the ones to watch, jan. - mar. 2010 -- pharma matters report

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Expert review from Thomson Reuters of the most promising drugs changing clinical phase, receiving approval and launched this quarter, based on the strategic data and insight of Thomson Pharma®, the world’s leading pharmaceutical competitive intelligence solution.

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THE ONES TO WATCHA PHARMA MATTERS REPORT.JAnUARY-MARCH 2010

PHARMA MATTERS | THE OnES TO WATCH

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As the dust settles after the passing of the new healthcare bill in the United States, the consensus seems to be that the pharmaceutical industry has emerged relatively unscathed. For example, legislation allowing Medicare to negotiate with the pharmaceutical industry on the price of drugs was eliminated, protecting future revenues, and the estimated additional 32 million Americans receiving insurance over the next decade should boost drug sales significantly. Policy analysts are suggesting drug industry revenues could increase by US$30 billion in that time.

Similarly, producers of biologic drugs will be relieved that biologics will have patent exclusivity for 12 years – rather than the 5-7 that generics companies were lobbying for. Biologic drugs represent only a small portion of industry sales, but they are a fast-growing area and the new legislation could inject optimism – vital in a field that requires much larger R&D investment than other types of drugs.

But the drug industry will pay out US$85 billion in new fees, rebates and discounts under the new legislation, which could mean a rocky road for drug development in the short term if companies tighten belts and wait for the promised revenue growth.

Will the industry optimistically pour money into drug development in the hope of capturing this new market or divert funds into ensuring it can survive in this new environment? Only time will tell. But this quarter’s The Ones to Watch sees a diverse range of products moving through the pipeline.

Many could make drug administration easier for patients. Merck & Co’s Elonva® will slash the number of injections required by women undergoing follicle stimulation for assisted reproduction, while Zelos Therapeutics’ ZT-034, entering phase I trials this quarter, could potentially make nasal treatment for osteoporosis a reality.

Small patient populations and those who suffer from serious diseases with few treatment options are also set to benefit. BioMarin is hoping that its BMN-195 candidate, also beginning phase I trials, will be the first treatment to reach the market specifically for Duchenne muscular dystrophy, while the same company’s Zenas® has been launched for the rare Lambert-Eaton myasthenic syndrome.

Let’s take a closer look at the five most promising drugs launched or receiving approval, and moving through each of the clinical phases, between January and March 2010.



THE FIvE MOST PROMISIng dRUgS lAUnCHEd OR RECEIvIng APPROvAl

dRUg dISEASE COMPAnY

Resolor® Constipation Movetis

Ampyra™ Multiple sclerosis Acorda

Elonva® Assisted reproduction

Merck & Co

Zenas® Lambert-Eaton myasthenic syndrome

BioMarin

Menveo® Meningitis Novartis Vaccines & Diagnostics

First in this edition of The Ones to Watch we have an oral treatment that could benefit women suffering from chronic constipation. Women make up the majority of the estimated 35-50% of the patient population who have constipation associated with impaired gut motility and do not respond to dietary and lifestyle changes in combination with laxatives.

Resolor™ (prucalopride) was launched in Germany in January 2010 and in the UK in March 2010 after European approval in October 2009. Developed by Movetis, under license from Janssen (a subsidiary of Johnson & Johnson), Resolor offers a new treatment option for these women. Resolor is the first in a new class of selective, high-affinity agonists for serotonin 5-HT4 receptors, which trigger peristalsis, and is also under investigation for the treatment of chronic constipation in men and children, and for opioid-induced constipation.

Next up is Ampyra™ (dalfampridine), the first ever oral therapy available to improve walking ability in multiple sclerosis (MS) patients. Ampyra™, a tablet formulation of fampridine, the potassium channel blocker, is the only drug to have been shown in phase III trials to improve walking ability – demonstrated by an increase in walking speed – in MS patients, most of whom experience a decline in their mobility as their disease progresses.

Developed by Acorda, under license from Elan, Ampyra™ was launched in the United States in March 2010. Crucially, Ampyra™ can be taken by patients with acute and chronic MS and alongside other drugs, including disease-modifying agents.

Rather than reducing the inflammation that damages the central nervous system, as other MS treatments do, Ampyra™, which is an extended-release formulation of fampridine, was found in preclinical studies to increase signal transmission in the nerves with damaged myelin sheaths that characterize MS. Thomson Pharma forecasts sales of US$411.5 million in 2013 and analysts at Merriman Curhan Ford & Co expect sales to rise to US$1 billion by 2015 or 2016.


