Industry Update: the Latest Developments in Therapeutic Delivery

Abstract

The time period 6 November 2011 to 5 December 2011 included the following developments. Roche completed its exit from RNAi through the sale of its Kulbach, Germany facility to some of the original site founders. Arrowhead Research Corporation detailed siRNA delivery advances made by Roche Madison Inc., which they acquired in October 2011. Pfizer purchased an antisense company with an anti-scarring treatment, Isis spin-off Excaliard Pharmaceuticals. The competitive GLP-1 agonist field saw the split of Amylin, developer of Byetta^®, and long-time partner Eli Lilly. Meanwhile GSK‘s long-acting GLP-1 agonist albiglutide failed to meet a non-inferiority end point when compared with Novo Nordisk‘s Victoza^®. Unigene provided updates on two oral peptide programs. Phase III results from a trial of oral calcitonin, conducted by partner Novartis, failed to meet efficacy end points. In contrast, a Phase II study of oral parathyroid hormone, conducted as part of an agreement with GSK, hit its primary end point, but shortly thereafter GSK returned their rights in the product. Stem cell therapy saw mixed news. Geron, a leading embryonic stem cell company, completed a Phase I in spine patients, and then announced it was abandoning all stem cell work to focus on other areas. Separately, AlloCure and Mesoblast both announced positive results from clinical studies utilizing mesenchymal stem cells obtained from donated bone marrow. Finally, Amgen surprised would-be developers of biosimilars of blockbuster Enbrel^® when it announced issuance of a patent, filed in 1995, covering the product through 2028, approximately 16 years beyond what Enbrel‘s period of exclusivity had been generally considered to be.

Business development

Acquisitions & mergers

Roche completes exit from RNAi

Following its acquisition of RNA therapeutics assets from Roche, reported in the January 2012 issue of Therapeutic Delivery[1], Arrowhead Research Corporation (Pasadena, CA, USA) published a white paper on 7 November 2011 detailing previously undisclosed improvements to a core asset, the Mirus Dynamic Polyconjugate™ platform technology. These included implementation of controlled radical polymerization for improved polymer homogeneity and process scaleability, in addition to inclusion of hydrolysable linkages in the polymer backbone and side chains to avoid material accumulation on repeat dosing. Masking chemistries with improved chemical stability and prolonged circulation times are purported to enable access to tumor tissues by an extravasation mechanism. New classes of targeting ligands have been incorporated to enable access to new tissue types. The report disclosed potency (efficacious dose of 0.1 mpk) and therapeutic index (>10) results in nonhuman primates for a liver target, claiming a leading position among siRNA delivery options currently available. [101–103]

Shortly after the sale of its Madison, Wisconsin-based RNA facility, announced in October 2011, Roche found a buyer for their European RNA operations located in Kulmbach, Germany. Axolabs, a start-up associated with the founders of Ribopharma, the progenitor of Roche Kulmbach, is purchasing the site and starting a new venture servicing pharmaceutical and biotechnology companies in the areas of RNAi-based lead identification, high-throughput RNA synthesis up to the gram scale and consultancy services. The acquisition included neither the 60 former Roche (Kulmbach) employees nor the Roche RNA intellectual property portfolio, which was included in its entirety with the Roche Madison Inc. assets acquired by Arrowhead Research Corporation [104].

Pfizer acquiring Excaliard

Pfizer, which announced closure of its own Oligonucleotide Therapeutics Unit in February 2011, completed an acquisition of Isis spin-out Excaliard Pharmaceuticals on 5 December 2011. Excaliard announced positive results from their Phase II trial of EXC001, an antisense oligonucleotide against connective tissue growth factor for the reduction of scarring, in January 2011 [2]. Terms were not disclosed, but Isis expects up to US$14 million for its equity stake, plus milestones and royalties [105,106].

Mylan acquiring Pfizer‘s respiratory platform

Mylan announced its acquisition of Pfizer‘s (NY, USA) Sandwich, UK-based respiratory delivery technology. The deal includes rights to develop, manufacture, and commercialize Pfizer‘s generic equivalents of GlaxoSmithKline (GSK) asthma and chronic obstructive pulmonary disease products, Advair^® Diskus and Seretide^® Diskus. Further included are development and commercialization rights for other, undisclosed branded and generic products. Deal terms include an up-front payment to Pfizer of $17.5 million, with subsequent payments and profit sharing contingent on regulatory and commercial success [107,108].

Licensing agreements & collaborations

Lilly & Amylin split

Amylin Pharmaceuticals (San Diego, CA, USA) and Eli Lilly (Indianapolis, IN, USA) announced an end to their nearly 10-year-old alliance to commercialize GLP-1 agonist exenatide (Byetta^®) for the treatment of diabetes. Amylin had filed suit against Lilly in May 2011 for allegedly violating their agreement when they agreed to work with Boehriner Ingelheim to commercialize a competing product, DPP-4 inhibitor linagliptin (Tradjenta™). Terms of the separation include a one-time payment of $250 million by Amylin to Lilly, plus 15% revenue sharing toward repayment of a $1.2 billion note. Amylin‘s relationship with Alkermes (Dublin, Ireland), whose microsphere technology is used in a weekly depot formulation of exenatide called Bydureon™, is reportedly unaffected by the split with Lilly. An new drug application for Bydureon was resubmitted to the US FDA in July 2011 with additional safety data to address potential cardiovascular side effects. Bydureon, which could exceed $1 billion in annual sales according to analysts, was approved in Europe in June 2011. US approval could come as soon as January 2012 [109–112].

