Sun, Dec 28, 2014, 5:14 AM EST - U.S. Markets closed

Recent

% | $
Quotes you view appear here for quick access.

Synopsys Inc. Message Board

lakers_w 474 posts  |  Last Activity: 23 hours ago Member since: Jun 13, 2000
SortNewest  |  Oldest  |  Highest Rated Expand all messages
  • MNKD short interest goes down from 79,738,493 shares to 79,738,493. Days to cover from 22.00 to 20.07.
    News Story

    Short Interest Rises in Facebook (FB), Google (GOOG), Tesla (TSLA); Falls in 31% in Apple (AAPL)
    Print
    9:09 AM 12/26/2014 - StreetInsider

    On Christmas Even, NASDAQ released short interest data for the two-week period ended December 15, 2014. Overall, short interest in all 2,910 NASDAQ securities totaled 8,441,763,186 shares at the December 15, 2014 settlement date, compared with 2,910 issues and 8,507,937,827 shares at the end of the previous reporting period.
    Below are some notable short interest updates for several notable and heavily shorted NASDAQ stocks (NOTE: We added three biotechs to the list to track - GILD, BIIB, CELG - although the days coverage doesn't include the recent biotech rout.)
    HIGHER SHORT INTEREST:Facebook (NASDAQ: FB) short interest goes up from 34,210,393 shares to 34,842,204. Days to cover from 1.40 to 1.37.Google (NASDAQ: GOOG) short interest goes up from 2,303,569 shares to 2,876,401. Days to cover from 1.38 to 1.49. NOTE: Google (NASDAQ: GOOGL) short interest goes down from 2,374,772 shares to 2,363,748. Days to cover from 1.38 to 1.03.Tesla (NASDAQ: TSLA) short interest goes up from 22,613,117 shares to 23,474,178. Days to cover from 5.15 to 3.45.Biogen Idec (NASDAQ: BIIB) short interest goes up from 2,482,567 shares to 2,848,915. Days to cover from 1.61 to 1.26.BlackBerry (NASDAQ: BBRY) short interest goes up from 111,375,334 shares to 111,509,772. Days to cover from 9.12 to 11.43.Keurig Green Mountain (NASDAQ: GMCR) short interest goes up from 10,558,122 shares to 6,156,295. Days to cover from 2.11 to 3.71.GoPro, Inc. (NASDAQ: GPRO) short interest goes up from 10,558,122 shares to 12,755,375. Days to cover from 1 to 1.92.First Solar (NASDAQ: FSLR) short interest goes up from 8,451,951 shares to 8,939,981. Days to cover from 3.93 to 4.08.El Pollo Loco (NASDAQ: LOCO) short interest goes up from 2,242,902 shares to 2,910,539 shares. Days to cover from 1.00 to 1.87.SolarCity (NASDAQ: SCTY) short interest goes up from 17,384,965 shares to 18,643,049. Days to cover from 7.51 to 7.57.Zynga (NASDAQ: ZNGA) short interest goes up from 64,113,958 shares to 70,485,894. Days to cover from 6.87 to 7.04.Intercept Pharmaceuticals, Inc. (NASDAQ: ICPT) short interest goes up from 2,162,189 shares to 2,370,067. Days to cover from 4.97 to 4.29.
    LOWER SHORT INTEREST:Apple (NASDAQ: AAPL) short interest goes down from 78,182,668 shares to 53,673,391. Days to cover from 1.69 to 1.00.Microsoft (NASDAQ: MSFT) short interest goes down from 67,099,529 shares to 58,708,012. Days to cover from 2.35 to 2.06.Gilead Sciences (NASDAQ: GILD) short interest goes down from 56,571,917 shares to 55,467,752. Days to cover from 3.49 to 3.97.Celgene (NASDAQ: CELG) short interest goes down from 11,165,661 shares to 10,373,953. Days to cover from 3.22 to 2.20.Netflix (NASDAQ: NFLX) short interest goes down from 6,002,352 shares to 5,997,113. Days to cover from 2.75 to 3.22.Micron (NASDAQ: MU) short interest goes down from 91,013,63 shares to 88,342,760. Days to cover from 5.23 to 4.74.lululemon athletica (NASDAQ: LULU) short interest goes down from 23,433,941 shares to 23,349,907. Days to cover from 9.05 to 4.26.SodaStream International (NASDAQ: SODA) short interest goes down from 3,412,532 shares to 3,064,343. Days to cover from 7.27 to 4.86.Groupon (NASDAQ: GRPN) short interest goes down from 89,267,776 shares to 86,567,261. Days to cover from 6.73 to 6.43.MannKind (NASDAQ: MNKD) short interest goes down from 79,738,493 shares to 79,738,493. Days to cover from 22.00 to 20.07.Plug Power (NASDAQ: PLUG) short interest goes down from 36,553,762 shares to 78,755,843. Days to cover from 7.36 to 4.79.
    The prior period's short interest report can be found here.

  • freshpatentsDOTcom/-dt20140703ptan20140187490.php
    Val (8) glp-1 composition and method for treating functional dyspepsia and/or irritable bowel syndrome

    A composition and method of treating functional dyspepsia and/or irritable bowel syndrome in a mammal is disclosed herein. The composition comprising a diketopiperazine and a glucagon-like peptide 1 (GLP-1), a GLP-1 analog, including the analog ROSE-010 (Val (8) GLP-1), or a combination thereof. The method further comprises administering to the mammal a GLP-1 formulation by inhalation.

    BACKGROUND
    Drug delivery systems for the treatment of disease which introduce active ingredients into the circulation are numerous and include oral, transdermal, subcutaneous and intravenous administration. While these systems have been used for quite a long time and can deliver sufficient medication for the treatment of many diseases, there are numerous challenges associated with these drug delivery mechanisms. In particular, delivery of effective amounts of proteins and peptides to treat a target disease has been problematic. Many factors are involved in introducing the right amount of the active agent, for example, preparation of the proper drug delivery formulation so that the formulation contains an amount of active agent that can reach its site(s) of action in an effective amount.

    The active agent must be stable in the drug delivery formulation and the formulation should allow for absorption of the active agent into the circulation and remain active so that it can reach the site(s) of action at effective therapeutic levels. Thus, in the pharmacological arts, drug delivery systems which can deliver a stable active agent are of utmost importance.

    Making drug delivery formulations therapeutically suitable for treating disease depends on the characteristics of the active ingredient or agent to be delivered to the patient. Such characteristics can include, in a non-limiting manner, solubility, pH, stability, toxicity, release rate, and ease of removal from the body by normal physiologic processes. For example, in oral administration, if the agent is sensitive to acid, enteric coatings have been developed using pharmaceutically acceptable materials which can prevent the active agent from being released in the low pH (acid) of the stomach. Thus, polymers that are not soluble at acidic pH are used to formulate and deliver a dose containing acid-sensitive agents to the small intestine where the pH is neutral. At neutral pH, the polymeric coating can dissolve to release the active agent which is then absorbed into the systemic circulation. Orally administered active agents enter the systemic circulation and pass through the liver. In certain cases, some portion of the dose is metabolized and/or deactivated in the liver before reaching the target tissues. In some instances, the metabolites can be toxic to the patient, or can yield unwanted side effects.

