Replies to post #97783 on Biotech Values

[DewDiligence]

From #msg-49185209:

Onbrez Breezhaler (QAB149)…a once-daily long-acting bronchodilator for adult patients with chronic obstructive pulmonary disease (COPD), was launched in Germany in December 2009 as well as Ireland and Denmark in March 2010 after European regulatory approval in November 2009. More than 20 launches are planned globally for the second half of 2010, including in the UK, Spain, Brazil and Mexico. Regulatory submissions are also planned for 2010 in Japan and China. In the US, all clinical studies to support resubmission have been started following a Complete Response letter from the FDA in October 2009 requesting additional data.

[DewDiligence]

NVS’ Onbrez (QAB149) Non-Inferior to Spiriva in COPD

[On the primary endpoint of FEV1, Onbrez was slightly better numerically than Spiriva, but not by nearly enough to achieve a statsig finding of superiority. Onbrez is approved in the EU and is awaiting an FDA response to a resubmitted NDA in Sep 2010.]

http://www.novartis.com/newsroom/media-releases/en/2010/1458359.shtml

›Onbrez® Breezhaler® from Novartis provides greater clinical benefits than tiotropium in new study of COPD patients

* Study shows Onbrez Breezhaler superior to tiotropium in reducing breathlessness and use of rescue medication and in improving overall health status

* INTENSITY is first blinded head-to-head study with primary goal of comparing once-daily Onbrez Breezhaler with tiotropium, an established COPD therapy

* Study shows once-daily Onbrez Breezhaler was as effective as tiotropium in improving patients' lung function

* Phase III study adds to comprehensive data supporting Onbrez Breezhaler as effective and well-tolerated treatment for chronic obstructive pulmonary disease

Basel, November 3, 2010 - Novartis today announced new results from a blinded Phase III head-to-head study showing that once-daily Onbrez® Breezhaler® (indacaterol) was as effective as tiotropium in improving lung function in patients with chronic obstructive pulmonary disease (COPD), while providing greater clinical benefits in terms of reduced breathlessness, lower use of rescue medication and improved health status.

The results were presented at the annual CHEST meeting of the American College of Chest Physicians (ACCP) in Vancouver, Canada.

INTENSITY is the first blinded head-to-head study whose primary objective was to compare Onbrez Breezhaler, a novel long-acting beta-2 agonist (LABA), with tiotropium (Spiriva® HandiHaler®), a long-acting anti-muscarinic (LAMA) and an established treatment for COPD. The two medicines have different modes of action but are both inhaled once-daily to provide bronchodilation, i.e. increased airflow into the patient's lungs.

"These results add to the growing body of evidence supporting the use of indacaterol in COPD, delivering sustained improvements in lung function that can translate into real patient benefits,'' said Leonard Dunn, MD, FCCP, Medical Director for Pulmonology at Clinical Research of West Florida, Clearwater, Florida, and lead investigator in the INTENSITY study. "The study confirms that indacaterol is an effective and well-tolerated treatment that should be considered, where available, as a maintenance therapy option for COPD patients."

A total of 1,598 patients with moderate-to-severe COPD were enrolled in the blinded, double-dummy study in which they received once-daily treatment with either Onbrez Breezhaler 150 mcg or tiotropium 18 mcg. The study met its primary endpoint by demonstrating non-inferiority of Onbrez Breezhaler to tiotropium after 12 weeks in terms of lung function, measured by forced expiratory volume of breath in one second (FEV1). Results showed that baseline-adjusted trough FEV1 at 12 weeks was 1.44 L with Onbrez Breezhaler and 1.43 L with tiotropium (mean of 23 hrs 10 mins and 23 hrs 45 mins post-dose, p<0.001 for non-inferiority). FEV1 superiority to tiotropium, one of the secondary endpoints, did not reach statistical significance.

Onbrez Breezhaler showed superiority to tiotropium on other secondary endpoints relating to key patient outcomes. Breathlessness improved significantly more with Onbrez Breezhaler than tiotropium (total scores of 2.01 vs. 1.43 in transition dyspnea index, p<0.001). Onbrez Breezhaler patients used less albuterol rescue medication (change of -1.40 vs. -0.85 puffs/day, p<0.001) and had a higher percentage of days without rescue medication use (46.1 vs. 41.4, p=0.004). Patients using Onbrez Breezhaler reported significantly better health status than those on tiotropium (mean change of -5.1 vs. -3.0 in St George's Respiratory Questionnaire, p<0.001).

