Upcoming events – Array and Achaogen head to US regulators

It's all about the label for plazomicin, and Array’s Braf-Mek project stacks up well against the competition.

Welcome to your weekly digest of approaching regulatory and clinical readouts. Achaogen is likely to gain US approval for plazomicin at the end of this month after a positive adcom vote in urinary tract infections. But all eyes will be on the antiobiotic’s label after concerns over efficacy in the more lucrative bloodstream infection indication, and the potential for off-label use remains an unknown.

A few days later the FDA will decide whether to approve Array’s Braf/Mek inhibitor combination encorafenib and binimetinib in Braf-positive unresectable or metastatic melanoma. The combo showed impressive overall survival versus Roche’s Zelboraf but Array trails behind competitors.

Label uncertainty

At the May adcom panellists voted unanimously in favour of plazomicin’s use in complicated urinary tract infections (cUTIs), but were less positive in bloodstream infections (BSI) caused by carbapenem-resistant enterobacteriaceae, voting 11-4 against. A final decision on the antibiotic is due by June 25.

The vote against in BSI was due to several reasons including the small size of the clinical trial and uncertainty over the source of the bacteraemia.

There was also the issue of negative blood cultures at baseline. Patients eligible for the trial only needed a positive culture within 96 hours of randomisation even if cultures taken closer to the time were negative, which suggests that the infection could have been cleared before treatment started.

Achaogen’s shares fell 25% on the panel outcome, but off-label use in BSI cannot be ruled out due to the limited treatment options for this patient population. According to Leerink analysts plazomicin is expected to sell $290m in the BSI indication by 2025, compared with $170m in cUTI.

The FDA seems likely to approve the cUTI indication and could include the BSI trial data with language around dosing, while not giving a specific labelled indication for this setting.

Lagging behind

Array’s Braf/Mek inhibitor combination is due an FDA decision by June 30 in Braf-positive unresectable or metastatic melanoma. The specific doses are 450mg of encorafenib once daily and 45mg binimetinib twice daily, and Array refers to the combination as Combo450.

The decision will be based on results of the 921-patient, phase III Columbus trial. In the first part of the trial Combo450 showed a significant median PFS benefit over Roche’s Zelboraf, meeting the primary endpoint. Overall survival data also showed the combination beating Zelboraf (see table).

When compared with encorafenib alone Combo450 narrowly missed significance on the PFS endpoint. Bizarrely, this measure was met in the second part of the trial in which encorafenib was given at a lower dose – 300mg – in the combo. The second part of the trial was designed to help evaluate the contribution of binimetinib to the combination.

Columbus trial results
Part 1 (n=577) Part 2 (n=344)
Combo450 Encorafenib (300mg) Combo300 Encorafenib (300mg)
PFS (months) 14.9 9.6 12.9 9.2
HR (95% CI) 0.75 (0.56-1.00) 0.77 (0.61-0.97)
p value 0.051 0.029
Primary endpoint Combo450 Zelboraf (960mg) N/A N/A
PFS (months) 14.9 7.3
HR (95% CI) 0.54 (0.41-0.71)
p value <0.001
Combo450 Zelboraf (960mg) N/A N/A
OS (months) 33.6 16.9
HR (95% CI) 0.61 (0.47-0.79)
p value <0.001
PFS measured by blinded independent central review.
COMBO450: 45mg binimetinib twice daily, 450mg encorafenib once daily. COMBO300: 45mg binimetinib twice daily, 300mg encorafenib once daily. Source: company press releases. Trial ID: NCT01909453.

While Array’s Braf-Mek combo will likely be third to market it could be the most effective – a cross-trial comparison suggests that it outperforms both Novartis’s and Roche’s Braf-Mek combos on overall survival (Snippet roundup: Cash for Rani and positive data for Array and Bavarian Nordic, February 9, 2018).

The safety profile of Combo450 also looks good, with infrequent cases of fever and photosensitivity, which are common with competing products.

However, Novartis’s Tafinlar/Mekinist is already entrenched in the Braf-Mek segment and is forecast to sell $1.4bn in 2024, according to EvaluatePharma consensus (see table). Meanwhile the rise of immuno-oncology agents has limited the size of the market meaning Array has a lot to do to play catch-up.

Braf/Mek melanoma market
Global indication sales ($m)
Combination Company 2018e 2020e 2022e 2024e Global indication status
Tafinlar + Mekinist Novartis 1,066 1,286 1,377 1,421 Marketed
Encorafenib (Braftovi) + binimetinib (Mektovi) Array BioPharma 89 330 570 719 Filed
Zelboraf + Cotellic Roche 250 416 446 472 Marketed
Source: EvaluatePharma

To contact the writer of this story email Joanne Fagg in London at joannef@epvantage.com or follow @ByJoFagg on Twitter

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