    Similarly, subcutaneous and intravenous administrations of pharmaceutically-active agents are not devoid of degradation and inactivation of the active ingredients. With intravenous administration of drugs, the drugs or active ingredients can also be metabolized, for example in the liver, before reaching the target tissue. With subcutaneous administration of certain active agents, including various proteins and peptides, there is additionally degradation and deactivation by peripheral and vascular tissue enzymes at the site of drug delivery and during travel through the venous blood stream. In order to deliver a dose that will yield an acceptable quantity for treating disease with subcutaneous and intravenous administration of an active agent, dosing regimes will always have to account for the inactivation of the active agent by peripheral and vascular venous tissue and ultimately the liver.

    SUMMARY

    The present disclosure relates to a pharmaceutical composition comprising GLP-1, a GLP-1 analog including the Val8 glucagon-like peptide-1(7-37)OH (ROSE-010) having the following amino acid sequence:

    (ROSE-010; SEQ ID NO: 1) H-His-Val-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser- Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala- Trp-Leu-Val-Lys-Gly-Arg-Gly-OH wherein Val (8) GLP-1 is a truncated version of human GLP-1, and wherein human GLP-1 has the following amino acid sequence: His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly (SEQ ID NO: 2). Furthermore Val (8) GLP-1 has an Ala→Val amino acid substitution at position 8 of human GLP-1.

    The pharmaceutical composition further comprises a diketopiperazine. In one embodiment, the diketopiperazine is selected from the group consisting of 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine; wherein X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaryl, or a pharmaceutically acceptable salt thereof.

    Also disclosed is a method of treating any disease or disorder wherein GLP-1 is indicated including, but not limited to, diabetes, ischemia, reperfused tissue injury, dyslipidemia, diabetic cardiomyopathy, myocardial infarction, acute coronary syndrome, obesity, catabolic changes after surgery, hyperglycemia, irritable bowel syndrome, stroke, neurodegenerative disorders, memory and learning disorders, islet cell transplant functional dyspepsia and/or regenerative therapy in mammals in need of treatment. The method comprises administering to the mammal a formulation by pulmonary inhalation, wherein the formulation avoids first pass metabolism of the active ingredient. In one embodiment, the method of treating functional dyspepsia and/or irritable bowel syndrome in a mammal in need of treatment comprises administering to the mammal a therapeutically effective amount of a formulation by pulmonary inhalation, comprising a diketopiperazine having the formula: 3,6-bis[4-(N-carboxy-2-propenyl)amidobutyl]-2,5-diketopiperazine (fumaryl diketopiperazine, FDKP) and ROSE-010, a GLP-1 analog.

    In yet another embodiment, there is provided a method for treating irritable bowel syndrome in a patient having the disease, the method comprising administering to the patient a therapeutically effective amount of a formulation by pulmonary inhalation, which formulation comprises FDKP and GLP-1 or a GLP-1 analog, such as the GLP-1 analog ROSE-010, which inhibits gastrointestinal smooth muscle motor activity and inhibits secretory activity of gastroinstestinal glands for about 6 to 8 hours after administration.

    In another embodiment, the method of treating irritable bowel syndrome comprises a dry powder inhalation system comprising a cartridge containing a dry powder formulation for pulmonary delivery and a breath powered inhaler. In one aspect of this embodiment, the inhaler can be a high resistance inhaler.

    In one embodiment disclosed herein, a pharmaceutical composition is provided comprising Val (8) glucagon-like peptide-1 (GLP-1) and a diketopiperazine or a pharmaceutically acceptable salt, solvate or prodrug thereof. In another embodiment, the composition is an inhalable dry powder composition.

    In another embodiment, the diketopiperazine is a diketopiperazine having the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaryl. In another embodiment, the diketopiperazine is a diketopiperazine salt. In yet another embodiment, the diketopiperazine is 2,5-diketo-3,6-di(4-fumaryl-aminobutyl)piperazine.

    In another embodiment, Val (8) GLP-1 is an amidated Val (8) GLP-1.

    In one embodiment disclosed herein, a process is provided for forming a particle comprising Val (8) GLP-1 and a diketopiperazine comprising the steps of: providing a Val (8) GLP-1; providing a diketopiperazine in a form selected from particle-forming diketopiperazine, diketopiperazine particles, and combinations thereof; and combining said Val (8) GLP-1 and said diketopiperazine in the form of a co-solution, wherein said particle comprising said Val (8) GLP-1 and said diketopiperazine is formed.

    In another embodiment, the process further comprises removing a solvent from said co-solution by lyophilization, filtration, or spray drying. In another embodiment, the particle comprising Val (8) GLP-1 and a diketopiperazine is formed by removing solvent. In another embodiment, the particle comprising Val (8) GLP-1 and a diketopiperazine is formed prior to removing solvent.

    In another embodiment, Val (8) GLP-1 is provided in the form of a solution comprising a Val (8) GLP-1 concentration of about 0.001 mg/ml-50 mg/ml. In another embodiment, the Val (8) GLP-1 concentration is about 0.1 mg/ml-10 mg/ml. In another embodiment, the Val (8) GLP-1 concentration is about 0.25 mg/ml.

    In another embodiment, the diketopiperazine is provided in the form of a suspension of diketopiperazine particles. In yet another embodiment, the diketopiperazine is provided in the form of a solution comprising particle-forming diketopiperazine, the process further comprising adjusting the pH of the solution to form diketopiperazine particles. In another embodiment, the process further comprises adding an agent to the solution or suspension, wherein the agent is selected from the group consisting of salts, surfactants, ions, osmolytes, chaotropes and lyotropes, acids, bases, and organic solvents, in one embodiment, sodium chloride. In another embodiment, the agent promotes association between Val (8) GLP-1 and the diketopiperazine particles or the particle-forming diketopiperazine.

    In one embodiment disclosed herein, a method is provided of administering an effective amount of a Val(8) GLP-1 to a subject in need thereof, the method comprising providing to the subject an inhalable dry powder formulation comprising Val(8) GLP-1 and diketopiperazine, in particularly wherein the administration is carried out by pulmonary delivery.

    In another embodiment, the pulmonary delivery is obtained using a dry powder inhalation system. In another embodiment, the dry powder inhalation system comprises a cartridge. In yet another embodiment, the dry powder formulation further comprises a pharmaceutically acceptable carrier or excipient.

    In another embodiment, the need comprises the treatment of a condition or disease selected from the group consisting of diabetes, ischemia, reperfused tissue injury, dyslipidemia, diabetic cardiomyopathy, myocardial infarction, acute coronary syndrome, obesity, catabolic changes after surgery, hyperglycemia, irritable bowel syndrome, functional dyspepsia, stroke, neurodegenerative disorders, memory and learning disorders, islet cell transplant and regenerative therapy. In another embodiment, the need comprises the treatment of irritable bowel syndrome.

    In another embodiment, a dosage of from about 10 μg to about 900 μg of Val(8) GLP-1 is administered per administration, or a dosage of from about 25 μg to about 500 μg of Val(8) GLP-1 is administered per administration, or a dosage of from about 50 μg to about 300 μg of Val(8) GLP-1 is administered per administration.

    In one embodiment disclosed herein, a method is provided of administering an effective amount of a GLP-1 molecule or a GLP-1 analog to a subject in need of treatment of irritable bowel syndrome, the method comprising providing to the subject an inhalable dry powder formulation comprising a GLP-1 molecule or GLP-1 analog and a diketopiperazine, wherein the administration is carried out by pulmonary delivery.