Turning to assisted reproduction, a new drug from Merck & Co, gained from its November 2009 acqusition of Schering-Plough, could reduce the number of injections received by women undergoing fertility treatment. Elonva® (corifollitropin alfa) is the first drug to sustain multiple follicular stimulation in the ovaries for a whole week, potentially doing away with the need for the first seven daily injections of recombinant follicle stimulating hormone (FSH) given to women during a controlled ovarian stimulation cycle. The subcutaneous injection, an agonist of FSH, is used in combination with a gonadotropin-releasing hormone (GnRH) antagonist.

Elonva® was approved in the EU in January 2010 after a set of phase III trials, including the ENGAGE trial of over 1,500 women in which the Elonva® regimen resulted in a similar amount of pregnancies as the standard follicle-stimulating treatment.

Returning to potassium channel blockers, BioMarin Pharmaceutical announced in January 2010 the approval of the oral treatment Zenas® (amifampridine phosphate) for Lambert-Eaton myasthenic syndrome (LEMS). As this issue of The Ones to Watch was going to press, this drug was launched in the UK and Germany. Developed by the pharmaceutical unit (AGEPS) of the Paris Public Hospital Authority, Zenas® is the first approved treatment for LEMS so has Orphan drug protection and a decade of marketing exclusivity in Europe, and Orphan drug designation in the United States.

LEMS is a rare autoimmune disease in which auto-antibodies reduce the amount of acetylcholine released by nerve endings, resulting in muscle weakness, particularly in the legs and trunk. About 4-10 people per million have LEMS. Most treatment options focus on treating small-cell lung cancer, which half of LEMS patients also have, but treatment options are limited for this type of cancer. While immunosuppressive drugs to treat LEMS itself have been tested, issues with toxicity, and the difficulty of administering the necessary regimens, has limited their use.

Amifampridine phosphate has been central to treating LEMS, but as an unapproved drug was available only on a compassionate basis. The approval of Zenas® will open up this treatment option to many more patients. BioMarin is also investigating Zenas® for the potential treatment of MS.

We finish our review of newly approved or launched drugs with Menveo®, a quadrivalent meningitis vaccine approved by the FDA in February 2010 and in Europe in March 2010. Developed by Novartis Vaccines & Diagnostics, following the merger of Novartis and Chiron, it is the first quadrivalent vaccine against Neisseria meningitidis to be approved in Europe.


Menveo® targets the A, C, Y and W-135 serogroups of N. meningitidis and has been approved for the treatment of people 11-55 years of age after success in a non-inferiority phase III trial comparing it with an existing commercially available quadrivalent vaccine.

The vaccine targets four of the five major bacterial groups that cause meningococcal diseases and can lead to bacterial meningitis and sepsis. This ability to target four subgroups is important because the dominant forms of N. meningitidis in a region can change over time and people travelling to new regions may encounter new varieties of subgroups – meaning protection from as many subcategories as possible is highly desirable.

Meningococcal disease progresses rapidly and patients can die within 24-48 hours of the first symptoms. Up to one fifth of survivors suffer life-long complications such as brain damage, learning disabilities, hearing loss and limb loss.

The vaccine is being investigated for use in infants and toddlers, another group at serious risk from bacterial meningitis.

THE FIvE MOST PROMISIng dRUgS EnTERIng PHASE III TRIAlS


custirsen Solid tumors OncoGenex Pharmaceuticals/Teva Pharmaceutical Industries

otamixaban Thrombosis/cardiovascular events

sanofi-aventis

aleglitazar Type 2 diabetes Roche

ethynylestradiol and Nestorone® vaginal ring

Contraception Population Council

Seprehvir Glioblastoma multiforme

Crusade Laboratories

We kick off our roundup of promising drugs entering phase III trials with custirsen (OGX-011), an intravenous infusion formulation of an antisense oligonucleotide that inibits clusterin, a protein overproduced by cancer cells.

In January 2010 licensee Teva Pharmaceutical Industries, which is developing the drug along with OncoGenex Pharmaceuticals, announced that custirsen was in phase III trials for solid tumors. Phase III studies of the drug for first- and second-line therapy of castration-resistant prostate cancer are due to begin later in 2010, and a phase III trial as a first-line therapy for advanced, unresectable non-small cell lung cancer is planned for early 2011.


