Oral presentations on data from two clinical trials in chronic lymphocytic leukemia or small lymphocytic lymphoma
Poster presentation on data from clinical trial of BRUKINSA combined with tislelizumab in B-cell malignancies
BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, today announced clinical data from three trials of its BTK inhibitor BRUKINSA™ (zanubrutinib) were presented at the 61st American Society of Hematology (ASH) Annual Meeting in Orlando, FL. In two oral presentations of BRUKINSA in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the drug candidate demonstrated consistent safety and a high overall response rate (ORR); in the poster presentation of BRUKINSA combined with BeiGene’s investigational anti-PD-1 antibody tislelizumab in patients with previously treated B-cell malignancies, the combination treatment showed preliminary efficacy and was generally well tolerated.
“The data presented today showing clinical activity and tolerability of BRUKINSA in patients with CLL or SLL are promising for its potential use in patients living with these cancers,” said Constantine S. Tam, M.D., Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at the Peter MacCallum Cancer Center and Director of Hematology at St. Vincent’s Hospital, Australia. “BTK inhibitors have become an important standard of care for B-cell malignancies, offering the potential for durable responses with manageable safety profiles. It’s encouraging to have more evidence that zanubrutinib can be effective in treating CLL or SLL, including in patients with del(17p) who typically have a worse prognosis and few treatment options.”
Brandon Warne, a Minnesota Twins beat reporter for the sports news outlet Zone Coverage, started taking cannabidiol (CBD) in August after growing increasingly frustrated with his depression and anxiety medications over the past four years.
“I was just at a point where nothing was working for me,” Warne, 33, of Minnesota’s Twin Cities area, told MarketWatch. “I was just trying to branch out because I was just so upset [and] distraught with my lack of progress towards mental health.”
Under the guidance of his psychiatrist and therapist, Warne started taking CBD and pared down his medication list. He tapered off the antidepressants bupropion GSK, +0.66% and Effexor PFE, +0.68% , but continued to take his anti-anxiety medication, buspirone TEVA, +1.02% , after experiencing “wicked side effects” from trying to go off of it. He now takes CBD in the form of a 0.5-ml dose of Clean Remedies full-spectrum hemp extract oil every morning, and plans to eventually try to taper the buspirone as well.
Warne, who received his diagnoses after his grandfather’s death, wonders whether he was misdiagnosed. But the results he has seen since taking CBD, he said, have been “moderately positive.” “I’ve been feeling great since I got off my meds,” he said.
‘We remain concerned that some people wrongly think that the myriad of CBD products on the market, many of which are illegal, have been evaluated by the FDA and determined to be safe, or that trying CBD ‘can’t hurt.’
Warne isn’t entirely sure whether it’s the CBD oil or being off his meds that’s causing the improvement, but he is willing to continue trying CBD when he’s done with his current bottle. He said he still has “research” to do on the matter — and a new FDA warning backs him up.
The Food and Drug Administration said late Monday that what you don’t know about CBD might hurt you and warned that it could cause serious health problems, including liver damage.
The warning comes as millions of consumers have jumped on board with the non-psychoactive cannabis compound for reasons relating to health, wellness and recreation, and CBD has popped up on restaurant menus, in post-workout salves and in bath bombs.
The FDA sent letters warning 15 companies for illegally selling CBD-containing products. The federal agency also updated its position to clarify that the substance increasingly infused in pills, lotions, food products and wellness beverages “has the potential to harm you, and harm can happen even before you become aware of it.”
“We remain concerned that some people wrongly think that the myriad of CBD products on the market, many of which are illegal, have been evaluated by the FDA and determined to be safe, or that trying CBD ‘can’t hurt,’” Amy Abernethy, the FDA’s principal deputy commissioner, said in a statement.
The only CBD product approved by the FDA is the prescription drug Epidiolex, which treats pediatric epilepsy. It’s illegal to market CBD as a dietary supplement.
The compound can cause liver injury, interact with other drugs, and increase the risk of drowsiness and sedation when used with alcohol, the FDA said. Studies using lab animals have also shown negative impacts on the male reproductive system, though the takeaway for human patients remains unclear, the FDA said.
The agency also provided a list of potential side effects related to CBD, including sleepiness, diarrhea and/or a decrease in appetite, and mood changes such as agitation and irritability.
Many questions, not many answers
Scientists still don’t know what happens if a person consumes CBD daily for sustained time periods; the compound’s effect on children who take CBD, growing fetuses or breastfed newborns; its interactions with herbs and botanicals; and whether it leads to the same male reproductive problems in men as observed in animals, the FDA said.
