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SEPTEMBER 7 , 2016 VOLUME 27, NO.173BIOTECH’S MOST RESPECTED NEWS SOURCE FOR MORE THAN 20 YEARS

BIOWORLD TODAYTM

THE DAILY BIOPHARMACEUTICAL NEWS SOURCE

See Colucid, page 3 See GSK, page 4

See DBV, page 8

See Rigontec, page 6 See Takeda, page 7See Astrazeneca, page 5

NEW THERAPY KEY RELIEF FOR PATIENTS AT CV RISK?

IN THE CLINIC

IN THE CLINIC

FINANCINGS

THE BIOWORLD BIOME

BATTLING ZIKA

See Variants, page 9 See Regulatory, page 10

REGULATORY

RARE VARIANTS, COMMON FEATURES

Gene diversity can alter metabolic individualityBy John Fox, Staff Writer

HONG KONG – A new Japanese study of the effects of environmental and genetic influences on individual differences in proteomics and metabolomics has identified biomarkers for early disease

DBV extending allergy patch technology into vaccine developmentBy Cormac Sheridan, Staff Writer

DUBLIN – DBV Technologies SA is extending its patch-based antigen delivery technology, which is currently undergoing a pivotal phase III trial in a food allergy indication, into its first

Japan’s Takeda wins Zika funding from BARDA; initial $19.8MBy Richard Smart, Staff Writer

TOKYO – Takeda Pharmaceutical Co. Ltd., of Osaka, Japan, will attempt to develop a vaccine to tackle the Zika virus with funding from the U.S. government worth up to $311 million.

Final closing takes Rigontec’s series A financing to $33MBy Cormac Sheridan, Staff Writer

DUBLIN – A syndicate of European venture capital investors has followed its own money in a sizable third closing of Rigontec GmbH’s series A round, adding €15 million (US$16.7 million) in new

FDA: Celator’s ASCO exhibit stepped over the OPDP lineBy Mari Serebrov, Regulatory Editor

In its third letter of the year, the FDA’s Office of Prescription Drug Promotion (OPDP) came down on Celator Pharmaceuticals Inc. for promoting a promising but yet-to-be-approved

GSK touts real-world data for COPD drug in Salford lung studyBy Nuala Moran, Staff Writer

LONDON – Glaxosmithkline plc has reported statistically significant results in what it claims is the world’s first real-world randomized control trial, the Salford lung study (SLS).The trial showed that patients taking its new treatment for chronic obstructive pulmonary disease (COPD),

Abides by SAMURAI, heartened for SPARTAN: No pain for Colucid on phase III migraine dataBy Randy Osborne, Staff Writer

A slightly higher-than-previous placebo response on the primary endpoint of two hours’ freedom from headache did little to take the shine off top-line phase III migraine data disclosed by Colucid Pharmaceuticals Inc. with lasmiditan tablets in the trial known as SAMURAI.CEO Thomas Mathers pointed out that the rate on that endpoint “has actually been trickling up over the last few studies,” so about 15 percent “is not completely out of whack,” although the Cambridge, Mass.-based firm was expecting a slightly lower

Astrazeneca looks to benralizumab as next-gen asthma standoutBy Marie Powers, News Editor

Looking to mine more gold from its respiratory drug franchise, Astrazeneca plc offered up full data from the pivotal phase III trials of benralizumab at the European Respiratory Society (ERS)

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WEDNESDAY, SEPTEMBER 7, 2016 BIOWORLD™ TODAY PAGE 2 OF 16

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Coming Thursday in BioWorld Highlights:

LEFT ON THE GARBAGE HEAP OF 114TH CONGRESS?Add this to the list of things the 114th U.S. Congress likely won’t get done before it fades into history on Jan. 3: Providing relief from the inter partes review (IPR) intimidation racket. It’s not for want of trying. But the only attempts were specifically aimed at keeping drug companies from being pushed around by the government-sanctioned playground bullies who use the threat and filing of IPR patent challenges to demand a lot more than lunch money. To read more, see tomorrow’s edition of BioWorld Highlights, a free weekly ezine that provides articles from BioWorld Today, BioWorld Insight and BioWorld Asia, plus insight and opinion from the BioWorld Perspectives blog, http://bioworld.blogs.bioworld.com. If you don’t already receive this complimentary e-zine, click here to opt in.

FINANCINGS

Aequus Pharmaceuticals Inc., of Vancouver, British Columbia, inked an agreement with a syndicate of agents led by Cormark Securities Inc. and including Canaccord Genuity Corp. to sell, on a best efforts basis, 6.667 million to 13.34 million of its common shares priced at 30 cents apiece, potentially raising $2 million to $4 million. The company granted the agents a 30-day option to purchase up to an additional 15 percent of the number of shares sold to cover overallotments. Aequus did not disclose specific use of proceeds.Azurrx Biopharma Inc., of Brooklyn, N.Y., disclosed in an SEC filing that it reduced the size of its proposed IPO from approximately 2.14 million to 1.7 million shares, which are expected to price in a range of $6 to $8. The maximum proposed raise, including a 45-day option to issue additional shares to underwriters to cover overallotments, was lowered from $17.25 million to $13.7 million. Azurrx, which has two therapeutic proteins in development to treat gastrointestinal disorders, is seeking to list on Nasdaq under the ticker AZRX.C4X Discovery Holdings plc, of Manchester, U.K., raised £5 million (US$6.7 million) by placing approximately 4.9 million ordinary shares with current and new investors at 102 pence apiece. The price represented a discount of about 4.2 percent to the closing mid-market price of the company’s shares (LONDON:C4XD) on Sept. 5. C4X said Calculus Capital Ltd. agreed to invest £3 million in the placement, while Polar Capital LLP and several existing shareholders agreed to support the round. Clive Dix, CEO, also pledged to invest £475,000 in the placement. Proceeds will be used to advance the company’s existing preclinical pipeline toward development and to invest in developing new lead compounds against drug targets, including those identified by the company’s Taxonomy3 in silico platform technology. Hemostemix Inc., of Toronto, closed a private placement offering of secured debentures and promissory notes for gross proceeds of $1.644 million, representing an oversubscription of

$34,000. The company said the offering included a $1 million convertible senior secured debenture from an undisclosed arm’s-length party and $644,000 of unsecured convertible promissory notes, including $464,000 advanced from current company insiders. Proceeds will fund the company’s ongoing working capital requirements. Hemostemix is in a proxy battle with a group of shareholders that allege the company is effectively insolvent, with a cash position of $127,267 and no active clinical trials. The shareholder group said it advanced plans to raise a minimum of $4 million to stabilize Hemostemix and fund the continuation of the collection of interim data and a phase II trial of the company’s stem cell therapy.

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Colucid Continued from page 1

rate. The placebo response, anyway, is “well within the norm of trials that have been published, especially those more recently,” he said.Shares of Colucid (NASDAQ:CLCD) closed Tuesday at $23.83, up 123.6 percent, or $13.17, on word of results from the study, which is one of two phase III experiments conducted under a special protocol assessment (SPA) with the FDA for the acute treatment of migraine in adults, with or without aura. The company said SAMURAI achieved the primary and key secondary efficacy endpoints with statistical significance (p < 0.001). Lasmiditan, which selectively targets 5-HT1F receptors expressed in the trigeminal pathway, was well-tolerated in the randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of 100 mg and 200 mg in comparison to placebo. Bernice Kuca, head of clinical and regulatory operations, noted that most adverse events (AEs) were mild or moderate, and cited “random AEs like vomiting, fatigue. In the placebo group, there’s decreased appetite. It’s really hard to make anything out of [them] because the number of severe AEs was so low across all dosing arms,” she said. Company officials were in meetings and could not be reached, but execs spoke to investors on a conference call regarding the SAMURAI data and what they might mean for the in-progress phase III study called SPARTAN. CEO Mathers said the company is “hopeful that the read-through [for SPARTAN] is quite clear from SAMURAI. Both are very large and well-powered studies,” with the same endpoints and same statistical powering, he said. “The only difference with SPARTAN is that we’re enrolling subjects into a 50-mg arm as well as 100 mg and 200 mg, and we’re also doing this trial not only in the U.S. but also in the U.K. and Germany.”The key secondary endpoint in SAMURAI was the efficacy of lasmiditan based on freedom from the most bothersome associated symptom (MBS) of migraine (nausea, phonophobia or photophobia) two hours after dosing. Data from the study were collected using electronic diaries during the treated attack. Beginning pre-dose, patients indicated their degree of headache pain on a four-point scale: 0, no pain; 1, mild pain; 2, moderate pain; or 3, severe pain. Patients also indicated the presence or absence of nausea, phonophobia or photophobia, and at the pre-dose time point identified the associated symptom present that was “most bothersome.” At each time point assessment, patients were asked to indicate the degree of headache pain and the presence or absence of each associated symptom. The MBS endpoint was patient-centric and measured treatment effect of study drug on associated symptoms. The primary and key secondary endpoints of SAMURAI conform to the FDA’s draft guidance for migraine

studies, issued two years ago. In SAMURAI, 2,231 patients were randomized at about 80 U.S. sites to treat a single migraine. Enrolled subjects had a mean age of 41.6 years, 83 percent were females (following real-world migraine demographics) and 74 percent were Caucasian, with a mean migraine history of more than 19 years. Patients randomized experienced an average of more than five migraines per month and suffered severe disability from migraine, with an average Migraine Disability Assessment score of 31. More than 25 percent of patients randomized used prophylactic medication to reduce the frequency of migraine, and 82 percent had multiple cardiovascular risk factors (CVRF) or cardiovascular (CV) conditions. The most prevalent CVRFs were obesity, family history of coronary artery disease, smoking, hypertension, postmenopausal women, men older than 40, hyperlipidemia and type 2 diabetes. The most prevalent CV conditions were arrhythmias, mitral valve disease, angina, atrial fibrillation, congestive heart failure, prior myocardial infarction, Raynaud’s disease, deep vein thrombosis, ischemic stroke and cerebral infarction.

