Kenya first country to launch ‘Novartis Access’, expanding affordable treatment options against chronic diseases


FDA Panel to Consider Biosimilar for Filgrastim


FDA staff are strongly supportive in pre-meeting report. In advance of an FDA advisory committee meeting this week, FDA staff showed clear support for a new biosimilar for filgrastim, the recombinant granulocyte colony-stimulating factor currently sold as Neupogen and used to promote white-cell recovery after treatments that lead to neutropenia.

The Oncologic Drugs Advisory Committee (ODAC) will discuss whether to recommend approving EP2006 at a meeting here on Wednesday. EP2006 is a product of the Sandoz subsidiary of Novartis.

According to briefing documents by FDA’s technical staff, the already licensed Neupogen is indicated for use in “reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with AML2 [acute myeloid leukemia],” as well as “to reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia.” Other approved indications include promoting myeloid recovery following autologous bone marrow transplant and for mobilizing hematopoietic stem cells in preparation for autologous peripheral blood transplants.

Sandoz-Novartis is seeking approval for all the same indications.

Based on supporting evidence from the EP2006’s clinical development program, authors of the FDA briefing documents endorsed the new drug. “[T]he Applicant’s data meets the requirement for a demonstration of ‘no clinically meaningful differences’ between the proposed product and the reference product in terms of safety, purity, and potency.” They cited the “extensive and robust” comparative pharmacodynamic and pharmacokinetic studies in normal human healthy subjects as supporting the biosimilarity. No particular issues that might call the product’s equivalence to branded filgrastim into question were raised in the briefing documents.

On Wednesday the advisory committee will agree or disagree with the FDA’s assessment of EP2006.

Another biosimilar to Neupogen, tbo-filgrastim (Granix), was approved in 2012 for patients with “nonmyeloid malignancies treated with myelosuppressive chemotherapy.” However, that product underwent placebo-controlled clinical trials with efficacy and safety outcomes in cancer patients. The studies submitted on behalf of EP2006 were limited to pharmacokinetic and pharmacodynamic studies in healthy people plus lab analyses intended to demonstrate biochemical similarity.

Notwithstanding the committee’s vote on Wednesday, an Amgen lawsuit asserting that Novartis might be infringing on Amgen’s patent could still derail the biosimilar’s entrance onto the market, the Wall Street Journal reported on Monday

New heart drug significantly reduces deaths and hospitalisation.


A new heart medication has been shown to cut instances of heart failure mortality by a fifth, and is expected to be on the market as early as next year.

heart-pills

Image: Julija Sapic/Shutterstock

Named LCZ696, the new drug is still in the trial phase, but has been shown to dramatically reduce cardiovascular deaths and the risk of hospitalisation for people with chronic heart failure.

The drug is being developed by Swiss pharmaceutical company Novartis, and was recently put to the test in the largest trial ever undertaken in heart failure, involving more than 8,400 patients. Compared to an existing heart drug, called enalapril, LCZ696’s effects were so significant and so overwhelmingly positive throughout this trial, a team of independent investigators ended it early. This is the first time in 25 years that a new drug has been proven to be more effective than existing heart medications.

According to Ben Hirschler at Reuters, not only does LCZ696 reduce deaths and hospital admissions, patients who were treated with it also reported feeling measurably better than those who were treated with enalapril. One of the principle investigators, John McMurray from the Clinical Research Initiative in Heart Failure at the University of Glasgow in the UK, reported its effects as “astonishing”.

“Once this drug becomes available, it would be difficult to understand why physicians would continue to use traditional (drugs) … for the treatment of heart failure,” said another of the principle investigators, Milton Packer from the Department of Clinical Sciences at the University of Texas in the US.

While the trial ended five months ago, the full results were only just released at the 2014 European Society of Cardiology Congress, the world’s largest cardiology conference. The results will also be published online by the New England Journal of Medicine.

“This result is better than we ever could have anticipated,” Novartis’s head, David Epstein, told Reuters.

According to the results of the trial, patients who took LCZ696 were 20 percent less likely than those on enalapril to die from cardiovascular causes and 21 percent less likely to be admitted to hospital, says Hirschler at Reuters. The results can be converted to approximately 90,000 fewer deaths per year in the US and Europe if patients with heart conditions were switched to the new LCZ696 drug, Epstein adds. The drug is expected to be on the market as early as next year.

Mariell Jessup, a heart failure expert from the University of Pennsylvania in the US, who was not involved in the study, commented that the new drug, “may well represent a new threshold of hope for patients with heart failure”.

Novartis announces positive clinical trial results for novel H7N9 vaccine.


  • 85% of subjects immunologically protected after receiving second dose of investigational cell culture vaccine when combined with proven MF59® adjuvant

  • Vaccine now in large scale production highlighting rapid response capability of novel FDA licensed cell culture technology

  • 135 confirmed cases and 45 deaths from H7N9 virus since emergence in March according to the World Health Organization.

Novartis announced today interim results from a Phase 1 clinical trial with its proprietary cell culture vaccine for the H7N9 avian influenza virus involving 400 healthy volunteers (18-64 years of age). The data shows 85% of subjects achieved a protective immune response after two doses of the 15 ug MF59 adjuvanted vaccine. Only 6% of subjects achieved a protective response when given two doses of the 15ug un-adjuvanted vaccine. The full data set from the trial will be submitted to a peer-reviewed journal for publication in the near future. 