What’s more, the FDA is concerned about “a lack of appropriate processing controls and practices”: Many products tested by the FDA have contained different CBD levels than what manufacturers claimed, and there have been reports of products containing unsafe levels of pesticides, heavy metals and THC, the agency said.
“I still don’t think it’s so harmful that I shouldn’t use what I have,” Warne said in response to the new FDA warning. “But it certainly makes me question how settled the science is … and maybe it’s not as ironclad as I thought it was before.”
64 million Americans have tried CBD
Research published this year by the consumer-data firm MRI-Simmons estimated that 3.7 million U.S. adults were CBD consumers, with a median age of 45. Even more appear to have dabbled in the substance: Some 64 million Americans — 26% of the country — report having tried CBD in the last two years, according to a nationally representative Consumer Reports survey of more than 4,000 people conducted in January. One in seven of those respondents reported daily use.
And many CBD users use the compound for its health potential, though their outcomes tend to be mixed.
More than a third of respondents to the Consumer Reports survey said they used CBD to reduce stress or anxiety or promote relaxation; 63% of those people said the compound was “extremely or very effective” at doing so, while 16% said it was not at all or only slightly effective. Nearly one in four respondents said they used CBD to help with joint pain, with 38% calling it “extremely or very effective” and 27% saying it was slightly or not at all effective.
The Mayo Clinic says that “although some research appears to indicate that CBD might hold benefit for treating anxiety-related disorders, more study is needed.” And physician Peter Grinspoon, writing on the Harvard Health Blog, noted that an animal study had shown that applying CBD to the skin could help lower arthritis-related pain and inflammation. “More study in humans is needed in this area to substantiate the claims of CBD proponents about pain control,” he added.
Warne is not alone in using CBD to replace or supplement a medication: 30% of respondents to the Consumer Reports survey said they had taken CBD in addition to a prescription or over-the-counter medication, while 22% said they replaced the medication with CBD entirely. A third of those who replaced a medication with CBD said that the drug was a prescription anti-anxiety drug.
Still, Warne called the FDA’s words of caution “prudent” and agreed that more research should be conducted on CBD’s benefits and risks.
“Hopefully it stands up — because otherwise, we’re kind of all owed an explanation for why this was pushed on us for the past year or however long this has been popular,” he said. “Hopefully we get an explanation one way or the other.”
This year’s Ash features numerous duelling anti-BCMA therapies in multiple myeloma, and the first clinical data for JNJ-4528 impress.
With Bluebird missing the deadline for getting its registrational Karmma dataset into the Ash conference, the way was left clear for Johnson & Johnson to seize the early spotlight. Today’s Ash presentation of the first human data with J&J’s anti-BCMA Car-T project JNJ-4528 has shown a staggering 100% remission rate.
Bluebird/Bristol-Myers Squibb did unveil the Karmma data yesterday, but only by press release. The results certainly seem good enough to secure approval for ide-cel/bb2121 in late-line multiple myeloma, but relapses remain the elephant in the room, and care has to be taken when attempting cross-study comparisons owing to differing patient characteristics.
In Karmma, for instance, all 128 treated subjects had failed at least three therapy lines, and 84% were triple-refractory. The key efficacy data – a 73.4% overall response rate, including 31.3% complete remissions – look reasonable compared with the 77% ORR (31% CR) rates seen in the earlier study of bb2121 in subjects who had failed an average seven prior therapies.
However, the worry is relapses: remissions in Karmma lasted only 10.6 months on average, and median progression-free survival was 8.6 months. Against such a backdrop, the threat of J&J’s JNJ-4528 in what is already a highly competitive field has suddenly become real.
At Ash today J&J said its Cartitude-1 trial of JNJ-4528 had so far treated 29 subjects, 86% of whom were triple-refractory, and 31% of whom were penta-refractory. All patients responded to JNJ-4528, an amazing 69% showing complete remission or better.
Source: Dr Deepu Madduri & Ash.
Followers of J&J will thus breathe a sigh of relief. The company had licensed JNJ-4528, a bispecific Car against two different epitopes on the BCMA protein, from Nanjing Legend, a subsidiary of China’s Genscript Biotech, for $350m up front, but Legend’s own data have since then drawn criticism (Ash 2018 – Legend’s mystery CAR raises more questions, December 3, 2018).
Cartitude-1’s presenting author, Dr Deepu Madduri of Mount Sinai Medical Center, suggested preferential expansion of CD8+ central memory T cells as one reason behind JNJ-4528’s impressive efficacy. That said, the real test is durability, and here it is early days: 27 of the 29 subjects are progression free at a median six months’ follow-up.