MATCHES IMS-REPORTED CV POPULATIONIn accord with the SPA agreement for SAMURAI, the protocol pre-specified the analysis population as the modified intent to treat (mITT), defined as all randomized patients who used at least one dose of study drug to treat a qualifying migraine attack and had any post-dose assessments. Patients were evaluated by the study medication to which they were randomized, and a qualifying migraine attack was defined as one treated with study drug within four hours of onset. Similar to other migraine trials, about 30 percent of patients randomized in SAMURAI were not included in the mITT, due to either a failure to dose a qualifying migraine, failure to use the electronic diaries for any time point assessment or post-randomization ineligibility (i.e., their clinical lab values). In the trial, 1,239 patients took at least one dose of lasmiditan vs. 617 who took at least one dose of placebo. The mITT consisted of 1,021 patients who took the drug and 524 who didn’t. Analysis was conducted using a one-sided test from a logistic regression model with treatment group and background use of medication to reduce the frequency of migraines as covariates.Piper Jaffray analyst Charles Duncan hailed the SAMURAI data as “the first battle won” with the drug. “We suspect the slightly higher placebo rate vs. phase II may be due to expectation bias, but we are not concerned by this magnitude of increase, and the company will investigate if this is driven by any particular subgroups,” he wrote in a research report. Lifesci Capital analyst David Sherman seemed to agree, with a pointed nod to the fact that the study turned up “no significant signs of CV-related side effects, which is important in light of Colucid’s focus on treating migraine sufferers with CV

See Colucid, page 6



GSK Continued from page 1Relvar/Ellipta (fluticasone furoate/vilanterol), were 8.4 percent (p=0.025) less likely to suffer a moderate or severe exacerbation than patients receiving “usual care,” including inhaled corticosteroids, long-acting muscarinic antagonists (LAMA), long-acting beta2-agonists (LABA) and inhaled corticosteroids, administered as monotherapy, dual or triple combinations.The results were presented at the European Respiratory Congress in London and have been published in the New England Journal of Medicine.In contrast to a formal randomized controlled trial with multiple grounds for exclusion, the 2,802-patient open-label SLS recruited anyone older than 40 with COPD who had suffered an exacerbation in the previous three years and who was being treated at any one of 80 primary care centers in the city of Salford in northwest England.All COPD patients in the city who met the criteria were invited to take part. Recruits had co-morbidities including heart disease, cancer and diabetes.The all-comers trial was initiated by GSK in response to the pressure all pharma companies are coming under to demonstrate the value new treatments offer to health care systems as early as possible in the life cycle of a drug.In addition to being open to all, the trial reflected real life by minimizing interventions. Rather than being required to attend specialist centers for review, patients were recruited by their general practitioners and tracked via their electronic health records (EHRs).In Salford, EHRs are integrated and can be accessed by both general practitioners in primary care and hospital clinicians in the emergency room and outpatient clinics. Once patients were recruited to the trial and randomly assigned to Relvar/Ellipta, or to remain on usual care, their EHRs were tagged and all subsequent interactions with health care providers monitored.During the study physicians were allowed to modify or switch treatment at any point as would happen in normal clinical practice, the only exception being a switch from usual care to Relvar/Ellipta.When SLS started in 2012, Relvar/Ellipta was not licensed in the U.K. Now, just two years after U.K. approval, GSK has 12-month treatment data confirming the effectiveness of the product in a real-world setting, compared to usual care with corticosteroids and compared to patients who were taking another corticosteroid/LABA combination therapy.Neil Barnes, global medical head of GSK’s respiratory franchise, said the results “provide robust evidence that will enable the health care community to begin understanding how the choice of COPD treatment can significantly influence patient outcomes.”SLS involved a large-scale collaboration across hospitals,

general practitioners, pharmacies and health informatics experts at Manchester University. The trial used bespoke software developed by Northwest Electronic Health, a not-for-profit set up by the university and Salford hospital, which integrates the EHRs of patients across all interactions with the health care service. That allowed monitoring of patients in near real time, but with minimum intrusion.“This is not about big data,” said Martin Gibson, chief executive of Northwest Electronic Health. “This is about understanding the way patients interact with medications in their everyday lives.”

A NEW APPROACHThe real-world, yet randomized control design used in SLS represents a new approach to conducting clinical trials. The study methodology could be used in other trials, not only in Salford, but anywhere else in the world where EHRs are in use, according to the clinical partners in SLS. For the primary effectiveness analysis, the patient population was restricted to patients who had exacerbated in the previous 12 months prior to randomization, rather than in the previous three years prior to randomization. While delivering statistical significance on the primary endpoint, there were no differences between Relvar/Ellipta and usual care on secondary endpoints, including the time to the first moderate or severe exacerbation and the rate of severe exacerbations, the rate of secondary health care contacts and COPD-related primary care contacts.A moderate exacerbation is defined as a patient receiving an exacerbation-related prescription to treat an acute worsening of COPD symptoms, of oral corticosteroid and/or antibiotic with or without contact with a health care provider, not requiring hospitalization. A severe exacerbation is defined as an exacerbation-related hospitalization required as a direct result of an acute worsening of symptoms of COPD, or a prolonged hospitalization as a result of a COPD exacerbation.In the COPD assessment test, which measures the impact of disease on health status, 45 percent of patients in the Relvar/Ellipta arm improved their scores by a clinically relevant two or more points, compared to 36 percent in the usual care group.The incidence of serious adverse events was similar, at 29 percent in Relvar/Ellipta and 27 percent in usual care.In the formal clinical trials of Relvar/Ellipta that led to the regulatory approval of the product, there was an increase in the incidence of pneumonia in COPD patients in the active arms. SLS demonstrated the risk of pneumonia was similar in Relvar/Ellipta, at 7 percent, to usual care, where the incidence was 6 percent.That finding enabled GSK to comply with a post-authorization measure requested by the EMA.

See GSK, page 11

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Astrazeneca Continued from page 1

See Astrazeneca, page 12

meeting in London, seeking to position the company’s first biologic respiratory medicine as a key differentiator in the space. SIROCCO and CALIMA evaluated the effect of two dosing regimens of benralizumab 30 mg, administered in four- and eight-week regimens as add-on therapy to standard of care, including high-dosage inhaled corticosteroids and long-acting beta 2 agonists. Both studies met their primary and key secondary endpoints by reducing exacerbations and improving lung function and symptoms in severe asthma patients with an eosinophilic phenotype, positioning the anti-eosinophil monoclonal antibody (MAb) for regulatory filings in the U.S. and Europe this year.Specifically, data showed reductions of up to 51 percent in the annual rate of asthma exacerbations along with sustained improvement in lung function – measured as change in forced expiratory volume in one second, or FEV1, of up to 159 mL – beginning at four weeks after the first benralizumab dose and improvement in asthma symptoms such as wheeze, cough, chest tightness and shortness of breath. With outcomes shown for the eight-week dosing regimen and no additional benefit observed with four-week dosing, Astrazeneca officials posited that benralizumab also could be dosed less frequently. Post-hoc analysis also showed greater improvements in exacerbation rate reduction, FEV1 and total asthma symptom scores in patients with a history of three or more asthma exacerbations in the previous year. The frequency of adverse events (AEs) in both trials was similar between patients treated with benralizumab and those who received placebo: 72 percent and 74 percent for benralizumab-treated patients vs. 76 percent and 78 percent for placebo-treated patients in SIROCCO and CALIMA, respectively. In SIROCCO, the most common (≥5 percent) AEs in benralizumab-treated patients were asthma, nasopharyngitis, upper respiratory infection, headache, bronchitis, sinusitis, influenza and pharyngitis. In CALIMA, they were nasopharyngitis, asthma, bronchitis, upper respiratory tract infection, headache and sinusitis.In addition to the ERS presentation, detailed findings from SIROCCO and CALIMA were published in The Lancet.Officials said data from the both trials will be included in the U.S. and EU regulatory submissions for benralizumab.

