Juno Stresses Differences Between Its CAR-Ts As JCAR015 Trial Put On Hold Again

Juno stressed structural differences, safety record and potential of its JCAR017 CAR-T therapy during a Nov. 23 call about the disappointing hold on its ROCKET ALL study for JCAR015 – the second clinical hold for the company’s most advanced development program.

Juno Therapeutics Inc. is stressing the structural differences between the chimeric antigen receptor T-cell therapies in its pipeline after two fatalities caused it to put the brakes on a study of JCAR015 in adult acute lymphoblastic leukemia.

Juno announced the voluntary hold on the Phase II ROCKET clinical trial in relapsed and refractory ALL on Nov. 23, noting that two patients died from cerebral edema. The news followed a prior clinical hold on the trial after three patients – and later a fourth – died from similar adverse events, but the company blamed the deaths at that time on the use of fludarabine in a preconditioning chemotherapy regimen.

In the two new cases of cerebral edema, one patient had a relatively low tumor burden and the other had high burden disease. The cerebral edema developed very rapidly, so even if a control switch for the therapy were available, it would have to be used very early on, Juno said.

JCAR015 targets CD19 in B-cell malignancies. The company said that development of another anti-CD19 candidate – JCAR017 – is not affected and pointed out differences between the candidates during a Nov. 23 investor call.

Juno's stock price tumbled by 24.5% to close at $22.56 on Nov. 23.

CAR-T competitor Kite Pharma Inc. was not particularly affected by the news, closing down just 1.53% at $50.90. The company is gearing up to start a rolling BLA submission on an accelerated approval filing of its KTE-C19 in diffuse B-cell lymphoma, based on results from the Phase I/II ZUMA-1 study, by the end of this year. (Also see "New Interim CAR-T Data Support Kite’s BLA Submission Plans" - Scrip, 27 Sep, 2016.) Kite is set to present data from the study in a late-breaking presentation at the American Society of Hematology annual meeting in early December.

Another key CAR-T player – bluebird bio Inc. – closed up 2.54% at $62.50 on Nov. 23.

FDA had placed a clinical hold on Juno's ROCKET study this summer after three patients with cerebral edema died and required the company to submit a revised patient consent form, trial protocol and investigator brochure. (Also see "Three Deaths In Trial Mean Clinical Hold For Juno’s Lead CAR-T Therapy" - Scrip, 7 Jul, 2016.)

Juno's position was that the deaths were caused by the use of fludarabine in a preconditioning cyclophosphamide chemotherapy regimen and the agency lifted the hold on research after the company revised the protocol to stop using that agent. (Also see "Juno ROCKETs On Fast Clinical Hold Resolution" - Scrip, 12 Jul, 2016.)

If Not Fludarabine, Then What?

Chief Medical Officer Mark Gilbert said during the Nov. 23 call that removing fludarabine from the preconditioning regimen was the right response following the deaths reported this summer, but noted that the company had not expected this would entirely eliminate the risk of neurotoxicity or cerebral edema.

"Unfortunately, it is clear now that fludarabine is not the sole cause (or any cause) of the cerebral edema, although officials in the call were adamant that the removal of the chemotherapy did lessen the toxicity of the treatment," Biomedtracker analyst Robert Jeng commented in a note.

Twelve patients had been treated since the study was restarted in August, ten of whom had morphologic disease or high burden ALL.

JCAR015 is also in Phase I for diffuse large B-cell lymphoma (DLBCL) and non-Hodgkin lymphoma (NHL).

CEO Hans Bishop said during the Nov. 23 call that going forward all options are on the table for JCAR015, including continuing the study with a modified protocol, beginning a new study and terminating the program.

"We are faced with a difficult decision considering the encouraging early efficacy data in this trial and the poor prognosis of these relapsed/refractory ALL patients who have few, if any, treatment options," Bishop said.

The company will provide an update at the ASH meeting, which will be held Dec. 3-6 in San Diego.

"I think it's important to say we see a likely path forward for JCAR015 in ALL, but it's just too early right now to speak to that with regards to the actual risk/benefit profile, and that's what we are primarily going to judge this on," Gilbert said,

There could have been multiple factors behind the cerebral edema effect, including underlying disease, the amount of accessible antigen, dosing and the intensity of conditioning chemotherapy, he explained. Adult ALL appears to be the most challenging disease targeted so far in terms of striking a balance between efficacy and safety, Gilbert said.