    In one embodiment disclosed herein, a method is provided of forming a powder composition with an improved GLP-1 pharmacokinetic profile, comprising the steps of: providing a Val (8) GLP-1; providing a particle-forming diketopiperazine in a solution; forming diketopiperazine particles; combining the Val (8) GLP-1 and the solution to form a co-solution; and removing solvent from the co-solution by spray-drying to form a powder with an improved GLP-1 pharmacokinetic profile.

    BRIEF DESCRIPTION OF THE DRAWINGS

    FIG. 1 depicts a graph of a GLP-1 analog, ROSE-010, adsorption onto fumaryl diketopiperazine (FDKP) particles as a function of suspension pH.

    FIG. 2 depicts a representative high pressure liquid chromatograph (HPLC) chromatogram of an FDKP-GLP-1 analog profile in an initial assay for powder adsorption studies of the powder.

    FIG. 3 depicts a representative HPLC chromatogram of an FDKP-GLP-1 analog in a refined assay for powder and test article analysis of the powder.

    FIG. 4 depicts a representative HPLC chromatogram of an FDKP-GLP-1 analog in a related assay of the powder.

    FIG. 5 depicts a representative HPLC chromatogram of the GLP-1 analog ROSE-010 alone and FDKP-ROSE-010.

    FIG. 6 depicts the particle size distribution for a powder sample of FDKP-ROSE-010 prepared at pH 4.5 using a SYMPATEC™ RODOS procedure.

    FIG. 7 depicts a representative SYMPATEC™ RODOS profile of the particle size distribution of the FDKP and ROSE-010 powder formulation prepared at pH 3.0.

    FIG. 8 depicts a representative scanning electron micrograph of the powder particles comprising the GLP-1 analog ROSE-010, and FDKP, the powder which was used in the further pharmacodynamic studies.

    FIG. 9 depicts a graphic representation of the data obtained from pharmacodynamic studies comparing intravenous, subcutaneous and pulmonary administration of the GLP-1 analog ROSE-010 in plasma of rats for a period of time up to 90 minutes after administration.

    FIG. 10 depicts a bar graph showing the effects of FDKP-ROSE-010 on myotonic muscle contraction in the gastrointestinal tract of rats, which measures the duration of effect in MMC model. INS=insufflation.

    FIG. 11 depicts the mean plasma concentration of active and native GLP-1 in subjects treated with an inhalable dry powder formulation containing a GLP-1 dose of 1.5 mg measured at various times after inhalation.

    FIG. 12 depicts the plasma concentration of GLP-1 in subjects treated with an inhalable dry powder formulation containing a GLP-1 dose of 1.5 mg measured at various times after inhalation compared to subjects treated with a subcutaneous administration of GLP-1.

  • freshpatentsDOTcom/-dt20141030ptan20140318875.php
    I intentionally do not cut and paste here as there are many detailed descriptions and drawings. You have to read in its entirety to do its justice. Expect a report on its merit from engineering minded folks here. Any daring taker?

  • Novel Diabetes Drugs Expanding

    Austin, Texas—An unprecedented growth in treatment options for type 2 diabetes mellitus (DM) means more patients can achieve disease control, experts told attendees of the 2014 annual meeting of the American College of Clinical Pharmacy (ACCP).

    Many patients have enthusiastically embraced the efficacy, convenience and added weight loss associated with sodium glucose co-transporter 2 (SGLT2) inhibitors and glucose-like peptide 1 receptor agonists (GLP-1 RAs), according to R. Keith Campbell, PharmD, CDE, the Distinguished Professor in Diabetes Care and Pharmacotherapy at Washington State University College of Pharmacy, in Pullman. “The more patients use these agents, the more they like them,” said Dr. Campbell, an expert who did not take part in the ACCP presentations.

    image
    New Oral Agents: SGLT2 Inhibitors

    Because they can be used as monotherapy or as add-ons to other oral agents, SGLT2 inhibitors have proven versatile, said Matthew Strum, PharmD, a clinical assistant professor in the Department of Pharmacy Practice, University of Mississippi School of Pharmacy, in Oxford. He pointed to data showing that the recently approved SGLT2 inhibitor, empagliflozin (Jardiance; Boehringer Ingelheim), which joins canagliflozin (Invokana, Janssen) and dapagliflozin (Farxiga, Bristol-Myers Squibb), is most effective in combination with metformin.

    The data are from an open-label, 78-week extension study that compared empagliflozin (10 or 25 mg) with sitagliptin (Januvia, Merck), metformin alone, or metformin combined with one of these two agents (Diabetes Care 2013;36:4015-4021).

    The results showed that after 78 weeks of treatment, empagliflozin 25 mg in combination with metformin led to a mean 0.77% reduction in hemoglobin A1c (HbA1c) and a mean 32 mg/dL reduction in fasting plasma glucose. In contrast, sitagliptin with metformin was associated with a mean 0.13% reduction in HbA1c and a decrease of 16 mg/dL in fasting plasma glucose.

    Weight Loss Advantage

    The combination of empagliflozin 25 mg with metformin also led to reductions in systolic blood pressure (mean 3 mm Hg) and significant weight loss (mean 2.5 kg), Dr. Strum noted. “The weight reduction we’ve seen with both SGLT2 inhibitors and GLP-1 RAs gives them a significant advantage over other agents,” he said.

    CANTATA-SU, a randomized, double-blind, Phase III trial, included 1,450 patients with type 2 DM, who received metformin with once-daily canagliflozin 100 or 300 mg, or with glimepiride, a long-acting sulfonylurea anti-diabetic drug (Lancet 2013;382:941-950). After 52 weeks of treatment, canagliflozin 300 mg with metformin led to a mean 4.0 kg reduction in weight, compared with a mean 0.7 kg weight increase in the glimepiride with metformin group, Dr. Strum said.

    Subjects receiving the canagliflozin 300 mg/metformin combination also experienced a mean 0.93% reduction in HbA1c and a mean 27 mg/dL decrease in fasting plasma glucose. In contrast, subjects administered glimepiride with metformin experienced a mean 0.81% reduction in HbA1c and a mean 18 mg/dL decrease in fasting plasma glucose.

    “One striking finding from a study of dapaglifozin as an add-on to pioglitazone was that dapagliflozin mitigated the weight increases that occur with pioglitazone monotherapy,” noted Dr. Strum, pointing to findings showing a mean 1.3-kg increase in weight in patients receiving 10 mg of dapaglifozin with at least 30 mg of pioglitazone daily, versus a mean 3 kg rise in weight in patients administered pioglitazone alone (Diabetes Care 2012;35:1473-1478). The greatest reductions in both HbA1c and fasting plasma glucose also occurred with a combination of the two agents, Dr. Strum said.

    SGLT2 and Risk For Genitourinary Infections

    A caveat to these positive findings is a risk for genital and urinary tract infections that accompanies all of the SGLT2 inhibitors, Dr. Strum noted. “The most common reason my patients have had to discontinue these agents is because they’ve developed a urinary tract infection, or in women, vulvovaginitis, or in uncircumcised men, balanitis [swelling of the head of the penis],” he said. The mechanism of action? “You are putting more glucose in the urine as a result of using these medications,” he explained. “A high-glucose environment is something that bacteria can thrive in; hence the increased risk for infection.”

    GLP-1 Receptor Agonists

    Two recent additions to the GLP-1 RA class of drugs, albiglutide (Tanzeum, GlaxoSmithKline) and exenatide synthetic (Bydureon, AstraZeneca), have the added convenience of once-weekly administration, said Krystal Edwards, PharmD, who is an associate professor in the Pharmacy Practice Department–Ambulatory Care Division at Texas Tech University Health Sciences Center’s School of Pharmacy, in Dallas/Fort Worth. “There are also strong efficacy data supporting their use,” said Dr. Edwards, who spoke at the same ACCP session.