‘WE REALIZED WE HAD SOMETHING REALLY GOOD’Benralizumab directly binds to the receptors on eosinophils, making them visible to the body’s immune system, where natural killer cells then bind to the eosinophils and cause programmed cell death, efficiently removing them. The interleukin-5 antagonist was in-licensed about a decade ago from Biowa Inc., a wholly owned subsidiary of Kyowa Hakko Kirin Co. Ltd., of Tokyo, which retained rights to the drug in

Japan and certain Asian territories. The drug’s development, however, was overseen by Astrazeneca unit Medimmune, which noticed important differences from other respiratory agents right from the beginning, according to Bing Yao, Medimmune’s senior vice president of R&D and head of respiratory, inflammation and autoimmunity.In 2007, a phase I study of benralizumab at a very low dose – only 0.03 mg/kg rather than more conventional dosing of 1 mg/kg, 2 mg/kg or 3 mg/kg for a biologic safety study, Yao said – induced direct depletion of eosinophils to undetectable levels in just 24 hours. Eosinophils, the white blood cells that drive inflammation and airway hyper-responsiveness in patients with asthma, lead to frequent exacerbations, impaired lung function and symptoms in about half of those individuals. Alleviating that destructive cycle “is really what this compound is about,” Yao told BioWorld Today. With benralizumab dramatically mediating those effects, “we realized we had something really good,” he said. “Not only did we see a reduction in disease exacerbation but also improved lung function, improvement in symptoms and improvement in quality of life.”Medimmune quickly moved the compound into additional studies, which revealed that the MAb didn’t just tamp down eosinophils in the blood of patients with asthma. Phase II data showed a reduction of more than 95 percent of the eosinophils in lung tissue and complete depletion in the bone marrow, where the cells originate.To date, Medimmune and Astrazeneca have undertaken a program of some 25 trials to validate the company’s early faith in the candidate, according to Thomson Reuters Cortellis. The WINDWARD program in asthma, which enrolled 3,068 patients across six phase III trials, included the randomized, double-blind, parallel-group, placebo-controlled SIROCCO and CALIMA trials – which, together, encompassed 2,511 patients – to evaluate the efficacy and safety of benralizumab for up to 56 weeks in exacerbation-prone adult and adolescent patients 12 and older.Benralizumab doses were administered subcutaneously using an accessorized pre-filled syringe – another advantage in treating the patient population, according to Yao. The company’s initial focus on individuals with severe asthma represents a target market of up to 5 million patients, or up to 10 percent of those with asthma in major global markets, Yao said. But benralizumab won’t be the first biologic to market in the indication. Last year, the FDA approved Glaxosmithkline plc’s Nucala (mepolizumab) as an add-on maintenance therapy for patients with the eosinophilic phenotype who have a history of severe asthma attacks despite treatment. (See BioWorld Today, Nov. 6, 2015.)Earlier this year, Teva Pharmaceutical Industries Ltd. gained an FDA nod for Cinqair (reslizumab) to treat adults with asthma who had elevated blood eosinophils, following support from the



Rigontec Continued from page 1cash, which takes the final tally to €29.25 million. Even if some U.S. firms do raise that and more, it’s an unusual level of funding for a European startup. The investment will enable Bonn, Germany-based Rigontec to push into the U.S. earlier than it might otherwise have done and to expand its clinical ambitions for its first-in-class, RNA-based immuno-oncology therapy, which is based on the selective activation of an innate immune pathway, in order to obtain a broad antitumor effect.Through its participation in the German Accelerator Life Sciences program, established by Germany’s Federal Ministry for Economic Affairs and Energy, Rigontec is tapping into the vast knowledge network in the Cambridge, Mass., area, by locating a U.S. subsidiary in the Cambridge Innovation Center. That will raise the company’s profile, particularly among potential investors and partners, and enable the company to start thinking about engaging with the FDA. Its immediate clinical development plans are confined to Europe, however. Rigontec plans to move its lead program, RGT100, into clinical development in early 2017. The groundwork is almost complete at this stage. “We made sure we established CMC [chemistry, manufacturing and controls] in a way that is acceptable to big pharma companies,” CEO Christian Schetter told BioWorld Today. “We now have developed a robust process that can be transferred to a CMO,” he added. Delivery of a final preclinical GLP toxicity report is imminent. “We have not seen any red flags at this point,” he said. The company will shortly complete its clinical trial application. “We now have a very ambitious and exciting program for the intravenous route as well as the intratumoral route of administration,” Schetter said. That expands the potential range of indications considerably. “So the value proposition has significantly increased,” he added. The phase I trial will recruit patients with cutaneous lesions initially, but it will follow an adaptive design and will expand to other cancer indications once it reaches an optimal dose. The company will also explore RGT100’s potential in combination therapy as well, although it will not be limited to that setting. “Definitely, our preclinical data suggest we have an opportunity to see single-agent activity,” Schetter said.Rigontec, a spinout from the University of Bonn, is commercializing the work of scientific founders Gunther Hartmann and Veit Hornung, who (around the same time as a rival group based at the University of London) identified an uncapped double-stranded viral RNA species, the 5’ triphosphate RNA (3pRNA), as the ligand for retinoic acid inducible gene I (RIG-I). The binding event between the two triggers the activation of an antiviral defensive cascade, leading to tumor-specific cell killing as well as long-term

immunological memory. “It is not a natural defense mechanism against tumors. It is a defense mechanism against certain viruses,” he said. Its absence from naturally occurring antitumor defenses leaves a tumor cell particularly vulnerable, in comparison with healthy tissue. The immune system responds to cancer cells that take up RIG-I agonists as it would a virus-infected cell. “This is hitting them out of left field. They cannot react to it.” The company is developing a series of RIG-I agonists, which are more selective for the RIG-I pathway than viral RNA. “We dialed out crosstalk to Toll-like receptors,” Schetter said. The company raised €9.45 million almost two years ago, with a view to taking the total to just €12 million initially, but its second closing in 2015 took it to €14.25 million. The investor syndicate includes a mix of European funds, including Boehringer Ingelheim Venture Funds, Forbion Capital Partners, High-Tech Gründerfonds, NRW.BANK, MP Healthcare Venture Management, Sunstone Capital and Wellington Partners Life Sciences. The company aims to tap into U.S. investors for its series B round, Schetter said.Several other firms are pursuing opportunities in the wider space of targeting nucleic acid sensing pathways, for immuno-oncology and antiviral indications. The targets include Toll-like receptors (TLRs), Nod-like receptors and the stimulator of interferon genes, or Sting, receptor. The latter was the subject of a deal worth up to $750 million between Novartis AG, of Basel, Switzerland, and Aduro Biotech Inc., of Berkeley, Calif. Hopkinton, Mass.-based Spring Bank Pharmaceuticals Inc., is developing SB 9200, an oral prodrug of a dinucleotide species called SB 9000, which is thought to activate both RIG-I and the pattern recognition receptor nucleotide-binding oligomerization domain-containing protein 2, or NOD2. A phase IIa trial in hepatitis B patients is underway. Several agonists of TLR3, TLR7 and TLR8 are also in clinical development as cancer vaccine adjuvants or cancer therapeutics. //

Colucid Continued from page 3

conditions or risk factors. In addition, patients in the SAMURAI trial experienced lower rates of dizziness, fatigue, vertigo and somnolence than observed in the phase IIb study, which are important indicators of the drug’s tolerability,” he wrote in a report. The percentage of CV-risky patients enrolled in the trial “closely corresponds with the results of an IMS [Health] study, which reported CV conditions or risk factors in 76 percent of individuals receiving a migraine diagnosis. Given this makeup of the trial, the SAMURAI study provides an accurate look at the safety and efficacy of lasmiditan in Colucid’s target patient population,” in his view. //