The vaccine was produced utilizing full-scale cell-culture manufacturing technology, an alternative technology that can significantly accelerate vaccine production versus traditional egg-based methods.[2] Cell-culture technology utilizes a well-characterized mammalian cell line rather than chicken eggs to grow virus strains.[3]

“This rapid response underscores our leadership position in pandemic preparedness” said Andrin Oswald, Division Head, Novartis Vaccines. “Thanks to our investments into innovative production technologies and adjuvants, we are now able to offer a protective solution for a potentially deadly pandemic virus within a few months after the emergence of the H7N9 virus.”

Reports of H7N9 infection first emerged in China in March 2013. Novartis, along with its partners at the Craig Venter Institute, first synthesized the viral strain several days after it was shared with global researchers by the Chinese Centers for Disease Control. Novartis then produced clinical trial lots, began clinical trials in August, and initiated large-scale production in its Holly Springs (NC), USA and Marburg, Germany facilities in October.

Novartis announces positive results from final Phase III omalizumab registration study in severe form of chronic skin disease CSU.


  • Omalizumab significantly reduced itch and hives caused by chronic spontaneous urticaria (CSU) as early as Week 1; benefit sustained over  24 weeks of active treatment[1]
  • Omalizumab 300 mg was nearly twice as effective in improving patients’ quality of life within 12 weeks of treatment versus placebo[1]
  • ASTERIA I is the final omalizumab CSU registration study to be presented; regulatory applications were filed with EU and US authorities in Q3 2013
  • CSU is a debilitating form of hives and chronic itch; more than 50% of patients do not respond to approved doses of antihistamines, the only licensed treatment

Novartis announced today new results from the Phase III ASTERIA I study showing omalizumab was effective and safe in the treatment of chronic spontaneous urticaria (CSU)[1], a chronic and debilitating form of hives. ASTERIA I is the final pivotal registration study for omalizumab in CSU to be announced, and results were presented today for the first time at the 22nd Congress of the European Association of Dermatology and Venereology (EADV) in Istanbul, Turkey. Omalizumab is currently not approved for the treatment of CSU.

The ASTERIA I data support the positive and consistent results from two previously reported pivotal Phase III registration studies of omalizumab in CSU (ASTERIA II and GLACIAL), which were presented at major medical congresses earlier this year[2],[3]. Regulatory applications for omalizumab in CSU were filed with US and EU health authorities in the third quarter of 2013, based on data from nearly 1,000 patients included in these Phase III studies.

“The positive new data clearly show the potential of omalizumab to treat CSU, a disease where more than 50% of patients don’t respond to approved doses of antihistamines, the only licensed treatment option,” said Tim Wright, Global Head of Development, Novartis Pharmaceuticals. “With submissions to EU and US regulatory authorities now completed, we are on track to bring omalizumab to people suffering from this chronic and debilitating disease.”

Specifically, the ASTERIA I study showed that patients treated with omalizumab responded as early as Week 1 (300 mg dose), compared to Week 4 in the placebo group (p=<0.0001)[1]. By Week 12 all three omalizumab doses (300 mg, 150 mg and 75 mg) were significantly superior to placebo in improving patients’ weekly Itch Severity Score (ISS), which was the primary endpoint of the study[1]. This benefit was maintained throughout active treatment (Week 24)[1].

The study also showed patients treated with omalizumab 300 mg experienced nearly twice the improvement in their quality of life compared to those taking placebo by Week 12 (p<0.0001)[1]. Quality of life measures are critical to assessing CSU treatments, because the disease can frequently lead to other negative consequences such as sleep deprivation, depression and anxiety[4].

In addition, by Week 12 more than half (52%) of omalizumab 300 mg patients in the study had their CSU symptoms (itch, hives) well controlled and 36% had no symptoms at all (p<0.0001)[1]. At the same time point, omalizumab 300 mg treated patients also experienced a significant increase in the proportion of days free of deep tissue swelling, also known as angioedema (p<0.0001)[1].

The study met all pre-specified secondary efficacy endpoints for omalizumab 300 mg and 150 mg compared to placebo, except the 150 mg group did not reach statistical significance versus placebo for the quality of life measurement at Week 12.

The incidence and severity of adverse events (AEs) was similar across all ASTERIA I treatment groups. Five omalizumab patients experienced serious AEs during the treatment period (75 mg group n=2, 150 mg group n=3, 300 mg group n=0), compared to four patients in the placebo group[1]. No deaths were reported during this study[1].

CSU is also known as chronic idiopathic urticaria (CIU) in the US, and is a severe and distressing skin condition characterized by red, swollen, itchy and sometimes painful hives or wheals on the skin[5],[6] that spontaneously present and re-occur for more than six weeks[2].At any given time, the prevalence of CSU is 0.5% to 1% worldwide[4].

Omalizumab is being jointly developed by Novartis and Genentech, Inc. for CSU.

About the ASTERIA I Study ASTERIA I was a 40-week, global, multi-center, randomized double-blind study that evaluated the efficacy and safety of omalizumab compared to placebo. It involved 318 patients between the ages of 12 and 75 with moderate-to-severe CSU who remained symptomatic despite prior treatment with H1 antihistamine treatment. Patients were randomized to omalizumab 300 mg, 150 mg, 75 mg or placebo (1:1:1:1), given subcutaneously every four weeks for a total period of 24 weeks, and subsequently monitored during a 16 week follow-up period when there was no active treatment[1].

