Novartis out to prove its oncology doubters wrong

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Anyone who thought Novartis had taken its eye off the ball in immuno-oncology was in for a rude awakening yesterday. At an R&D day the Swiss group went out of its way to demonstrate the breadth of its cancer portfolio and the fact that its development has, if anything, speeded up.

Novel CAR-T targets have entered first-in-human studies, while an immune checkpoint pipeline has been built around an anti-PD-1 agent that a year ago few even knew Novartis had (see tables below). The contrast with the group’s cell and gene therapy unit closure, and recent reticence about immuno-oncology, could hardly be starker.

Novartis was the first big company to jump at the promise of CAR-T therapy, but last year moved to disband this standalone unit and take its assets back into internal R&D (A day of soul-searching for CAR-T bulls, August 31, 2016). The unit’s high-flying chief, Usman Azam, left, only to resurface at Tmunity, a rival spin-out from the same academic team that gave Novartis CAR-T.

But if anyone at Novartis has been “distracted by changes in leadership, and in the forced integration of R&D, it doesn’t show”, James Bradner, president of Novartis’s institute for biomedical research (NIBR), told the R&D day. Mr Bradner himself is a relative newcomer, taking over after the retirement of Mark Fishman, who had set Novartis drug discovery on its current trajectory.

Mere puff?

Of course the group’s immuno-oncology R&D is early and, with Novartis clearly lagging behind the likes of Merck & Co, Bristol-Myers Squibb and Roche, talking up the business could be little more than puff.

Then again, the pipeline is impressive. Its cornerstone is the anti-PD-1 MAb PDR001, which along with MAbs targeting PD-L1, Lag3 and Tim3 arrived via Novartis’s takeout of the private group Costim in 2014. Thanks to internal fast-tracking PDR001 took just over two years to establish clinical proof of concept, and a pivotal monotherapy trial is set to begin next month.

PD-1 as cornerstone of Novartis's immuno-oncology effort
PDR001 combined with… Combo mechanism Trial ID
(Monotherapy)* PD-1 NCT02404441
NIS793 PD-1 + TGF-beta NCT02947165
FAZ053 PD-1 + PD-L1 NCT02936102
MBG453 PD-1 + Tim3 NCT02608268
LAG525 PD-1 + Lag3 NCT02460224
BLZ945 PD-1 + CSF-1R NCT02829723
MCS110 PD-1 + CSF-1 NCT02807844
GWN323 PD-1 + GITR NCT02740270
Ilaris/CJM112/Mekinist/EGF816 PD-1 + IL-1/IL-17/Mek/EGFR NCT02900664
Chemotherapy PD-1 + chemo NCT02605967
Capmatinib PD-1 + cMet NCT02795429
Sorafenib PD-1 + kinase NCT02988440
Tafinlar & Mekinist PD-1 + Braf + Mek NCT02967692
LXH254 PD-1 + B/Craf NCT02607813
LCL161 PD-1 + IAP NCT02890069
Note: *phase III starting Feb 2017.

Among the combinations being studied is one with the in-house anti-PD-L1 agent, FAZ053. This might seem surprising, but it mirrors combo trials of Astrazeneca’s durvalumab and MEDI-0680, and suggests that the receptor and its ligand could affect non-overlapping pathways.

Indeed, Glen Drahoff, the NIBR’s immuno-oncology leader, suggested that interaction of PD-L1 with B7-1, not just with PD-1, could play a role in cancer survival, and the group has not yet decided whether hitting PD-1 will work better than PD-L1. The only company beyond Astra and Novartis that has both in house is Bristol, though its anti-PD-L1, BMS-936559, is no longer in oncology trials.

Novartis’s chief medical officer, Vas Narasimhan, said last week’s patent settlement between Merck and Bristol had created a path forward in negotiating the complex IP involved (Bristol catches a break at last, January 23, 2017). However, in this fast-paced field he could offer no assurance beyond saying PDR001 was “performing in line with” anti-PD-1 competitors.

Novartis's clinical CAR-T pipeline
Project Antigen Note Trial ID
CTL019 CD19 Paediatric ALL (Eliana trial) filing Q1 2017; DLBCL (Juliet) 3mth data Q1 & Q2, filing Q4 2017 NCT02435849 (Eliana)
NCT02445248 (Juliet)
CTL119 CD19 ALL retreatment study ongoing NCT02228096 
MCM998 BCMA New code confirming this as a Novartis project NCT02546167
LXF821 EGFRvIII New code confirming this as a Novartis project NCT02209376
MIH911 CD123 New code confirming this as a Novartis project NCT02623582
NIU440 Mesothelin Earlier Penn data had disappointed Trial starting 2017

It was especially in cell therapy that Novartis came out swinging, reiterating its planned US filing of CTL019 for paediatric ALL in the current quarter. But the key to meeting Novartis’s new blockbuster estimates for CTL019 is lymphoma – a bigger indication in which it would compete against Kite’s KTE-C19.

Thus interim readouts of the Juliet trial over the first half of the year are vital, and could lead to a lymphoma filing by the end of 2017. Novartis also showed renewed commitment to developing CAR-T therapies against targets beyond CD19 – these had not featured in updates for a while.

And through Crispr capabilities, courtesy of a deal with Intellia, Novartis touted the possibility of developing genome-edited allogeneic CARs that, together with “next-generation regulated CARs”, put the Swiss group back into direct competition with most of its peers in this space.

Remarkably, while the cell therapy unit was closed the NIBR doubled its investment in CAR-T – quite a shock for anyone assuming that Novartis had dismissed cell therapy as an interesting but marginally viable niche.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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