Industry Update: the Latest Developments in Therapeutic Delivery

Abstract

This month‘s snapshot of events in the therapeutic delivery arena covers the period 21 June–21 July 2010 inclusive. Overall it was a highly successful month for companies working in the field, with five products based on nonstandard formulation technologies achieving regulatory approval either in the USA or in the EU. It also saw a number of business negotiations come to fruition, including the announced merger between Biovail and Valeant and the takeover of Abraxis by Celgene. However, the period also witnessed some disappointments, one of the most notable of which is Pfizer‘s planned withdrawal of Mylotarg^® from the market. The information is sourced from company websites and press releases.

Business development

Acquistion & merger:

Biovail & Valeant

On 21 June the Biovail Corporation (Mississauga, ON, Canada) and Valeant, Pharmaceuticals International (Aliso Viejo, CA, USA) issued a joint press statement that they had agreed to merge to form Valeant Pharmaceuticals International, Inc. [1]. The fused company plans to capitalize on its complementary product lines and operations in specialty CNS, dermatology, Canada and emerging markets/branded generics and will also have an expanded presence in North America and operations in eight different countries. Following the merger, Biovail and Valeant stockholders will own approximately 50.5 and 49.5% of the shares, respectively, in the combined company on a fully diluted basis. The new company will be headquartered in Mississauga, Canada. The merger is still subject to shareholder and regulatory approval and customary closing conditions.

Acquistion & merger:

Celgene & Abraxis

On 30 June the Celgene Corporation (Summit, NJ, USA) announced that it has agreed to acquire Abraxis BioScience Inc. (Los Angeles, CA, USA) in a deal that values Abraxis in upfront payments at approximately US$2.9 billion net cash [2]. As part of the agreement, Abraxis shareholders will be eligible to share in future regulatory milestone payments and commercial royalties. The acquisition of the developer of the proprietary nanoparticle albumin-bound nAb™ technology [3] is part of Celgene‘s strategy to become a global player in oncology, and adds Abraxane^® for injectable suspension (paclitaxel protein-bound particles for injectable suspension) to its portfolio. It also provides access to Abraxis‘ clinical pipeline and discovery platform.

Joint venture:

Midatech & Immunotope

Midatech Group Ltd (Abingdon, UK) and Immunotope Inc. (Doylestown, PN, USA) issued a press statement on 12 July on their agreement to form a joint venture, Syntara LLC, to develop antigen-based products for immune therapies to treat chronic viral infections and certain cancers [4]. The joint venture will build on Midatech‘s expertise and intellectual property in the area of self-assembling nanoparticles and Immunotope‘s experience in antigen discovery and validation. The two companies will initially fund the joint venture, with Syntara LLC charged with finding additional capital within the next 6–9 months.

Licensing & co-development agreement:

Diamyd Medical & Ortho-McNeil-Janssen Pharmaceuticals

Diamyd Medical AB (Stockholm, Sweden) a company specializing in the development of vaccines against diabetes caused by autoimmune disease (Type 1 and latent autoimmune diabetes in adults), announced on 22 June that it had signed an agreement with Ortho-McNeil-Janssen Pharmaceuticals, Inc. (Raritan, NJ, USA) [5]. The agreement concerns the development and worldwide commercialization of glutamic acid decarboxylase (GAD65) antigen-based therapy (Diamyd^®) for the treatment and prevention of Type 1 diabetes and associated conditions. This enzyme is one of the most important targets for immune system attack on pancreatic β cells, and vaccination is thought to induce tolerance to it, thus preserving cell function and the patients‘ ability to produce insulin [6].

Under the terms of the agreement, Diamyd will receive US$45 million upfront and has the potential to obtain additional development and sales milestone payments of up to US$580 million, as well as tiered royalties, on future sales. Both companies will share costs equally for the development program until results from the ongoing EU Phase III study are known, after which Ortho-McNeil-Janssen Pharmaceuticals, Inc. has the right to assume full responsibility for it. As part of the deal Diamyd will retain exclusive rights for product commercialization in Nordic countries and the therapeutic use of the GAD65 gene and derivatives, fragments and variants of the GAD65 protein [5].

