Thank you for the invitation to present these data. This is a primary analysis of the JULIET trial which is a global trial that’s phase II using tisagenlecleucel, an anti-CD19 directed CAR T-cell in patients with relapsed or refractory diffuse large B-cell lymphoma. As Dr Brentjens said, this product, tisagenlecleucel, has been used to treat paediatric patients, children and young adult patients, with a B-cell acute lymphoblastic leukaemia and was approved earlier this year for that indication. So it’s the first gene therapy product that has been approved for clinical use. Here I’ll present the use of the same product in patients with large B-cell lymphoma.
Patients that have large B-cell lymphoma that has failed our available therapies, that has either relapsed or it has just been primarily resistant to these therapies, have a very poor prognosis. The response rate to existing and available therapies is about 8% for complete response and 18% for partial response but these tend to be short-lived and the median survival for these patients is about four months. So contrast that with what Dr Neelapu just showed you and you can see that we’re dealing with a breakthrough therapy. The standard care has been, up until this point, salvage chemotherapy, meaning second line or third line chemotherapy and if patients are able to respond to collect stem cells, give high dose chemotherapy and do a stem cell transplant. That has been the best we could do to date.
This slide shows a summary that’s derived from a slide shown at an ASH educational session a few years ago. If you have 100 patients with relapsed refractory diffuse large B-cell lymphoma only about half of them, or 50, will actually be eligible for transplant and only half of that 50 will be responsive to chemotherapy and able to go on to transplant. Then those that are transplanted will have a relapse rate. So in the end you can see that auto transplant is capable of long-term survival but only in a few patients. The patients that we’re going to discuss that were on the JULIET trial and in Dr Neelapu’s trial were patients that either were not eligible for transplant or had relapsed after a transplant. So you can see from this slide it’s a large unmet need.
Tisagenlecleucel, it just rolls off your tongue, I know, is a chimeric antigen receptor or CAR T-cell therapy that is composed of a region outside that binds to CD19. This is a protein that’s on the surface of the malignant large B-cells as well as on the B-cell ALL cells so it’s a useful product for B-cell cancers. It’s fused together with some T-cell signalling domains that make the T-cells respond to interaction of that CD19 receptor to its target on the tumour cells. This was, as I said, the first approved CAR T-cell therapy indicated for children and young adults up to 25 years of age who had B-cell precursor ALL that was refractory to therapy or relapsed after second or later therapy. The success rate in ALL is phenomenal, it’s 80% response rate and at a year 75% of the kids had ongoing remissions. Again, children without alternatives and many of whom had already had donor transplants.
We studied this in diffuse large B-cell lymphoma in a phase II trial that was done at the University of Pennsylvania and actually that was published today as well in the New England Journal of Medicine alongside of Dr Neelapu’s article. This actually gives a median follow-up of 29 months for these patients. In that study we saw a complete remission rate of 57%, very similar to what has been presented, and in the diffuse large B-cell lymphoma cohort a complete remission rate of 43%, very much what has been presented by Dr Neelapu. What’s remarkable, though, is we have been now following these patients for over two years, over three years in many cases, median follow-up of 29 months, these remissions are durable. So recall that I said the overall survival for this group of patients, the median overall survival, is about four months so these patients have not relapsed at a median follow-up of 29 months. So this therapy clearly has the power to fulfil the unmet need for patients with large B-cell lymphoma that’s not responsive to our current therapies.
The JULIET trial took the same trial that we did at Penn and made it global. What is unique about this trial is that it was global. So we used T-cells that were collected locally, cryopreserved and shipped all over the world. This was 27 centres in ten countries on four continents and as the results I’ll show you will demonstrate that this technology is exportable and can be safely administered in multiple centres by adequately trained personnel.
The primary endpoint was overall response rate, best overall response rate, and it met the protocol specified endpoint with a 53% overall response rate. What is important, though, is not the overall response rate, what’s important is the response rate at three months because most of those patients will stay in remission for years. The durability of the responses from the JULIET trial are shown here; you can see that the overall response rate at three months was 38%, at six months it was still 37% and the CR rates similarly 32% and 30%, stable. 95% stability between three and six months. So it’s really important to see the effect of the cells is to look at three, six months and beyond.
This is the Kaplan-Meier curve which shows that in this trial the median duration of response and the overall survival have not been reached. The median follow-up here is just under six months but I anticipate that, like the trial that has been published today from Penn, we’ll see similarly durable remissions that will last for years. By the way, this is in response to a single treatment. There is no ongoing treatment or subsequent transplant or whatever, this is a single treatment.
These are the adverse events of special interest. Unlike chemotherapy this form of cellular therapy has some unique toxicities and these include what we call cytokine release syndrome, which is analogous to what one would have if they had a serious infection with immune system activation, or neurologic toxicity. We grade these toxicities in terms of severity on a numerical scale and really grade 3 and grade 4 are the serious toxicities that require intensive management. We had 15% grade 3 and 8% grade 4 serious cytokine release syndrome. Neurologic events were fairly uncommon, 8% for grade 3 and 4% for grade 4. Actually these patients, this tends to be a transient thing that’s self-limited and I don’t know that we even know how to treat it or need to treat it in most cases. There were no deaths related to tisagenlecleucel, no deaths related to cytokine release syndrome, no deaths from cerebral oedema. Also, the chemotherapy was a little lighter in this protocol so we were able to actually treat a quarter of these patients as outpatients and many of them would develop a fever several days later and get admitted for observation but it was really easy to give as an outpatient.
In conclusion, tisagenlecleucel, the same product approved for paediatric and young adult ALL produces a high percentage of durable responses in patients with relapsed and refractory diffuse large B-cell lymphoma, another B-cell cancer. Our analysis confirms the durable benefit that was observed at the trial that we ran at Penn. Again, it’s a long follow-up for the patients from the Penn study, I urge you to look at that paper. The JULIET shows the feasibility of globally distributing these cells that are manufactured centrally and these data have been submitted both in the US and in the EU to the regulatory agencies for approval. The sponsor of the study, Novartis, is geared up for large scale production of this in 2018. We’ve met a 22 day manufacturing time which is substantially better than the 30 day that we got to on the clinical trial so the technology continues to improve.
I have to thank everyone that was involved in this study. Obviously it’s not just me, it was a large team of a lot of people, the sponsor Novartis and, of course, the patients who were willing to enrol on the studies and, in many cases, travel from far away to be treated. Thank you.