for discovery and research activities. If these activities are successful, various development, regulatory and sales-based milestone payments of up to $97 million could follow for each product that results from the collaboration. In return, BMS will receive the global rights to develop and commercialize these products, while Ambrx will receive royalties on net sales.

Grifols & Aradigm

On 21 May 2013 it was made public that Grifols SA (Barcelona, Spain) had obtained an exclusive worldwide license from the Aradigm Corporation (CA, USA) for its proprietary formulations of inhaled ciprofloxacin (Pulmaquin™ and Lipoquin™) [109]. These formulations are being developed for the local treatment of lung infections associated with severe conditions, such as cystic fibrosis and non-cystic fibrosis bronchiectasis (BE), and for biodefense purposes. BE is a condition that results in abnormal dilatation of the bronchi and bronchioles, making sufferers prone to chronic respiratory infections. Currently there is no specific drug treatment for this condition, which is said to affect around 110,000 people in the USA alone.

Lipoquin consists of the broad-spectrum antibiotic, ciprofloxacin, encapsulated in liposomes to sustain release of the drug at the site of infection in the lung and improve lung tolerability to the drug. It is being clinically evaluated in cystic fibrosis patients. Pulmaquin is a mixture of unencapsulated and encapsulated antibiotic allowing the rapid attainment of effective antibiotic concentrations in the airways followed by a second phase of prolonged release to maintain drug levels. In a Phase IIb study in patients with BE, Pulmaquin was found to be safe, have good antimicrobial activity and to prevent exacerbations compared with a placebo. Phase III trials with Pulmaquin, which has orphan status in BE in the US, are planned.

The terms of the agreement make Grifols responsible for development and clinical costs up to a maximum of $65 million with respect to advancing the product for the BE indication. The Spanish company will also have the responsibility for all commercialization activities involving Pulmaquin and Lipoquin products. In return, Aradgm will receive up to $25 million if it achieves certain development milestones and tiered royalties on global sales of products utilizing Aradigm‘s proprietary inhaled ciprofloxacin formulations. In addition, Grifols will be granted an option to license Aradigm‘s AERx^® pulmonary drug delivery platform for use with another molecule [110].

Grifols will also take a 35% share of Aradigm‘s common stock on a fully diluted basis at a price per share of $0.124 and appoint two directors to the Board. This represents a total investment of approximately $26 million and is subject to Aradigm shareholder approval. Further Aradigm common stock to the tune of around $15.4 million will be purchased by certain existing and new investors such as Tavistock Life Sciences Company, First Eagle Investment Management, LLC, and Great Point Partners, LLC. The deal is expected to close in the second half of 2013, if it meets certain closing conditions.

Eleven Biotherapeutics & ThromboGenics

Eleven Biotherapeutics (MA, USA) released a press statement on 28 May 2013 that they had signed a research collaboration and license agreement with ThromboGenics NV (Leuven, Belgium) to research and develop a protein therapeutic based on a novel biologic target implicated in diseases of the posterior eye, such as diabetic macular edema [111]. The aim of the collaboration is to use Eleven‘s proprietary AMP-Rx protein design platform to optimize a novel therapeutic of ThromboGenics‘ choice. This platform is based on proprietary yeast display system and employs computational design and analysis to rapidly screen custom libraries of diverse proteins and, hence, identify and engineer protein molecules with optimal properties including those related to stability, production and delivery [112].

In return for its services and the granting of an exclusive license for the therapeutic protein that results from the collaboration, Eleven will receive an up-front payment in addition to being eligible for development, regulatory and sales milestone payments as well as royalties on potential future sales if the product reaches the market. ThromboGenics will develop and commercialize the licensed protein and both companies will work together on preclinical research. The financial sums involved were not disclosed.

pSivida

pSivida Corp (MA, USA) announced on 29 May 2013 that it had signed a funded technology evaluation agreement with a leading global pharmaceutical company [113]. The agreement relates to pSivida‘s proprietary Durasert™ technology and its application to this pharmaceutical company‘s ophthalmology products. This technology involves a miniaturized implant that delivers drug to the back of the eye for specific periods of time ranging from weeks to months [114]. It is already used in three products marketed in either the USA or Europe including Iluvien^® (sustained release fluocinolone acetonide) for the treatment of diabetic macular edema (partnered with Alimera Sciences Inc., GA, USA); Retisert™ (fluocinolone acetonide intravitreal implant) indicated for posterior uveitis and Vitrasert^® for the treatment of AIDS-related cytomegalovirus retinitis (both licensed to Bausch & Lomb). The products release their active ingredients over a period of approximately 3 years, 6–9 months and 2.5 years, respectively. Using the Durasert technology, pSivida are developing the Iluvien™ micro-insert (the third generation of the Durasert technology) for posterior uveitis and also have a collaboration/license agreement with Pfizer (NY, USA) to develop a bioerodible version of the technology containing latanoprost for injection into the subconjunctival space of the eye to treat ocular hypertension and glaucoma.