The primary endpoint, ISS at Week 12, was assessed via a 21-point scale at Week 12[1]. Omalizumab significantly improved the mean weekly ISS from baseline by 9.4 in the 300 mg treatment arm (p<0.0001), 6.7 in the 150 mg treatment arm (p=0.0012) and 6.5 in the 75 mg treatment arm (p=0.0010), compared to a 3.6 improvement in patients on placebo[1].

Health-related quality of life was assessed using the Dermatology Life Quality Index (DLQI) questionnaire (range of 0-30, with a higher score representing greater impairment)[1]. Control of CSU symptoms was assessed by a measure of itch and hives called the weekly urticaria activity score (UAS7), where any score of 6 or less out of a 42 point score is considered to represent a well-controlled disease and a score of zero represents a complete resolution of symptoms[1]. In addition, time to response was measured by the median time to Minimally Important Difference (MID)[1].

About Omalizumab (Xolair®) Omalizumab is a targeted therapy unique in binding to immunoglobulin E (IgE). It is currently not approved for the treatment of CSU. Omalizumab suppresses histamine-induced skin reactions, probably through its reduction of IgE and downstream effects on cellular activation mechanisms[7]. Research is ongoing to understand the mechanism of action of omalizumab in CSU, which could lead to deeper understanding of how the disease develops[8].

Omalizumab is approved for the treatment of moderate to severe persistent allergic asthma under the brand-name Xolair® in more than 90 countries, including the US since 2003 and the EU since 2005. In the EU it is approved for the treatment of severe persistent allergic asthma in children (aged six and above), adolescents, and adults. Following approval in the EU, a liquid formulation of Xolair in pre-filled syringes has been launched in most European countries. In the US, Xolair (omalizumab) for subcutaneous use in appropriate allergic asthma patients is co-promoted by Novartis Pharmaceuticals Corporation and Genentech, Inc.

Novartis data presented at ERS showcases once-daily COPD portfolio and further demonstrates efficacy of Ultibro® Breezhaler® (QVA149) .


 

  • BLAZE study also demonstrated significant improvements in shortness of breath with QVA149 compared to tiotropium 18 mcg in patients with moderate-to-severe COPD[3]

 

  • SPARK study showed similar rates of reduction in exacerbations with once-daily Seebri® Breezhaler®(glycopyrronium bromide) and open-label tiotropium 18 mcg in patients with severe-to-very severe COPD[4],[5]

 

Novartis announced today new analyses of data for once-daily Ultibro® Breezhaler®(investigational QVA149 – indacaterol 85 mcg/glycopyrronium 43 mcg delivered dose, equivalent to 110 mcg/50 mcg metered dose per capsule), which showed significant improvements in lung function, shortness of breath and health-related quality of life for chronic obstructive pulmonary disease (COPD) patients versus all comparators[1],[2].These data were part of 39 respiratory abstracts presented at the European Respiratory Society (ERS) Annual Congress in Barcelona, Spain.

 

First results from a pooled analysis of 4,891 COPD patients in the IGNITE clinical trial program (SHINE, ILLUMINATE and SPARK studies) showed that QVA149 provided superior, rapid and sustained improvements in lung function, and significantly reduced shortness of breath, compared to placebo, once-daily indacaterol maleate 150 mcg,glycopyrronium 50 mcg, open-label (OL) tiotropium 18 mcg and twice-daily salmeterol/fluticasone fixed dose combination (FDC SFC) 50 mcg/500 mcg[1],[2]. These improvements were maintained throughout the duration of the trials[1],[2].

 

“COPD is known to affect an estimated 210 million people worldwide[6] and is projected to be the third leading cause of death by 2020[7].Many patients find COPD symptoms really tough to cope with – even if they’re already taking treatment,” said Tim Wright, Head of Development, Novartis Pharmaceuticals. “Novartis is pleased that these new analyses further support that the efficacy of dual therapy, which has the potential to make a real difference to peoples’ lives.”

 

Currently being assessed in a clinical trial program involving over 10,000 patients[8]-[18], investigational QVA149 is a Fixed-Dose Combination (FDC) of two bronchodilators, Onbrez® Breezhaler® (indacaterol maleate), a long-acting beta2-adrenergic agonist (LABA) and Seebri® Breezhaler® (glycopyrronium bromide), a long-acting muscarinic antagonist (LAMA). Both are currently used by healthcare professionals as individual therapies to treat COPD.

 

QVA149 recentlyreceived a positive opinion for approval from the European Medicine Agency’s (EMA) Committee for the Human use of Medicinal Products (CHMP) in July 2013 as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.

 

About additional data presented at ERS

A new evaluation of patients with moderate-to-severe COPD from the BLAZE study showed that QVA149 provided significant improvements in patient-reported shortness of breath compared to tiotropium 18 mcg[3].

 

Clinical data for Seebri® Breezhaler® (glycopyrronium bromide) presented at ERS included efficacy and safety results from the SPARK study[4],[5]. At Week 64, once-daily glycopyrronium 50 mcg showed similar efficacy to OL tiotropium 18 mcg in reducing the rate of exacerbations, improving lung function and health-related quality of life, and reducing rescue medication use in patients with severe-to-very severe COPD[4].