Encouraging phase II trials saw patients given custirsen in combination with docetaxel and prednisone experience better survival rates, less pain and a reduction in prostate-specific antigen compared with those on docetaxel and prednisone alone.

Clusterin has been shown in preclinical testing to enhance cancer cell survival and is linked with faster disease progression and treatment resistance in patients. The protein is also produced in response to a range of cancer therapies, including hormone ablation therapy, chemotherapy and radiation therapy, and increased clusterin levels have been observed in a range of cancers, including prostate, non-small cell lung, breast, ovarian, bladder, renal, pancreatic and colon cancers, anaplastic large cell lymphoma, and melanoma. This suggests custirsen has the potential to treat many different cancers, including those that are treatment-resistant.

Second in the group entering phase III trials is otamixaban from sanofi-aventis, a potential intravenous treatment for thrombosis and the prevention of cardiovascular events. Otamixaban is an antagonist of Factor Xa, preventing the formation of thrombin which is key to the formation of blood clots.

Phase I/II trials in healthy patients and those with coronary artery disease showed otamixaban to be fast-acting – being rapidly distributed throughout the blood plasma – and with a shorter half-life, at just 30 minutes, than other synthetic Factor Xa inhibitors. It entered phase III trials for acute coronary syndrome, an umbrella term for signs and symptoms associated with heart attack, in February 2010. Such patients represent an unmet clinical need as almost one in ten die or suffer a second myocardial infarction in the week after an initial cardiovascular event.

Cardiovascular complications are also the largest cause of death in type 2 diabetes patients. Roche is hoping that aleglitazar, for which enrollment for a phase III trial began in March 2010, will reduce the impact of cardiovascular events such as myocardial infarction and stroke in type 2 diabetes patients with recent acute coronary syndrome.

Aleglitazar is an oral dual PPAR alpha and gamma agonist, designed to balance PPAR alpha/gamma activation. More specificially, PPAR gamma activation should result in increased peripheral insulin sensitivity – therefore improving glucose control – and PPAR alpha activation is associated with control of blood lipids. The phase II SYNCHRONY trial showed this to be the case, along with good safety and tolerability in type 2 diabetes patients. While type 2 diabetics are encouraged to reduce their risk of high glucose and lipid levels, many fail to, leaving them vulnerable to cardiovascular events.


The Population Council, along with North American marketing partner Watson Pharmaceuticals, is developing a hormone-releasing vaginal ring that could provide women with a unique long-term, user-controlled method of contraception. The device entered phase III trials in March 2010.

The one-year ring formulation releases Nestorone®, a novel syntheic progestin, and the estrogen ethynylestradiol to inhibit ovulation and maintain menstrual bleeding. It is designed to simultaneously release both hormones for 13 cycles (one year), with three continuous weeks in the vagina and one week ring-free. Women should be able to insert and remove the ring themselves, without the need for help from a healthcare professional. Another advantage is that the overall exposure to hormones is lower than the dose delivered by the daily self-administration of a pill, for example.

Crusade Laboratories is exploiting the ability of the cold sore virus, herpes simplex (HSV), to target the brain and cause encephalitis by using an oncolytic gene-deleted variant to kill brain tumor cells. Phase III trials of Seprehvir (HSV-1716) were underway by March 2010 in patients with glioblastoma multiforme, for which there is no treatment.

A single gene called ICP34.5, which is responsible for virus replication and virulence, has been removed from HSV type 1, rendering it lethal only to replicating tumor cells, which it enters and replicates in until it causes cell lysis. The therapy which has shown no toxicity in early trials is also being investigated for head and neck cancers, and melanoma.

THE FIvE MOST PROMISIng dRUgS EnTERIng PHASE II TRIAlS


ACU-4429 Dry age-related macular degeneration

Acucela/Otsuka

CK-2017357 Amyotrophic lateral sclerosis

Cytokinetics

ErepoXen® Anemia Lipoxen/Serum Institute of India

CMX-2043 Reperfusion injury Ischemix

VB-201 Psoriasis VBL

The first of our agents beginning phase II trials mentioned in this edition is a treatment for dry age-related macular degeneration (dry AMD) from Acucela and licensee, Otsuka Pharmaceutical.

Dry AMD accounts for 90% of AMD cases – around 26 million worldwide – and is a leading cause of sight loss in the over 50s, yet has no approved treatment. As light is converted into electrical signals in the retina as part of the normal visual cycle of the eye, toxic by-products build up over time, gradually


breaking down cells in the center of the retina (the macula), affecting visual acuity and color vision. Cases of the disease are expected to double worldwide in the next 20 years as the population ages.