No details of the latest technology evaluation agreement were released.

Product approvals

DESolve^® Novolimus Eluting Bioresorbable Coronary Scaffold System

On 15 May 2013 the Elixir Medical Corporation (CA, USA) made public that it had received CE (Conformité Européenne) Mark approval for its DESolve^® Novolimus Eluting Bioresorbable Coronary Scaffold System [115]. The scaffold is manufactured from a poly-L-lactide-based polymer using a proprietary fabrication process and degrades in around 1 year [116]. The stent has a wide margin of expansion and the ability to self-appose to the nominal vessel wall size in cases of malapposition. It maintains radial strength and vessel support for the necessary period of vessel healing.

Approval was based on the results of the pivotal DESolve Nx trial, which involved 120 patients in 15 centers in Europe, Brazil and New Zealand. The primary safety endpoint was the composite of major adverse cardiac events comprising cardiac death, target vessel myocardial infarction and clinically indicated target vessel revascularization, while the primary angiographic endpoint was in-scaffold late lumen loss at 6 months. The later was assessed by quantitative coronary angiography. The stent will be available in several international markets later in 2013.

Sustained-release HGH

At their May meeting, the Committee for Medicinal Products for Human Use of the European Medicines Agency gave a positive opinion on Biopartners GmbH (Baar, Switzerland) once-weekly HGH subcutaneous depot injection, Somatropin Biopartners [117,118]. This product, for the treatment of growth hormone deficiency in children and adults, is a microparticulate powder to be reconstituted as a suspension in medium chain triglycerides prior to injection. It is available in a variety of strengths: 2, 4, 7, 10 and 20 mg. The product was developed in collaboration with LG Life Sciences Ltd (Seoul, Korea).

Clinical trials

N9-GP

On 17 May 2013 Novo Nordisk (Bagsværd, Denmark) reported the results from the first Phase III Paradigm™ 2 trial, which assessed the safety and efficacy of the long-acting factor IX derivative, N9-GP in hemophilia B patients [119]. N9-GP is a proprietary glycopegylated recombinant factor IX for patients with hemophilia B. Glycopegylation increases the circulation half-life of recombinant factor IX resulting in lower bleeding frequency and enabling less frequent dosing.

The multi-center, blinded Paradigm™ 2 trial evaluated N9-GP used on-demand for 6 months or prophylactically for 12 months at a dose of 40 or 10 U/kg once-weekly. Overall, N9-GP proved safe and was well tolerated. The study results demonstrated that the median bleeding rate for patients treated on-demand was 15.6 episodes per year. This was compared with an annualized bleeding rate of 1.0 and 2.9 episodes per year, when patients were treated with weekly doses of 40 and 10 U/kg, respectively. In addition, in the 40 U/kg N9-GP cohort, 99% of bleeding episodes were treated with only one infusion and two-thirds of the patients experienced complete resolution of bleeding in their target joints. For this group, an improvement in the quality of life was also reported.

Two other Phase III trials of N9-GP in pediatric patients and those undergoing surgery are ongoing. Regulatory submission of N9-GP is expected in 2015.

Sufentanil NanoTab patient-controlled analgesia system

On 21 May 2013 AcelRx Pharmaceuticals, Inc. (CA, USA) released top-line data from its final placebo-controlled Phase III study on the sufentanil NanoTab patient-controlled analgesia system (NanoTab PCA System) [120]. This system involves self administration of the highly potent opioid, sufentanil, in the form nanotablets to the sublingual mucosa using a preprogrammable device. This device has a lock-out feature that prevents accidental or deliberate over-dosage [121]. This randomized US-based study involved 419 patients and evaluated the ability of sufentanil NanoTab PCA to control pain intensity compared with baseline in the 48 h immediately following knee or hip replacement surgery. The primary endpoint for the study was the summed pain intensity difference to baseline 48 h after surgery (i.e., SPID-48), as requested by the US FDA. The study results indicated that administration of sufentanil NanoTabs resulted in a significantly greater SPID-48 than placebo (+76.1 vs -11.5, p < 0.001). The SPID at 24 and 72 h was also significantly greater (p < 0.001 in each case).