Bend collaborations with Merck & Pfizer

Bend Research (OR, USA) announced a new collaboration with Merck, with a focus on Bend‘s spray-dried dispersion technology. Access to modified-release technologies and drug-discovery formulation tools may also be included in the deal. Separately, Bend is also collaborating with Pfizer on a nanoparticle technology for improved delivery to joints for the treatment of osteoarthritis [113,114].

DSM

Dutch concern DSM, a major supplier of active pharmaceutical ingredients, announced two deals related to their expansion in drug delivery. An alliance with AdeTherapeutics (Canada) will focus on treatments for pain reduction and scar management following spinal and head injuries. AdeTherapeutics‘ technology portfolio includes a dipeptide used for the prevention of scarring. The initial focus is epidural fibrosis following spinal surgery.

DSM further announced a license and supply agreement with Svelte Medical Systems (New Providence, NJ, USA), which grants the latter rights to DSM‘s proprietary bioerodible amino acid-based carrier for design of a next-generation drug-eluting coronary stent. Svelte will use the antiproliferative sirolimus with the DSM delivery technology [115–117].

Roche & Aileron

Aileron Therapeutics (Cambridge, MA, USA) announced an expansion of their 2010 agreement with Roche for the evaluation of the former‘s ‘stapled peptide‘ technology. The original agreement provided Aileron with $25 million plus up to $1.1 billion in milestone payments. The agreement expansion adds a new program in inflammation, supplementing two earlier cancer-based programs. Stapled peptides are protein fragments, which are chemically linked to provide improved metabolic stability and to enhance penetration through cell membranes, providing access to disease targets within cells. Since the company‘s founding in 2005, circulating half-lives have been extended to over 1 week using this approach [118,119].

Merck Serono partners with Ablynx

Merck Serono (Geneva, Switzerland) announced an expansion of its relationship with nanobody-focused company Ablynx (Ghent, Belgium). The companies joined forces 3 years ago with an initial focus on programs in oncology and immunolgy. An inflammation target was added in a second agreement in October 2010. The most recent agreement further augments the relationship to include two osteoarthritis programs, with a $28 million payment up front and $41 million in milestones. Ablynx‘s nanobodies exhibit multispecific properties with extended half-lives [120].

Initial public offerings & other funding milestones

Cancer vaccine player NewLink Genetics (Ames, IA, USA) raised $43.4 million in an initial public offering, one of the few biotechnology initial public offerings of 2011. The company is advancing a late-stage therapeutic vaccine against pancreatic cancer, HyperAcute^® Pancreas. The therapy, which has been granted fast-track and orphan status by the FDA, is the subject of an ongoing Phase III clinical trial. The company also has programs for lung cancer and melanoma, which are at an earlier development stage [121,122].

Avaxia Biologics (Lexington, MA, USA) announced completion of a Series A round, bringing in $2.2 million. The company is developing therapeutic antibodies, which are isolated from cow‘s milk and dosed orally. The lead program AVX-470, an antibody against TNF-α, is being developed for treatment of inflammatory bowel disease and for gastrointestinal acute radiation syndrome [123].

Leonardo Biosystems (Houston, TX, USA) received $1.25 million from the Texas Emerging Technology Fund for development of its mesoporous silicon delivery technology. The silicon particles can be loaded with a variety of drug-containing nanoparticles such as liposomes or micelles, for delivery of various drugs including siRNA. The company achieved a manufacturing process milestone, which triggered the second tranche of a $2.5 million award announced in 2010 [124].

Regulatory news & approvals

Product approvals & rejections

Intermezzo^®

Transcept (Point Richmond, CA, USA) announced approval of its sleep drug Intermezzo^®, a low-dose sublingual formulation of zolpidem based on a fast-dissolve technology. Zolpidem is the active ingredient in the widely subscribed insomnia treatment Ambien^®. The reformulated generic drug is partnered with Purdue Pharma, which obtained an option to commercialize Intermezzo in a 2009 deal with Transcept [125].

PROMUS™ Element™

Boston Scientific (Natick, MA, USA) announced approval of its next generation drug-eluting stent, termed PROMUS™ Element™. The stent is based on a platinum–chromium alloy and contains the antiproliferative everolimus, which is eluted from a fluorinated copolymer stent coating [126].

Abilify^®

Otsuka Pharmaceuticals (Tokyo, Japan)announced that the FDA accepted its new drug application for aripiprazole depot formulation, a 1-month formulation of their schizophrenia treatment Abilify^®. The product candidate is ahead of the similar ALKS 9070 from Alkermes, who planned to initiate Phase III trials in the USA by the end of 2011. In contrast to Otsuka‘s offering, ALKS 9070 does not require reconstitution prior to administration, considered to be a modest advantage [127,128].