    Such evidence is documented in the randomized, open-label DURATION-3 trial, which compared exenatide synthetic 2 mg once weekly to glargine in 456 patients with type 2 DM who had not achieved adequate glycemic control with at least three months of treatment with oral glucose-lowering drugs at the maximum tolerated doses. Exenatide synthetic was found to effectively control hyperglycemia (Lancet Diabetes Endocrinol 2014;2:464-473). Some patients continued treatment with metformin or combined metformin and sulfonylurea during the trial.

    After three years of treatment, the researchers found that HbA1c levels decreased by a mean 1.01% in patients receiving exenatide synthetic with or without the other oral agents, compared with a mean 0.81% reduction in those administered glargine, with or without the oral agents (P=0.03). Notably, rates of hypoglycemia were three times lower in patients treated with exenatide than in those given the other drug regimens (0.3 episodes per patient-year vs. 0.9 episodes with exenatide vs. glargine, respectively).

    In contrast, safety data were less favorable: More exenatide synthetic recipients experienced gastrointestinal adverse events, including nausea (15% vs. 2% for exenatide synthetic vs. glargine, respectively), vomiting (6% vs. 3%) and diarrhea (14% vs. 7%).

    “Although gastrointestinal adverse events with GLP-1 RAs are not uncommon, they are generally transient and do not require treatment discontinuation,” Dr. Edwards said.

    Similar to the SGLT2 inhibitors, GLP-1 RAs are associated with weight loss, Dr. Edwards said, pointing to research demonstrating reductions of 1.5 kg to 4 kg after six to 18 months of type 2 DM treatment with exenatide or liraglutide (Diabetes Obes Metab 2014;16:9-21). In a trial of liraglutide in obese individuals, 64% of patients lost at least 5% of their body weight after a year of treatment with liraglutide 2.4 or 3 mg (Int J Obes [Lond] 2012;36:843-854).

    FDA Acts on Positive Data

    Results like these were impressive enough to prompt an FDA advisory panel to recommend approval of liraglutide for use as a treatment for obesity.

    GLP-1 RAs may have other non-endocrine benefits, Dr. Edwards said. Investigators are analyzing potential related improvements in blood pressure, total cholesterol, low-density lipoprotein and triglycerides, Dr. Edwards noted (Diabetes Obes Metab 2014;129:2305-2312). “These effects are particularly useful in type 2 DM patients, since they frequently have these comorbidities,” she said.

    According to Dr. Edwards, a barrier to wider clinical adoption of GLP-1 RAs is the accompanying risk for pancreatitis and pancreatic duct metaplasia. “Given reports of these complications, I would not administer these agents in patients with a history of pancreatitis, alcohol abuse or pancreatic cancer,” she said.

    But there’s a caveat: The extent of the risk for pancreatitis and pancreatic cancer is disputed, and the FDA said in February 2014 that studies suggest there aren’t enough data showing a direct link (N Engl J Med 2014;370:794-797). However, the adverse effect is listed in the Warnings and Precautions section of the prescribing information for exenatide, liraglutide and albiglutide. Moreover, in a population-based, case-control study use of GLP-1 RAs within the past 30 days increased the risk for acute pancreatitis by 2.24 times, and use for between 30 days and two years increased the risk by 2.01 times (JAMA Intern Med; 2013;173:534-539).

    Despite the risk for pancreatitis, the American Association of Clinical Endocrinologists recommends GLP-1 RAs as a possible first-line monotherapy for patients with type 2 DM who have a HbA1c less than 7.5%, but as part of combination therapy if HbA1c is equal to or greater than 7.5%, Dr. Edwards said (http://bit.ly/​1ARfQwo). “Nevertheless, GLP-1 RAs may or may not be available on all formularies.”

    That lack of access may be a loss for patients, she suggested. “More and more data are coming out showing GLP-1 RAs have the potential to preserve §-cells” (Diabetes Obes Metab 2013;15:485-502).

    Afrezza Approval Makes Splash

    Although SGLT2 inhibitors and GLP-1 RAs are important additions to clinicians’ armamentarium, “the biggest news in diabetes treatment is the approval of the pulmonary insulin, Afrezza [MannKind],” stressed Dr. Campbell. “It begins working within minutes, peaks within 15 minutes, and is associated with few instances of hypoglycemia,” he said.

    The failed launch of Pfizer’s Exubera, another inhaled insulin that was approved by the FDA in 2006 and quickly removed from the market due to low sales, may not bode well for Afrezza. But in Dr. Campbell’s view, differences between the two agents make it more likely that Afrezza will be widely adopted into clinical practice.

    “Afrezza has greater pulmonary absorption and requires less patient education,” he said. “Patients needed half an hour of training to understand how to use Exubera. Afrezza, in contrast, requires one minute of training.”

    Dr. Strum reported serving on the speaker’s bureau for Janssen and as a consultant for Insulet, Medtronic and Tandem as a certified insulin pump trainer. Drs. Edwards and Campbell reported no relevant financial conflicts of interest.

    Ultra Long-Acting Basal Insulins on the Horizon

    Austin, Texas—Clinicians can expect the ultra long-acting basal insulin degludec (Tresiba, Novo Nordisk) to be approved in 2015, Robin Koffarnus, PharmD, told attendees of the 2014 annual meeting of the American College of Clinical Pharmacy. She said the agent can be injected at intervals up to 40 hours apart, while conferring the same reliable efficacy of shorter-acting insulin formulations.

    “In patients who do not achieve glycemic control with oral medications, insulin will likely be effective,” said Dr. Koffarnus, an assistant professor of pharmacy practice at Texas Tech University Health Sciences Center School of Pharmacy, Dallas/Fort Worth campus.

    In the 26-week, open-label, BEGIN FLEX trial, insulin degludec administered at intervals of up to 40 hours was as effective as the shorter-acting insulin glargine (Lantus, Sanofi) in reducing hemoglobin A1c (HbA1c) level, with better patient compliance and fewer incidents of hypoglycemia (Diabetes Care 2013;36:858-864).

    Novo Nordisk filed for FDA approval of its product in 2013, but after the FDA’s own analyses showed an increased risk for cardiovascular events, the company was asked to conduct clinical trials focusing solely on major cardiovascular events (http://goo.gl/​csDrHN).

    R. Keith Campbell, PharmD, CDE, the Distinguished Professor in Diabetes Care and Pharmacotherapy at Washington State University College of Pharmacy in Pullman, commented that the drug should have been approved the first time around. “I was truly shocked that the FDA required more data on Tresiba,” said Dr. Campbell, referring to the European trade name of insulin degludec, approved there in early 2013. “Myself and other insulin experts agreed the many studies of Tresiba showed it to be an excellent, safe and effective basal insulin, and there did not appear to be any reason to conduct further studies.”

    According to Dr. Koffarnus, clinicians could see two other ultra long-acting basal insulin drugs approved in the next couple of years. The first, insulin glargine U300 (Sanofi), was found to be as effective as its shorter-acting formulation (Lantus, Sanofi) in reducing HbA1c and fasting plasma glucose levels, while proving superior in reducing incidents of hypoglycemia (see Riddle, MC, et. al. 73rd Scientific Sessions of the American Diabetes Association; abstract 43-LB).