Licensing & co-development agreement:

Midatech & MonoSol Rx

The formation of its joint venture with Immunotope was not the only agreement announced by Midatech in recent weeks. On 24 June it made public that, following the successful delivery of a 6000-Da polypeptide in a preclinical model, it had agreed to expand its cooperation with MonoSol Rx (Warren, NJ, USA) to develop buccal and sublingual formulations of Midatech‘s protein- and peptide-loaded glyconanoparticles using Monosol‘s PharmFilm^® technology as a vehicle [7]. Under the terms of the expanded agreement, MonoSol Rx made an equity investment in Midatech and its Executive Vice President and Chief Financial Officer, Keith Kendall, will join the Midatech Board of Directors.

Licensing & co-development agreement:

SurModics & Clinuvel

On 7 July, SurModics (Eden Prairie, MN, USA) announced that it has licensed certain of its biodegradable polymer implant technology to Clinuvel Pharmaceuticals Ltd, Melbourne, Australia for the treatment of sun-induced skin disorders [8]. The deal, whose terms remain undisclosed, follows years of collaboration between the two companies on Clinuvel‘s sustained release implant of afamelanotide (Scenesse^®). The implant is being developed as a prophylactic treatment for a range of UV and light-related skin disorders and is currently in Phase II and III clinical studies [9].

Development & manufacturing contract:

OctoPlus

The past few weeks have been good for the Dutch company, OctoPlus NV (Leiden, The Netherlands). On 30 June it announced that it had signed an agreement with Novartis (Basel, Switzerland) to develop (up to in vivo feasibility) a controlled release formulation of an undisclosed compound using its proprietary drug delivery technology, PolyActive^®[10]. This was followed by a further press release on 8 July making public the signing of a contract with a US biotechnology company to develop a sustained release formulation of a product already in clinical development also using PolyActive^®[11]. This technology is built around biodegradable polymers of poly(etherester) multiblock copolymers, based on poly(ethyleneglycol) and poly(butyleneterephthalate) that can be manufactured into a variety of configurations (e.g., microspheres and wafers) and is suitable for controlling the release of proteins and small lipophilic molecules [12].

Further to these two announcements, OctoPlus released a press statement on 12 July that it had signed a pharmaceutical development and manufacturing contract with The Medicines Company (Parsippany, NJ, USA) [13]. The contract relates to The Medicines Company‘s MDCO-216 (ApoA-I Milano/phospholipid complex), a naturally occurring variant of a component of human high-density lipoprotein. This compound was licensed from Pfizer in 2009 and has been shown to have potential to reduce the volume of atherosclerotic plaques in a Phase I/II trial [14]. The value of all three contracts is undisclosed.

Government contract:

Tekmira Pharmaceuticals & the US Department of Defense

On 15 July Tekmira Pharmaceuticals Corporation (VN, Canada) announced that it had been awarded a contract worth up to US$140 million by the US Department of Defense Chemical and Biological Defense Program [15]. The contract is to develop an RNAi therapeutic using Tekmira‘s stable nucleic acid–lipid particle technology to treat Ebola virus infection. Under the terms of the contract the company could receive up to US$34.7 million over the next 3 years to fund preclinical development and Phase I testing of the product. If successful, the contract could be extended to enable the Ebola stable nucleic acid-lipid particle product to progress through clinical testing and US FDA approval.

Regulations & approvals

Product approval:

Namenda XR^® capsules

On 21 June, Forest Laboratories, Inc., NY, USA and Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany announced that the FDA had approved Namenda XR capsules, an extended release formulation of memantine hydrochloride for the treatment of the moderate to severe dementia of the Alzheimer‘s type [16]. Several product strengths (7, 14, 21 and 28 mg) were approved. However, 28 mg once daily is the standard maintenance dose. The efficacy of Namenda XR was assessed at this dose in a double-blind placebo-controlled 24-week Phase III trial involving 677 patients suffering from moderate to severe dementia, who were already receiving acetylcholinesterase inhibitor (either donepezil, galantamine or rivastigmine) medication. The trial showed that the addition of Namenda XR capsules to the monotherapy produced a statistically significant improvement in a validated clinical measure of cognitive impairment (the severe impairment battery) and clinical global status compared with placebo [17]. Forest licensed memantine hydrochloride from Merz in 2000 [18].

