Industry Update: the Latest Developments in Therapeutic Delivery

Abstract

This present industry update covers the period 16 September–15 October 2010, with information sourced from company press releases and websites, regulatory agencies and patent search engines. The imminent patent expiration of a number of key drug patents remains a major concern for many of the large pharmaceutical companies. Consequently, the acquisition of King Pharmaceuticals by Pfizer, whilst still assimilating Wyeth, is likely to set the scene for further sizable mergers and acquisitions to strengthen pipelines and mitigate risk. The regulatory approval of Gilenya™ (fingolimod) by the US FDA represents an exciting and major step forward in the provision of treatment options for multiple sclerosis, and the results of the Phase III clinical study with abiraterone acetate demonstrate a much needed new advancement in the treatment of metastatic, castration-resistant prostate cancer, a stage of the disease that currently has few treatment options and a high mortality rate.

Business development

Acquisition & merger

Pfizer & King Pharmaceuticals

A definitive agreement was announced on 12 October under which Pfizer will acquire King Pharmaceuticals for US$3.6 billion in cash, a premium of 40% over King‘s closing price on 11 October [101]. The acquisition will further broaden the Pfizer product portfolio and strengthen the pipeline as King Pharmaceuticals brings with it new and established formulations for the treatment of pain as well as the Meridian auto-injector business for emergency drug delivery. Thus, Pfizer‘s Lyrica^® and Celebrex^® will be complemented by Avinza^®, the Flector^® patch and the recently launched Embeda^®, a controlled-release anti-abuse formulation containing granules comprising morphine sulphate, an opioid-receptor agonist, surrounding an inner core of naltrexone hydrochloride, an opioid receptor antagonist [102]. King Pharmaceuticals also has an animal health business that represents a good strategic fit with Pfizer‘s existing Animal Health business unit. Execution of the agreement remains subject to regulatory approval in the USA and other jurisdictions.

Acquisition & merger

Bristol-Myers Squibb & ZymoGenetics

Bristol-Myers Squibb announced the completion of its US$885 million acquisition of ZymoGenetics on 12 October [103]. The companies have previously collaborated on pegylated interferon-λ, currently in Phase IIb of development. The acquisition will bring Recothrom^® to the expanded portfolio, a US FDA-approved topical recombinant thrombin indicated as an aid to hemostasis to control nonarterial bleeding during surgical procedures [104]. Promising pipeline candidates include a recombinant IL-21 protein for which favorable results have recently been reported in a Phase IIb clinical trial of 40 subjects with stage 4 melanoma [105], and an anti-IL-31 antibody in preclinical development for atopic dermatitis.

Licensing & collaboration agreement

ImmunoGen & Novartis

ImmunoGen, Inc. announced a collaboration agreement with Novartis on 11 October to discover and develop targeted anticancer therapeutics using antibodies to several antigen targets to be named by Novartis [106]. Under the agreement, Novartis will pay a US$45 million upfront fee to ImmunoGen for exclusive rights to use the proprietary targeted antibody payload technology. The targeted antibody payload platform provides for a tumor-targeting manufactured antibody with highly potent anticancer agents attached as a payload. For each target that results in an anticancer therapeutic, ImmunoGen is entitled to receive milestone payments potentially totaling US$200.5 million plus royalties on product sales. The company is also entitled to receive financial compensation for research and for any manufacturing done on behalf of Novartis. Novartis is responsible for the development, manufacturing and marketing of any products resulting from the agreement.

Licensing & collaboration agreement

Lundbeck & Genmab

H Lundbeck A/S announced an agreement on 13 October to create and develop human antibody therapeutics for disorders of the CNS with Genmab A/S [107]. Lundbeck will have access to Genmab‘s antibody creation and development facilities, including its fully automated preclinical antibody screening and characterization capabilities, and its proprietary stabilized IgG4 and UniBody therapeutic antibody platforms. Genmab will create novel human antibodies to a defined number of targets identified by Lundbeck, who have an option to take selected antibodies into clinical development at its own cost and subject to the payment of milestones and single digit royalties to Genmab upon successful development and commercialization. Genmab will have a similar option to take selected antibodies into clinical development for certain non-CNS indications at its own cost and subject to the payment of milestones and single digit royalties to Lundbeck. Under the terms of the agreement, Genmab will receive an upfront payment of €7.5 million with antibody development fully funded by Lundbeck. In the event all agreed milestones are achieved, the total value of the agreement to Genmab is estimated to be approximately €38 million plus single digit royalties.