"This study provides further evidence of the potential additional benefits that Onbrez Breezhaler can bring to COPD patients compared to medicines that are widely used in current clinical practice," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "Our Phase III program involves 16,000 patients in a series of clinical trials which together provide a comprehensive understanding of the efficacy and safety of Onbrez Breezhaler."

The incidence of adverse events in the INTENSITY study was similar for both treatments, with adverse events reported in 39.7% vs. 37.2% of patients using Onbrez Breezhaler and tiotropium respectively, and serious adverse events in 2.8% vs. 3.8% respectively. The most common adverse events were COPD worsening (including exacerbations), cough, and nasopharyngitis.

A third-party blinding system was used under which the drug was dispensed to patients by a person at each site who was neither the investigator nor the study coordinator. Both the investigator staff and patient were therefore blinded to treatment assignment.

Another study to be presented at the CHEST meeting investigated patients' use of different inhaler devices, an important factor in the success of COPD therapy. The seven-day, open-label, crossover study called INDEED compared patients' handling and preference for the Onbrez Breezhaler and the tiotropium HandiHaler®* devices. Results will be presented on November 3.

Onbrez Breezhaler was first approved in November 2009 in the European Union, where it is indicated for the maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD. It is now approved in more than 40 countries and has been launched in 12 of them. Indacaterol is currently under regulatory review in the US. Following a Complete Response Letter received in October 2009, data from additional studies were submitted to the Food and Drug Administration (FDA) in September 2010.

COPD is a progressive, life-threatening disease associated with tobacco smoking, air pollution or occupational exposure, which causes obstruction of airflow in the lungs resulting in debilitating bouts of breathlessness. COPD affects 210 million people worldwide and is projected to be the third leading cause of death by 2020. Although often considered a disease of the elderly, research has shown that a majority of COPD patients are under the age of 65 when they are likely to be at the peak of their earning power and family responsibilities.‹

[DewDiligence]

Novartis’ Next Mega-Blockbuster?

[No, I’m not talking about Gilenya, but rather QVA149, an inhaled combination treatment for COPD that could take share from Advair and Spriva (#msg-56227067, #msg-41509884). One of the constituent drugs in QVA149 is Indacaterol (a/k/a/ Onbrez Breezhaler, QAB149), a LABA that goes before an FDA advisory panel next week as a monotherapy. (The other drug in QVA149 is NVA237, a LAMA that NVS licensed from Vectura.)

QAB149 received an FDA CRL in Oct 2009 (#msg-42658767) despite its being approved in the EU a month earlier (#msg-41904142 ). If there is any hang-up in getting QAB149 approved as a monotherapy, it would lessen the probability that NVS could launch QVA149 as planned in 2013.]

http://www.reuters.com/article/2011/03/02/novartis-gsk-respiratory-idUSLDE72108F20110302

›Wed Mar 2, 2011 10:14am EST
By Ben Hirschler and Katie Reid

LONDON/ZURICH, March 2 (Reuters) - Novartis (NVS) and GlaxoSmithKline (GSK) are battling to dominate the market for next-generation respiratory drugs, with the Swiss upstart banking on a positive U.S. review next week to help its cause.

A green light for new drug indacaterol from a U.S. panel on March 8 would give Novartis the cornerstone it needs for its key combination drug, QVA149, which some analysts are already tipping as a potential $5 billion-a-year seller.

If successful, that two-in-one inhaled treatment for chronic lung disease would eat into sales of both GSK's $8 billion drug Advair and Pfizer's (PFE) $3.6 billion Spiriva.

"This could be a $20 billion market and Novartis may set a new standard in COPD (chronic obstructive pulmonary disorder)," said Helvea analyst Karl-Heinz Koch.

"There is still so much potential to improve what is out there. COPD is still not well treated."

A smooth ride, however, is not guaranteed because indacaterol is a so-called long-acting beta agonist (LABA) -- a class of drugs that has raised safety concerns at the Food and Drug Administration (FDA) when given to asthmatics.