Takeda Continued from page 1The money will be paid to the pharma giant in stages, with an initial $19.8 million granted to the company to cover costs during phase I trials. Further funds will be given to the company if the vaccine enters phase III trials and a biologics license application is filed in the U.S.“We expect for phase I clinical trials to start in 2017,” Tsuyoshi Tada, the head of Japan public relations at Takeda, told BioWorld Today. “We can only say that the vaccine will be an inactivated, adjuvanted, whole Zika virus vaccine and we do not disclose the detailed technology we have at this moment.”Rajeev Venkayya, president of the Global Vaccine Business Unit at Takeda, said the work is a part of Takeda’s efforts to help vulnerable populations around the world. “The Zika emergency demands swift action by governments, public health agencies, medical and scientific communities, the industry and others, and partnerships are essential for success,” he said.Funds will be given to Takeda by the Biomedical Advanced Research and Development Authority (BARDA), a U.S. government body under the Office of the Assistant Secretary for Preparedness and Response (ASPR) within the U.S. Department of Health and Human Services. “If this work is successful and additional funds are made available, ASPR’s BARDA also could sponsor phase II and III clinical trials as well as large-scale manufacturing work needed for the company to apply to the FDA to license the vaccine,” the authority said. “With this additional work, BARDA would provide up to a total of $311 million through 2022.”Takeda is also looking to cooperate with the Japanese government as it develops the vaccine. Prime Minister Shinzo Abe at the recent Tokyo International Conference on African Development in Nairobi, Kenya, said the Japanese government will train 20,000 experts “to tackle infectious diseases in three years.”Tada said the company could not comment on the position of the government. However, “Takeda is working with the Japanese government to explore these opportunities further,” he added.Companies and governments are racing to find a vaccine for the Zika virus, fearing that the disease would get out of control. The fourth meeting of the Emergency Committee on Zika and microcephaly convened by the World Health Organization (WHO) was held Sept. 1. “The Committee agreed that due to continuing geographic expansion and considerable gaps in the understanding of the virus and its consequences, Zika virus infection and its associated congenital and other neurological disorders continue to be a public health emergency of international concern,” the WHO said.Companies such as France’s Sanofi SA and U.S.-based Inovio Pharmaceuticals Inc. are also in the race to get a vaccine to the market. Takeda said it believes it has a chance of developing a vaccine

because of know-how it has developed during research to find cures for similar diseases. The firm also is developing vaccines for dengue and chikungunya, and while Zika is a different virus, it is in the same class as dengue (flavivirus) and is transmitted by the same species of mosquito (Aedes aegypti), according to Rajeev Venkayya, president of the Vaccine Business Unit at Takeda.In February, Venkayya announced that a team of eight at Takeda would be working on finding a Zika vaccine. “[The team] has been expanded with the original eight core members, but we do not disclose the current number of the team members,” Tada told BioWorld Today.The Philippines on Monday confirmed its first case of the virus this year and said it believed the disease had been transmitted locally, meaning there would likely be more people infected with Zika. The finding comes roughly a week after Singapore saw the number of cases within its borders surge from zero to 258 within seven days.Zika is associated with microcephaly, a brain disease causing babies to be born with smaller heads than normal, and Guillain-Barré syndrome, which causes rapid-onset muscle weakness by attacking the immune system. According to the WHO, there are likely to be as many as 4 million cases of Zika reported over the course of this year.BARDA is looking to tackle the virus by developing a vaccine, implementing new rapid diagnostics to identify people with symptoms, tightening safety measures for blood donations, and putting in place countermeasures in case of a serious outbreak of the disease. //

FINANCINGS

Proteostasis Therapeutics Inc., of Cambridge, Mass., disclosed in an SEC filing that it plans to offer 4.25 million shares in its proposed underwritten public offering, potentially increasing proceeds to $74.5 million from $60 million. Pricing was not disclosed, but the company’s common shares (NASDAQ:PTI) closed on Sept. 2 at $15.24 apiece. The company said it plans to grant underwriters the 30-day option to purchase up to 637,500 additional common shares to fill overallotments. Proteostasis also said certain existing stockholders indicated interest in purchasing up to approximately $7 million in shares at the offering price. Leerink Partners LLC and RBC Capital Markets LLC are joint bookrunners. On Tuesday, the company’s shares closed at $14.72 for a loss of 52 cents. (See BioWorld Today, Sept. 1, 2016.)

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DBV Continued from page 1vaccine study. The company is collaborating with the Geneva University Hospitals group in Switzerland and with Bangkok, Thailand-based Bionet-Asia Co. Ltd. on a phase I trial of a booster vaccine to provide additional protection against Bordetella pertussis infection.The trial follows a preclinical proof-of-concept study in a murine model of pertussis immunity, which demonstrated that a single application of DBV’s Viaskin patch containing recombinant pertussis toxin, along with two pertussis virulence factors, pertactin and filamentous hemagglutinin, reactivates immunity and protects against subsequent challenge. The data appeared in the July 9, 2015, issue of Vaccine, in a paper, titled “Needle-free and adjuvant-free epicutaneous boosting of pertussis immunity: Preclinical proof of concept.”The upcoming study will recruit 60 adult healthy volunteers in Switzerland, who will be randomized to receive either two doses of 25 mcg of recombinant pertussis toxin (rPT), two 50 mcg doses or placebo. The primary endpoint is safety; participants’ antibody responses will be assessed as a secondary endpoint. Cellular immune responses will also be measured. All participants will also receive, after the treatment period, a conventional booster shot.It may seem paradoxical to use an antigen delivery system designed to induce immune tolerance to food allergens as a vehicle for inducing immunity against a bacterial pathogen, but the dosing regimen employed makes the difference. In the allergy setting, the Viaskin patch is used to deliver food allergen, such as peanut protein, to the dendritic cells of the skin (Langerhans cells) in a repeated fashion. After an initial immune exacerbation, repeated delivery of the antigen leads to the induction of tolerance or desensitization, through the activation of a population of Foxp3+ regulatory T cells. “It is a universal process,” Pierre-Henri Benhamou, CEO and chairman of Paris-based DBV, told BioWorld Today.In the vaccine setting, the initial exacerbation is the actual clinical goal. That can be obtained with one or two administrations of antigen, but the approach only works if subjects have had previous exposure to the antigen. “You cannot prime with the patch. It’s not possible,” Benhamou said.Since many industrialized countries switched during recent decades from a whole-cell vaccine to an acellular alternative, there has been a resurgence in B. pertussis infection. The older vaccine was more effective at eliciting long-term immunity, but adverse reactions were more frequent. The cell-free vaccine is safer, but protection wanes over time – about half of 20-year-olds no longer have immunity, Benhamou said. That creates a risk for newborn children – even if they receive their routine pediatric vaccinations, full protection does not kick in until about six months.

A needle-free alternative to a booster shot could carve out a niche therefore. However, DBV is “not morphing into a vaccine company,” Chief Operating Officer David Schilansky told BioWorld Today. “We have not thought about this as a market opportunity but as an extension of our technology beyond food allergy.” The company would out-license the program to a vaccine player if it demonstrated potential.

FUTURE OPPORTUNITIESIf it does deliver promising data, the program could reawaken interest in patch-based vaccines, a concept that was explored but largely abandoned during the last decade. Intercell (now part of Lyon, France-based Valneva SE) gained a foothold in the space through its 2008 acquisition of Iomai Corp., of Gaithersburg, Md. London-based Glaxosmithkline plc backed the technology a year later in a wide-ranging deal that included two clinical programs, a needle-free, patch-based vaccine for travelers’ diarrhea and an enhancement patch for pandemic flu vaccine. Neither came to fruition, however. The travelers’ diarrhea vaccine failed in a phase III trial, while the flu adjuvant failed a phase II trial. The precise administration method may have been the problem. “If you use stripped skin, you’re targeting dendritic cells that are different from the Langerhans cells at the surface of the skin,” Benhamou said.DBV holds rights to the program, but Bionet-Asia, as developer of the nontoxic rPT protein, also has an economic interest in the program. A formal license agreement has not yet been executed. DBV has formed a scientific committee with its Geneva-based clinical collaborator, Claire-Anne Siegrist, to investigate future opportunities. It is also collaborating with the molecular virology and immunology unit of the French national agricultural institute INRA on the development of a patch-based pediatric vaccine for respiratory syncytial virus.Food allergy remains the core focus, however, and the company is gearing up for significant news flow during the next 12 to 18 months. The Pepites phase III pivotal trial of Viaskin Peanut completed recruitment of 350 patients with peanut allergy ahead of schedule in the second quarter. “Top-line data will be released by the company in the second half of 2017 – a little bit more than a year from now,” Schilansky said. A parallel phase III safety study, Realise, will extend the safety database and also provide some real-world data, as all subjects, after a six-month blinded treatment period, will cross over into an open-label extension study, in which immunological markers will be followed over time. Recruitment into a phase II study in milk allergy is near completion – it will read out in late 2017 or early 2018. An investigator-initiated study at the Children’s Hospital of Philadelphia in children with milk-induced eosinophilic esophagitis, a newly recognized allergic condition characterized by white blood cell infiltration of the esophagus, will read out in a similar time frame. //