It will not go unnoticed that Cartitude-1 and Karmma each featured a report of a patient death owing to cytokine release syndrome. This might be surprising given the prevailing view that this Car-T-related side effect is now largely controllable.
As an interesting aside, Legend is still running its own Chinese study, Legend-2, and will update the results at Ash on Monday. It continues to call its project LCAR-B38M; this is identical to JNJ-4528, though J&J has previously told Vantage that it uses different manufacturing and scale-up processes.
And a separate Car-T asset against multiple myeloma was unveiled at Ash today by another Chinese group, Cellyan Therapeutics. This targets BCMA and CD38, and yielded a 90.9% ORR, with 12 CRs, in 22 multiple myeloma subjects who had failed two to nine prior therapies.
15 of 20 responses were ongoing at 12-72 weeks, said Huazhong University of Science and Technology’s Dr Heng Mei. However, given the differing standards of treatment, any prospective western partner for this project would be well advised to run a confirmatory study in the US – as J&J is doing with JNJ-4528.
Contingent value
So where does this all leave Bluebird and Bristol? For investors ide-cel is an important consideration because it is one of three elements of the contingent value right that Bristol issued when it bought Celgene, Bluebird’s original partner.
The CVR will be triggered if, among other things, ide-cel is approved in the US by 31 March 2021. On the strength of Karmma this is certainly looks achievable, and a filing based on this dataset looks likely to go ahead imminently.
The broader question is how big ide-cel could turn out to be, and unfortunately for Bluebird Karmma provides little solace. A potent though short-lived therapy offers little hope of expanding ide-cel into earlier lines of therapy.
And bb21217, which Bluebird had played up as a potentially improved version of ide-cel, actually looks little better, according to its Ash abstract. Attention now turns to Bristol’s bispecific anti-BCMA MAb CC-93269, whose first clinical data presented at Ash today have impressed.
Ide-cel kicked off the BCMA revolution in multiple meyloma, but by the time this year’s instalment of Ash is over it might look remarkably vulnerable.
Celgene CVR holders have been desperate to find out whether JCAR017 is approvable. Yesterday at Ash they got their answer… kind of.
Since Bristol-Myers Squibb completed its $74bn Celgene takeover the latter’s investors have been left holding an unusual financial instrument: the contingent value right. For this to pay out the Car-T therapy JCAR017 must secure US approval, which is why yesterday’s unveiling of data from the Transcend-NHL study at Ash was pivotal.
The best news came in the shape of a safety profile that appears meaningfully better than that of Gilead’s Yescarta and Novartis’s Kymriah. But with JCAR017’s me-too efficacy – and a worryingly low manufacturing success rate – there is little pressure on the US FDA to bust a gut to get this third Car-T therapy over the line.
And speed will be needed. The contingent value right (CVR) will only be triggered if three conditions are met, one being that JCAR017 (liso-cel) must secure US approval for lymphoma by December 31, 2020. Yesterday Bristol said that based on Transcend-NHL a US BLA filing would be completed by the end of 2019.
True, a 12-month turnaround for the filing is not impossible. But CVR holders will continue to fret over whether the FDA will actually deem the Transcend-NHL data sufficiently robust given that this is still, when all is said and done, a single-arm trial whose analysis paints JCAR017 in the best possible light.
Source: Professor Jeremy Abramson & Ash. CRS=cytokine release syndrome; NE=neurological events.
Yesterday’s analysis was the first meaningful data cut from Transcend-NHL for over a year. The lymphoma study was started by Juno, was then taken over by Celgene and deemed pivotal, and is now in the hands of Bristol.
At Ash Professor Jeremy Abramson, of Massachusetts General Hospital, said only 2% and 10% of Transcend-NHL subjects suffered serious cytokine release syndrome and neurotoxicity respectively. Given that rates of 10-30% are more typical of Car-T therapy, this represents a major argument in favour of JCAR017.
The finding could also justify JCAR017’s extra manufacturing step to yield a product with a 50/50 ratio of CD4+ and CD8+ T cells. This is meant to result in a Car-T therapy that is more controllable and therefore safer.
However, this does make manufacturing more complex and more expensive. And, at a time when cytokine release and neurotoxicity are becoming controllable thanks to protocols suggesting use of Actemra and steroids, whether JCAR017 offers a real advantage is not clear.