Product approval:

Sycrest^® sublingual tablets

Sycrest^® sublingual tablets from N.V. Organon, a subsidiary of Merck & Co., Inc. (Whitehouse Station, NJ, USA), were recommended by the EMA‘s Committee for Medicinal Products for Human Use (CHMP) for marketing authorization within the EU on 24 June [19]. The tablets contain 5 or 10 mg of asenapine (as maleate) and are indicated for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults. The CHMP based on its decsion on Sycrest‘s ability to reduce manic symptoms in bipolar I disorder (moderate to severe manic episodes) for up to 12 weeks. In addition, study results showed that, as an adjunct therapy, the tablets can improve control of manic symptoms compared with lithium or valproate monotherapy. The drug was approved under the tradename Saphris^® last year in the USA where it is also licensed for the treament of schizophrenia [20]. However, its use for this latter indication was rejected by the CHMP.

Product approval:

PecFent^® nasal spray

In the same meeting the CHMP adopted a positive opinion recommending PecFent^®, from Archimedes Development Ltd. (Nottingham, UK), for marketing authorization [21]. It is a nasal spray containing the µ-agonist fentanyl at a concentration of 100 µg/100 µl or 400 µg/100 µl and is indicated for the management of breakthrough pain in adults who are already receiving maintenance opioid therapy for chronic cancer pain. The drug is formulated as the citrate salt in an aqueous solution using the company‘s pectin-based PecSys™ technology. The pectin gels on contact with calcium ions on the nasal mucosa, thus retaining the formulation at the target site and allowing rapid but controlled drug absorption into the systemic circulation. The product was studied in three Phase III clinical trials including an active comparator study and a large long-term safety and acceptability trial [22]. Archimedes Pharma submitted a new drug application for PecFent with the FDA in August 2009 and is setting up its own US commercial organization to market the drug once approved [22].

Product approval:

Butrans™ Transdermal System CIII

On 30 June the FDA approved Purdue Pharma LP‘s Butrans™ Transdermal System CIII containing buprenorphine for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time [23]. The patches, which are available in different strengths, deliver 5, 10 or 20 µg of drug per hour on a continuous basis over 7 days. Drug release from all patch strengths is proportional to the active surface area of the system as the proportion of drug in the polyacrylate-based matrix remains constant. The safety and efficacy of the product was assessed in four 12-week double-blind clinical studies in opioid-naive and -experienced patients with moderate to severe chronic low back pain or osteoarthritis. In two of these studies the product met its primary endpoint to control back pain as measured by pain scores. However, in another study of back pain and one in osteoarthritis, which included an active comparitor, efficacy of the product was not demonstrated. In the latter the comparitor also failed to meet the pre-defined end-point. Purdue Pharma LP (Stamford, CT, USA) expects to launch Butrans commercially in the USA early in 2011 [24].

Product approval:

Zuplenz^® oral soluble film

Just 2 days later, on 2 July, Strativa Pharmaceuticals‘ (Woodcliff Lake, NJ, USA) received the good news that they had been granted US approval for their Zuplenz^® (ondansetron) oral soluble film [25,26]. This product contains 4 or 8 mg of the 5-HT₃ receptor antagonist, ondansetron, which is applied to the top of the tongue where it dissolves in seconds. It is indicated in adults for the prevention of post-operative nausea and vomiting and that associated with moderately or highly emetogenic cancer chemotherapy and radiation treatment to the whole body or abdomen. It is also licensed for use in pediatric chemotherapy patients of 4 years and above [26]. Approval was granted based on a study comparing the bioequivalence of Zuplenz 8 mg to Zofran ODT^® (orally dissolving tablet) 8 mg (GlaxoSmithKline, London, UK) under fed and fasting conditions [25].

Zuplenz films were developed using MonoSol Rx LLC‘s (Warren, NJ, USA) proprietary PharmFilm^® technology. Under the terms of an amended exclusive licensing agreement initially signed between Strativa and Monosol Rx in 2008, FDA approval triggers approval and prelaunch milestone payments to Monosol Rx of US$4.0 million and 2.0 million, respectively [25].