    Furthermore, in a 12-week, randomized, open-label Phase II trial, the second drug, insulin peglispro (Eli Lilly), also proved as effective as insulin glargine in improving these outcomes, but was associated with less intraday plasma glucose variability, fewer instances of nocturnal hypoglycemia and notable weight loss (Diabetes Care 2012;35:2140-2147).

    Although findings on the three agents are encouraging, Dr. Koffarnus believed they should be taken with a grain of salt. “Real-world use and outcomes can be very different than what we see in clinical trials,” she said. “We’ll see how they do in the clinic.”

    —David Wild

  • lakers_w lakers_w Dec 23, 2014 7:39 PM Flag

    Torcon was construction manager on MannKind Corporation’s Technosphere Insulin manufacturing plant project.

    The project consisted of interior demolition and renovations to an existing two story production building. Approximately 70,000 sq. ft. of the existing space was renovated to house new manufacturing operations. An attached 12,000 sq. ft. central utility plant was also upgraded with new equipment and services. Renovations occurred within the same building as MannKind’s ongoing clinical manufacturing suite, which remained in operation throughout construction. Extensive planning and phasing were used to keep these areas cGMP compliant.

    At the same time as the renovation work was proceeding, Torcon built a 180,000 sq. ft. addition to the plant. Two fill and packaging suites with associated support rooms were fit-out as part of this phase of work. Each of the four suites (two finished and two shelled for future) can accommodate three fill/packaging lines. The entire second floor of the new building was fit-out for office, meeting, dining and support operations. The new building also includes 9500 sq. ft. of material and product storage space, most of which is refrigerated.

    The project provides space for bulk manufacturing operations with solution prep, formulation, a Cryogranulator, and two lyophilizers for freeze drying bulk product. Product is then transferred to the packaging building for primary packaging into the cartridges for inhalation.

    Utility upgrades encompassed new WFI stills, tanks and distribution loops and clean steam generation and distribution. New HVAC systems were also installed including new electrical gear, boilers and chillers.

    Torcon provided comprehensive preconstruction services including estimating, scheduling and procurement, working closely with the designers and owner as an integrated team. Our team participated in design reviews and made significant value engineering and constructability recommendations.

    Work was phased to complete the renovation prior to the new packaging area. This approach permitted commissioning, validation and regulatory review to begin early.

    The MannKind facility is the first project ever to receive ISPE’s Facility of the Year awards in two categories.

  • ukmi.nhsDOTuk/applications/ndo/record_view_open.asp?newDrugID=4631

    UK: Phase III Clinical Trials

    The NHS was born out of a long-held ideal that good healthcare should be available to all, regardless of wealth – a principle that remains at its core. With the exception of some charges, such as prescriptions and optical and dental services, the NHS remains free at the point of use for anyone who is a UK resident. That is currently more than 63.2 million people.

    The NHS employs more than 1.7 milion people. Of those, just under half are clinically qualified – including 39,780 general practitioners (GPs), 370,327 nurses, 18,687 ambulance staff, and 105,711 hospital and community health service (HCHS) medical and dental staff.

    Only the Chinese People’s Liberation Army, the Wal-Mart supermarket chain and Indian Railways directly employ more people.

    The NHS in England is the biggest part of the system by far, catering to a population of 53 million and employing more than 1.35 million people. The NHS in Scotland, Wales and Northern Ireland employs 153,427 – 84,817 and 78,000 people respectively.

    The NHS deals with over 1 million patients every 36 hours.

    Funding

    Funding for the NHS comes directly from taxation and is granted to the Department of Health by Parliament. When the NHS was launched in 1948, it had a budget of £437 million (roughly £9 billion at today’s value). For 2012/13, it was around £108.9 billion.

  • Reply to

    Afrezza Commercial coming soon

    by michaelhaywood9 Dec 19, 2014 8:09 PM
    lakers_w lakers_w Dec 22, 2014 3:38 AM Flag

    Picx in
    dropboxDOTcom/s/kyvufilx19metiy/Photo%20Dec%2020%2C%2012%2010%2051%20AM.png

  • AMD Getting Key Design Wins in Commercial And Enterprise Desktops, Thin Clients And Notebooks

    There is no denying that while Advanced Micro Devices is making headway in the embedded and semi-custom markets, the PC CPU business has been a challenging one for them. They have struggled to maintain share in both the consumer and commercial PC space, but have recently been very quietly clawing back into the market and getting major design wins with all of the important commercial and enterprise players. All of these design wins are powered by AMD’s APUs which are delivered on a single piece of silicon, vary in performance, size, and price. Much of that has come as a result of their recent focus on enterprise client products and delivering value to business customers with their “PRO” brand of APUs. Advanced Micro Devices is carefully positioning these products in ways that allow them to be competitive in terms of price to performance as well as enterprise features.

    The three APUs that Advanced Micro Devices is pushing into enterprise notebooks, thin clients and desktops are their latest Kaveri APUs accompanied by the lower power Beema and Kabini, Beema’s predecessor. Kabini is actually one of AMD’s most successful APUs of all time and Beema could offer an even better result for AMD if they can get the key design wins to ship in volume. Kaveri is AMD’s first APU with HSA features, but since there isn’t any agreed upon HSA compliance test, it cannot technically be “HSA compliant”. This could give AMD’s APUs an advantage in the form of improved performance and efficiency, but this will be directly dependent on how many applications fully leverage it.AMD_Logo.svg

    Right now, AMD has major design wins with Acer, HP, Dell and Lenovo in the commercial and enterprise notebook, thin client and desktop space, which is much better than where they were only a few years ago.

    HP: From HP, the design wins come in the form of the HP t620 and t520 thin clients, the HP EliteDesk 705 Desktop Mini and Micro Towers, the HP EliteOne 705 all-in-one and three of the HP EliteBook 700 series notebooks (HP EliteBook 725, HP EliteBook 745 and EliteBook 755). The biggest deal with the EliteBook and EliteDesk is that these are true enterprise-grade design with enterprise features and warranties, not just commercial or small business, with all the advantages that come with Elite brand.
    Dell: All of Dell’s Wyse 5000 series thin clients utilize AMD’s APUs as do their Dell Vostro 3445 and 3555 notebooks.
    Lenovo: Lenovo’s designs that utilize AMD hardware include the Lenovo B50-45 notebook, ThinkPad E555 and E545 notebooks and the ThinkCentre M79 and M78 desktops. Like HP’s EliteBook, the ThinkPad and ThinkCentre brands are fully enterprise worthy.
    Acer: AMD has also managed to get design wins with Acer and their Veriton line of desktops with the Acer Veriton N 2120G, Veriton M 2120G and the Veriton X 2120G.
    The reason that this is happening is for a multitude of reasons, but primarily because of AMD’s solutions offer outside of raw CPU performance at the high end. Intel still beats AMD at the highest end when you look at single threaded CPU performance, but AMD wants businesses to understand that a business does not succeed purely on the single threaded performance of their PCs. Because of that fact, AMD’s APUs offer acceptable CPU performance alongside impeccable GPU performance to allow for smooth user experiences regardless of resolution.

