Astra seeks a survival benefit with its lung triplet

Astrazeneca’s battle with Glaxosmithkline is set to ramp up next year with Breztri Aerosphere mortality data in COPD on the horizon.

Trial Results

Astrazeneca has lagged behind its respiratory rival Glaxosmithkline in the quest to bring a triple therapy to the COPD market. But Astra could have a trick up its sleeve: it is set to report mortality data with its Breztri Aerosphere triplet next year.

If Astra can get a result here it would help Breztri Aerosphere compete against Glaxo’s approved triplet, Trelegy Ellipta. All Astra is saying for now is that its latest study, Ethos, has met its primary endpoint, showing improvement in exacerbations with Breztri Aerosphere; full data, including secondary endpoints such as time to death, will feature at an upcoming medical meeting.

Both Breztri Aerosphere and Trelegy Ellipta combine a long-acting beta agonist (LABA), long-acting muscarinic antagonist (LAMA) and corticosteroid in a single inhaler.

Glaxo’s triplet has been approved in the US for COPD since 2017; Breztri Aerosphere, meanwhile, got its first approval in Japan in June and is due a decision from the US FDA next year (Astra cannot breathe easy despite first triplet approval, June 19, 2019).

Breztri Aerosphere’s regulatory filings were partly based on the Kronos study, conducted in moderate to severe COPD patients who were not required to have a history of exacerbations. The primary endpoint was FEV1, a measure of lung function, at six months.

New Ethos

Now Astra can add the data from the 8,500-patient Ethos trial, which enrolled more severely affected patients: those who had had at least one severe, or two moderate to severe, COPD exacerbations in the preceding year. The primary outcome was COPD exacerbations after one year's therapy.

There was another difference with Ethos: as well as looking at a triplet containing a standard steroid dose, 320µg, it also evaluated a combo containing a 160µg steroid dose, which might eventually allow better tailoring of therapy to individual patients, Tom Keith-Roach, head of Astra's respiratory division, told Vantage.

Lowering the steroid dose could be beneficial because these drugs are linked with a risk of pneumonia in COPD patients.

In Ethos both Breztri Aerosphere regimens showed a significant reduction in exacerbations versus both Astra’s Astra’s marketed LAMA/LABA Bevespi Aerosphere, and its marketed LABA/steroid inhaler Symbicort. These were the same comparators used in Kronos.

Investors will want to see more details on the exacerbation benefit, but the mortality data, if positive, could really help Astra gain ground on Glaxo. Mr Keith-Roach previously told Vantage that Astra would compete on clinical data rather than price, so it will need something special to grab share from Trelegy Ellipta, which has become a surprise success story for Glaxo.

What Impact?

Glaxo’s own exacerbations trial of Trelegy Ellipta, Impact, found a significant 29% reduction in all-cause mortality with the triplet versus Anoro Ellipta, that company’s LAMA/LABA combo. However, the 10% reduction in deaths seen with Trelegy Ellipta versus the steroid/LABA doublet Breo Ellipta was not significant.

Glaxo is seeking an expanded label for Trelegy Ellipta to include the mortality data versus Anoro Ellipta. Vantage understands that the company has no plans for a mortality study with Trelegy Ellipta. Perhaps the company has been burnt by its previous attempts to prove a survival benefit with COPD drugs; it came close in the Torch trial of its LABA/steroid doublet Advair, and later the Summit study of a follow-on doublet, Breo Ellipta, also fell short (Glaxo shoots itself in the foot... again, September 9, 2015).

As for Astra, Mr Keith-Roach said that a separate survival study for Breztri Aerosphere was not envisaged, but that the company would review plans in light of the full Ethos dataset.  

A lot now depends on the upcoming data but, depending on what they show, perhaps the investment would be worth it if it allowed Astra to gain an edge over Glaxo.

The COPD landscape
      Annual indication sales ($m)
Product Company Description 2018 2024e
Spiriva Boehringer Ingelheim LAMA 2,849 1,761
Trelegy Ellipta Glaxosmithkline LABA + LAMA + steroid 208 1,692
Anoro Ellipta Glaxosmithkline LABA + LAMA 636 870
Stiolto Respimat Boehringer Ingelheim LABA + LAMA 381 760
Incruse Ellipta Glaxosmithkline LAMA 379 645
Breo Ellipta Glaxosmithkline LABA + steroid 684 582
Utibron Neohaler Novartis LABA + LAMA 454 562
Advair Glaxosmithkline LABA + steroid 1,377 532
Atrovent HFA Boehringer Ingelheim SAMA 452 508
Breztri Aerosphere Astrazeneca LABA + LAMA + steroid - 404
Source: EvaluatePharma.

This story has been updated to include details on Glaxo's plans for Trelegy Ellipta.

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