Forest Laboratories is a U.S.-based pharmaceutical company with a mission statement of “identifying, developing, and delivering products that make a difference in people’s lives,” with an underlying foundation of innovation, integrity, and commitment. Specific strategies include licensing novel drug candidates at every stage of development from companies worldwide and performing rigorous scientific R&D of drugs with the potential for a unique niche in healthcare. Forest Research Institute (FRI) is the scientific subsidiary of Forest Laboratories, developing products and offering medical and scientific support for currently marketed products.

Over the past 10 years, Forest has continued to increase its investment in R&D, enhancing its ability to license innovative new products in a wider range of therapeutic fields and earlier in the development cycle. Initial areas of concentration for Forest have been the central nervous and cardiovascular systems, with currently available products including Bystolic (nebivolol), Daliresp (roflumilast), Lexapro (escitalopram oxalate), Namenda (memantine HCl), Savella (milnacipran HCl), Teflaro (ceftaroline fosamil) for injection and Viibryd (vilazodone HCl).

The current pipeline contains two phase III drugs and one phase II drug in the Psychiatry/Psychology field, two phase III drugs in Cardiovascular, one phase III drug and one phase II drug in Pulmonary/Respiratory, two phase II drugs in Immunology/Infectious disease, one phase II drug in Neurology, and one phase I drug in Endocrinology.

In the Psychiatry/Psychology arena, cariprazine is an orally active, potent dopamine D3-preferring D2/D3 receptor antagonist in phase III trials for schizophrenia and bipolar mania, and in phase II trials for schizophrenia and depression. Gedeon Richter and Mitsubishi Tanabe Pharma are collaborating with Forest on development. A potential advantage of this drug is its low potency at receptor sites associated with adverse events, including 5-HT2C, histamine H1, muscarinic and adrenergic receptor sites.

In collaboration with Pierre Fabre, Forest is in phase III development of levomilnacipran (1S, 2R-milnacipran F2695,) a selective norepinephrine and serotonin reuptake inhibitor intended to treat adults with major depressive disorder (MDD). In vitro, this enantiomer of racemic milnacipran has been shown to have greater potency for norepinephrine reuptake inhibition than for serotonin reuptake inhibition, while it does not directly affect the uptake of dopamine or other neurotransmitters. The sustained-release formulation of levomilnacipran allows once-daily dosing. Forest and its collaborating companies plan to submit a new drug application (NDA) to the FDA in the third quarter.

The Cardiovascular pipeline includes azimilide, originally developed by Procter & Gamble Pharmaceuticals and now in phase III testing as a class III antiarrhythmic agent. The FDA has reviewed this drug for patients who have an implantable cardioverter defibrillator and a history of life-threatening ventricular arrhythmias, as there is currently no approved treatment for this group.

Apadenoson, in phase III trials for coronary artery disease, is a highly selective adenosine A2a receptor agonist and coronary vasodilator used for pharmacologic stress myocardial perfusion imaging. When given intravenously, it has been shown to cause rapid and dramatic increase in coronary blood flow velocity, lasting several minutes. The response is similar to that associated with intravenous adenosine, but without significant harmful hemodynamic effects.

In the Pulmonary/Respiratory field, aclidinium bromide (a long-acting, inhaled muscarinic antagonist) plus formoterol is in phase III development with Almirall for maintenance treatment of chronic obstructive pulmonary disease (COPD). Aclidinium has a long residence time at M3 muscarinic receptors and a shorter residence time at M2 receptors. Its mechanism of action is to inhibit smooth muscle contraction in the airways, resulting in bronchodilation when inhaled.

In clinical trials, aclidinium bromide was administered using an investigational multi-dose dry powder inhaler (GENUAIR inhaler) with a feedback system to confirm that the patient has inhaled correctly. It contains multiple doses of aclidinium and is equipped with a visible dose-level indicator. Other safety features include an anti-double-dosing mechanism and an end-of-dose lock-out system to prevent use of an empty inhaler.

