Combination treatment is emerging as the latest focus in the Nash craze, and today’s clinical trial tie-up between Novartis and Allergan lends more support to the dual therapy hypothesis.
The deal is also important because the two companies will likely use it as a dry run for internal assets that will also progress as part of a combo. This could bring into play Conatus, a biotech with which Novartis struck an option last year, and an asset Allergan gained through its recent acquisition of Akarna (see table below).
In the meantime, it is Allergan’s earlier and much larger acquisition – that of Tobira – that will be tested under the Novartis tie-up. Tobira, which Allergan bought at a 600% premium for up to $1.7bn, brought with it the CCR2 and CCR5 blocker cenicriviroc. Today’s deal will see it combined in a phase II study with an unspecified Novartis farnesoid X receptor (FXR) agonist.
Not only could this indicate whether the Tobira purchase was money well spent, it should also show Allergan whether there is mileage in combining cenicriviroc with its own FXR agonist, AKN-083. This came via the $50m Akarna takeover but is still in preclinical development for Nash (non-alcoholic steatohepatitis).
FXR agonism is an increasingly popular mechanism, though its potential as a standalone therapy for the broad indication of Nash rests on Intercept’s Ocaliva, which for now is approved only in primary biliary cholangitis. Recent discontinuations include Gilead’s Px-102 and Exelixis’s XL335.
|Selected farnesoid X receptor (FXR) agonists|
|Ocaliva||Intercept Pharmaceuticals||Marketed||Approved for primary biliary cholangitis|
|GS-9674||Gilead Sciences||Phase II||Via <$470m Pfenex acquisition|
|LJN452||Novartis||Phase II||Most advanced Novartis FXR asset|
|EDP-305||Enanta Pharmaceuticals||Phase I|
|EYP001||Poxel/Enyo Pharma||Phase I||Focus is hepatitis B|
|AKN-083||Allergan||Preclinical||Via $50m Akarna acquisition|
|M480||Metacrine||Preclinical||Run by ex-Aragon/Seragon team|
|Px-102||Gilead||Abandoned - phase II||Via <$470m Pfenex acquisition|
|XL335||Exelixis||Abandoned - preclinical||Work by the subsequent founder of Akarna|
There are two Novartis FXR inhibitors with which Allergan’s cenicriviroc could be combined: LMB763 and LJN452, a slightly more advanced asset that recently secured US fast-track designation.
The cenicriviroc combo trial could inform Novartis’s decision whether to exercise the option it took out last year over Conatus’s emricasan, a pan-caspase inhibitor. This is because emricasan’s potential is thought to lie as part of a dual therapy, and Conatus has made much of its possible combination with LJN452.
Bernstein analysts wrote today that the Allergan/Novartis deal partly validated Allergan’s Tobira acquisition, and made them suspect that the Swiss firm might have been the other bidder. They also said FXR agonism looked like becoming a “foundational class” in Nash combinations.
The attraction of this mechanism was underlined by Allergan’s takeout of Akarna – a nine-month-old biotech that had barely generated preclinical data. Akarna’s founder, Raju Mohan, had worked on designing FXR-targeting molecules at X-Ceptor and Exelixis.
Another interesting, though also preclinical, FXR asset is Metacrine’s M480. This private group, run by the team that sold Aragon Pharmaceuticals to Johnson & Johnson and Seragon to Roche, is presenting preclinical data at the upcoming EASL meeting.
If Nash treatment has a future – many investors and an increasing number of pharma groups think it does – then knowing which assets to combine will play a key role. Already one Gilead combo showed that adding simtuzumab on top of selonsertib gave no additional efficacy, leading to the former’s discontinuation.
Bernstein analysts caution that Nash is effectively still being defined and noted that, in the absence of something as fundamental as agreed-upon measures of efficacy, commercialisation would be tough. However, this does not seem to be holding back Allergan or Novartis.