 

In analyses from the SPARK study, glycopyrronium 50 mcg (via Breezhaler®) showed a safety profile in patients with severe-to-very severe COPD that was similar to OL tiotropium 18 mcg (via HandiHaler®)[5].

 

These results build upon the data previously presented from the glycopyrronium bromide Phase III GLOW trials and provide further evidence for Seebri® Breezhaler® as a once-daily LAMA option for COPD patients.

 

About the IGNITE clinical trial program

In the Phase III IGNITE clinical trial program, QVA149 is being investigated for the treatment of COPD patients as aninhaled, once-daily, FDC of indacaterol maleate and glycopyrronium bromide. IGNITE is one of the largest international clinical trial programs in COPD comprising 11 studies in total (ILLUMINATE, SHINE, BRIGHT, ENLIGHTEN, SPARK, BLAZE, ARISE, BEACON, RADIATE, LANTERN, FLAME) with more than 10,000* patients across 52 countries[8]-[20]. The first eight studies (ILLUMINATE, SHINE, BRIGHT, ENLIGHTEN, SPARK, BLAZE, ARISE, BEACON) completed in 2012. The studies are designed to investigate the efficacy, safety and tolerability, lung function, exercise endurance, exacerbations, shortness of breath and quality of life in patients treated with QVA149.

 

Results from the Phase III IGNITE trials[8]-[18]demonstrated statistically significant improvements in bronchodilation with QVA149 versus comparator treatments widely used as current standards of care[21]. Data showed that QVA149 significantly improved bronchodilation compared to OL tiotropium 18 mcg, SFC 50 mcg/500 mcg, indacaterol maleate 150 mcg, glycopyrronium 50 mcg and placebo providing a rapid onset within five minutes, and sustained bronchodilation during a 24 hour period which was maintained for up to 26 weeks[22]. In the IGNITE Phase III trial program, QVA149 also showed symptomatic improvements versus placebo in COPD patients[8],[9],[11],[21]. These symptomatic improvements included shortness of breath, exercise tolerance, rescue medication use and health-related quality of life[8],[9],[11],[21].

 

In clinical studies, QVA149 demonstrated an acceptable safety profile with no meaningful differences between the treatment groups (placebo, indacaterol 150 mcg, glycopyrronium 50 mcg, OL tiotropium 18 mcg, SFC 50 mcg/500 mcg) in the incidence of adverse and serious adverse events[8],[9],[10],[11],[22].

 

*Total refers to all 11 IGNITE studies.

 

About the Novartis COPD portfolio

Novartis is committed to addressing the unmet medical needs of COPD patients and improving their quality of life by providing innovative medicines and devices.

 

Onbrez® Breezhaler® (indacaterol maleate) is a long-acting beta2-adrenergic agonist (LABA) that offers clinically relevant 24 hour bronchodilation combined with a rapid onset of action within five minutes at first dose, as demonstrated in the INERGIZE Phase III trial program[23]-[27]. Onbrez® Breezhaler® 150 mcg once-daily provided greater clinical benefit in terms of reduced shortness of breath, lower use of rescue medication and improved health status, compared with blinded tiotropium bromide 18 mcg in patients with moderate-to-severe COPD[34]. Onbrez®Breezhaler®is approved in approximately 100 countries around the world for maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD[38]. It was first launched in the EU (150 mcg and 300 mcg once-daily doses) and has since received approvals in markets worldwide including Japan (Onbrez® Inhalation Capsules 150 mcg once-daily) and US (ArcaptaTM NeohalerTM 75 mcg once-daily).

 

Once-daily Seebri® Breezhaler® (glycopyrronium bromide) is a novel inhaled long-acting muscarinic antagonist (LAMA; also referred to as a long-acting anticholinergic) indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD[39]. Glycopyrronium bromide was exclusively licensed to Novartis in April 2005 by Vectura and its co-development partner Sosei. Phase III data from the GLOW 1, 2 and 3 studies demonstrated that glycopyrronium 50 mcg delivered rapid and significant sustained improvements in lung function (measured by mean FEV1) from Day 1 compared with placebo and sustained this for 24 hours over 52 weeks, and significantly improved exercise endurance versus placebo[40]-[42]. Seebri® Breezhaler® is approved in the EU/EEA, Japan, Switzerland, Canada, Australia and a number of other countries.

 

Novartis continues development of respiratory products for delivery via a single-dose dry powder inhaler (SDDPI) called the Breezhaler® device which has low air flow resistance, making it suitable for patients with different severity of airflow limitation[43]. The Breezhaler® device allows patients to hear, feel and see that they have taken the full dose correctly[39].

 

Novartis is committed to addressing the unmet medical needs of COPD patients and improving their quality of life by providing innovative medicines and devices.

 

About COPD

COPD is a progressive life-threatening disease that makes it hard to breathe, with symptoms that have a destructive impact on patients’ function and quality of life[7],[44]. It affects an estimated 210 million people worldwide[7] and is projected to be the third leading cause of death by 2020[6]. COPD is often considered to be a disease of later years, but estimates suggest that 50% of those with COPD are now less than 65 years old, resulting in increases in absenteeism, premature retirement and reductions in workforce participation

Source: Novartis Newsletter.