The ENVISION phase II trial began in January 2010 of an oral formulation of ACU-4429, a non-retinoid visual cycle modulator. By slowing the eye’s processing of light, ACU-4429 should decrease the build up of by-products and if given in the early stages of the disease, stop it progressing to blindness. The drug, which is easier to administer due to its oral formulation than laser surgery, photodynamic therapy and injections that are the mainstay of early wet AMD treatment, was developed using Acucela’s proprietery visual cycle modulation (VCM) technology. It received Fast Track status from the FDA in March 2010.

Next up is a potential treatment of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease associated with muscle wasting. ALS sufferers rarely survive more than 3-5 years, and death is usually caused by weakness in the skeletal muscles associated with breathing. Few treatment options exist. Cytokinetics is developing CK-2017357, the lead from a series of small-molecule, troponin complex activators that increase muscle cell sensitivity to calcium and increase skeletal muscle contractility.

Phase I trials showed that CK-2017357 was well-tolerated and dose-dependently increased strength in the tibialis anterior muscle. A phase II trial began in March 2010.

Patients with renal failure often experience anemia as the kidneys no longer produce enough erythropoietin (EPO), the hormone responsible for maintaining red blood cell production. Patients are treated with one to three injections of erythropoietin per week to prevent anemia. Lipoxen is hoping that its injectable ErepoXen® (polysialic erythropoietin) formulation of EPO can improve patient experience by reducing the frequency of doses to just once a month. Phase II trials of ErepoXen® began with partner Serum Institute of India under European regulations in March 2010.

The EPO in ErepoXen® is a polysialylated form. Polysialic acid (PSA) is a biodegradable polymer of sialic acid which is found naturally in the human body, suggesting that ErepoXen® may prove to be less immunogenic and toxic that standard EPO. In phase I trials, it caused a sustained rise in hemoglobin levels for 28 days after dosing.

Reperfusion injury, caused by damaging inflammation to tissues upon re-entry of blood after ischemia during surgery, is a common side effect for which there is no prevention. Ischemix is hoping that its candidate CMX-2043, which began phase II trials in March 2010, could meet some of this clinical need. CMX-2043 has two pharmacophores and works by both reducing calcium entry to the ischemic tissue and preventing oxidative stress. It


acts through the PI3 kinase pathway to activate Akt.

Preclinical tests in rodents showed reductions in reperfusion arrhythmia and other markers of reperfusion injury in CMX-2043-treated animals.

Moving on to auto-inflammatory diseases, VBL Therapeutics is developing VB-201 (CI-201), a small-molecule oxidized phospholipid for the oral treatment of a range of inflammatory diseases. A phase II trial for mild to moderate psoriasis, along with a sub-group of atherosclerosis patients, began in January 2010. VB-201 is the first in a new class of drugs and is believed to act by inhibiting the production of the pro-inflammatory cytokines IL-12/23p40 by dendritic cells and macrophages, counterbalancing pro-inflammatory immune system activity without affecting system-wide immune factors.

Psoriasis is a chronic, immune-mediated disease for which there is no treatment. Current therapies focus on minimizing the symptoms of the disease, which include raised, dry skin lesions. A significant number of psoriasis patients also have atherosclerosis caused by chronic inflammation. VB-201 has shown a strong anti-atherosclerosis effect in preclinical studies.

VB-201 is also being investigated for the treatment of rheumatoid arthritis, MS and inflammatory bowel disease.

THE FIvE MOST PROMISIng dRUgS EnTERIng PHASE I TRIAlS


BMN-195 Duchenne muscular dystrophy

BioMarin

ZT-034 (nasal spray) Osteoporosis Zelos

IMO-3100 Autoimmune diseases

Idera

DPX-0907 Cancer Immunovaccine

MyoCell SDF-1 Cardiovascular disease

Bioheart

Our first candidate making the leap from the laboratory to the clinic in this quarter is BMN-195, a potential treatment for Duchenne muscular dystrophy (DMD), a muscle-wasting disease for which there is no approved treatment. Around 40,000 people suffer from DMD in the developed world, most of whom will die by their early 20s from respiratory and cardiac function failure due to muscle wastage.

