Novartis on track to bring first CAR-T to market

Novartis says its chimeric antigen receptors (CAR-T) candidate is on track for filing in 2017, which could make it the first of the novel drugs to hit the market.

The Swiss company presented data on its CAR-T candidate CTL019 at the American Society of Hematology (ASH) meeting in Orlando, Florida. The drug showed a good response in phase II trials. The drug produced an overall response rate at three months of 47% in diffuse large B-cell lymphoma (DLBCL) and 73% in patients with follicular lymphoma (FL).

There are an estimated 25,000 new US cases of DLBCL and 10,000 deaths each year.

Among the other companies in the field are bluebird bio, Juno Therapeutics and Cellectis.

Bluebird biotech has been hit by a 'downgrade' rating after mixed results from its pipeline of innovative CAR-T drugs presented at ASH.

The firm announced results for its LentiGlobin BB305 candidate for the rare blood disorder beta-thalassemia (BT) major, but only had mixed data on the drug's efficacy.

A number of equities analysts have now downgraded bluebird from 'buy' to 'neutral' after data suggest clinical efficacy is more limited, while serious side effects remain a major problem.

Results from the LentiGlobin BB305 study showed that, out of nine patients, five with semi-functional beta-globin genes remained transfusion-free for 7.1-16.4 months. However the remaining four with a genetic variant still required new blood, but the transfusion volume needed was reduced.

The drug maker plans to carry out two more studies on BB305, but it will only target patients with a less severe form of BT.

Bluebird says it is shifting its clinical strategy in response to evidence increasingly suggesting that treatment works differently with every patient.

As a single conclusive result can't be achieved, it will split up patient cohorts further in future studies.

These further complications won't mean BB305 is written off by analysts, but bluebird's lead candidate looks to be losing ground in the fast-developing field.

Early multiple myeloma data

On Saturday remarkable data presented by the US National Cancer Institute (NCI) suggested the technology could offer a cure in multiple myeloma – at least in some patients.

James N Kochenderfer presented a proof-of-concept study of 12 people treated with allogeneic T cells modified by an anti-B-cell maturation antigen (BCMA) chimeric antigen receptor.

This study is in the same field, but nonetheless separate from Kochenderfer's trial for bluebird bio's bb2121, due to begin in phase I next year.

The genetically-engineered T cells eradicated multiple myeloma cells in one chronically ill patient with advanced disease – who still shows no sign of the disease 14 weeks later. However this patient also suffered severe toxicities from the treatment. These included fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase, but were resolved within two weeks.

The other participants didn't show the same response: one achieved a very good partial response, two others had partial responses, and the remaining eight had stable disease.

OncLive reported that Kochenderfer said the patient initially had more than 90% multiple myeloma cells in his bone marrow, but that was reduced to 0% one month after an infusion of the treatment.

"This is the first example of CAR T-cells, any kind of T-cell therapy, completely eradicating or decreasing measurable multiple myeloma," said Kochenderfer, of the NCI's Experimental Transplantation and Immunology Branch. "For the first time, we have demonstrated that CAR-T cells can eradicate large burdens of multiple myeloma."

However there are numerous obstacles remaining, including the potentially dangerous side effects seen in some patients. Researchers need to find a way of reducing CAR therapy toxicities without reducing efficacy.

There are also major difficulties in manufacturing the molecules at speed and with minimum expense.

France's Cellectis, may have bypassed many of these problems by using an alternative approach.

The platforms being developed by Novartis, Kite and Juno all require a complicated and expensive process of personalising the treatment for each individual patient. In contrast, Cellectis' UCART19 is derived from 'off-the-shelf' CAR-Ts, which can be used in any patient.

Cellectis has also produced eye-catching results, producing a complete remission for one paediatric patient with advanced acute lymphoblastic leukaemia (ALL) in a compassionate use setting.