Peginesatide

In a development that could shake up the market in erythropoiesis-stimulating agents, an FDA panel backed Affymax‘s (Palo Alto, CA, USA) once-monthly peginesatide as being equivalent to Amgen (Thousand Oaks, CA, USA) blockbusters Epogen^® and Aranesp^®. The panel reviewed data from patients suffering from chronic kidney disease (CKD) who received dialysis along with the Affymax treatment. The FDA, which is currently reviewing an new drug application for peginesatide, is expected to respond to the application by 27 March 2012 [129,130].

Iluvien^®

The FDA rejected Alimera‘s (Alpharetta, GA, USA) application to market Iluvien^®, a treatment for diabetic macular edema associated with diabetic retinopathy. Iluvien is based on pSivida‘s (Watertown, MA, USA) injectable, non-erodible intravitreal implant technology and incorporates the corticosteroid fluocinolone acetonide [131].

Clinical trials

Unigene

Novartis disclosed results from its Phase III trial of an oral calcitonin formulation co-developed with partner Unigene (Boonton, NJ, USA). The product, which utilizes technology from Cedar Knolls, NJ, USA-based Emisphere, failed to meet primary and key secondary end points in postmenopausal osteoporosis patients. The 3-year trial failed to show a significant reduction in the rate of new vertebral fractures.

Separately, Unigene announced favorable results from a Phase II study of its oral parathyroid hormone formulation, conducted as part of a licensing agreement with GSK. The primary end point was an increase in bone mineral density of the lumbar spine. Despite this outcome shortly after the announcement, GSK, which first partnered with Unigene in 2002, returned its rights to the parathyroid hormone program. Unigene is now seeking a new partner [132–136].

Stem cell trials

Stem cell pioneer Geron (Menlo Park, CA, USA) announced it has halted the first US-approved human trial using embryonic stem cells. The Phase I study involved injection of stem cells into the spines of patients, with evaluation of safety. The company reported the treatment was well-tolerated with no serious adverse events. Geron further announced its plans to exit the stem cell field completely, and to shrink its work force by one-third in order to conserve cash for unrelated cancer projects at the company. The announcement was viewed by some as a serious setback for the stem-cell field given Geron‘s extensive investment over a 10-year period and its leadership position. Nevertheless Geron‘s announcement was followed by positive news by another player in the space. AlloCure (Burlington, MA, USA) announced favorable findings from its Phase I study of an experimental stem-cell treatment AC607 in heart surgery patients considered at risk for acute kidney injury. With safety as well as efficacy end points, 16 patients were treated with mesenchymal stem cells from donated bone marrow. The company reported improvements in acute kidney injury incident rate, as well as reduced hospital stays and rates of readmission compared with the control group. The company plans to initiate a Phase II study in the first half of 2012.

Mesoblast (Australia), another adult stem cell therapy player, announced positive results from its Phase II study of Revascor™, its mesenchymal precursor cell therapy for cardiovascular disease. The therapy reduced cardiac mortality and major adverse cardiac events in patients with congestive heart failure. Revascor is being jointly developed with Teva Pharmaceuticals (Petah Tikva, Israel). A Phase III study is planned to start in the first half of 2012. Mesoblast is 20% owned by Cephalon (Frazer, PA, USA), which paid $220 million as part of a December 2010 agreement [137–139].

GSK GLP-1 Phase III failure

GSK announced that its Phase III evaluation of albiglutide, a weekly GLP-1 agonist, failed to meet efficacy end points in a non-inferiority study against daily Victoza^® (liraglutide). GSK has placed a big bet on albiglutide, with seven additional Phase III studies underway. Albiglutide, originally known as albugon, is based on albumin fusion technology from Human Genome Sciences [140–142].

Patents

Amgen announced issuance of US patent 8063182, covering the fusion protein etanercept (Amgen‘s blockbuster Enbrel^®). The patent, owned by Roche, was exclusively licensed to Immunex in 1999; Amgen acquired the rights as part of its 2002 acquisition of Immunex. The patent, originally filed in 1995, has a lifetime of 17 years from date of issue, posing a new obstacle to the introduction of Enbrel biosimilars in the US market. Enbrel had been expected to go off patent in October 2012 [143–146].

Santarus announced that two of its key patents covering their locked nucleic acid technology for antisense oligonucleotides were upheld against a challenge by Isis. The re-examination focused on US patent 6268490 and US patent 6770748. Patentability of all claims was confirmed and the ruling is not subject to appeal. The technology enables development of very high affinity antisense drugs with small size and unique pharmaceutical properties that are claimed to enable access different tissue types without the need for delivery vehicles [147,148].

Financial & competing interests disclosure

Dr Paul Burke is Principal of Burke Bioventures LLC (www.burkebioventures.com), providing consultancy and advisory services to pharmaceutical and biotechnology companies, including those working in the drug delivery space. Current and ongoing clients cannot be named for confidentiality reasons but may be featured in industry news stories covered. The author is a share holder in Pfizer Inc. The author has no other 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 apart from those disclosed. No writing assistance was utilized in the production of this manuscript.