Targeting Interleukin-17 in Patients With Active Rheumatoid Arthritis.


Abstract

Clinical and experimental evidence suggest that interleukin-17A (IL-17A; also known as IL-17) is an attractive therapeutic target in rheumatoid arthritis (RA). Rheumatoid synovial tissue produces IL-17A, which causes cartilage and bone degradation in synovial and bone explants. Overexpression of IL-17A induces synovial inflammation and joint destruction in animal RA models. These effects are attenuated in IL-17A-deficient animals and by agents that block IL-17A. Serum IL-17A levels and, to a greater extent, synovial fluid IL-17A levels are elevated in many patients with RA. In some RA cohorts, higher IL-17A levels have been associated with a more severe clinical course. Several IL-17A blockers, including the anti- IL-17A monoclonal antibodies secukinumab and ixekizumab, and the anti-IL-17 receptor subunit A monoclonal antibody brodalumab have been evaluated in phase II clinical trials. Of these, secukinumab is the most advanced with respect to clinical evaluation in RA, with phase III trials ongoing in patients on background methotrexate who had inadequate responses to previous tumor necrosis factor blocker therapy.

Source: Medscape.com

 

<}� t� �5� -family:”Arial Unicode MS”,”sans-serif”; border:none windowtext 1.0pt;mso-border-alt:none windowtext 0in;padding:0in’>n = 35) while the other half had no personal or family history of a psychiatric disorder, including substance abuse (n = 30). Assessments were made of eating behavior and dietary food intake, estimation of body composition, and measurement of plasma leptin. Although cocaine users reported significantly higher levels of dietary fat and carbohydrates as well as patterns of uncontrolled eating, their fat mass was significantly reduced compared with their non-drug using peers. Levels of leptin were associated with fat mass, and with the duration of stimulant use. Tobacco smoking status or concomitant use of medication did not affect the significance of the results. Weight changes in cocaine users reflect fundamental perturbations in fat regulation. These are likely to be overlooked in clinical practice but may produce significant health problems when cocaine use is discontinued during recovery.

 

 

Novartis first in class once-daily dual bronchodilator Ultibro® Breezhaler® (QVA149) gains positive CHMP opinion for the treatment of COPD.



  • QVA149 (indacaterol/glycopyrronium) is the first once-daily fixed-dose combination of both a LABA and a LAMA bronchodilator to gain positive CHMP opinion 
  • Pivotal Phase III IGNITE data showed QVA149 significantly improved lung function and patient-reported outcomes including breathlessness and rescue medication use, compared to current standard of care[1] 

  • QVA149 demonstrated significantly reduced rates of COPD exacerbations and improved health-related quality of life compared to open-label tiotropium 18 mcg and glycopyrronium 50 mcg[2],[3]

Basel, July 26, 2013 – Novartis announced today that the European Medicines Agency‘s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for approval of once-daily Ultibro® Breezhaler® (indacaterol 85 mcg/glycopyrronium 43 mcg delivered dose, equivalent to 110 mcg/50 mcg metered dose per capsule), as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Ultibro Breezhaler was developed under the name of QVA149.

“The CHMP’s positive opinion supports a major breakthrough in the treatment of COPD, where many patients do not have adequate treatment options,” commented David Epstein, Division Head, Novartis Pharmaceuticals. “QVA149 has shown significant improvements compared with some of the most commonly used treatment options for COPD, which is projected to be the third leading cause of death by 2020.”

QVA149 is an investigational fixed dose combination of two bronchodilators, indacaterol, a long-acting beta2-adrenergic agonist (LABA) and glycopyrronium, a long-acting muscarinic antagonist (LAMA).

QVA149 significantly improved the rate of all exacerbations compared to open-label (OL) tiotropium 18 mcg, glycopyrronium 50 mcg and was comparable to salmeterol/fluticasone (SFC) 50 mcg/500 mcg[3]. The rate of moderate or severe exacerbations was significantly lower compared to glycopyrronium 50 mcg and numerically lower compared to OL tiotropium 18 mcg[2],[3].

In clinical studies, QVA149 demonstrated an acceptable safety profile with no meaningful differences between the treatment groups (placebo, indacaterol 150 mcg, glycopyrronium 50 mcg, OL tiotropium 18 mcg, SFC 50 mcg/500 mcg) in the incidence of adverse and serious adverse events[2],[4],[5].

The European Commission generally follows the recommendations of the CHMP and normally grants a marketing authorization within three months of the opinion. Worldwide submissions and reviews of QVA149 are ongoing with US filing expected at the end of 2014.

About the IGNITE clinical trial program
In the Phase III IGNITE clinical trial program, QVA149 is being investigated for the treatment of COPD patients as an inhaled, once-daily, fixed-dose combination of indacaterol maleate and glycopyrronium bromide. IGNITE is one of the largest international clinical trial programs in COPD comprising 11 studies in total (ILLUMINATE, SHINE, BRIGHT, ENLIGHTEN, SPARK, BLAZE, ARISE, BEACON, RADIATE, LANTERN, FLAME) with more than 10,000* patients across 52 countries[3],[6]-[9],[10]-[17]. The first eight studies (ILLUMINATE, SHINE, BRIGHT, ENLIGHTEN, SPARK, BLAZE, ARISE, BEACON) completed in 2012. The studies were designed to investigate the efficacy, safety and tolerability, lung function, exercise endurance, exacerbations, shortness of breath and quality of life in patients treated with QVA149.