    In industry benchmarks like 3DMark Firestrike and PCMark 8 V2 Work, AMD’s PRO Kaveri processors outperform the competition at similar price points while offering serious value for the money. With those industry standard benchmarks out of the way, AMD has put a greater focus on things that help run a business’ IT and with that they’ve partnered with Broadcom to enable in-band and out-of-band DASH functionality through Broadcom’s TruManage. This allows for an enterprise’s IT management software and teams to easily monitor and maintain the devices on their network. Partnering with Broadcom on connectivity also gives AMD an opportunity to provide quality wired and wireless communications, which they lack when you look at them compared to their major competitors that offer complete processing and connectivity solutions. Broadcom lacks major processing and graphics capabilities and AMD lacks connectivity, so the two are almost a match made in heaven. As a result, AMD’s partnership with Broadcom has enabled for a smarter and more enterprise-friendly solution that companies’ IT departments will find attractive.

    AMD also tries to differentiate their PRO line of APUs with the addition of key features that might be found on other platforms or simply unique to AMD’s APUs. Some features include AMD Face Login, AMD Gesture Control, AMD Picture Perfect image stabilization, AMD Quick Stream bandwidth management, AMD Start Now, AMD Wireless Display and AMD Enduro power management. Those are in addition, of course to that DASH enterprise functionality that AMD’s hardware supports, allowing for sophisticated yet cost effective IT management across the enterprise.

    When you add all of these features up, you can start to see why AMD’s PRO APUs could be an attractive alternative for an OEM trying to differentiate its new products while still appealing to the budget conscious enterprise and commercial customer.

    As for Intel… AMD isn’t going head to head with Intel on vPro as AMD doesn’t have the investment power to go toe to toe with Intel’s enterprise client investments. They are slotting themselves in between Intel’s classic Core i3, i5 and vPro. AMD offers many features important to commercial and enterprise OEMs and end users across the entire line, not just their premium SKUs. AMD won’t nor will they want to keep up with Intel’s investments in Security with McAfee, one of the biggest vPro differentiators. Nor does AMD appear interested in investing tens of millions to build a commercial ecosystem for a wireless conference room experience. AMD is essentially offering commercial features across their entire line, delivering base level and industry standard manageability features in processors that score well on a few key industry benchmarks at a decent price. And that value proposition has obviously been attractive to commercial and enterprise OEMs like HP, Lenovo, Dell, and also Acer. AMD now needs to convert their sales in to sales out.

  • lakers_w lakers_w Dec 15, 2014 8:42 PM Flag

    From my experience, GS is positioning itself for an opportunity to upgrade MNKD shoud the launch is successful as Piper Jaffrey thinks.

    Piper Jaffray Joshua Schimmer's '15 Top 15 potential "Surprise" Biopharma Events: #7 SNY/MNKD Afrezza launch goes well.

    1. Gene therapy establishes proof of concept in hemophilia
    2. Heart failure explodes on the biopharma scene with gene therapy success
    3. Biopharma does even better in 2015 than it did in 2014
    4. Failed trials get approved, starting with BMRN's drisapersen
    5. BLUE cures sickle cell anemia
    6. BIIB finishes the year with the best large-cap pipeline and freedom to operate on
    Tecfidera
    7. SNY/MNKD Afrezza launch goes well
    8. PD1 antibodies start to look like a thing of the past
    9. AMGN blocks REGN/SNY's PCSK9 antibody
    10. A biosimilar Soliris enters Phase 3
    11. Gene therapy cures blindness
    12. Iran gets the nuke; military spending hikes force other budget cuts
    13. Two large-cap biotechs get acquired
    14. CBD hits the radar screen for autism
    15. ProQR transforms the CF landscape

  • December 15, 2014 10:19 AM EST
    streetinsiderDOTcom/Analyst+Comments/MannKind+(MNKD)%3A+Sanofi+Management+Continues+Support+for+Afrezza%3B+Goldman+Sachs+Maintains+Neutral+Rating/10096557.html

    Goldman Sachs maintained a Neutral rating on MannKind (NASDAQ: MNKD) with a price target of $6. Analyst Jay Olson said Sanofi (NYSE: SNY) management meeting shows continued support for Afrezza.

    "Sanofi Chairman and interim CEO, Serge Weinberg, has been meeting with investors to address concerns in the wake of leadership changes. Our London Analyst who covers Sanofi, Steve Chesney, met with Mr. Weinberg and came away with a positive message regarding the company’s commitment to Afrezza as an important component of Sanofi’s diabetes portfolio. Recall Sanofi guided to flat to slight growth for its diabetes franchise out to 2018. We note that pricing pressures referenced as a headwind for Sanofi’s outlook on the diabetes market have been discussed in the context of basal insulin, although we suspect those same pressures are likely apply to rapid acting insulins as well," said Olson.

    "Within its diabetes guidance, management highlighted optimism for the launch of Afrezza. In our analyst’s recent meeting, Mr. Weinberg continued to express enthusiasm for the commercial potential of Afrezza. With regard to the ongoing CEO search, Mr. Weinberg reinforced the company’s plan to pursue a candidate with international pharma experience including a particular emphasis on the US market, which is critical to the launch of Afrezza in our view," continued the analyst.

    "We are encouraged by Mr. Weinberg’s continued support of Afrezza and we believe Sanofi should maintain a steady course of action in diabetes based on the recent discussion. However, as detailed in our 10/19 initiation note, we believe MNKD is facing low profitability and delayed profits based on a slow ramp of Afrezza, patient-driven market dynamics requiring heavy SG&A spending and challenging deal terms with Sanofi," he added

  • Medtronic's China Ambitions

    Ten years ago, Medtronic’s sales in China amounted to $50 million. Today, the company will sell more than $900 million across China during 2014. The strategy Medtronic has embraced to achieve this stunning amount of growth has been multi-faceted: exporting innovative products from the US to China, establishing a R&D facility in China to design products specifically for the unique needs of the Chinese market, crafting partnerships with government to educate patients around under-served therapeutic areas, and acquiring domestic Chinese medical device manufacturers such as Medtronic’s 2012 purchase of Kanghui Medical for $816 million. Taken together, Medtronic’s China ambitions point towards a company confident in their ability to navigate one of the most complex and turbulent healthcare economies in the world.

    The last two years have introduced some turbulence to foreign device manufacturers working in China. Earlier this year, China’s National Health and Planning Commission (NHPC) put in place a new policy that said it would “pursue policies explicitly designed to favor domestic manufacturers over foreign manufacturers.” Since the summer of 2013, when the GSK scandal broke, the device community has kept a watchful eye on whether a similar crackdown would take place within the device space.

    Thus far, beyond a survey initiated during the summer of 2013 by the China Association for Medical Devices Industry (CAMDI), this has not transpired. Because device sales within hospitals do not appear to be vulnerable to the same sort of economic-rent seeking behavior by doctors and hospital administrators as pharmaceuticals have been, it is likely any issues device foreign device companies will face are likely to involve anti-monopoly (price fixing) questions versus the particularly toxic bribery allegations the pharmaceutical sector has been forced to work through.

    In the midst of these uncertainties, device manufacturers can take great solace in a handful of undeniable facts, each of which is a reason to remain positive about the opportunity in China. First, China’s demographics mean demand for cardiovascular, cerebrovascular, and orthopedic goods is going to explode. The numbers may be familiar to some readers, but they bear repeating here: by 2050, one-third of all China’s population will be 65 or older. Beijing already has over 1.7 million people living within the city who are 65 or older; Shanghai has over 2.3 million. This aging population means that by 2015, China will be the world’s second largest orthopedic market. The country has upwards of 350 million people who are active smokers, and the combination of tainted air, food and water all point towards significant demand for surgical procedures specific to cancer, heart disease and, thanks to the Chinese appetite for western food, growing rates of obesity and diabetes.