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Variants Continued from page 1prevention and diagnosis, through the identification and quantification of blood metabolites. Such genomic studies can contribute significantly to the advancement of personalized prevention and treatment of human diseases, in addition to identifying previously unknown disease mechanisms, and possibly to the development of new treatments.“Most of the common diseases are caused by combinations of many kinds of genetic and environmental factors, and metabolites in blood are largely influenced by both genetic and environmental (lifestyle) factors, so association studies between metabolites and genetic variants are important for finding the causal variants affecting metabolites,” said study leader Seizo Koshiba, an associate professor in the Department of Integrative Genomics at Tohoku University.“Therefore, metabolomics in combination with genetics is important for estimating the effects of such genetic and environmental factors for individual health, resulting to biomarker discovery. These biomarkers are important not only for finding diseases but also estimating the effects of treatments,” Koshiba told BioWorld Today.The researchers reported their research on genetic diversity and the metabolome in the Sept. 1, 2016, edition of the open access journal Scientific Reports. Their findings were based on an analysis of blood samples taken from 512 healthy participants in the Tohoku Medical Megabank Project Community-Based Cohort Study and the Birth and Three-Generation Cohort Study.“Such cohort studies were originally designed as part of the reconstruction project from the damage of [the] Great East Japan Earthquake [in] 2011. We can search and [monitor] the longitudinal effect on the residents’ health of the disaster, by the cohort studies. We also planned to establish the base for the next-generation medicine through biobank-constructed thorough cohort studies,” Fuji Nagama, a professor and the public communication director of researchers, the Tohoku Medical Megabank Organization at Tohoku University, told BioWorld Today.“We discovered genetic variants affecting enzymatic activities in healthy people,” said Koshiba. “Our study shows that genetic polymorphisms, structural location of mutation and effect for phenotype correlate with each other in the human population, [which implies] that metabolic individuality and susceptibility for diseases are possibly resulted from the moderate variants and much more deleterious, but rare, variants.”That is a highly significant finding, noted Koshiba. “Most common diseases are caused by the combinations of a number of genetic and environmental factors. However, it was not well known which genetic variants really affect the individual nature. Our results revealed the variants significantly affecting metabolites in blood, and metabolic profiles are significantly

different, even if in healthy people because of genetic variants. These effects may also influence the individual susceptibility [to] diseases.”In their analyses, the researchers investigated the relationship between structural variants of enzymes and metabolic phenotypes in the human population and surveyed the association between metabolite concentrations and whole genome sequence analysis data.Five associations between metabolites and gene variants were identified, with four of the gene variants being known to be related to metabolic diseases. The residues substituted by those variants were located in the peripheral regions of the catalytic sites or related regulatory domains of enzymes. “Most of the genetic variants in this work are located in enzymes involved in metabolic disorders. These results are important as they indicate that metabolic individuality may influence the susceptibility for diseases,” noted Koshiba.“In this study, we showed that the effects of rare genetic variants are larger than those of the common variant,” he explained. “These variants are located in phenylalanine hydroxylase, one of the most famous enzymes involved in metabolic disorders. We also found that the common variants are located in peripheral regions of the catalytic sites or related regulatory regions, while the rare variants are located near the catalytic site. These results firstly demonstrate that variant frequency, structural location and effect for phenotype correlate with each other in [a] human population, and imply that metabolic individuality and susceptibility for diseases may be elicited from the moderate variants and much more deleterious but rare variants.”Asked about future research, Koshiba said that “metabolites in blood are largely influenced by both genetic and environmental factors. Therefore, in the future, we will perform large-scale metabolomics research in our cohort studies to investigate these factors as they affect metabolic individuality, in order to elucidate the way for the prevention of diseases. We have also opened our website, in order to share our data with researchers worldwide.” //

OTHER NEWS TO NOTE

Aeolus Pharmaceuticals Inc., of Mission Viejo, Calif., said data confirmed the efficacy of AEOL 10150 as a medical countermeasure against sulfur mustard gas inhalation, with results showing doubled survival at 28 days after exposure to lethal sulfur mustard gas and a median survival time for animals treated with AEOL 10150 of 4.5 times greater than untreated animals. Survival at 28 days in the AEOL 10150-treated animals improved to 36 percent from 14 percent in the control group. Median survival improved from four days in the control group to 18 days in the AEOL 10150-treated group. There was also improvement in blood oxygenation in the AEOL 10150-treated group.



Regulatory Continued from page 1cancer drug in an exhibit at the American Society for Clinical Oncology’s (ASCO) annual meeting in June. Celator’s ASCO exhibit included a panel identifying CPX-351 only by its proposed brand name Vyxeos, along with two claims about in vitro research and phase III results in patients newly diagnosed with high-risk acute myeloid leukemia. The panel made conclusions that the investigational cytarabine-daunorubicin combination “has been ‘proven’ to be optimal for the treatment of cancer and improves survival relative to ‘7+3’ chemotherapy . . . when FDA has not approved CPX-351 for any use,” OPDP said. The letter pointed out that there’s a difference between promoting an investigational drug and exchanging scientific findings. OPDP viewed the panel as promotional, noting that nothing in the panel or Celator’s display suggested that Vyxeos had not been approved and the panel appeared in the main ASCO exhibit hall alongside displays for approved products.A month after the ASCO meeting, Jazz Pharmaceuticals plc completed its $1.5 billion acquisition of Celator. The carrot of the deal was Vyxeos, which was granted breakthrough therapy designation in May. The company has said that it plans to submit an NDA for the drug by the end of this quarter. (See BioWorld Today, June 1, 2016.)In addition to the OPDP letter to Celator, the FDA posted three warning letters Tuesday to drug manufacturers in Brazil, China and India after putting APIs and finished drugs from their facilities on import alert. For the Chinese and Indian firms, the warning letters came several months after the import alert.Zhejiang Hisoar Pharmaceutical Co. Ltd., an API manufacturer in Taizhou City, China, was put on import alert in January, following an FDA inspection in August 2015 in which several data problems were observed, including uncontrolled access to software, deletion of data and failure to document test results at the time the tests were performed.The company also was cited for not producing requested records during the inspection. When the investigators requested the microbial quality control worksheet for a specific API batch, they were taken to a different room where the document supposedly was located. After a 30-minute wait, the inspectors went back into the lab where they saw a microbiologist with a partially completed worksheet for the batch. They were later told that the original completed worksheet never existed.Pan Drugs Ltd., of Vadodara, India, was placed on import alert in December, just a few days after staff tried to delay the inspection and refused to provide requested records. On the first day of the inspection, the FDA investigator allegedly saw the warehouse supervisor tearing pages from the company’s annual report and placing them in his pocket. Eventually, the supervisor gave the pages to the investigator. Two days later, staff failed to provide printed chromatograms the investigator requested.

The company was cited for using APIs from one of its facilities that was under import alert in finished drugs shipped to the U.S. Other problems observed at the Pan Drugs facility included disrepair and sanitary issues with the building and equipment. For example, FDA investigators observed mold-like substances on the walls of the drug processing area, along with gaps and holes in the walls around piping and air ducts. They watched a lizard exiting one of the holes and saw what appeared to be rodent droppings within three feet of bags of drug product.In addition, investigators spotted rust, dirt and lubrication leaks, as well as non-food-grade oil, on and around manufacturing equipment. They were told the company had no cleaning procedure for the equipment or facility.Products from Lima & Pergher Industria e Comercio S/A, of Uberlandia, Brazil, were placed on import alert in July following an inspection a few months earlier. Several problems were cited, including that the company failed to perform microbiological testing on each lot of finished product and had no stability data to support the expiration date on its drugs, according to the FDA.

HHS GRILLED ABOUT MYLAN REBATEReports that Mylan NV is claiming the “generic” Medicaid rebate for its Epipen is stirring the coals for both the Canonsburg, Pa., drug company and the U.S. Department of Health and Human Services (HHS).Sen. Ron Wyden (D-Ore.), ranking member of the Senate Finance Committee, and Rep. Frank Pallone (D-N.J.), ranking member of the House Energy and Commerce Committee, wrote to HHS Secretary Sylvia Burwell wanting an explanation of why Mylan has been paying the 13 percent generic Medicaid rebate for the Epipen (epinephrine) auto-injector instead of the 23.1 percent rebate that’s supposed to be paid for brand drugs and authorized generics.The letter noted that the generic rebate for Epipen stems from an HHS opinion issued in 1997 under the Clinton administration to Dey Laboratories Inc., which Mylan acquired 10 years later. According to that opinion, even though Epipen was an NDA, it was “entirely fitting and proper” for Dey to report Epipen to the Drug Rebate Program as a non-innovator multiple-source drug “and be subject to the lowest rebate amount.”By reporting it as a non-innovator, Dey – and subsequently Mylan – also could avoid an additional rebate that goes into effect when the average manufacturer price of a brand drug increases more than inflation. (Beginning next year, generics will be exposed to the inflationary rebate, too.)Besides wanting to know if Mylan is now in compliance with the rebate program, Pallone and Wyden asked Burwell how much the federal and state governments have lost in revenue because of the Epipen rebate. They also want to know if CMS has reviewed Epipen’s rebate classification and whether other

See Regulatory, page 11



Regulatory Continued from page 10

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BIOPHARMA SECTOR NEEDS TO TRY HARDER TO GET A PASSING GRADE

The summer is over and industry executives and investors alike will be getting back to work in earnest for the final four-month push until the end of the year. Both groups will be hoping for a much better period going forward. By all metrics the sector has struggled to build any sustained momentum that provides any confidence that it will close its books on 2016 in positive territory. What can we expect? More of the same or a resurgence of fortunes? BioWorld Insight provides the biopharmaceutical industry’s current report card and highlights some of the key events that are likely to impact its performance.

PUTTING PTSD TO SLEEP WITH A DECADES-OLD DRUGPost-traumatic stress disorder (PTSD) has been a challenging indication for companies to tackle, but Tonix Pharmaceuticals Holding Corp. might have found a solution in a decades-old drug. TNX-102 SL is a sublingual formulation of cyclobenzaprine, which was originally approved in 1977 as a muscle relaxant. In a phase II study, the drug, taken at bedtime, appears to help patients suffering from PTSD sleep better, resulting in recovery of daytime symptoms. BioWorld Insight looks at the trials and tribulations of past PTSD drug candidates and how Tonix and others might overcome them.