This is the third positive result for the sufentanil NanoTab PCA System in Phase III and the company plan to submit a new drug application to the FDA in the third quarter of 2013.

Naloxegol

At the Digestive Disease Week 2013 in Orlando, Florida, Astra Zeneca (London, UK) presented data from two pivotal Phase III studies of naloxegol, a peripherally acting mu-opioid receptor antagonist, which the company is developing for the treatment of opioid-induced constipation [122]. This compound was licensed from Nektar Therapeutics (CA, USA) in 2009 [123] and is derived from naloxone using Nektar‘s oral small-molecule polymer conjugate technology.

The two 12-week, multicenter, randomized, double blind, placebo-controlled studies evaluated the administration of naloxegol, once-daily at a dose of 12.5 and 25 mg. The 25-mg dose met the primary end-point (percentage of responders vs placebo during the trial duration) and the secondary endpoints for the study. The latter included the 12-week response rate in a laxative inadequate response population, the median time to first spontaneous bowel movement and the number of days per-week with at least one bowel movement.

At the time of writing this article Astra Zeneca was in the process of finalizing its plans for naloxegol following discussions with various regulatory authorities.

Controlled-release misoprostol vaginal insert

On 24 May 2013 Ferring Pharmaceuticals (Saint-Prex, Switzerland) presented clinical data from the EXPEDITE study at First European Congress on Intrapartum Care (Amsterdam, The Netherlands) [124]. This Phase III trial compared the use of a controlled release misoprostol vaginal insert containing a reservoir of 200 µg of misoprostol to a dinoprostone vaginal insert with a reservoir of 10 mg dinoprostone. It involved 1,358 women and was conducted in the USA. The results demonstrated that, compared with the reference product, the misoprostol insert significantly reduced the median time to vaginal delivery from 32.8 h (95% CI: 30.2–34.9; p < 0.001) to 21.5 h (95% CI: 20.0–23.4). Administration of the misoprostol insert also reduced the time to any delivery, time to active labor and predelivery oxytocin administration compared with the dinoprostone insert. However, rates of cesarean operations did not differ between both treatments.

No details were given of Ferring‘s plans to submit this product for regulatory approval or to commercialize it. However, it is interesting to note that the market for labor induction products in Europe is rising, due to the increase in the number of inductions, a phenomenon fuelled by the fact that women are having their babies later in life.

Patents

ImmunoCellular Therapeutics

Immunocellular Therapeutics Ltd (CA, USA) made public on 16 May 2013 that the US Patent and Trademark Office had issued a patent protecting methods of use of IL-13Rα2 in cancer immunotherapy [125]. This protein is a good vaccine target as it is specifically expressed in glioblastoma, ovarian and other solid tumors, but not in normal tissue.

The company, which is developing vaccines for the treatment of brain and other cancers, sub-licensed the intellectual property [1] from Targepeutics, Inc. which, in turn, licensed it from Pennsylvania State University. IL-13Rα2 is a target for two of ImmunoCellular‘s autologous dendritic vaccines: ICT-107, a dendritic cell vaccine directed against glioblastoma antigens and cancer stem cells and; ICT-140, a dendritic cell vaccine to treat ovarian cancer. The former is the company‘s lead compound and is currently in Phase II trials.

Collegium Pharmaceuticals

On 28 May 2013 the US Patent and Trademark Office issued Patent No. 8449909 entitled “Abuse-deterrent drug formulations” [2]. The patent is assigned to Collegium Pharmaceutical, Inc. (Canton, MA, USA). It covers the company‘s Oxycodone DETERx^® product that is currently in clinical development. DETERx is a drug delivery technology that enables prolonged release formulations of substances prone to abuse to be developed, while hindering that abuse by having tamper-resistant properties. It is based on a multiparticulate bead system within a capsule. The beads are formed using a spray-congealing process and contain the drug in the form of a solid dispersion. The formulation is so designed that the beads will not release substantial amounts of drug even when they are ground or crushed. The product can therefore be safely administered as a sprinkle formulation [126,127].

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.