Novartis Makes Its Case For Driving A CAR Into The Real World

| About: Novartis AG (NVS)
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Rather like Kite’s (NASDAQ:KITE) registrational Zuma-1 trial of KTE-C19 in lymphoma, Novartis’ (NYSE:NVS) Eliana study has generated a fileable response rate. In the case of the Swiss firm’s rival CAR-T therapy, CTL019, this is in childhood leukemia patients.

While safety has likely taken on fresh importance with the US FDA, Novartis confirmed that CTL019 would be submitted early next year, putting it neck and neck with Kite to bring the first CAR product to market. But perhaps underappreciated is Eliana’s demonstration that a complex autologous cell therapy has real-world potential, with one commercial site manufacturing product for three continents.

The University of Pennsylvania’s Dr Stephan Grupp, who presented the interim Eliana readout at Ash on Saturday, said the trial was the first of a CAR-T product to be truly global. It took in 25 hospitals at sites in North America, Europe and the Asia/Pacific region.

In contrast, Zuma-1 was limited to the US, but of course did comprise 23 sites. Dr Grupp said in Eliana CTL019 was produced at Novartis’s manufacturing facility at Morris Plains, New Jersey, and shipped to the various international sites, with site-specific training undertaken in logistics and patient management.

Investors are keen to see whether CAR-T manufacturing by a big pharma company, at commercial scale, can overcome academia’s production problems. Failure to produce the CAR has been as high as 26% previously, and Dr Grupp’s revelation that there were only five manufacturing failures in 81 patients enrolled will have brought added comfort.

Efficacy

All that said, the efficacy of CTL019 was always going to seize the limelight, and naturally remission rates were expected to have fallen off in the multicentre Eliana versus where they had been in Penn’s earlier study.

Again the headline number – an 82% initial complete response (CR) rate among the 50 evaluable pediatric ALL patients – did not disappoint; the earlier trial had put 93% of children into CR. Dr Grupp said the “single-centre data [had now been] confirmed in a worldwide, multicentre trial”.

In Kite’s Zuma-1 study there was also some loss of efficacy in moving to a multicentre trial, though both companies reckon they have done enough to file their projects based on data with six months' follow-up (Kite flies, but durability remains the key unknown, September 27, 2016).

This of course draws attention to durability of responses, which are sometimes overlooked when headline initial CR rates are reported, especially in the ALL setting. In Eliana about 60% of the 82% responding patients at three months were still in remission at month six.

This is in line with Penn’s earlier finding when the 93% one-month CR rate fell to 46% at one year. Durability of Kite’s KTE-C19 at six months is an important unknown, though in lymphoma three-month CRs – in Zuma-1 33%, versus 47% at one month – tend to be more durable than in ALL.

In terms of safety Dr Grupp said there were no deaths due to cytokine storm, though 59% of patients went into intensive care because of it. Two deaths within 30 days of CTL019 infusion included one from cerebral hemorrhage, but there were no cases of cerebral edema.

Toxicity

Neurotoxicity has become a hot issue since deaths due to this side effect caused the third halt of Juno’s trial of JCAR015 in adult ALL. Assuming that Juno’s problems have not rendered the whole field toxic in the FDA’s eyes, the saving grace might come from JCAR017, an unrelated Juno project that uses a defined composition of cells.

Yesterday Seattle Children’s Hospital’s Dr Rebecca Gardner presented an update of the Plat-02 trial in childhood ALL, showing a 93% initial remission rate among subjects infused with JCAR017, 50.8% 12-month event-free survival and no toxic deaths. Defined-composition products are more uniform and predictable, as well as more costly.

The lifeline JCAR017 could throw to Juno would nevertheless not allow a filing before 2018, with the company falling behind Novartis in the pediatric ALL indication. Juno (NASDAQ:JUNO) is due to provide a keenly awaited update to investors on Monday evening, with the fate of JCAR015 likely the main topic of conversation.

With Kite yesterday kicking off its rolling BLA for KTE-C19, now known as axicabtagene ciloleucel, and aiming to complete it in the first quarter, first to market is now a straight Kite versus Novartis fight.

Project

Company

Study

Indication

Trial ID

CTL019

Novartis

Eliana

Pediatric ALL

NCT02435849