    Second, device companies working in China know that the Chinese government is rapidly moving to expand reimbursement for procedures that use foreign manufactured devices. Huang Wei, Medtronic’s Director of Channel Management for all of China, recently shared with me that “government reimbursement is crucial to Medtronic’s future successes, particularly in disease states such as diabetes.” The move to get basic healthcare insurance coverage to greater than 95% of the Chinese populace was the first step in this direction. Discussions underway between industry groups, business and the Chinese government all suggest that coverage for additional services is likely to continue, an important trigger for overall market demand of devices, diagnostics and pharmaceuticals.

    Third, regardless of the intrigue that has characterized the Chinese pharmaceutical market for the last two years, the fact remains that China’s government understands it needs strong partnerships with pharma and device manufacturers in order to deal with the onslaught of healthcare needs that will grow in China over the next several decades. However, the onus is on the private sector to make sure a viable and sustainable partnership exists between the Chinese government and business. During interviews for this column, Medtronic’s spokesman pointed to one specific partnership the company believes is the sort that will allow the needs of patients, the government as payer, and business to all work together productively: the 3-year partnership Medtronic has had with the Ministry of Health and the NHFPC. The partnership will focus on the optimization of care both in and outside the hospital for Type-1 diabetes, as well as the role insulin pumps may play in delivery of care. To make sure that the economic and clinical value of therapies is understood by physicians, patients and government officials, Medtronic is partnering with the National Institute of Hospital Administration, a think tank linked to the NHFPC, to carry out a series of research projects focused on building an integrated care pathway for people in China with Type 1 diabetes.

    This sort of care pathway has become an accepted way to evaluate treatment protocols that may utilize more expensive therapies and products in the short-term, but have proven their ability to lower overall costs long-term if these pathways are maintained. This sort of total-cost approach for specific population health management may be new to China, but it will be extremely important if the government is to bend the cost curve down in ways that ensure foreign medical device and pharmaceutical companies view the China market positively.

    The project, which is supported by the China Ministry of Health, will engage a panel of expert Chinese endocrinologists as advisors and include pilots at roughly a dozen regional hospitals of various sizes across China. The goal is to gather insight that will support a Chinese nationwide system leveraging Medtronic’s expertise to improve treatment of Type 1 diabetes patients and reduce the likelihood of costly complications. This sort of public-private partnership may be new in China, but it is an important way to educate everyone on the potential benefits of technologies and therapies whose value may require a longer-term view.

    It may seem all but certain that a company such as Medtronic has every reason to be confident in its ability to be successful in China; however, there are challenges beyond those touched on earlier. Distribution partnerships remain critical in China, and these relationships are rife with compliance risks. China’s highly fragmented pharmaceutical and medical device distribution network relies on thousands of dealers.

    Medtronic has over 700 independent distributors in China alone. Many distributors have an intermediary – commonly referred to as a dealer – who acts as the interface between the distributor and the hospital’s purchasing agent. The further away from the manufacturer the product gets, the more difficult it can be to ensure compliant sales behaviors are taking place. In a market like China where extraordinary growth also means strained government budgets to pay for newly demanded medical services, political pressures to identify non-compliant behavior and tie that back to a larger entity are always a concern.

    In addition, a company like Medtronic is coming to terms with how quickly Chinese medical device manufacturers have proven themselves capable of building medical devices that, if not as of today world-class, are definitely on-par with the needs of the domestic Chinese market. Why is this? One possible explanation for not only how quickly Chinese device makers have been able to close the gap between their best-in-class and the offerings from western device manufacturers is that medical devices (unlike pharmaceuticals) do not rely on intensive R&D and bench science. Medical device designs and manufacturing are inherently mechanical, reliant on processes, which are familiar to the Chinese manufacturing world. As complicated as they may be, medical device manufacturing is driven by injection molding, plastic extrusion, specialty metal treatment and fabrication, and assembly methods that Chinese manufacturers have proven themselves world-class in for complex electronics, to name just one analog industry.

    What could handicap a company like Medtronic’s Chinese ambitions? Certainly un-friendly government policies that favor domestic manufacturers over foreign-owned companies. Absolutely reimbursement policies that stagnate and never speak for more of the patient’s out of pocket expenditures. But one of the easiest to overlook ways that Medtronic’s China ambitions could struggle would be to see domestic manufacturers close the gap between the best-in-class product offering from Medtronic and what the domestic owned companies are capable of producing.

    This recognition in no small way illuminates the reasoning behind Medtronic’s various acquisitions within the Chinese device sector, but it also shows the ways in which Chinese companies are winnowing down the competitive advantages that established western businesses have long assumed would be their best protection and ultimate competitive advantage. Today, the pressure to innovate and allow frugal engineering to drive costs down for medical devices is creating a new standard of excellence that western device companies will have to embrace if they are to be successful in China over the next decade.

  • lakers_w lakers_w Dec 15, 2014 2:27 PM Flag

    Piper Jaffray Joshua Schimmer's '15 Top 15 potential "Surprise" Biopharma Events: SNY/MNKD Afrezza launch goes well.

    Another interesting potential "Surprise" event in the sector, according to Schimmer, is that two large cap biotechs gets acquired. "The number of large-cap ( $10B) biotech companies which offer attractive long-term growth opportunities to meaningfully inflect EPS trajectories for large pharma companies continues to grow," the analyst commented. "The list now includes BIIB, CELG, BMRN, PCYC, VRTX, ALXN, REGN and INCY. All could be appealing M&A targets and fit needs of larger pharma partners. While many investors may agree that one would be a boon for an industry, two of these could lead to a broader sector revalidation."

    Yet another potential "Surprise", is that MannKind and Sanofi Afrezza launch goes well.

    Below is a list of Schimmer's Top 15 Potential "Surprise" Biopharma Events For 2015:

    1. Gene therapy establishes proof of concept in hemophilia
    2. Heart failure explodes on the biopharma scene with gene therapy success
    3. Biopharma does even better in 2015 than it did in 2014
    4. Failed trials get approved, starting with BMRN's drisapersen
    5. BLUE cures sickle cell anemia
    6. BIIB finishes the year with the best large-cap pipeline and freedom to operate on
    Tecfidera
    7. SNY/MNKD Afrezza launch goes well
    8. PD1 antibodies start to look like a thing of the past
    9. AMGN blocks REGN/SNY's PCSK9 antibody
    10. A biosimilar Soliris enters Phase 3
    11. Gene therapy cures blindness
    12. Iran gets the nuke; military spending hikes force other budget cuts
    13. Two large-cap biotechs get acquired
    14. CBD hits the radar screen for autism
    15. ProQR transforms the CF landscape

  • lakers_w lakers_w Dec 14, 2014 1:20 PM Flag

    The most common adverse reactions associated with Afrezza in clinical trials were hypoglycemia, cough, and throat pain or irritation. In the approval, Afrezza was asked to print a boxed warning advising that acute bronchospasm has been observed in patients with asthma and chronic obstructive pulmonary disease (COPD). Regarding hypoglycemia, in all 3 active comparator-controlled trials of this drug, subjects had overall 20-65% less hypoglycemia, and based on an A1C stratification analysis, it turned out that the decreased hypoglycemia occurred irrespective of subjects’ A1C levels.

