Data at Ash have suggested that the industry’s most important Imbruvica follow-on, acalabrutinib, might be able to carve out a niche in Imbruvica-intolerant patients. However, this alone will not bring Astrazeneca close to a return on its investment, which so far stands at a $2.5bn payment for majority control of the asset’s originator, Acerta Pharma.
The key to acalabrutinib’s success will be broad market adoption, partly dependent on data from a head-to-head trial against Imbruvica, Abbvie/Johnson & Johnson’s market incumbent. And investors are likely to pay close attention to safety, which has tended to be seen as one of acalabrutinib’s strong suits.
No patients in acalabrutinib’s CLL study discontinued because of treatment, but there were two deaths, one from stroke and the other from a fungal infection – neither was deemed to be related to study drug, said Dr Farrukh Awan at Ash. He was updating a cohort of 33 patients intolerant of Imbruvica – a logical initial use.
Imbruvica sales are set to break the blockbuster threshold this year and reach $8.4bn in 2022, according to EvaluatePharma consensus of sellside forecasts. 2022 acalabrutinib revenue is expected to hit $875m, and will need to climb much higher still to justify the Acerta valuation at which Astra bought in (Astra signals a late run on BTK inhibition, December 14, 2015).
By the end of 2018 or when acalabrutinib is approved in the US, whichever is earlier, Astra must pay Acerta’s former holders a further $1.5bn, and of course it can buy out the remaining 45% stake it does not already own. Recent signs that all was not well came when the UK group delayed its acalabrutinib filing plans from this year to the first half of 2017.
This filing is likely to come in late-stage treatment of B-cell leukaemia, with broader uses being sought later. In the Imbruvica-intolerant patients the overall remission rate, mostly with partial responses, was 79%, with 81% of those persisting beyond 12 months.
Avoiding prior Ibrutinib-related adverse events is one way for acalabrutinib to show a benefit; 36% of the study patients experienced adverse event recurrence, with most of these being decreased or of the same severity as with Imbruvica, said Dr Awan.
Acalabrutinib’s 500-patient head-to-head trial versus Imbruvica – a brave strategy, but one that Astra must take to persuade doctors and payers – will not read out until 2019. Further back in development Imbruvica could face a threat from Beigene’s BGB-3111, a molecule designed to bind selectively and irreversibly to BTK, the target of Imbruvica and acalabrutinib.
In a separate Ash presentation Dr Constantine Tam said BGB-3111 put 96% of 46 CLL patients into partial remission, though median follow-up was a relatively short 8.6 months. Of particular note was that in patients with the aggressive 17p and 11p deletion forms of CLL the overall response rate was 100%.
That BTK inhibition was enjoying a resurgence in popularity was shown when Lilly paid $50m for Hanmi’s phase I agent HM71224 last year.
Conversely, since a cripplingly restrictive label caused Gilead’s rival CLL drug Zydelig to fall by the wayside, the value of PI3K inhibitors has been plummeting, with Roche selling GDC-0084 to Novogen for $5m and Infinity offloading the once-promising duvelisib for zero up front.
Some investors live in the hope that TG Therapeutics’ anti-PI3K offering, TGR-1202, can differentiate itself with a good safety profile. Evidence to back this up at Ash came from Dr Matthew Davids, who ran an investigator-sponsored trial of TGR-1202 and Imbruvica at Dana-Farber.
Dr Davids highlighted the fact that in 165 TGR-1202-treated patients there have only been low levels of liver enzyme elevation. In his trial of the oral combo, in CLL and mantle cell lymphoma, there were no dose-limiting toxicities, though he said one CLL patient’s death was "unlikely" to have been related to study drugs.
He said he thought his trial was the first ever to combine a PI3K and BTK inhibitor doublet in B-cell malignancy. However, for now this does not reflect TG’s focus, which remains on combining TGR-1202 with the in-house anti-CD20 MAb ublituximab.
The Unity trial of this combo recently got data-monitoring board clearance to continue to readout in the first half of 2018, and this is now a key event for TG. Imbruvica will probably enjoy its entrenched position for a little while longer.