Array Biopharma is a rare beast in biotech: a kinase inhibition specialist that has both an oncology candidate before regulators and a rare heart disease project that could soon move into phase III.
Last week saw progress on both fronts, with the cardiomyopathy-targeting ARRY-797 yielding positive data at the European Society of Cardiology and a filing for the melanoma treatment binimetinib being accepted by the US FDA. The group's chief executive, Ron Squarer, acknowledges that this split focus raises some strategic issues for a small company.
“Array originated as a research company focused on kinases, building drugs for important biological targets that either had no drugs or didn’t have good drugs. Because that was our focus we were somewhat agnostic to therapeutic area,” he tells EP Vantage.
But with oncology leading the way for Array and biotech investors tending to focus on just a few assets – and these days having a laser-like focus on oncology – ARRY-797 might not necessarily have the visibility of binimetinib and the Novartis-originated encorafenib.
“Is it possible for them to recognise the value of [ARRY-797] within our portfolio or is it easier if they were given an opportunity to invest in a pure play?” Mr Squarer asks. “We are continuing to progress the programme within Array until a different strategy emerges. We believe it’s one more study to approval, so it’s a relatively short timeline to market, if successful, and in the realm of pharmaceutical clinical development a relatively small investment.”
Rare disease, not heart disease
ARRY-797 is being used to treat lamin A/C-related dilated (LMNA) cardiomyopathy, a genetically driven disease that leads to degeneration of cardiac muscle tissue because of dysfunctional muscle proteins. Blocking the p38 MAP kinase stimulated by the condition could stop the cell death and cardiac tissue remodelling characteristic of the disease.
Array estimates that 6,000-10,000 people in the US have this condition, and ARRY-797 has received FDA orphan drug designation.
Hence Mr Squarer’s belief of a short timeline to approval. Results of the 12-patient uncontrolled trial, which tested 100mg and 400mg twice-daily doses of the candidate, showed that patients on average improved the distance they could walk in six minutes – the six-minute walk test or 6MWT – by a mean 69m after 12 weeks of treatment. Baseline 6MWT scores were 246-412m.
Mr Squarer says Array is in talks with the FDA about phase III trial design. With the small population and unmet medical need, he believes that it will not be necessary to enrol the thousands required of many heart disease drugs – the two most recent entrants in heart failure, Novartis’s Entresto and Amgen’s Corlanor, have tens of thousands of patients in phase III.
“We expect to be able to get an approval, if our drug is shown to be effective on a number of measures, in dozens of patients – certainly not multiple hundreds,” he says. “While this is a cardiovascular indication, it’s really a rare disease approach with the rules of rare diseases applying.”
The 6MWT is still expected to be the primary endpoint as a way of measuring patient function, he says, and it may be tracked for longer than the 12 weeks. Other endpoints like the biomarker N-terminal pro-brain natriuretic peptide, ventricular output and quality of life will also be monitored.
The numbers might be small and the timeline short, but as a result of those small numbers FDA reviewers will be able to see every patient record to discern if the markers of benefit are “trending in the same direction”, he says. Array could include a placebo arm, but Mr Squarer says those patients will be given the opportunity to cross over to active treatment.
In the meantime, the company is in advanced stages with its oncology pipeline, with binimetinib now under FDA review for Nras-mutant melanoma, representing 20% of patients.
Its application is based on the Nemo trial, in which the Mek inhibitor showed a statistically significant improvement in progression-free survival compared with dacarbazine, 2.8 months versus 1.5. In patients previously treated with immunotherapy binimetinib produced 5.5 months of median PFS, compared with 1.6 months for dacarbazine.
Array is late to the kinase inhibition game in melanoma, with combinations Tafinlar and Mekinist from Novartis and Cotellic and Zelboraf from Roche having established themselves. But it believes that its similar combination of binimetinib with encorafenib can be more tolerable than those combinations in Braf-mutant melanoma, representing 50% of patients.
This belief will be subject to confirmation when the Columbus trial reads out later in September. But Array has also hedged its bets by initiating a phase III trial of the combo in Braf-mutant colorectal cancer (Asco 2016 – Array to test Braf/Mek combo in colorectal cancer, June 5, 2016).
Regardless of the relative size of the patient populations, getting approval for binimetinib monotherapy would be an important moment for Array, given that it has the first Mek inhibitor to show benefit in Nras-mutant melanoma. It will also build awareness of Array’s offerings. “It’s a great way to introduce ourselves to the exact same prescribers,” Mr Squarer says.