JCAR017 May Be Better Option Going Forward

Juno execs stressed that the company remains encouraged by both the efficacy and tolerability it is seeing for JCAR017 across a range of ongoing trials in pediatric ALL, adult ALL, NHL and CLL.

"The question now is what path forward remains for JCAR015 and whether similar toxicity will appear with JCAR017," Biomedtracker's Jeng said.

The candidates are different in a number of ways that could affect safety profiles. Whereas JCAR015 has a CD28 co-stimulatory domain, JCAR017 and JCAR014 have a 4-1BB domain.

The kinetics of T-cell expansion with a 4-1BB costimulatory domain is slower and "probably provides an improved tolerability profile" relative to a CD-28 co-stimulatory domain, Gilbert said.

"I do think we understand that there is a strong correlation with the rapid expansion of CAR T cells in these patients that seems to correlate directly with them developing cerebral edema. And I think that is the big focus for us in looking at the immediate investigations that we have, as well as the plans moving forward," Gilbert said.

The type of viral vector also differs in that JCAR017 and JCAR014 have a retroviral vector, versus a lentiviral vector for JCAR015.

Bishop said that the company expects FDA will look at JCAR015 and JCAR017 as "entirely separate products" and that the company continues to be "optimistic about its goal of launching JCAR017 in NHL as early as 2018," Bishop said.

Biomedtracker analyst Jeng, however, concluded that the execs remained "stubbornly optimistic and even defiant" in the face of patient deaths.

"This is quite a major setback for not only JCAR015 but for the Juno pipeline and perhaps the entire CAR-T class. It is simply not clear how much of the severe neurotoxicity is construct-specific or a characteristic of this still relatively new and complex class of therapy," Jeng commented.

However, other analysts accepted the argument that structural differences in the candidates mean that the ROCKET safety problems may not have implications for other CAR-T therapies. In a Nov. 23 note, Jefferies analyst Gena Wang concluded that there is "marginal read-through" to bluebird's bb2121 program, which is partnered with Celgene Corp., due to differences in the vectors, targets and indication (see table).

Comparison Of CAR-T Programs
Sponsor	Program	Vector	Target	Co-stimulatory domain	Indications
Novartis	CTL019	Lentivirus	CD19	4-1BB	DLBCL, ALL
KITE	KTE-C19	y-retrovirus	CD19	CD28	DLBCL, PMBCL, TFL MCL, ALL, FL, CLL
Juno	JCAR015	y-retrovirus	CD19	CD28	Adult ALL
	JCAR014	lentivirus	CD19	4-1BB	NHL, adult ALL, CLL
	JCAR017	lentivirus	CD19	4-1BB	Pediatric ALL, adult NHL
Bluebird	BB121	lentivirus	BCMA	4-1BB	Multiple myeloma
Source: Gena Wang, Jefferies analyst note, July 8, 2016

So Far, So Good With JCAR017

Gilbert noted that across the company's Phase I and Phase II experiences for JCAR015 and JCAR014 in 100 adults with relapsed/refractory ALL, the treatment-related mortality was under 10%. In contrast, the treatment-related mortality rate for salvage chemotherapy in this setting ranges from 11% to 23%, he said.

With JCAR014 in adult relapsed/refractory ALL, there was one case of cerebral edema early on in development, but there haven't been any cases since then, Chief Financial Officer Steve Harr said. As for JCAR017, cerebral edema has not been reported in adult NHL or pediatric ALL, but the therapy has not been tested in adult ALL, he said.

Forty-three pediatric ALL patients have been treated with JCAR017 and there has been no treatment-related mortality, Gilbert said. And out of 24 pediatric patients with relapsed or refractory chronic lymphocytic leukemia treated with JCAR014, there was one treatment-related mortality, he said.

In relapsed/refractory non-Hodgkin lymphoma, the company has reported data for JCAR017 in 14 patients, with no treatment related deaths. With JCAR014 in this setting, 41 patients have been treated, with treatment-related mortality of less than 5%, and all of the deaths occurred during the dose-finding portion of the Phase I trial at doses that are no longer used, Gilbert said.

The data give the company confidence that these products do behave differently, Bishop noted.

Juno will be presenting data across a range of relapsed or refractory B-cell malignancies at the upcoming ASH meeting.