In February 2012, the Pulmonary-Allergy Drugs Advisory Committee (PADAC) of the FDA endorsed the efficacy and safety of twice-daily aclidinium bromide 400μg, based on nine clinical trials enrolling a total of 2,717 patients with COPD. Aclidinium was associated with significant improvement in lung function and a good safety and tolerability profile, with the incidence of side effects comparable to that seen with placebo. FDA ruling on the NDA is anticipated by July.

Also intended for COPD is LAS 100977, an inhaled, once-daily, long-acting beta-2 agonist in phase II co-development with Almirall, which first developed LAS 100977 to treat bronchoconstriction in patients with asthma. The two are now developing LAS100977 in combination with an undisclosed corticosteroid using Almirall’s proprietary GENUAIR inhaler to treat COPD as well as asthma.

The Immunology/Infectious disease pipeline includes ceftazidime plus avibactam, in phase II development with AstraZeneca for abdominal infections and urinary tract infections. This combination antibiotic includes a broad-spectrum cephalosporin and avibactam, a novel investigational non-beta-lactam beta-lactamase inhibitor. Although avibactam alone has no antibacterial activity, inhibition of beta-lactamase enzymes may help to prevent development of bacterial resistance to other antibiotics.

AstraZeneca and Forest are planning phase III efficacy and tolerability trials of ceftazidime/avibactam in patients hospitalized with serious, complicated intra-abdominal infections and complicated urinary tract infections caused by Gramnegative bacteria. Global regulatory filings are anticipated for 2014.

Ceftaroline plus avibactam, a cephalosporin antibiotic plus a beta-lactamase inhibitor, is in phase II trials for bacterial infections of the skin and urinary tract. Cerexa, a wholly owned subsidiary of Forest, is developing ceftaroline plus avibactam with AstraZeneca. Ceftaroline plus avibactam, a cephalosporin antibiotic plus a beta-lactamase inhibitor, is in phase II trials for bacterial infections of the skin and urinary tract. Cerexa, a wholly owned subsidiary of Forest, is developing ceftaroline plus avibactam with AstraZeneca.

Forest’s candidate in Neurology is GRT 6005/06, licensed from Gruenenthal and now in phase II trials for moderate to severe chronic pain associated with diabetic neuropathy and osteoarthritis, as well as for post-operative pain. This novel, orally active small molecule analgesic has potent agonist activity at the opioid receptor like-1 (ORL-1) and the mu opioid receptor. The Endocrinology pipeline consists of GK1-399, a selective and orally available glucokinase activator in phase I testing for diabetes, being developed under a licensing agreement with TransTech Pharma.

Millennium is a biopharmaceutical genomics company focused exclusively on oncology. Its stated mission is “to deliver extraordinary medicines to patients with cancer worldwide through our science, innovation and passion.” Since its establishment in 1993, Millennium has discovered and developed novel treatments applying world-class recombinant technology to a wide variety of oncology disease targets. Parent company Takeda, established in 1781 and Japan’s largest pharmaceutical company.

Millennium’s largest commercial success to date has been Velcade (bortezomib), developed through Nobel Prize-winning protein homeostasis science and now approved in more than 87 countries for multiple myeloma and relapsed mantle cell lymphoma.

Millennium has formed more than 20 strategic alliances involving in- and out-licensing, collaborative research networks, co-development and global co-promotion agreements. These partnerships have centered mostly on clinical stage first-in-class or best-in-class molecules, particularly those targeting protein homeostasis, a field in which Millennium is acknowledged to be the scientific leader.

The Millennium pipeline includes two drugs in phase III and two in phase II for lymphoma; two in phase II for hematologic malignancies; one in phase III and one in phase II for prostate cancer; one in phase III for head and neck cancer; one in phase III for lung cancer; and one in phase III for ovarian cancer.

Velcade, now in phase III trials for mantle cell lymphoma and phase II trials for diffuse large B-cell lymphoma, is a highly selective injectable proteasome inhibitor co-developed with Janssen Pharmaceutical. Although initially approved for intravenous injection, the FDA recently approved subcutaneous administration for multiple myeloma and mantle cell lymphoma after at least one previous therapy.