Results from five of the Phase III IGNITE trials[3],[6]-[9]supported the CHMP’s positive opinion for QVA149 which demonstrated statistically significant improvements in bronchodilation versus treatments widely used as current standards of care[1]. Data showed that QVA149 significantly improved bronchodilation compared to OL tiotropium 18 mcg, SFC 50 mcg/500 mcg, indacaterol maleate 150 mcg, glycopyrronium 50 mcg and placebo providing a rapid onset within five minutes, and sustained bronchodilation during a 24 hour period which was maintained for up to 26 weeks, along with symptomatic improvements[1],[3],[7],[8]. These symptomatic improvements included breathlessness, exercise tolerance, rescue medication use and health-related quality of life[3],[4],[5],[6].

*Total refers to all 11 IGNITE studies.

About the Novartis COPD portfolio
Novartis is committed to addressing the unmet medical needs of COPD patients and improving their quality of life by providing innovative medicines and devices.

Onbrez® Breezhaler® (indacaterol maleate) is a long-acting beta2-agonist (LABA) that offers clinically relevant 24 hour bronchodilation combined with a rapid onset of action within five minutes at first dose, as demonstrated in the INERGIZE Phase III trial program[18]-[32]. Onbrez Breezhaler 150 mcg once-daily provided greater clinical benefit in terms of reduced shortness of breath, lower use of rescue medication and improved health status, compared with blinded tiotropium bromide 18 mcg[28]. Onbrez Breezhalerwas first approved and launched in the EU (150 mcg and 300 mcg once-daily doses) for maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD[33]. It has now received approvals in approximately 100 countries around the world including Japan (as Onbrez® Inhalation Capsules 150 mcg once-daily) and USA (as ArcaptaTM NeohalerTM 75 mcg once-daily).

Once-daily Seebri® Breezhaler® (glycopyrronium bromide) is a novel inhaled long-acting muscarinic antagonist (LAMA; also referred to as a long-acting anticholinergic) indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD[34]. Glycopyrronium bromide was exclusively licensed to Novartis in April 2005 by Vectura and its co-development partner Sosei. In Phase III studies (GLOW 1, 2 and 3) Seebri Breezhaler (glycopyrronium 50 mcg) once-daily demonstrated rapid improvements in lung function after first dose on Day 1 which was sustained for 24 hours and maintained over the 52 week study period compared with placebo. Glycopyrronium 50 mcg also significantly improved shortness of breath, health-related quality of life, exacerbation risk, and exercise endurance versus placebo[35].[36],[37]. Seebri Breezhaler is approved in the EU, Japan, Switzerland, Canada, Australia and a number of other countries.

Novartis continues development of respiratory products for delivery via a single-dose dry powder inhaler (SDDPI) called the Breezhaler® device which has low air flow resistance, making it suitable for patients with airflow limitation[38]. The Breezhaler® device allows patients to hear, feel and see that they have taken the full dose correctly[34].

Novartis is committed to addressing the unmet medical needs of COPD patients and improving their quality of life by providing innovative medicines and devices.

References:

[1] Vogelmeier C et al. Once-daily QVA149 provides clinically meaningful improvements in lung function and clinical outcomes versus placebo, indacaterol, glycopyrronium, tiotropium and salmeterol/fluticasone in patients with COPD. [ATS abstract 40759; Session C45; Date: May 21, 2013 Time: 8:15 -10:45].
[2] Decramer M et al. Safety and tolerability of QVA149, glycopyrronium and tiotropium in patients with severe to very severe COPD: the SPARK study. [ATS abstract 41616; Session A43; Date: May 19, 2013 Time:10:45-12:30].
[3] Wedzicha JA et al. Analysis of Chronic Obstructive Pulmonary Disease Exacerbations with the Dual Bronchodilator QVA149 Compared with Glycopyrronium and Tiotropium (SPARK): a Randomized, Double-blind, Parallel-group Study. Lancet Respir Med 2013 http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(13)70052-3/abstract [Accessed 18 July 2013]
[4] Welte T et al. QVA149 once daily is safe and well tolerated in patients with COPD: the SHINE study. [ATS abstract 41616; Session A43; Date: May 19, 2013, 8:15-16.30].
[5]Vogelmeier C et al. QVA149 once daily is safe and well tolerated in patients with COPD: the ILLUMINATE study. [ATS abstract 41633; Session A43; Date: May 19, 2013, 8:15-16.30].
[6] Beeh et al. QVA149 once daily improves exercise tolerance and lung function in patients with COPD: the BRIGHT study. [BTS Winter Meeting 2012, Poster presentation P191; Date: 6 December; Time: 16:00-17:30].
[7] Vogelmeier CF et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol/fluticasone in patients with COPD (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respiratory Medicine. 2013; 1 (1): 51-60.
[8] Bateman ED et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. European Respiratory Journalhttp://erj.ersjournals.com/content/early/2013/05/30/09031936.00200212.full.pdf [Accessed 18 July 2013].
[9] Dahl et al, 2012. QVA administered once daily provides significant improvements in lung function over 1 year in patients with COPD: The ENLIGHTEN study. Volume abstract 853405.
[10] Mahler D et al. Superior lung function with once-daily QVA149 translates into improvements in patient reported breathlessness compared with placebo and tiotropium in COPD patients: the BLAZE study. [ATS abstract 45308; Session C20; Date: May 21, 2013 Time: 8:15-10:45].
[11] ClinicalTrials.gov, November 2012. Long Term Safety and Tolerability of QVA149 Versus Tiotropium in Japanese Patients With Chronic Obstructive Pulmonary Disease (COPD) (ARISE). [Online] Available at: http://www.clinicaltrials.gov/ct2/show/NCT01285492?term=%28ARISE%29&rank=4 . [Accessed 18 July 2013].
[12] ClinicalTrials.gov, n.d. Comparison of Safety and Efficacy of the Combination Product QVA149A Against the Concurrent Administration of the Individual Components, QAB149 and NVA237, in Patients With Chronic Obstructive Pulmonary Disease (COPD) (BEACON). [Online]
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[14] ClinicalTrials.gov, n.d. A 26-week Treatment Randomized, Double-blind, Double Dummy, Parallel-group Study to Assess the Efficacy, Safety and Tolerability of QVA149 (Indacaterol / Glycopyrronium Bromide) Compared to Fluticasone/Salmeterol in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease. [Online]. Available at: www.clinicaltrials.gov/ct2/show/NCT01709903?id=01709903&rank=1.[Accessed 18 July 2013].
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[17] ClinicalTrial.gov, n.d. A 52-week Treatment, Multi-center, Randomized, Double-blind, Double Dummy, Parallel-group, Active Controlled Study to Compare the Effect of QVA149 (Indacaterol Maleate / Glycopyrronium Bromide) With Salmeterol/Futicasone on the Rate of Exacerbations in Subjects With Moderate to Very Severe COPD (FLAME). [Online] Available at: http://clinicaltrials.gov/ct2/show/NCT01782326?term=COPD+novartis+52&rank=2 .[Accessed 18 July 2013].
[18] Vogelmeier K et al. Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded comparison with tiotropium. Respir Res 2010;11:135.
[19] Balint B et al. Onset of action of indacaterol in patients with COPD: comparison with salbutamol and salmeterol- fluticasone. Int J Chron Obstruct Pulmon Dis2010; 5:311-8.
[20] La Force C et al. Sustained 24-hour efficacy of once-daily indacaterol (300 Mu g) in patients with chronic obstructive pulmonary disease: a randomized, crossover study. Pulm Pharmacol Ther 2011; 24:162-8.
[21] Beeh et al. Effect of indacaterol maleate on dynamic lung hyperinflation in patients with COPD.  Eur Respir J 2009; 34 (suppl 53): E4357.  Entire results are also included at: http://www.novctrd.com/ctrdWebApp/clinicaltrialrepository/displayFile.do?trialResult=2737 [Accessed 18 July 2013]
[22] O’ Donnell DE et al. Effect of indacaterol on exercise endurance and lung hyperinflation in COPD.  Respir Med 2011; 105(7): 1030-6.
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[32] Mahler DA et al. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised double-blind comparison. Thorax 2012. Doi:10.1136/thorax8jnl-2011-201140.
[33] EMA, 2012. Onbrez® Breezhaler® (indacaterol) EU Summary of Product Characteristics. [Online] July 26, 2012 Available at:http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001114/human_med_001219.jsp&mid=WC0b01ac058001d124. [Accessed 18 July 2013].
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Source: Novartis Newsletter.

Fluticasone furoate and vilanterol for COPD.


The Article by Mark Dransfield and colleagues1 reports replicate studies of the efficacy of fluticasone furoate and vilanterol on exacerbations in chronic obstructive pulmonary disease (COPD). The primary objective was to test the effect of a once-daily combination inhaler, so it is surprising that there was no comparator group of conventional twice-daily dosing. The distinctly modest improvement in comparison to the once-daily long-acting β agonist is certainly not greater, and perhaps even less than, that seen in several other studies using the twice-daily regimen. One cannot conclude that superior efficacy has been demonstrated for the once-daily dosing. Compliance may be improved with once-daily therapy but remains unproven for this class of drug.

Furthermore, as in many other studies of inhaled corticosteroid and long-acting β agonists, the significance of pre-study therapy is ignored. Over two thirds of patients in the studies of Dransfield and colleagues were taking an inhaled corticosteroid at study entry. Thus, those randomised to vilanterol alone underwent steroid withdrawal. Figure 4 in the Article shows that any difference in exacerbation rate occurs within 90 days of treatment initiation. The hypothesis that withdrawal of steroids increases exacerbations in COPD is well established.2 Re-analysis of the OPTIMAL study by Suissa and colleagues3 demonstrated no advantage for inhaled corticosteroids in addition to long-acting β agonists in steroid-naive patients, whereas those previously taking inhaled corticosteroids who were assigned to long-acting β agonist alone had a worse prognosis. We ask the authors to present the effects of fluticasone furoate and vilanterol on exacerbation rates stratified by inhaled corticosteroid pre-trial therapy. Until such evidence is forthcoming, we cannot rule out that any positive effects reported may be due to a simple artefact of trial design.