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brand drugs or authorized generics from Mylan are getting the generic rebate.Pallone and Wyden aren’t the first lawmakers to question the Epipen rebates. Last week, Sens. Amy Klobuchar (D-Minn.), Chuck Grassley (R-Iowa) and Richard Blumenthal (D-Conn.) asked about the rebates in a letter to CMS Acting Administrator Andy Slavitt. (See BioWorld Today, Sept. 2, 2016.)

U.S.-CHINA ACCORD TARGETS FENTANYLAs part of an agreement with the U.S. government, China will target U.S.-bound exports of fentanyl and other substances that are controlled in the U.S. but not in China.The two countries also will increase their exchange of law enforcement and scientific information to coordinate efforts and better control substances and chemicals used in illicit synthetic drugs, according to the White House.

The new agreement comes on top of China’s commitments over the past year to take steps to control more than 100 substances that are a threat to world health and public safety. However, China remains the primary source of chemicals used to manufacture methamphetamine and the majority of fentanyl and its analogues brought to the U.S.In addition to being mixed with heroin, fentanyl, a potent schedule II synthetic opioid, is increasingly being pressed into pill form and sold as counterfeit prescription opioid pills, the White House said. //

The all-comers, open-label approach improved recruitment, with up to 200 patients per month joining once the study was up and running. In another trial of Relvar/Ellipta in asthma, 4,236 patients have been recruited.Patient safety was increased through the near real-time monitoring by a central clinical group, which reviewed all instances of patients attending health care facilities. The resulting data offer breadth and depth, providing information on all primary, secondary and pharmacy EHR data for participants both before and during their time on the trial.Iain Buchan, professor of public health informatics at Manchester University, said SLS “has broken the mold” of randomized control trials by harnessing an approach to health care data and computing that “focuses on populations, not hospitals or other organizations.” //

GSK Continued from page 4

IN THE CLINIC

Almirall SA, of Barcelona, reported that a randomized, double-blind, vehicle-controlled phase III study evaluating the efficacy and safety of Actikerall (5-fluorouracil (5-FU) 0.5 percent/salicylic acid 10 percent), applied once daily as field-directed treatment to actinic keratosis (AK) lesions, met its primary efficacy endpoint. A significantly higher proportion of patients (49.5 percent) achieved complete skin clearance eight weeks following the end of the treatment compared with vehicle (18.2 percent, p=0.0006). Patients in the study had a 25 cm2 area of skin on the face, bald scalp or forehead that contained four to 10 clinically confirmed AK lesions (grade I/II). Secondary endpoints included partial clearance and percentage change from baseline in number of AK lesions eight weeks following treatment. The percentage of patients achieving partial clearance of AK lesions following eight weeks of Actikerall treatment was approximately twice that of those treated with vehicle (69.5 percent vs. 34.6 percent, p<0.0001), while the number of lesions treated with Actikerall decreased by 78 percent compared to 47 percent with vehicle (p<0.0001). Almirall said safety outcomes were consistent with the agent’s known tolerability profile. The findings were presented at the 16th World Congress on Cancers of the Skin & 12th Congress of the European Association of Dermato-Oncology in Vienna.



Astrazeneca Continued from page 5

OTHER NEWS TO NOTE

Allergan plc, of Dublin, acquired privately held Retrosense Therapeutics LLC, of Ann Arbor, Mich., in an all-cash transaction that included a $60 million up-front payment along with the potential for regulatory and commercialization milestone payments related to lead development program, RST-001. The gene therapy program, in development to treat retinitis pigmentosa (RP), is an application of optogenetics, which confers light sensitivity to cells that were not previously, or natively, light sensitive by employing a photosensitivity gene, called channelrhodopsin-2, from green algae to create photosensors in retinal ganglion cells, offering the potential to restore vision in retinal degenerative conditions. In 2014, the FDA granted orphan drug designation to RST-001 to treat RP. In August, Retrosense completed dosing in the low-dose cohort

of patients in a phase I/IIa trial evaluating the safety of RST-001. (See BioWorld Today, Jan. 23, 2012.)Arsanis Inc., of Waltham, Mass., said data published in Antimicrobial Agents and Chemotherapy confirmed the activity of ASN-1 and ASN-2, the human monoclonal antibodies (MAbs) that comprise its lead candidate, ASN100, which targets Staphylococcus aureus pneumonia by neutralizing six relevant S. aureus cytotoxins implicated in its pathogenesis. The data showed that ASN-1 displayed superior protective efficacy against severe S. aureus pneumonia in an established rabbit model compared with a single-toxin neutralizing MAb targeting only Hla. The data also suggested the rabbit pneumonia model was more clinically relevant than traditional murine models, since rabbits more closely mimic human sensitivity. Athenex Inc., of Buffalo, N.Y., and Gland Pharma Ltd., of Hyderabad, India, said they partnered to launch and market injectable products in the U.S. The initial deal is for more than 20 products developed by Gland that will be marketed in the U.S. by Athenex. Financial terms were not disclosed.Biomotiv LLC, of Cleveland, expanded its strategic partnership with Biogen Inc., of Cambridge, Mass., adding ophthalmology to an existing partnership in neurology. The therapeutic accelerator said Biogen committed to an additional investment of $10 million.Bristol-Myers Squibb Co., of New York, said the European Commission approved Orencia (abatacept) intravenous infusion and subcutaneous injection, in combination with methotrexate, for the treatment of highly active and progressive disease in adult patients with rheumatoid arthritis not previously treated with methotrexate. With that approval, Orencia is the first biologic therapy with an indication in the EU specifically applicable in that indication. Cyclacel Pharmaceuticals Inc., of Berkeley Heights, N.J., presented preclinical data demonstrating that both Cyclacel’s CYC065, a clinical-stage, second-generation, cyclin-dependent kinase CDK2/9 inhibitor, and CCT68127, a preclinical-stage CDK2/9 inhibitor, prolong survival in MYCN-addicted neuroblastoma models. The data were presented at the Childhood Cancer Meeting in London. Cynata Therapeutics Ltd., of Melbourne, Australia, and Fujifilm Corp., of Tokyo, signed a term sheet for the development and commercialization of certain Cynata technology, including Cynata’s lead induced pluripotent stem cell-derived therapeutic mesenchymal stem cell product, CYP-001. Pursuant to the term sheet, the parties will work together to seek to finalize a definitive agreement, which could happen in the fourth quarter of this year. The term sheet anticipates that, under a definitive agreement, Cynata will grant Fujifilm an option to an exclusive, worldwide license to market and sell Cynata’s lead product for prevention and treatment of graft-vs.-host disease, as well as an option to negotiate a license for manufacturing those products, and certain rights to Cynata’s Cymerus technology for the prevention and treatment of other diseases.

agency’s Pulmonary-Allergy Drugs Advisory Committee for the company’s development program. (See BioWorld Today, Dec. 10, 2015.)Astrazeneca is staking its claim based on “comparative efficacy,” maintaining that benralizumab works faster and more completely than earlier-to-market competitors. During the company’s second-quarter earnings call in July, Sean Bohen, executive vice president of global medicines development and chief medical officer, noted that, “as far as differentiation goes, what we previously published is that benralizumab depletes eosinophils more rapidly and more completely than other drugs that we’ve seen in this class. And it is our hope that then translates into a superior profile.”The company also is selling symptom management and quality of life improvement as differentiators. Yao said patients provided significant feedback during the clinical program about the impact of benralizumab on both metrics. Cortellis pegs the five-year consensus sales forecast at $485.9 million.The London-based pharma also has the phase III VOYAGER program underway to evaluate benralizumab in patients with severe chronic obstructive pulmonary disease, which represents up to 30 percent of that patient population, Yao said.“Beyond that, we are looking to a number of life cycle opportunities,” he added, acknowledging that the pharma will seek to move treatment upstream. “The major focus for now is in the severe asthma population, because we think that’s where there is the highest unmet medical need. But over the long term, we want to determine whether the treatment can modify the disease. For example, can you really change the course of the disease and prevent structural damage in these patients? If that works, benralizumab has the potential to be introduced much earlier in this patient population.” //



