Symbicort's rapid onset of action and lack of pneumonia signal could be competitive advantages as the drug enters the market with its newly approved use for chonic obstructive pulmonary disease.

Symbicort (budesonide/formoterol fumarate dihydrate), AstraZeneca's asthma management drug, received FDA approval for COPD Feb. 27 - giving it nearly identical indications as GlaxoSmithKline's blockbuster Advair. Advair (fluticasone/salmeterol inhalation powder), though, has an added advantage and one that is hard to come by - a claim for reduced exacerbations.

Exacerbations, which can result in hospitalizations, are a major concern for COPD patients and GSK had to push for approval of that claim for Advair from FDA. The agency issued a "not approvable" letter for the firm's initial application for a survival and reduced exacerbations claim in 2007 (¹ Also see "Avandia Market Share Stabilizing, GSK CEO Garnier Says" - Pink Sheet, 23 April, 2008.). Advair received an FDA OK last April, around the same time AstraZeneca filed the sNDA for Symbicort.

Symbicort 160/4.5 mcg is approved for the twice daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema, with twice-daily inhalations, like Advair 250/50 mcg. Both are long-acting beta-2 agonists, which recently were in the spotlight because of FDA safety concerns regarding use by asthma patients (² Also see "FDA Panels Favor Advair, Symbicort Over Single-Entity LABAs For Asthma" - Pink Sheet, 15 December, 2008., p. 20).

Though Advair has the advantage of an exacerbation indication, a slight cost difference may sway some patients to use Symbicort. Decision Resources analyst Regina Jammen estimated that Symbicort will be priced at about $2.46 per day for COPD versus Advair at about $4.98 per day, taking into account differences in prescribing across indications, based on the ex-manufacturers price data from IMS Health.

[Editor's note: The original version of this story incorrectly reported Symbicort's indication and Advair's dosing. Also AstraZeneca clarified that it will not promote Symbicort based on its risk profile. "While obviously a factor the medical community may consider in deciding whether to prescribe Symbicort, we are not promoting by differentiating its risk profile. Onset of action is included in our label, and is a valid differentiator and an attribute of Symbicort we do intend to highlight with physicians," the firm said. Further, AstraZeneca offered a pricing estimate that differs from the one offered by Descision Resources. The wholesale acquisition cost for Symbicort is $5.87/day and the WAC for Advair is $6.35/day, according to Firstdata Bank, the firm notes.]

"There is a price difference that is meaningful, but physicians are reluctant to switch patients from one drug to another if they're well managed. However, we have to see if cost constraints are going to impact [sales] and how meaningful onset of action will be," she continued. "But Symbicort does provide an excellent alternative for patients, for a variety of reasons - it could be a device issue, a cost issue, preference in molecules..."

AstraZeneca estimates that about 12 million people in the U.S. have moderate to severe COPD, and about 40 percent of those have more severe cases of the disease.

AstraZeneca will have to aggressively market Symbicort to gain share in a competitive COPD market, and focusing on new patients may be the firm's best bet, analysts offered.

"We anticipate there will be some switching [from other treatments to Symbicort], but the majority of patients will be new patients," Jammen said.

AstraZeneca Touts Rapid Onset

A clear advantage to Symbicort is its rapid onset to action, which pivotal trial investigator Donald Tashkin, UCLA Geffen School of Medicine, said could improve overall patient compliance.

"The formoterol component significantly improves lung function within five minutes. Patients feel better right away and that will probably translate into improved adherence," Tashkin said in an interview.

Although this improvement has not been shown in clinical studies, Tashkin said it is a "reasonable inference" based on patients' ability to perceive how rapidly the drug works. Other treatments can take up to half an hour, he said.

Symbicort also has an edge in safety with no difference in pneumonia incidents compared to placebo (unlike Advair), though there was a higher incidence of lung infections other than pneumonia in patients studied in the SUN (1 year) and SHINE (6 month) Phase III trials.

Sun-Shiny Data For Symbicort

Symbicort's SHINE and SUN trials evaluated more than 3,600 patients age 40 and older with severe to very severe COPD using a pressurized metered-dose inhaler. In order for patients to be considered severe they have to have lost up to 50 percent of lung function on the test. Improvement is measured by forced expiratory volume, or how quickly patients can push air out of the lung in one second.