BioMarin Pharmaceutical, under license from Summit, began a phase I safety trial in healthy volunteers of BMN-195 in January 2010. The candidate has been shown to upregulate expression of the utrophin gene – a homolog of the missing or damaged dystrophin gene that characterizes DMD – in human muscle cells in the laboratory, and in mouse models of DMD where


animals given BMN-195 have become stronger. Utrophin is present only in fetal muscle cells, and it is hoped its presence in the muscles of DMD patients will ameriolate the disease. BMN-195 is the first candidate drug to work via utrophin stimulation to enter development.

Elli Lilly’s teriparatide (Forteo™) is a synthetic human parathyroid hormone (hPTH) for the treatment of severe osteoporosis. An injectable formulation, Forteo acts by increasing bone formation by regulating calcium and phosphate levels in bones, and in combination with calcium and vitamin supplements increases bone growth and reduces the risk of fractures in people with severe osteoporosis. But the drug must be injected daily and Zelos Therapeutics is hoping that its nasal formulation of teriparatide, ZT-034, will provide simple, convenient administration for patients. ZT-034 is being compared with Forteo in a phase I trial that began in January 2010. ZT-034 uses Aegis Therapeutics’ Intravail technology, which has been successful in the intranasal delivery of other peptides.

Sales of Forteo reached US$816.7 million in 2009. Zelos believes the nasal spray formulation could expand the market to US$1 billion annually. Zelos is also investigating a subcutaneous formulation of teriparatide.

Idera is hoping to use a completely novel mode of action to treat autoimmune and inflammatory conditions such as lupus, rheumatoid arthritis, multiple sclerosis, psoriasis, colitis and hyperlipidemia. In January 2010, a phase I safety trial of subcutaneously administered IMO-3100, a DNA-based antagonist of toll-like receptors 7 and 9, began in healthy volunteers. TLR-7 and TLR-9 are found in cells of the innate immune system and play a key role in autoimmune disorders.

IMO-3100 has shown strong ability to suppress immune responses mediated via TLR-7 and TLR-9 in preclinical studies, and has been effective against a range of autoimmune and inflammatory diseases in mouse and non-human primate models. Idera will select an autoimmune indication for further clinical development of the drug after completing two phase I trials.

Our penultimate drug in this edition of the The Ones to Watch is a therapeutic anticancer vaccine delivered by a novel method. DPX-0907, the first Immunovaccine product to enter clinical trials, is made up of seven proprietary peptide cancer antigens licensed from Immunotope that are believed to be found on the surface of breast, ovarian and prostate cancer cells. These antigens are delivered, along with an adjuvant, by Immmunovaccine’s novel sustained-release technology, DepoVax.


A phase I study for ovarian, breast and prostate cancer began in March 2010 as Immunovaccine announced plans to outlicense the vaccine after phase I or II trials. Preclinical data have shown DPX-0907 to effectively eliminate tumors.

The seven antigens are encapsulated in liposomes within an oil carrier which is then freeze dried. Upon preparation for injection, these active components remain in the oil phase, creating a depot effect, or store of vaccine in the subcutaneous tissue, presenting the antigens and adjuvant to the immune system for a long period and producing a significant immune response against the cancer cells, but not healthy cells.

And finally, Bioheart, under license from the Cleveland Clinic, is developing an improved formulation of its MyoCell therapy, MyoCell SDF-1. MyoCell involves the injection of autologous skeletal myoblasts into the scar tissue of the heart and has been shown in clinical trials to induce the expression of markers important for muscle contraction and so could improve contractile function of the heart.

MyoCell SDF-1 differs in that the myoblasts are genetically modified to express the growth protein SDF-1 before injection. It is hoped that higher levels of SDF-1 will stimulate the recruitment of the patient’s existing stem cells to the cell transplanted area, aiding in tissue repair and blood vessel formation. In preclinical animal studies MyoCell SDF-1 improved heart function by 54%, compared with 27% with the original MyoCell formulation and 10% with placebo.

A phase I trial began in February 2010 in congestive heart failure (CHF) patients in Jordan and is the first FDA approved trial of a combined gene/cell therapy for CHF.

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THE OnES TO WATCH Focuses on the latest phase changes in the pharmaceutical pipeline.

MOvERS And SHAKERS Unravels the most significant game-play in the US generics market.

THE CUTTIng EdgE OF CHEMISTRYInsights into the chemistry advances transforming drug discovery and development.

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the ones to watch, jan. - mar. 2010 -- pharma matters report

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