Licensing & collaboration agreement

Fate Therapeutics & Becton, Dickinson & Company

On 14 October, Fate Therapeutics announced a 3 year collaboration and license agreement with Becton, Dickinson and Company (BD) for the joint development and worldwide commercialization of induced pluripotent stem cell (iPSC) tools and technologies for drug discovery and development [108]. Fate Therapeutics and BD will also endeavor to co-develop certain stem cell products using the iPSC technology platform, and BD will commercialize these stem cell products on a worldwide basis. Under the terms of the agreement, Fate Therapeutics will receive an upfront payment, research funding, commercialization milestones and royalties on the sale by BD of co-developed products. The iPSC technology provides a new way to create stem cells without relying on embryos. The iPSCs can be created from any adult somatic cell and have been shown to behave similarly to embryonic stem cells in their ability to differentiate into various cell types, including cardiomyocytes, hepatocytes, neurons and pancreatic cells [109]. Fate Therapeutics is applying iPSC technology to develop stem cell modulators, small-molecule or biologic compounds that guide cell fate for therapeutic purposes in areas such as regenerative medicine, hematological diseases, metastatic cancer, traumatic injury and degenerative diseases.

Regulatory news & approvals

Product approval

Gilenya™ (fingolimod)

Novartis gained FDA approval on 22 September for Gilenya™, the first oral treatment indicated for relapsing forms of multiple sclerosis (MS) in the USA [110].The approval was based on the largest clinical trial program ever submitted to date to the FDA for a new MS drug, and included combined data from clinical studies showing significant efficacy in reducing relapses, the risk of disability progression and the number of brain lesions detected by MRI. Gilenya is the first in a new class of drugs called sphingosine-1-phosphate receptor modulators, which are thought to work by promoting retention of lymphocytes within the lymph nodes, thereby inhibiting their ability to attack the protective myelin sheath surrounding the nerve fibers and reducing inflammatory damage [111]. Novartis is actively pursuing regulatory approval in Europe and the rest of the world.

Product approval

Vivitrol^®

On 12 October, Alkermes, Inc. announced the FDA approval of Vivitrol^® for the prevention of relapse to opioid dependence following opioid detoxification, a new indication [112]. Vivitrol is based on the proprietary Medisorb^® drug-delivery technology that enables the drug naltrexone to be gradually released into the body at a controlled rate over a period of 1 month [113].It is currently the only once-monthly, extended-release injectable medication for the treatment of alcohol and opioid dependence. Its approval was primarily based on data from a 6 month, multicenter, randomized, Phase III study that showed patients treated once a month with Vivitrol demonstrated statistically significant higher rates of opioid-free urine screens compared with patients treated with placebo (p < 0.0002).

Product withdrawal

Avandia^®

Following a review of GlaxoSmithKline‘s Avandia^® (rosiglitazone maleate), an orally administered drug for the management of Type 2 diabetes, both the FDA and EMA separately announced their individual regulatory decisions and resulting actions on 23 September [114,115]. The regulatory reviews were prompted by data that suggested an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia. In the EU, the EMA has suspended marketing authorization for all rosiglitazone-containing medications including Avandia, Avandamet^® and Avaglim^®. As a result, physicians in Europe are being advised that affected patients should be transitioned to alternative treatment options. In the USA, the use of such drugs will be significantly restricted, but will remain available with additional safety labeling. The FDA has, in addition, required a risk evaluation and mitigation strategy program to ensure the safe use of the medicine. GlaxoSmithKline has voluntarily ceased promotion of Avandia in all the countries in which it operates [116].

Clinical trials

SOM230 (pasireotide)

On the 22 September, Novartis announced positive results for a Phase III pivotal clinical study of SOM230 conducted in patients with Cushing‘s disease, a rare but life-threatening condition in which a benign pituitary tumor causes the adrenal glands to produce excess cortisol, a potent steroidal hormone, leading to severe cardiovascular and metabolic problems [117]. There are currently no approved medicines to treat Cushing‘s disease. The most common treatment approach is surgical removal of the tumor; however, persistent disease and/or relapse can occur in up to 50% of cases. Other treatment options include radiotherapy and removal of the adrenal glands. SOM230 is a pituitary-directed therapy that targets multiple subtypes of the receptor for somatostatin (sst), a hormone that controls the pituitary gland. Its highest affinity is to sst₅, a receptor subtype frequently expressed by the pituitary tumors associated with Cushing‘s disease. Currently approved sst analogs preferentially bind to sst₂ and are ineffective in treating Cushing‘s disease. SOM230 has orphan drug designation for this indication in the USA and Europe. In the present study, patients with moderate-to-severe hypercortisolism were randomized to receive SOM230 by subcutaneous injection in doses of 600 µg (n = 82) or 900 µg (n = 80) twice-daily. At 6 months, the majority of evaluable patients experienced a reduction from baseline in urinary free cortisol (UFC) levels, the main measure of biochemical control of the disease. UFC levels were normalized in 26% of patients randomized to SOM230 900 µg twice-daily, meeting the primary end point of the study. Median UFC was reduced by 48% in both the 900 and 600-µg dose groups. As UFC levels were reduced, clinical symptoms of Cushing‘s disease improved, including reduction of blood pressure, total cholesterol, weight and body mass index. The study findings show that SOM230 has the potential to directly target the underlying pituitary tumor and suppress cortisol production, thereby helping patients achieve biochemical control of their Cushing‘s disease and its associated debilitating symptoms. The trial is part of a large-scale global clinical development program to assess the efficacy and safety of SOM230 in a range of pituitary and neuroendocrine tumors [118].