    The 2 most interesting trends in my opinion were the decreased postprandial excursions that were demonstrated with 7-point glucose curves and the decreased incidence of hypoglycemia in the trials where comparator insulin was used and in the placebo-controlled trials, the event rate for subjects on metformin plus sulfonylurea was the same as metformin plus TI. Although TI had PK/PD advantages compared to insulin aspart, these 2 benefits were not statistically significant. The early onset of action of Afrezza compared to insulin aspart likely helped control the postprandial rise in glucose and the early disappearance of Afrezza compared to insulin aspart likely led to less late postprandial hypoglycemia after a meal has been absorbed (Figure 1). This type of data would support the position that a valid effectiveness endpoint could be a reduction in such type of hypoglycemic events if a novel insulin or insulin delivery system is associated with ultra rapid absorption. At the same time, an ultra rapidly acting insulin like Afrezza might be expected to produce less hyperglycemia immediately after a meal and less hypoglycemia late after a meal and result in little decline in the A1C. Such a drug could still be helping not only to mitigate glycemic lows and highs, but to also decrease glycemic variability (GV), even though GV has not been proven to be a true problem requiring treatment.

    Figure 1.
    Figure 1.
    Seven-point glucose profile at week 52 in T2DM subjects in a trial of Technosphere Insulin vs insulin comparator. Red square and red line = TI with each meal plus basal glargine insulin once daily. Purple circle and purple line = 70/30 insulin twice daily. This figure was adapted from data provided by Dr Anders Boss from a study by MannKind.

    The risk of lung cancer has been raised as a safety concern to the use of inhaled insulin. In the registration trials 2 heavy smokers developed lung cancer—1 while in a controlled comparative clinical trial and 1 while in an extension. This incidence of lung cancer (0.8 cases per 1000 patient-years) was felt by the company to be within the range of lung cancer observed in the general population (approximately 0.23-1.22 cases per 1000 patient-years, according to the American Lung Association). These incidences with Afrezza can be compared to the incidence of primary lung cancer and the mortality of primary lung cancer which were observed in a follow-up study of users of Exubera, another type of inhaled insulin that was available from September 2006 through October 2007. Comparing Exubera to comparator agents according to person-years of use, the relative increased lung cancer incidence and mortality with Exubera were 3.75 and 2.81 respectively and FDA classified pulmonary malignancies as adverse events of special interest for inhaled insulins. At the Afrezza panel hearing on April 1, 2014, the FDA reviewers raised the issue of whether inhaled insulin causes preexisting lung cancers to grow more quickly than they would otherwise grow, but neither FDA nor MannKind officials could think of a good way to prove or disprove that hypothesis.

    The FDA is requiring the following postmarketing studies for Afrezza:

    a clinical trial to evaluate pharmacokinetics, safety, and efficacy in pediatric patients

    a clinical trial to evaluate the potential risk of pulmonary malignancy with Afrezza (this trial will also assess cardiovascular risk and the long-term effect of Afrezza on pulmonary function)

    2 pharmacokinetic-pharmacodynamic euglycemic glucose-clamp clinical trials, 1 to characterize dose response and 1 to characterize within-subject variability.

    Afrezza will fill a needed role for patients who do not wish to dose themselves for prandial insulin coverage with insulin from a needle injection. The rapid onset and offset of this insulin may well prove to be a great advantage in minimizing glucose fluctuations without much of the risk of late postinjection hypoglycemia. Now that MannKind signed a marketing agreement with the world’s largest insulin company, Sanofi, it is likely that Afrezza will soon be made available in many countries by way of a well-established distribution system. I look forward to seeing Afrezza used for mealtime insulin therapy in a closed-loop system and for many other situations where bolus insulin therapy is needed but late postprandial hypoglycemia is intolerable.

  • On June 27, 2014, the US Food and Drug Administration approved Afrezza (MannKind, Danbury, CT), an ultra-rapid-acting inhaled insulin to improve postprandial glycemic control in adults with diabetes mellitus. This is the only ultra-rapid-acting insulin on the market with faster pharmacokinetics and pharmacodynamics than the 3 rapid-acting insulin analogs currently on the market, which are insulin aspart, insulin glulisine, and insulin lispro.

    The name “Afrezza” refers to the drug/device combination product consisting of Technosphere insulin powder (known as TI), the inhaler, and the cartridges containing TI which is referred to as the Afrezza Inhalation System or the TI Inhalation System. TI is composed of recombinant human insulin and fumaryl diketopiperazine (FDKP), which is an inert excipient. Insulin powder particles are adsorbed onto uniform-sized (approximately 2 microns) carrier Technosphere particles which contain mostly crystallized FDKP. Upon inhalation, the Technosphere particles carry the insulin into the alveoli where the particles dissolve. Both the insulin and the FDPK are rapidly absorbed across the alveolar walls independently of each other. The insulin uptake into the blood stream is faster than that of any other approved insulin. The absorbed FDPK is not metabolized and is excreted in an inert form mostly by the kidneys.

    This approval was in response to the company’s third submission in 2013. After 2 previous cycles of review MannKind had received complete response letters on March 12, 2010, and January 18, 2011, because of multiple deficiencies identified by FDA in the prior applications. At one point in 2010, the company elected to drop their first generation delivery system (Medtone) and seek approval for their smaller second-generation delivery system (Gen2 also known internally as Dreamboat). FDA responded that a head-to-head comparison between the 2 inhalers would be needed, as well as a dose-proportionality study and a human factors study.

    The pharmacokinetic properties of TI are uniquely rapid of all approved insulins. The median time to maximum concentration in most subjects is 12-15 minutes. The PK of TI in subjects with type 1 diabetes, type 2 diabetes, and even smokers or those with chronic obstructive pulmonary disease is no different than that in unaffected controls. In asthmatic subjects insulin absorption may be decreased.

    Regarding the pharmacodynamics of TI, this drug has a more rapid onset of action and a shorter duration of action compared to rapid-acting insulin analogs. In glucose clamp studies, the maximum glucose infusion rate (tie of peak glucose-lowering activity) was 53 minutes for TI, 108 minutes for the analog insulin, and 3-4 hours for regular human insulin. The duration of Afrezza action is 2.5-3 hours.

    In their FDA submission, MannKind evaluated the safety and effectiveness of Afrezza in a total of 3017 subjects—1026 had type 1 diabetes and 1991 had type 2 diabetes. In 4 pivotal trials TI was either noninferior to comparator insulin in 2 of 3 trials and on the margin of noninferiority versus inferiority in 1 study (TI had a higher A1c than comparator with a 95% confidence interval as extreme as 0.40% worse than comparator with the prespecified noninferiority target set at

  • lakers_w lakers_w Dec 13, 2014 10:24 PM Flag

    When they signal an upgrade, they must be recovering shorts to repay the borrowed share. Then in Aug convert notes to stock at a fixed price to participate in the upside.

  • lakers_w lakers_w Dec 13, 2014 10:16 PM Flag

    Selling short against convertible notes is a common practice. They want shares lower than 5.55 to convert into stock. Nothing is unusual. Chances are A will do well. BofA will convert to repay the borrowed shrs. The conversion price is $6ish, right. They may miss a big run up though.

SNPS
43.96-0.03(-0.07%)Dec 26 4:00 PMEST

Trending Tickers

i
Trending Tickers features significant U.S. stocks showing the most dramatic increase in user interest in Yahoo Finance in the previous hour over historic norms. The list is limited to those equities which trade at least 100,000 shares on an average day and have a market cap of more than $300 million.
Safeway Inc.
NYSEFri, Dec 26, 2014 4:02 PM EST
Virgin America Inc.
NASDAQFri, Dec 26, 2014 4:00 PM EST