Product withdrawal:

Mylotarg^®

On 21 June, Pfizer (NY, USA) announced that it is voluntarily discontinuing Mylotarg^® (gemtuzumab ozogamicin for injection), its antibody-targeted cytotoxic treatment for relapsed acute myeloid leukemia in the USA. The decision was taken following discussions with the FDA and was based on a post-approval study in which a combination of chemotherapy and Mylotarg did not demonstrate improved survival compared with chemotherapy alone in patients with previously untreated acute myeloid leukemia. In addition, increased toxicity was observed. This study was required as Mylotarg was originally approved under the FDA‘s accelerated approval regulations and required submission of additional data to confirm clinical benefit. Pfizer plan to withdraw its new drug application for Mylotarg on 15 October 2010. Doctors have been advised that no new patients should be prescribed the product, although those already receiving Mylotarg may complete their treatment [27].

Clinical trials

Hematide™

On 21 June Affymax Inc. (Palo Alto, CA, USA) and Takeda Global Research & Development Center, Inc. (Deerfield, IL, USA) announced that Hematide™ (peginesatide), their novel pegylated peptidic compound for the treatment of anemia in chronic renal failure, had met its primary endpoint (the mean change in hemoglobin from baseline) in each of four open-label randomized active-controlled Phase III studies [28]. In the combined four studies the test compound also showed noninferiority to its comparitor products (either epoetin or darbepoetin) with regard to an important indication of cardiovascular safety, the adjudicated cardiovascular composite safety record. However, sub-group analysis of two studies involving patients not on dialysis brought to light an increase in cardiovascular events in the Hematide group (21.6%) when compared with comparitor (17.1%). The same subgroup analysis in dialysis patients receiving maintenance treatment failed to reveal any such differences. These findings are the subject of further investigation.

This press release was followed by another on 22 June stating that Affymax had received US$30 million in development milestone payments from Takada based on the attainment of database lock in the four aforementioned trials [29]. The latter company has an exclusive license to develop and market the product outside of the US.

Glumetza^® (metformin HCl extended release tablets)

Depomed Inc., Menlo Park and Santarus Inc., San Diego (both CA, USA) presented clinical data at the 70th Scientific Sessions of the American Diabetes Association (25–29 June, Orlando, FL, USA), which indicated that patients intolerant of metformin may be able to take higher doses of the drug when it is administered as Glumetza^®, a once-daily extended release formulation of this drug [30]. Glumetza is based on Depomed‘s gastroretentive AcuForm™ technology [31]. The 4-week observational study involving 87 patients compared the maximum tolerated dose of Glumetza with that achieved with the patients‘ existing metformin medication. The study results showed that patients on Glumetza were able to tolerate 1477 mg metformin versus only 1204 mg with other formulations (p < 0.001) [30].

Intellectual property

Epeius Biotechnologies

On 7 July Epeius Biotechnologies Corporation (San Marino, CA, USA) announced that it had received a notice of allowance from the US Patent and Trademark Office for a further patent relating to its tumor-targeted gene-delivery platform covering targeting to metastatic disease [32]. The company‘s technology consists of retroviral-based stealth-like nanoparticles of approximately 100 nm, loaded with a tumour killer gene and targeted specifically at diseased tissue. Its most advanced compound, Rexin-G^®, which includes a mutant cell cycle-control gene, is approved in the Philippines for all solid tumours refractory to standard chemotherapy and is currently in Phase I/II and II trials in the USA. It has orphan drug status from the FDA for the following indications: pancreatic cancer, osteosarcoma and soft tissue sarcoma [33].

Aphios

Aphios Corporation, Woburn, MA, USA announced on 23 June that it had been awarded US patent US7708915B2 for ‘Polymer microspheres/nanospheres and encapsulating therapeutic proteins therein‘ [34]. The patent covers an improved process and apparatus to formulate polymeric microspheres and nanospheres and encapsulate therapeutic proteins or other useful substances within them. It also details methods and equipment for the purification of protein-containing particles from unused polymer. The patent strengthens Aphios‘ SuperFluids™ platform, which concerns the production of polymeric particles using supercritical, critical or near-critical fluids with or without polar cosolvents for drug-delivery purposes.

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.