Abiraterone acetate

On 11 October, Johnson & Johnson affiliate Janssen announced positive results from a prespecified interim analysis of a Phase III study in which patients with metastatic advanced prostate cancer were treated with abiraterone acetate plus low-dose prednisone/prednisolone [119]. Abiraterone acetate is a novel, targeted, oral androgen biosynthesis inhibitor for the treatment of metastatic advanced prostate cancer that has progressed after developing resistance to conventional hormonal therapies – also termed castration-resistant prostate cancer. The randomized, double-blind, multicenter, placebo-controlled Phase III study included 1195 patients previously treated with one or two chemotherapy regimens, at least one of which contained docetaxel. Treatment groups comprised abiraterone acetate (1000 mg, once-daily) plus prednisone/prednisolone (5 mg twice-daily), and placebo plus prednisone/prednisolone; the primary end point was overall survival. Treatment with abiraterone acetate resulted in a 35% reduction in the risk of death and a 36% increase in median survival (14.8 vs 10.9 months) compared with placebo. Significant improvements in secondary study end points versus the placebo group were observed, including time to prostate-specific antigen progression, and an increase in radiographic progression-free survival. Total prostate-specific antigen response (≥50% decrease from baseline) was achieved in 38% of patients treated with abiraterone acetate versus 10% in the placebo group. The results of the study show that abiraterone acetate may extend survival for men with metastatic advanced prostate cancer that progressed after treatment with docetaxel. Based on the results of this Phase III study, the company plans to file marketing applications for abiraterone acetate with regulatory authorities worldwide.

Briakinumab (ABT-874)

The results from four separate pivotal clinical studies on Abbott‘s investigational IL-12/23 inhibitor (ABT-874) were presented at the 19th Congress of the European Academy of Dermatology and Venereology held on 6–10 October in Gothenburg, Sweden [120]. A greater percentage of moderate-to-severe chronic plaque psoriasis patients treated with briakinumab achieved 75% or better skin clearance rates than those treated with etanercept (Enbrel^®), methotrexate or placebo. Briakinumab is a human monoclonal antibody that targets IL-12/23 proteins linked to inflammation, and is the second medication in the IL-12/23 class to have completed Phase III trials for the treatment of plaque psoriasis. The most commonly prescribed biologics used to treat moderate-to-severe chronic plaque psoriasis target a protein called tumor necrosis factor. In the largest of the four Abbott clinical trials (M06–890), a 52-week study comparing briakinumab (n = 981) to placebo (n = 484), significantly more patients experienced skin clearance versus patients with placebo. At week 12, skin clearance of 75% in the psoriasis area and severity index (PASI 75) was achieved in 80.7% of patients receiving briakinumab every 4 weeks versus 4.5% with placebo. Skin clearance of 90% (PASI 90) was achieved in 61.6% on briakinumab versus 1.4% on placebo; 100% skin clearance (PASI 100) was achieved in 32.2% of briakinumab patients versus none in the placebo group. Of the 290 briakinumab patients that achieved PASI 75 and a physician‘s global assessment (PGA) of clear or normal at week 12, 82.4% maintained PASI 75 at week 52, versus 9.0% of the 144 patients on placebo. Of the 243 briakinumab patients that achieved PASI 90 and a PGA of clear or normal at week 12, 81.5% maintained PASI 90 at week 52, versus 9.2% of the 109 placebo patients. Of the 298 briakinumab patients who achieved a PGA of clear or normal at week 12, 63.4% of patients demonstrated PASI 100 at week 52, versus 4.0% of the 149 placebo patients.