And the news gets worse on the efficacy side of the equation, where the Bristol project looks no better than Yescarta across a variety of metrics including remission rates and survival. Of course the real devil will be in the detail of underlying patient characteristics.
CAR-T IN LYMPHOMA: A CROSS-TRIAL EFFICACY AND SAFETY COMPARISON
Yescarta
Kymriah
JCAR017 (liso-cel)
Zuma-1
Juliet
Transcend-NHL
Number of subjects*
101
115
256
ORR
82%
54%
73%
CR
54%
40%
53%
mPFS
5.9mth
<3mth
6.8mth
mOS
25.8mth
11.1mth
21.1mth
Any CRS
94%
74%
42%
≥grade 3 CRS
13%
23%
2%
Any neurotoxicity
87%
58%
30%
≥grade 3 neurotoxicity
31%
18%
10%
Note: *exludes subjects who were leukapharesed, but did not receive conforming Car-T product.
Then there is the question of manufacturing success. Transcend-NHL actually enrolled 344 subjects, but for one reason or other only 256 actually ended up getting JCAR017 that conformed to manufacturing standards; 256 rather than 344 is being used as the denominator for efficacy analyses, flattering the data presented at Ash.
The issue will soon be in the hands of the FDA. No doubt the agency will perform its own analysis and, as it did with Kymriah, decide for itself what number of subjects enrolled is the appropriate one to use to calculate efficacy.
In the meantime the debate over manufacturing failure will rumble on. JCAR017 could not be manufactured to specification in 8% of the 344 Transcend-NHL subjects, while 33 died before it could be infused; 12 exclusions from the final dataset are classified simply as “other”.
No doubt some Celgene CVR holders will hail yesterday’s data a great success. All should ask themselves one key question: in the absence of overwhelmingly better efficacy, and with two similar products already approved, why should the FDA allow a third onto the market on the basis of another uncontrolled, single-arm study?
INFUSION SUCCESS IN REGISTRATIONAL CAR-T STUDIES FOR LYMPHOMA
– Membrane bound IL-15 (mbIL15) improves anti-tumor effect of TCR-modified T cells –
– T cells expressing T-cell receptor (TCR) and mbIL15 can be infused day after gene transfer –
Ziopharm Oncology, Inc. (“Ziopharm” or the “Company”) (Nasdaq:ZIOP), today announced the presentation of pre-clinical data of Rapid Personalized Manufacture (RPM), in the “Adoptive Immunotherapy: Mechanisms and New Approaches” session at the 2019 American Society of Hematology (ASH) Annual Meeting in Orlando.
“These pre-clinical data demonstrate that T cells genetically modified using DNA plasmids from the Sleeping Beauty system to express TCR with membrane bound IL-15 (mbIL15) exhibit anti-tumor effects,” said Drew Deniger, Ph.D., leader of Ziopharm’s TCR program. “These data build on our approach to reduce the cost and complexity of T-cell therapies. We have previously demonstrated that mbIL15 can be combined with a CD19-specific chimeric antigen receptor (CAR) to shorten the time to generate clinical-grade T cells and an IND is cleared to evaluate this RPM technology.”
Data were presented today in the poster presentation “Rapid Personalized Manufacture (RPM) of Sleeping Beauty System-generated NY-ESO-1-specific TCR-T Cells Co-Expressing Membrane-bound IL-15 Yields Antitumor Responses” and demonstrated:
T cells can be genetically modified with the Sleeping Beauty system to express TCR and mbIL15;
T cells expressing TCR and mbIL15 exhibited superior anti-tumor effects compared with TCR-modified T cells without mbIL15;
T cells expressing TCR and mbIL15 are infused the day after gene transfer per RPM;
Low-dose of T cells genetically modified per RPM to express TCR and mbIL15 exhibit anti-tumor effects;
T cells expressing TCR and mbIL15 persist in mouse model.
This proof-of-concept study, reported today at ASH, targets a well-understood antigen (NY-ESO-1) which supports using DNA plasmids from the Sleeping Beauty platform to express TCRs with mbIL15 to improve the manufacture of T cells with specificity for neoantigens. The Company announced in October 2019 a new research and development agreement with MD Anderson Cancer Center relating to Ziopharm’s Sleeping Beauty immunotherapy program to use non-viral gene transfer to stably express and clinically evaluate neoantigen-specific TCRs in T cells. This agreement, along with the license of TCRs targeting neoantigens in three hotspots from the National Cancer Institute in May 2019, provide the Company with a platform to launch clinical trials utilizing TCRs from the library specific for hotspot mutations and personalized TCRs targeting patient-specific neoantigens.