Inadvertent intrathecal administration of Velcade may be fatal, so the updated label notes that this route of administration is contra-indicated .For post-transplant Hodgkin lymphoma, Millennium and Seattle Genetics are co-developing SGN-35 (Adcetris; brentuximab vedotin). Development is in phase II for Hodgkin lymphoma and for anaplastic large cell lymphoma. SGN-35 is an antiCD-30 monoclonal antibody-drug conjugate (ADC) in which the antibody is attached by a proteasecleavable linker to monomethyl auristatin E (MMAE), a microtubule disrupting agent.

In August 2011, the FDA granted accelerated approval to SGN-35 for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two previous multi-agent chemotherapy regimens in patients who are not ASCT candidates, as well as for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) who have failed one or more previous multi-agent chemotherapy regimens.

These indications are based on response rate, because data thus far have not shown improvement in patient-reported outcomes or survival. SGN-35 has not been approved as front-line therapy, nor has it been approved for use outside the U.S. However, the EMA began reviewing a marketing authorization application for SGN-35 in relapsed or refractory Hodgkin lymphoma and systemic ALCL in June 2011.

For hematologic malignancies and solid tumors, Millennium is in phase II testing of MLN8237 (alisertib), an orally active, selective, small molecule inhibitor of the serine/threonine protein kinase Aurora A. This kinase is over-expressed in a range of cancers and plays an essential role in cell division.

Also in phase II development for hematologic malignancies is the orally or intravenously administered proteasome inhibitor MLN9708 (ixazomib citrate). Phase I and phase I/II studies have assessed the safety, tolerability and dosing of oral MLN9708 given once or twice weekly as monotherapy, or part of a combination regimen, in patients with relapsed and/or refractory or previously untreated multiple myeloma.

Orteronel (TAK-700) is in phase III trials for chemotherapy-naïve and post-docetaxel patients with metastatic, castration-resistant prostate cancer, and in phase II testing for patients with non-metastatic prostate cancer. This orally administered drug is a selective, non-steroidal androgen synthesis inhibitor of the 17,20 lyase.

Vectibix (panitumumab), in phase III development only in Japan for head and neck cancer, is a fully humanized monoclonal antibody targeting the human epidermal growth factor receptor (EGFR). It is licensed from Amgen. Current indications are for treatment of patients with EGFR-expressing metastatic colorectal carcinoma (mCRC) with disease progression on or following treatment with chemotherapy regimens containing fluoropyrimidine, oxaliplatin and irinotecan.

Also in collaboration with Amgen, Millennium is in phase III trials with AMG 706 (motesanib), a small molecule angiogenesis inhibitor intended for patients with nonsquamous non-small cell lung cancer. Another angiogenesis inhibitor licensed from Amgen and in phase III trials in Japan only is AMG 386, intended for advanced recurrent ovarian cancer. This combination of a peptide and an antibody blocks angiogenesis by inhibiting angiopoietin-1 and -2, which interact with the Tie2 receptor controlling vascular remodeling.

Through its acquisition by Takeda and ongoing strategic partnerships, Millennium is well poised to continue to develop best-in-class and first-in-class antineoplastic agents, particularly those targeting protein homeostasis.

Lundbeck aims to become a world leader in psychiatry and neurology, and improve the quality of life of people suffering from disorders in these areas, by developing and providing innovative specialty therapies. Its web site describes its core values as imagination, passion and responsibility.

The company’s focused expertise, global resources, extensive academic and institutional research network, and reputation for effective partnering, make it a logical choice for other companies seeking mutually beneficial partnerships to advance clinical-stage and commercial pharmaceutical products.

Diseases targeted by Lundbeck include psychiatric conditions of depression and anxiety, psychosis, bipolar disorder, Alzheimer’s disease and alcohol dependence. In addition, Lundbeck is involved in developing treatments for neurological diseases including Parkinson’s disease, Huntington’s disease, epilepsy, stroke and Lennox-Gastaut syndrome.