Probuphine™

On 12 October, Titan Pharmaceuticals, Inc. announced the peer-reviewed publication of its Phase III randomized, placebo-controlled clinical trial of Probuphine in the 13 October issue of Journal of the American Medical Association[1,121]. Probuphine is a subcutaneous implant based on Titan‘s proprietary ProNeura™ technology, in which continuous controlled delivery of buprenorphine is achieved by diffusion from a small, solid rod comprising a mixture of ethylene-vinyl acetate and active. Implant placement and removal is straightforward and therapeutic buprenorphine levels are maintained over 6 months following a single treatment. Buprenorphine is a semi-synthetic opioid originally developed for analgesia, but has more recently been used in higher doses as a sublingual tablet in the treatment of opioid addiction. Buprenorphine delivery via a controlled-release formulation therefore provides a useful mechanism for controlling the potential abuse associated with conventional sublingual delivery. The article describes the 163-subject trial, and reported that the mean percentage of urine samples testing negative for illicit opioids across the full 24 weeks was 36.6% for the probuphine group versus 22.4% in the placebo group (p = 0.01). Almost 66% of patients receiving probuphine completed the study compared with 31% who received placebo implants (p < 0.001), and probuphine patients experienced fewer clinician-rated (p < 0.001) and patient-rated (p = 0.004) withdrawal symptoms. Titan is currently conducting a confirmatory Phase III clinical trial of probuphine for the treatment of opioid addiction with results expected in the second quarter of 2011.

Intellectual property

Essentialis, Inc.

Essentialis, Inc. announced on 11 October that the US Patent and Trademark Office has issued US Patent No. 7799777 entitled “Salts of potassium ATP channel openers and uses thereof” [122]. The patent claims a novel composition of a polymorph of diazoxide choline, the active ingredient in the Essentialis lead product diazoxide choline controlled-release tablet (DCCR), a new class of dyslipidemia treatment with a mechanism of action distinct from other dyslipidemia treatments. DCCR, a crystalline patent-protected salt of diazoxide in a controlled-release once-per-day tablet, reduces the production of triglyceride-rich lipoprotein particles before they can accumulate and contribute to the progression of pancreatitis and cardiovascular disease. Currently available dsylipidemia treatments work primarily by increasing clearance of triglycerides from the blood stream. Essentialis has successfully completed Phase IIb clinical trials with DCCR, showing a highly significant triglyceride reduction in dyslipidemic patients. Aaron Berg, Chief Commercial Officer of Essentialis commented, “The granting of this patent, combined with our previously issued patents, provides Essentialis with broad patent protection on our drug active, pharmaceutical formulations, methods of use and methods of manufacturing DCCR, which currently extends to 2028”. Essentialis is pursuing a 505(b)(2) registration process for DCCR.

Syndax Pharmaceuticals, Inc.

On 15 October, Syndax Pharmaceuticals, a clinical-stage epigenetics oncology company, announced taht the UK Intellectual Property Office has allowed application GB0907347.9 entitled ‘N-(2-aminophenyl)-4-[N-(pyridine-3-yl)-methoxycarbonyl-aminomethyl]-benzamide (MS-275) polymorph B‘ [123]. The patent covers the polymorph representing a preferred stable form of entinostat (SNDX-275 formerly MS-275) with key claims covering the polymorph form B and the manufacturing process by which it is derived. Entinostat is an orally bioavailable, highly selective, class I histone deacetylase inhibitor with a long half-life that allows for weekly or fortnightly dosing. Entinostat is currently being investigated in multiple Phase II clinical studies: in advanced breast cancer in combination with aromatase inhibitors; in combination with erlotinib in metastatic lung cancer and as a single agent in Hodgkin‘s lymphoma. This represents the first issuance for the patent application, which has been filed as a Patent Cooperation Treaty application providing a platform for additional filings worldwide including Japan, China, India, South Africa and Brazil. The patent application has also been filed in the USA, Europe, Argentina, Venezuela, Taiwan, Kuwait and Saudi Arabia. Joanna Horobin, President and CEO of Syndax commented: “Because this important patent covers the composition of the crystalline form and the manufacturing process, it provides potential for market exclusivity in all our target indications including metastatic breast and lung cancer”. Syndax holds 36 issued patents and pending patent applications related to the composition of matter, manufacturing and use of entinostat and histone deacetylase inhibitors in combination with other drugs. Syndax Pharmaceuticals holds rights to Entinostat from Bayer Schering Pharma.

Financial & competing interests disclosure

Gareth Rees is employed by Genesis Oral Bioscience. In his current role the author has received compensation from GSK as a consultant and scientific writer. Gareth Rees is a named inventor on four patents assigned to GSK, and owns shares in the company. 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.