OTHER NEWS TO NOTE

Dynavax Technologies Corp., of Berkeley, Calif., said the FDA canceled the scheduled Nov. 16 Vaccines and Related Biological Products Advisory Committee meeting to review the BLA for Heplisav-B hepatitis B vaccine. During recent conversations between Dynavax and the FDA, the agency communicated decisions to enable compliance with the current PDUFA date of Dec. 15. The agency informed Dynavax that the panel meeting was canceled and remaining questions will be addressed between Dynavax and the review team via the normal process. Shares of Dynavax (NASDAQ:DVAX) closed Tuesday at $14, up $3.09, or 28.3 percent. (See BioWorld Today, Jan. 8, 2016.)Galapagos NV, of Mechelen, Belgium, said the European Commission granted orphan drug status for GLPG1690 for the treatment of patients with idiopathic pulmonary fibrosis. GLPG1690 is a small-molecule inhibitor of autotaxin and is fully proprietary to Galapagos.Horizon Discovery Group plc, of Cambridge, U.K., disclosed a new collaboration with Fulcrum Therapeutics Inc., of Cambridge, Mass. The deal will utilize Horizon’s CRISPR-based screening platform to identify targets for regulating gene expression, the companies said, and will initially focus on genetic diseases where no effective treatment options currently exist. Terms were not disclosed. (See BioWorld Today, July 20, 2016.) Hsrx Biopharmaceutical Inc., of Tucson, Ariz., confirmed its orally administered broad-spectrum antiviral drug candidate, Hsrx 431, is effective against the Zika virus. The company expects to begin human trials early in 2017 and will seek accelerated drug approval from the FDA. Navidea Biopharmaceuticals Inc., of Dublin, Ohio, executed a letter of intent with Cardinal Health Inc., also of Dublin, Ohio, for the sale of all rights, title and interest to Navidea’s Lymphoseek product for all FDA-approved, pending and future oncology diagnostic indications in North America, subject to certain limitations, as well as certain other related assets. Under the terms, Navidea would receive $80 million at closing, with future consideration tied to annual sales of the Lymphoseek product and certain sales-based milestones. Total consideration to Navidea would be capped at $310 million.Northwest Biotherapeutics Inc., of Bethesda, Md., said Nasdaq has accepted Northwest’s proposed remediation plan to resolve Nasdaq’s finding that the company failed to comply with certain Nasdaq listing rules with regard to certain securities issuances to Cognate Bioservices Inc., a contract service company. During peak expense periods, the company paid substantial portions of Cognate’s invoices in restricted stock rather than cash, in order to conserve resources, pursuant to agreements entered in 2013 and 2014. Nasdaq said it violated listing rules. Following various communications with Nasdaq, Northwest regained

compliance and the matter is closed.Novo Nordisk A/S, of Bagsværd, Denmark, said the FDA extended the regulatory review period for Xultophy (ideglira), the fixed-ratio combination of insulin degludec and liraglutide in adults with type 2 diabetes. The three-month extension was required in order to complete its review of the NDA, which was submitted in September 2015, and with the extension of the review the action date is now expected in December.OGD2 Pharma SAS, of Nantes, France, is collaborating with Syndivia SAS, of Graffenstaden, France, to explore the potential of targeting chemotherapeutic drugs using anti-O-acetylated form of the GD2 ganglioside antibody-drug conjugates (ADCs) for difficult-to-treat solid tumors. The ADCs will be designed to release the cytotoxic drug both within tumor cells and in the tumor microenvironment. Financial terms were not disclosed.Peloton Therapeutics Inc., of Dallas, had two publications in Nature that describe the application of Peloton-invented antagonists to advance the understanding of hypoxia-inducible factor-2alpha (HIF-2alpha) and its role in kidney cancer. The first paper, titled “On-target efficacy of a HIF2α antagonist in preclinical kidney cancer models,” characterizes PT2399, an analogue of PT2385, Peloton’s first-in-class small-molecule antagonist of HIF-2alpha that is in clinical development for the treatment of clear cell renal cell carcinoma (ccRCC). Using multiple techniques, the researchers demonstrated the high specificity of PT2399 for HIF-2alpha and its efficacy in orthotopic, metastatic, and patient-derived models of ccRCC. In the second paper, titled “Targeting renal cell carcinoma with a HIF-2 antagonist,” PT2399 was found to be more potent, active in a greater number of models and less toxic than Sutent (sunitinib, Pfizer Inc.) in a large panel of patient-derived ccRCC xenografts. Genetic biomarkers that correlated with sensitivity to Peloton’s HIF-2alpha antagonists were identified.Phytopain Pharma Inc., of Ottawa, Ontario, a subsidiary of Growpros Cannabis Ventures Inc., submitted to the FDA two applications for orphan drug designation for delta-9-tetrahydrocannibinol and cannabidiol for the treatment of patients with complex regional pain syndrome type 1 and patients with central post-stroke pain. Peregrine Pharmaceuticals Inc., of Tustin, Calif., said the National Comprehensive Cancer Network Oncology Research Program has awarded three grants totaling $2 million to investigators to support research of bavituximab in combination with other therapeutics for the treatment of glioblastoma, head and neck cancer and hepatocellular carcinoma. Three phase I and II studies will test the company’s candidate, an investigational chimeric monoclonal antibody that targets phosphatidylserine, in unresectable hepatitis C-associated hepatocellular carcinoma, newly diagnosed glioblastoma and progressive recurrent metastatic squamous cell carcinoma of the head and neck. The trials will start in early 2017.



OTHER NEWS TO NOTE

Prometic Life Sciences Inc., of Laval, Quebec, will pursue tympanic membrane perforations as one of its new plasma-derived plasminogen targeted clinical indications. Prometic expects to file a clinical trial application in the fourth quarter to initiate a study in Sweden in patients suffering from chronic tympanic membrane perforations.Sage Therapeutics Inc., of Cambridge, Mass., said the FDA granted breakthrough therapy designation to SAGE-547 for the treatment of postpartum depression (PPD). Sage recently reported top-line results from a placebo-controlled phase II trial in women with severe PPD in which SAGE-547 achieved a significant, rapid and durable reduction in depression scores compared with placebo.Sangamo Biosciences Inc., of Richmond, Calif., said the FDA granted orphan drug designation to SB-FIX, the company’s zinc finger nuclease-mediated genome editing product candidate for the treatment of hemophilia B. Sangamo expects to initiate a phase I/II study in adults with the disease in 2016. SB-FIX is designed as a single treatment strategy intended to provide stable, continuous production of factor IX clotting protein for the lifetime of the patient. Spero Therapeutics LLC, of Cambridge, Mass., joined the ENABLE (European Gram-Negative Antibacterial Engine) project, which focuses on the development of promising early stage antimicrobial candidates to treat gram-negative infections. ENABLE is one of seven projects under the New Drugs For Bad Bugs program, which is part of the European private-public partnership Innovative Medicines Initiative. To actively pursue its new role in the ENABLE project and facilitate its current European activities, Spero has opened an office in the U.K.Themis Bioscience GmbH, of Vienna, Austria, said it will receive about $1.3 million in funding by the innovation agency of the U.K., Innovate UK. The funds will accelerate the further development of a vaccine candidate against the Zika virus infection and its first clinical trial, the company said. The vaccine candidate is based on Themis’ Themaxyn platform that uses a well-established measles vaccine vector whose core technology has been developed at the Institut Pasteur in France.

IN THE CLINIC

Aquinox Pharmaceuticals Inc., of Vancouver, British Columbia, said it started dosing in a phase III trial of AQX-1125 for the treatment of interstitial cystitis/bladder syndrome (IC/BPS). The three-arm, randomized, double-blind, placebo-controlled LEADERSHIP trial will enroll a minimum of 300 female patients and up to 300 male subjects and will investigate the ability of 200-mg and 100-mg oral, once-daily AQX-1125 to reduce bladder pain in patients with moderate to severe IC/BPS. The primary endpoint will measure the difference in the

change from baseline in the maximum daily bladder pain score based on an 11-point numeric rating scale at 12 weeks recorded by electronic diary. The trial will also include an open-label extension of up to 40 weeks affording all participating patients the opportunity for treatment with AQX-1125. Secondary endpoints will include urinary symptoms, including frequency and nighttime awakenings, as well as measures of quality of life. Top-line data are anticipated in the fourth quarter of 2017. (See BioWorld Today, Aug. 10, 2015.)Arrowhead Pharmaceuticals Inc., of Pasadena, Calif., said it started a phase II study of ARC-AAT, an RNAi-based medicine for the treatment of liver disease associated with alpha-2 antitrypsin deficiency (AATD). The open-label, multiple-dose-escalation trial will evaluate safety and tolerability and determine the effect of multiple doses of ARC-AAT on levels of circulating and intrahepatic alpha-1 antitrypsin as evidenced by changes in liver biopsy in patients with AATD. At least eight and a maximum of 12 subjects will be enrolled.Basilea Pharmaceutica Ltd., of Basel, Switzerland, said the first patient was dosed in a phase I/IIa continuous infusion study with its tumor checkpoint controller, BAL101553, in patients with advanced solid cancers. The open-label, Swiss trial will include adult patients who have failed standard therapy or for whom no effective standard therapy is available. Boehringer Ingelheim GmbH, of Ingelheim, Germany, presented results from the phase III CanoTinA-asthma trial at the European Respiratory Society meeting in London, showing that adding tiotropium Respimat to maintenance asthma therapy significantly improved lung function, as measured by FEV1(0-3h), in children ages 6 to 11, compared to placebo (p<0.0001). A new pooled analysis from four studies, VivaTinA-asthma, RubaTinA-asthma, PensieTinA-asthma and CanoTinA-asthma, showed adding tiotropium Respimat to maintenance therapy for children ages 6 to 17 has a comparable safety profile to placebo. That analysis also showed tiotropium Respimat significantly improved peak expiratory flow, a common measure of asthma control.Caladrius Biosciences Inc., of Basking Ridge, N.J., said it completed enrollment of the first patient cohort in its phase II Sanford Project: T-Rex Study, which is testing CLBS03 (autologous expanded regulatory T cells) for the treatment of recent-onset type 1 diabetes. Results from that cohort are expected by the end of this year. The complete study targets inclusion of 111 patients, by design divided into an initial cohort of about 18 patients for an initial safety evaluation followed by a second cohort to meet patient enrollment goals. CLBS03 has received fast track and orphan drug designations from the FDA as well as advanced therapeutic medicinal product classification from the EMA.Cerecor Inc., of Baltimore, said it completed patient enrollment in its phase II trial of CERC-501, a randomized, double-blind, placebo-controlled, crossover design study in smoking cessation. Top-line data are expected in December. CERC-501 is a selective oral kappa opioid receptor antagonist.