The FDA already rebuffed indacaterol once in October 2009 [#msg-42658767]

Its advisory committee will next week assess two doses of indacaterol and it is important for Novartis that the higher 150 microgram dose is endorsed along with the lower 75 mcg.

JP Morgan analysts peg the probability of backing for both doses at 60 percent -- a result they say would mark a big boost to confidence in Novartis's respiratory pipeline, which has the potential to add up to 8 percent to the company's value.

Crucially, it would consolidate Novartis's lead over GSK in the race to develop a treatment for COPD that combines a LABA with a long-acting muscarinic antagonist (LAMA) to produce a more effective, convenient therapy.

Once-daily QVA149 is well into final-stage clinical trials and may reach the U.S. market in 2013, while GSK's rival LABA/LAMA drug only entered Phase III testing last month.

Indacaterol is already on sale as a monotherapy in Europe under the brand name Onbrez Breezhaler [#msg-41904142 ] and had revenues of $33 million in 2010. Its U.S. name will be Arcapta Neohaler.

NEW KID ON THE BLOCK

Until recently, Novartis was not on the radar as a major force in lung drugs, which are typically difficult to make because of the inhaler devices they require for delivery.

Now the field is emerging as pivotal to its future -- not just through the drive into new branded drugs but also via its work with partner Vectura (VEC.L) on generic copies of products like GSK's Advair and AstraZeneca's (AZN) Symbicort [#msg-56771288].

Given the difficulties of developing respiratory drugs, a lot of analysts have so far been cautious about building big expectations for QVA149 into their models.

Many currently forecast QVA149 sales of $1.0-1.5 billion, although independent analyst BioMedTracker puts it at $3.3 billion by 2020 and JP Morgan sees a peak of $5 billion.

Andrew Weiss of Vontobel predicts $2.8 billion but thinks Novartis still faces significant challenges, especially if U.S. experts decide next week to play it safe on dosing.

"If it doesn't get the higher dose approved, then it will be stuck with a drug that is approved at a dose that is not that effective," he said.

What's more, a novel LABA/LAMA combination is not the only game in town. GSK also has high hopes for its "son of Advair" drug, Relovair, being developed with Theravance (THRX), which combines a LABA and an inhaled corticosteroid (ICS).

Here, the British company believes it has a clear edge, since Novartis has decided not to develop its rival LABA/ICS product for the U.S. market.‹

[DewDiligence]

NVS’ NVA237 Succeeds in ‘GLOW2’ Phase-3 Study in COPD

[NVA237 is a long-acting muscarinic antagonist (LAMA) that NVS is developing as a monotherapy for COPD and as a combination therapy with QAB149 (a LABA) for asthma and COPD. As a monotherapy, NVA237 has now succeeded in two large phase-3 trials: GLOW-2, the subject of this PR, and GLOW-1, a similar trial that reported data in Apr 2011 (#msg-62261390). The main difference between these two trials is that GLOW-2 contained an open-label comparator arm where patients received PFE’s Spiriva. According to this PR, NVA237 had “similar” efficacy to Spiriva, but the PR does not say NVA237 was statsig non-inferior; we’ll have to wait until the data are presented at a medical conference to find out, but my guess is that NVA237 missed the threshold for statisg non-inferiority to Spiriva, which could be detrimental from a marketing standpoint. In any case, NVS will submit regulatory applications for NVA237 monotherapy before the end of 2011, and this product would seem to be very likely to be approved.

On the other hand, NVS’ plans to combine NVA237 and QAB149 into a product called QVA149 (to compete with such 2-drug products as GSK’s Advair) have hit a bump in the road with respect to the QAB149 (LABA) component of the combination. Following an FDA CRL in 2009 and a resubmission with more data, an FDA advisory panel in Mar 2011 rejected the 150mcg dose of QAB149 monotherapy that is used in the QVA149 combination (#msg-60733567). QAB149 monotherapy (a/k/a Onbrez Breezhaler) was approved in Europe in 2009 (#msg-41904142), so perhaps the FDA and the FDA advisory panel are being overly cautious. The PDUFA date for QAB149 monotherapy is 7/31/11.]