Even if anticipated, the confirmation of a significant excess of pneumonia with fluticasone furoate in a 1 year study is disappointing. This excess of pneumonia has been difficult to demonstrate with other inhaled corticosteroids4 and may be due to the greater lipophilicity and slower clearance of fluticasone, which with repeated dosing results in accumulation in the lung. Given this confirmation of fluticasone toxicity, should the position of high-dose fluticasone drugs be re-examined? In England, the market leader is fluticasone propionate (250 μg), salmeterol (25 μg) metred-dose inhaler, with sales of £170 million in 2011.5 Although unlicensed for COPD, its market position indicates confusion among doctors as to the diagnostic subtleties between severe asthma and COPD. We believe that the withdrawal of high-dose fluticasone preparations on safety grounds is now justified, and would also save patients and health-care providers a great deal of money.

JBM has received speaker fees and sponsorship to attend the ERS, ATS, BPS, and BTS conferences, and educational grants from pharmaceutical companies including Novartis, Boehringer Ingelheim, GlaxoSmithKline, Chiesi, Merck Sharp & Dohme, Pfizer, Amgen, Napp, Almirall, and Teva. AHM has received speaker fees and sponsorship to attend the ERS, ATS, and BPS conferences from pharmaceutical companies including Novartis, Boehringer Ingelheim, GlaxoSmithKline, Chiesi, Proctor & Gamble, Almirall, AstraZeneca, Glenmark, and Philips Home Healthcare Solutions.

References

1 Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 2013; 1: 210-223. PubMed

2 Suissa S, Barnes PJ. Inhaled corticosteroids in COPD: the case against. Eur Respir J 2009; 34: 13-16. CrossRef | PubMed

3 Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of COPD. Eur Respir J 2008; 31:927-933. CrossRef | PubMed

4 Sin DD, Tashkin D, Zhang X, et al. Budesonide and the risk of pneumonia: a meta-analysis of individual patient data. Lancet2009; 374: 712-719. Summary | Full Text | PDF(174KB) | CrossRef | PubMed

5 Health and Social Care Information Centre, Prescribing and Primary Care. Prescription cost analysis—England.http://www.ic.nhs.uk/article/2021/WebsiteSearch?productid=5461&q=+prescriptions+cost+analysis+2011&sort=Relevance&size=10&page=1&area=both#top. (accessed May 10, 2013).

Source: Lancet

Do we need tougher drug patent laws?


History has witnessed numerous drug patent wars, but in April 2013, the Indian Supreme Court did something which captured the attention of the international media. It denied a patent to the beta crystalline form of Imatinib mesylate, a life saving anticancer drug, to the Swiss pharmaceutical company Novartis. The verdict was noteworthy because this drug is patented in more than 38 countries including the US, Russia, and China. Today this drug is being manufactured by generic drug companies in India. Is this a victory against the monopoly of pharmaceutical giants, or has India set a dangerous precedent which will discourage the innovation of future drugs?

As a researcher myself, I understand the importance of patent protection for any intellectual property. Patents give exclusive rights to the innovators for a limited period of time which acts as an incentive for future research and development (R&D). According to estimates, a company spends between US$ 500 million to US$ 2 billion for the discovery, research, testing, and marketing of a new drug. [1] In addition, patents encourage innovators to make their discoveries available for public use.

So why did the court rule against these relevant arguments?

Patentability of a product relies heavily on its novelty. The court argued that the product was not unique, but merely a tweaked version of an already known compound, noting that Imatinib was patented in many countries in 1996. Many researchers are making similar observations about other pharmacological agents and accusing the companies of “evergreening,” a practice which enables them to claim a new patent by slightly modifying the chemical composition of a known drug. Recently an article in the BMJ pointed out that about 85-90% of all new drugs since the mid 90s provide few or no clinical advantages for patients. [2] Even Brian Druker, who developed the beta version of Imatinib, believes in the need for novel, and not just modified drugs.

After the court’s decision, Novartis said it would pull out all R&D investments from India. It should be noted that India has never been a home to new drug discoveries as its priority is to provide cheap medicines to as many people possible. In other words, India has a different role to play in the pharmaceutical industry. India is a major market for manufacturing drugs in their generic form and providing them cheaply to patients in India as well as in other developing and poor countries. For instance, a 400mg pill of the drug in question is being manufactured by Novartis at US$99 each and the same by a generic drug manufacturer at a cost of around US$9. [3] No wonder Médecins Sans Frontières and other charitable health organisations hailed the court’s decision. This brings us to the question of affordability. 81% of the Indians live on less than US$2.5 a day. Predatory pricing and a market monopoly will make healthcare costlier for those living in the developing world as well as for those struggling in the developed. We do not want life saving drugs to be luxury goods.

It has been argued that stricter patent laws will encourage innovation. This is true to some extent as innovators will then be forced to push their limits to develop novel and better products. But we cannot afford to overstretch the strings. If the innovators are denied of their deserved rights and royalties, the intent to discover and invent will die. Some suggested that pharmaceutical companies should act morally and take into account the economic condition of the country they are selling in before pricing their products.

Coming back to our initial question: do we need tougher drug patent laws? There is no simple answer to this. Patients’ interests come first and they must be provided with the best medicines at an affordable price but we also need to incentivise the innovative thinking. A consensus on this patent vs patient issue can only be achieved by debate and discussion.

Source: BMJ