Novartis committed to CAR-Ts - but doubts about commercial viability remain

The announcement last week from Novartis that it is to break up its dedicated CAR-T research unit took the sector by surprise, as the company has become the front runner in the cutting-edge field.

The group of 400 Novartis employees in its Cell & Gene Therapies Unit (CGTU) has been working on a number of cutting-edge approaches, most notably CAR-T (Chimeric Antigen Receptor T-cell) and CRISPR technologies. The group will, however, now be split up and integrated into the company's larger cancer research division, with up to 120 people potentially being made redundant.

The decision has knocked confidence in the entire field, which has seen numerous concerns about safety and efficacy emerge from early-stage trials of CAR-T therapeutics.

However, on Friday, Novartis spoke out to clarify what it called 'misinformation' about its plans, saying its "commitment to CAR-T and CRISPR technologies remains strong".

Novartis says it will continue with plans to file what is likely to be the first CAR-T therapy to reach the market, CTL019. The treatment is being developed for paediatric acute lymphoblastic leukaemia, and is expected to be filed with the US FDA next year.

Nevertheless, the cost-cutting approach in integrating the unit may reflect larger concerns about the commercial potential of CAR-T therapies.

Dr Clive Stanway, Cancer Research Technology's chief scientific officer, said that, along with many in the scientific community, he had been surprised by Novartis' decision.

Stanway (pictured) said commercial concerns were the most likely reason for Novartis to get cold feet on the project.

He told pharmaphorum in an interview: “Some commentators say they may be backing off as they can't make it commercially viable, that is the interpretation most people go for.”

The scientific basis for CAR-T therapy is well established, and has been in development since the turn of the century.

CAR-T takes the concept of cancer immunotherapy a step further than marketed treatments, which use antibody drugs to flip chemical switches that instruct T-cells to attack cancers.

With CAR-T, the patients' T-cells are harvested and genetically modified to attack their cancers – it's a powerful, but highly risky, approach given the potentially destructive power of the immune system.

Novartis says it will continue with a partnership with the University of Pennsylvania, dedicated to development of CAR-T therapies.

It has shown promise in blood cancers, but as yet no-one has got CAR-T therapy to work in solid tumours in humans, Stanway noted, a key target area for Novartis.

Side effects concerns
There are concerns about the safety of CAR-T, which induces an extreme immune response that attacks cancer cells.

This cytokine storm is an unavoidable consequence of the therapy and can lead to extreme side effects such as high fever – if a patient feels sick, it means that the T-cells have taken effect.

“They can take you to the edge of death, you may not survive,” said Stanway, who said CAR-T will require the best – and probably the most highly-paid and costly – doctors and healthcare teams to ensure patients can manage the side effects.

Now Novartis is coming closer to the market with CTL019, its focus inevitably turns to making it a profitable venture. Apart from safety concerns, the greatest hurdle is the complexity and cost of  manufacturing CAR-T therapies. This involves extracting immune system T-cells from each individual patient and altering the DNA to create chimeric antigen receptors which 'seek and destroy' cancer cells.

The additional cost could create drugs with a price tag far in excess of anything seen before - some estimate it could cost $500,000-750,000 to treat one patient. While this treatment may represent a cure, it is still an extraordinarily high figure.

The potentially huge cost of CAR-T treatment will mean public, and even privately-funded, health providers could be unwilling to pay for CAR-T therapies.

“I can't see how the NHS would provide it, or even those in the US with great health insurance, or really deep pockets,” said Stanway, although he conceded that these costs may diminish as CAR-T becomes more established.

But there have already been problems in a phase 2 trial run by Novartis' rival, Juno, which is also collaborating with Celgene on CAR-T therapies.

The FDA called for a phase 2 ROCKET trial of Juno's JCAR015 therapy to be halted after three deaths.

Juno blamed the deaths on fludarabine used to precondition patients, and has been allowed to continue with a new protocol with different chemotherapy preconditioning, stressing that this should solve the emerging safety issue.

Stanway said doubts remain about Juno's candidate, nevertheless, particularly as rival Kite said it had no concerns about using fludarabine in combination with cyclophosphamide at low dose during preconditioning in a rival phase 2 trial.

Cold feet
Novartis has previously demonstrated a willingness to exit large research programmes, after losing confidence over RNA interference research a few years ago.

However the company has denied that it is in 'retreat' from the therapy area, and responded directly to Endpoints, the pharma news service which broke the news.

In a statement, it said it was "seeking to clarify misinformation".

"At Novartis, we are transforming the company to be more focused with a less complex, more agile structure. While the CGTU structure was critical to ramp up our capabilities in certain areas like manufacturing, clinical trials and commercialisation for a completely new way of treating cancer, now that the company has reorganised under a new operating model, the re-integration of CGTU is the logical next step in our evolution.

"The Novartis enterprise has all of the capabilities we need to efficiently re-integrate CGTU into the broader organisation: leadership in oncology and haematology specifically, a global commercial and development footprint, a strong enterprise manufacturing organisation, as well as support functions to enable a successful transition."

Meanwhile its nearest rivals, Juno and Kite remain very much in the running.

Juno has a long-term alliance with Celgene and Kite is working with Amgen, and the backing of these two commercial and research goliaths means there is great momentum behind CAR-T therapies.

So, while reports of Novartis' 'retreat' from CAR-T area have been misleading, the scale of the task ahead - both clinically and commercially - remains formidable.

About the author:

Richard Staines is Senior Reporter at pharmaphorum. Contact him via: Richard.Staines@pharmaphorum.com