Its state-of-the-art technologies focus on mechanisms of synaptic transmission, neurodegeneration and neuroinflammation. Corporate development for this medium-sized pharmaceutical company is based in Copenhagen, with offices worldwide. Multidisciplinary research teams in Denmark and in the United States integrate their advanced knowledge in R&D disciplines with clinical and therapeutic expertise.

Lundbeck’s Psychiatry/Psychology pipeline contains four drugs in phase III, one in phase II/III and three in phase II. In Neurology, Lundbeck has two drugs in phase III development.A once-monthly, depot injectable formulation of aripiprazole, a dopamine D2 partial agonist for maintenance treatment of schizophrenia, was co-developed with Otsuka Pharmaceuticals.

In November 2011, the FDA accepted the New Drug Application (NDA) for aripiprazole depot formulation for maintenance treatment of adults with schizophrenia. Also in phase III testing for schizophrenia is zicronapine (previously known as Lu 31-130), a monoaminergic agent that preferentially acts at the dopamine D4 receptors, with potent antagonistic effects at dopamine D(1), D(2) and 5-HT(2a) receptors.

For schizophrenia and adjunctive treatment of major depressive disorder (MDD), Lundbeck and Otsuka Pharmaceuticals are in phase III development of OPC-34712, a novel psychotherapeutic agent intended to offer improved efficacy and tolerability with less akathisia, restlessness and/or insomnia than currently available agents. It affects multiple monoamine systems and has reduced partial agonist activity at D2 dopamine receptors and enhanced affinity for specific serotonin receptors.

Also in phase III trials for depression and anxiety is Lu AA21004, a multimodal antidepressant with reuptake inhibition and receptor activity as a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter.

Nalmefene (Selincro), a specific opioid receptor antagonist with a distinct mu, delta and kappa profile, is in phase II/III testing for pathological gambling and in phase II testing for smoking cessation. It has been evaluated for the past two decades as a potential treatment for substance use disorders, and it has been shown to help regulate alcohol intake through its activity at the cortical mesolimbic circuit. Treatment, therefore, can be individualized to limit alcohol consumption rather than requiring full abstinence.

For treatment of depression, Lundbeck is partnering with Takeda on phase II testing of Lu AA24530, a monoamine enhancer with reuptake inhibition at monoamine transporters and antagonist activity at 5-HT3 and 5-HT2c. For Alzheimer’s disease, Lundbeck is in phase II testing of Lu AE58054, a potent and selective antagonist of the 5-HT6 receptor, which is mostly located in brain regions implicated in cognition. A long-term, multicenter, placebo-controlled trial of Lu AE58054 as add-on therapy to donepezil is underway in patients with moderate Alzheimer’s disease.

In the Neurology arena, intravenous carbamazepine is in phase III development for epilepsy. This sodium channel blocker is a novel injectable formulation of the oral antiepileptic drug, which has been in widespread use for nearly four decades for treatment of complex partial seizures. The intravenous formulation would be useful for patients who temporarily could not take carbamazepine by mouth because of surgery or for other reasons.

Also in phase III trials is desmoteplase, a novel plasminogen activator and highly fibrin-specific thrombolytic agent, licensed from Paion for treatment of acute ischemic stroke. When compared with alteplase, currently used to dissolve thrombosis in acute ischemic stroke, desmoteplase has high fibrin selectivity, no neurotoxicity, no apparent harm to the blood-brain barrier and a longer half-life (about four hours compared with about five minutes). The FDA has issued Fast Track designation to desmoteplase, a genetically engineered version of a thrombolytic protein found in the saliva of the vampire bat.

Lundbeck’s long track record of success in the Psychiatry and Neurology fields should continue to apply to the drugs in its pipeline, which primarily target highly prevalent conditions including depression, Alzheimer’s disease, epilepsy and stroke. In the Psychiatry arena, most of Lundbeck’s candidates involve neurotransmitter manipulation through receptor agonists or antagonists. In Neurology as well as in Psychiatry, some candidates are novel formulations of drugs with a long history of widespread use.