The SHINE study (the more complicated of the two) included six different treatment arms, showing that Symbicort is more effective in each component alone, adhering to FDA's combination rule, Tashkin said.

Results showed that Symbicort rapidly improved lung function within five minutes of the first dose, and subsequent doses, sustained for 12 months.

"Symbicort does have an acute bronchodilator effect. ... even though the trough is elevated at baseline, there still is a peak and that bronchodilator effect does kick in rapidly," he said. "The formoterol component doesn't last that long, so even though the trough increases due to anti-inflammatory effect, the effect is maintained through the study."

Patients using Symbicort had greater mean improvements from baseline in pre-dose forced expiratory FEV1 averaged over the treatment period, compared with formoterol 4.5 mcg and placebo. Additionally, patients using Symbicort had greater mean improvements from baseline in one hour post-dose over a treatment period, compared with the budesonide 160 mcg treatment and placebo arms in SHINE.

The most common drug-related adverse events were the common cold, oral candidiasis, bronchitis, sinusitis and viral upper respiratory tract infection.

That clean safety profile is something AstraZeneca should be able to turn into a competitive advantage for Symbicort. In Advair's pivotal TORCH trial for COPD, in contrast, there was a signal of increased pneumonia strong enough to lead an FDA advisory committee to request follow-up on pneumonia incidents (³ Also see "Advair Survival Claim In Question; Data Not Robust, But Can’t Confirm – Cmte." - Pink Sheet, 7 May, 2007., p. 12).

But Jammen said it still is too early in the game to rule the event out as a possible class-effect for LABAs. "In the TORCH trial and other trials there is a strong pneumonia signal. ... Some of our physicians have indicated that indeed this is a class effect, but some of them are skeptical," she said. "From a scientific perspective it seems more likely that this is a class effect."

Another key player in the COPD space is Boehringer Ingelheim/Pfizer's Spiriva HandiHaler (tiotropium bromide), which also shows no prominent pneumonia signal. Though the drug is used in more moderate patients, it could raise the bar for Symbicort, which physicians will likely prescribe in less severe patients as well, despite its indication.

Spiriva encountered a minor setback last fall after an FDA MedWatch alert led to publicized events of increased stroke, which the firms quickly countered with clear data (⁴ Also see "Spiriva’s “All-Clear” On CV Safety From FDA Could Raise Bar For COPD Candidates" - Pink Sheet, 8 October, 2008.).

Next Indication, Exacerbations

Moving forward, AstraZeneca will likely work towards a submission for reducing exacerbations in COPD patients. The firm also awaits a regulatory decision on an sNDA for maintenance treatment of asthma in pediatric patients ages six to 11 years, filed in June 2008.

"A major focus will be to look at the exacerbation issue," Tashkin said, noting that although pivotal studies did show ability to reduce exacerbations, the agency requires two Phase III trials using this as a primary endpoint before issuing an approval.

GlaxoSmithKline did the initial grunt work in gaining an approval. "It's definitely made it easier now that GSK has paved a path for approval with FDA and outlined criteria for how exacerbations are defined and understood in clinical trials," Jammen said.

In the meantime, GSK plans to use Advair's golden indication advantageously in the market, highlighting that the drug still has a "unique offering."

AstraZeneca, which runs direct-to-consumer ad campaigns for Symbicort's asthma indication, has not announced plans to do so for COPD, focusing now on physician education. The firm's asthma sales force is promoting Symbicort and speaker training sessions have commenced for its COPD indication, Tashkin said.

COPD - A Growing Market

The COPD market is an increasingly competitive space, with therapies that offer slight advantages to patients. For example, Sepracor's Brovana and Dey's Preforomist, nebulized LABAs for monotherapy, provide more inhaler device options though they are not market leaders.

There are several late-stage products in the pipeline, but getting past FDA could be challenging. Forest announced March 6 that FDA is requiring more clinical studies of its late stage compound aclidinium for COPD before submitting an NDA. Nycomed also has a COPD compound close to filing - Daxas - for reduced exacerbations in more severe patients, though such a narrow therapeutic window may make an FDA approval difficult, Jammen said. "It's not the best bronchodilator ... but the drug does impact exacerbation rates well in severe patients. It may provide another option to patients who continue to experience exacerbation despite being treated with Spiriva and a LABA/ICS combination."

- Carlene Olsen (c.olsen@elsevier.com)

AstraZeneca’s Symbicort On Advair’s Heels With COPD Approval

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