http://www.novartis.com/newsroom/media-releases/en/2011/1527049.shtml

›June 30, 2011 07:15 CET

Novartis Phase III study shows once-daily NVA237 is superior to placebo and similar to tiotropium in improving lung function in COPD

• GLOW2 study shows NVA237 provides superior 24-hour bronchodilation to placebo (p<0.001) with comparable efficacy to open-label tiotropium at 12 weeks

• NVA237 shown to be well-tolerated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD)

• Phase III data support first regulatory submission for NVA237 by end of 2011

Basel, June 30, 2011 - Results from the pivotal Phase III GLOW2 clinical trial show that once-daily NVA237 (glycopyrronium bromide) 50 mcg significantly improved lung function in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) relative to placebo (p<0.001), with similar efficacy to open-label tiotropium [Spiriva].

Further efficacy and safety results from GLOW2 will be presented at a scientific congress in 2012, and the data will be used to support an application for regulatory approval to be filed before the end of 2011.

"NVA237 has demonstrated its potential benefit for COPD patients in two large pivotal Phase III studies," said Trevor Mundel, MD, Global Head of Development at Novartis Pharmaceuticals. "This new study adds to the growing evidence that NVA237 could be an important treatment option for COPD, and supports our plans to develop a fixed-dose combination with our long-acting beta2-agonist Onbrez® Breezhaler® (indacaterol)" [a/k/a QVA149, a combination of NVA237 and QAB149].

In an exploratory arm of the study, NVA237 was compared with open-label tiotropium (Spiriva® HandiHaler®*) 18 mcg, another once-daily long-acting muscarinic antagonist (LAMA) indicated for the treatment of COPD. Results show that NVA237 produced similar improvements in lung function to tiotropium. [Were they statsig non-inferior?]

The study met its primary endpoint by demonstrating superior 24-hour bronchodilation to placebo at 12 weeks measured by trough FEV1 (i.e. forced expiratory volume in one second), a standard measure of lung function. NVA237 was delivered using the Concept1® device, a single-dose dry-powder inhaler.

Key secondary endpoints were improvement in breathlessness assessed using the Transition Dyspnea Index (TDI) at 26 weeks, and improved quality of life as measured by the St George's Respiratory Questionnaire (SGRQ) at 52 weeks. Important secondary endpoints were time to first COPD exacerbation and use of rescue medication during 52 weeks of treatment. The study met all of these endpoints.

The GLOW2 study also showed that NVA237 was well-tolerated with a similar incidence of adverse events for patients treated with NVA237, placebo and open-label tiotropium.

GLOW2 was a 52-week double-blind, placebo-controlled, parallel-group study involving 1,066 patients to assess the efficacy, safety and tolerability of NVA237 in patients with COPD. Patients were randomized into three treatment arms receiving either once-daily NVA237 50 mcg or placebo (double-blind), or once-daily tiotropium 18 mcg[1] (open label). They were also permitted to use COPD background therapy and rescue medication.

In April 2011 Novartis announced results from the first Phase III clinical trial with NVA237 [#msg-62261390]. The pivotal double-blind 26-week GLOW1 study met its primary endpoint by demonstrating superior bronchodilation to placebo at 12 weeks measured by trough FEV1 (p<0.001). The incidence of adverse events was similar in NVA237-treated patients and in those receiving placebo. Further data from GLOW1 will be presented at the European Respiratory Society congress in Amsterdam in September 2011.

COPD is a progressive, life-threatening disease associated with tobacco smoking, air pollution or occupational exposure, which causes obstruction of airflow in the lungs resulting in debilitating bouts of breathlessness. COPD affects 210 million people worldwide and is projected to be the third leading cause of death by 2020. Although often considered a disease of the elderly, research has shown that a majority of COPD patients are under the age of 65 when they are likely to be at the peak of their earning power and family responsibilities.

NVA237 was licensed to Novartis in April 2005 by Vectura and its co-development partner Sosei.‹

[DewDiligence]

NVS submits MAA for NVA237 (a/k/a Seebri Breezhaler) for COPD:

http://finance.yahoo.com/news/NVA237-Filed-in-Europe-and-prnews-3474119034.html?x=0&.v=1

NVS also presented new phase-3 data for this drug today at the ERS conference.

See the prologue of #msg-64761738 for background info.