IN THE CLINIC

CTD Holdings Inc., of Alachua, Fla., said the FDA cleared its investigational new drug application for a phase I study testing Trappsol Cyclo in Niemann-Pick type C disease. The study will evaluate the safety, tolerability, pharmacokinetic parameters and pharmacological effects of the intravenous administration of Trappsol Cyclo, a hydroxypropyl beta cyclodextrin. About 12 patients older than 18 are expected to be enrolled. Outcome measures will include cholesterol synthesis and cholesterol storage in major organs, including the liver. Trappsol Cyclo has orphan designation in both the EU and the U.S.Destiny Pharma Ltd., of Brighton, U.K., reported results from a U.S. trial, sponsored by the National Institute of Allergy and Infectious Diseases, with part one of the study yielding safety data in eight volunteers receiving antibacterial candidate exeporfinium chloride (XF-73) and allowing for the progression into part two. The second part of the study, involving 48 healthy volunteers with colonized nasal Staphylococcus aureus bacteria, showed that both concentrations tested were safe and well-tolerated, with no drug detected in the bloodstream. In general, exeporfinium chloride demonstrated a rapid, anti-staphylococcal effect after one day, with the 2 mg/g gel showing a statistical difference against placebo, which was sustained throughout dosing. The drug is being developed for use in preventing post-surgical staphylococcal infections.Glycomimetics Inc., of Rockville, Md., said it dosed the first healthy volunteers in a phase I trial testing its combined E-selectin and CXCR4 antagonist, GMI-1359, for safety, tolerability, pharmacokinetics and pharmacodynamics. Glycomimetics intends to develop GMI-1359 for hematologic malignancies. Karyopharm Therapeutics Inc., of Newton, Mass., reported top-line results from its phase IIb STORM study testing selinexor (KPT-330) in multiple myeloma, showing that among the 78 evaluable patients, the overall response rate (ORR) was 20.5 percent, based on independent review committee adjudication, including very good partial responses (VGPRs) and partial responses (PRs). Among the 48 patients in the quad-refractory group (defined as those having received previous treatment with two proteasome inhibitors and two immunomodulatory agents), the ORR was 20.8 percent. Among the 30 patients in the penta-refractory group (defined as those with quad-refractory disease that is also refractory to an anti-CD38 monoclonal antibody), the ORR was 20 percent. Several patients remain on study, including those with VGPRs, PRs and minor responses. The side effect profile for selinexor, a selective inhibitor of nuclear export, or SINE compound, was consistent with previous trials, and no new safety signals were identified. Last month, Karyopharm disclosed plans to expand the STORM trial to include an additional 120 patients with penta-refractory disease, with the hopes of seeking accelerated FDA approval or conditional EMA approval. Shares of Karyopharm (NASDAQ:KPTI) fell $1.65, or 15.5 percent, to

close Tuesday at $8.97.Morphosys AG, of Martinsried, Germany, said the first patient was dosed in the safety evaluation phase of a phase II/III combination trial of MOR208, an Fc-enhanced monoclonal antibody targeting CD19, with bendamustine. The B-MIND study will evaluate that combination vs. Rituxan (rituximab, Biogen Inc.) plus bendamustine and will enroll adults with relapsed or refractory diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplantation. Following the phase II safety evaluation part, the study is expected to transition into a pivotal phase III trial in 2017, with a primary endpoint of progression-free survival. Nordic Nanovector ASA, of Oslo, Norway, said two papers published in The Journal of Nuclear Medicine showed that pre-dosing with anti-CD37 antibody lilotomab (previously HH1), prior to injection with Betalutin, reduced hematological toxicity without adversely affecting the amount of radiation absorbed by the tumor. Betalutin is an anti-CD37 antibody-radionuclide conjugate currently in phase I/IIa testing.Santalis Pharmaceuticals Inc., of San Antonio, said it enrolled its first patient into a single-center, placebo-controlled, double-blinded study using a 5 percent East Indian sandalwood oil cream formulation for the treatment of atopic dermatitis. Up to 60 patients, between the ages of 3 months and 65 years, with a clinical stable diagnosis of atopic dermatitis with a total body surface area involvement of 2 percent to 15 percent will be enrolled. Efficacy will be measured after 28 days of the twice-daily treatment. Tonix Pharmaceuticals Holdings Corp., of New York, reported preliminary top-line data from its phase III study, AFFIRM, testing TNX-102 SL (cyclobenzaprine HCl sublingual tablets) in patients with fibromyalgia, which missed statistical significance in the primary endpoint, defined as the proportion of patients who reported a 30 percent or greater reduction in pain from baseline to the end of the 12-week treatment period based on the pre-specified primary analysis (p = 0.095.). The drug, however, did show statistically significant effects on pain when analyzed by other standard statistical approaches. Tonix said it plans to discontinue the fibromyalgia program and will focus on developing TNX-102 SL in post traumatic stress disorder, a program that is advancing toward phase III. Shares of Tonix (NASDAQ:TNXP) dropped 57.7 percent, or $1.26, to close Tuesday at 92 cents. (See BioWorld Today, May 14, 2015.)

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IN THE CLINIC

Vasopharm GmbH, of Wurzburg, Germany, said the first patient was enrolled in NOSTRA III (NO Synthase in TRAumatic Brain Injury), a phase III trial testing Ronopterin (VAS203) for the treatment of moderately to severely injured closed head traumatic brain (TBI) injury patients. The European confirmatory study is expected to enroll 232 patients with moderate to severe TBI who are hospitalized and have received an intracranial pressure probe. It is designed to evaluate the safety and efficacy of VAS203, a nitric oxide synthase inhibitor, administered intravenously between six hours and 18 hours after injury. The primary endpoint will be the extended Glasgow Outcome Scale evaluated at six months after the injury. Secondary efficacy assessments include quality of life as well as therapy intensity level over 14 days after brain injury. Data readout is estimated for mid-2019.Vectura Group plc, of Chippenham, U.K., said partner Novartis AG, of Basel, Switzerland, reported analyses from the head-to-head FLAME study, confirming that Ultibro Breezhaler (indacaterol/glycopyrronium bromide) is more effective for patients at risk of chronic obstructive pulmonary disease exacerbations vs. Seretide (salmeterol/fluticasone propionate, Glaxosmithkline plc). Data were presented at the European Respiratory Society meeting in London. Versartis Inc., of Menlo Park, Calif., reported data from up to 30 months of somavaratan treatment in the pediatric

long-term safety study at the International Congress of Endocrinology meeting in Beijing, showing that the drug, a long-acting form of recombinant human growth hormone for growth hormone deficiency, had a safety profile maintained at 30 months of dosing. HbA1c levels were stable overall during the treatment period and bone age advanced in line with height velocity over two years of treatment. The treatment adherence rate was 99.6 percent after 24 months of at-home dosing and more than 2,200 doses at the current phase III dose. Somavaratan also is being evaluated for the treatment of pediatric growth hormone deficiency in the pivotal phase III VELOCITY trial in the U.S., Canada and Europe, for which data are anticipated in the third quarter of 2017.Zynerba Pharmaceuticals Inc., of Devon, Pa., said it started a phase II trial, dubbed STOP (Synthetic Transdermal Cannabidiol for the Treatment of Knee Pain due to Osteoarthritis), testing ZYN002, a synthetic version of cannabidiol formulated as a permeation-enhanced gel. The double-blind, placebo-controlled, multidose study will enroll up to 300 patients, who will be followed for two weeks during a baseline phase, which includes a one-week washout period. Patients then will be randomized to receive either 250 mg of ZYN002 4.2 percent gel every 12 hours, 125 mg of ZYN002 4.2 percent gel every 12 hours or placebo every 12 hours for 12 weeks. The primary endpoint is the change from baseline in the weekly mean of the 24-hour average worst pain score. Top-line results are expected in the first half of 2017.

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