Ash 2019 – former Celgene holders look anxiously at contingent value

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
	Zuma-1	Juliet	Transcend-NHL
Subjects enrolled	111	141	344
…pending infusion	0	13	0
SAE/reassessment/withdrew consent etc	9*	34**	61#
Manufacturing failure (% excludes those pending)	1 (1%)	9 (7%)	27 (8%)##
Subjects who got conforming Car-T cells	101	85	256
Note: *2 disease progressions, 7 SAEs; **28 disease progressions, 2 SAEs, 2 investigator decisions, 1 withdrawal, 1 protocol violation; #33 deaths, 6 disease progressions, 4 disease reassessments, 19 other; ##2 inabilities to manufacture, 25 infused with non-conforming product.

https://www.evaluate.com/vantage/articles/events/conferences/ash-2019-former-celgene-holders-look-anxiously-contingent-value

Ziopharm Preclinical Data on Rapid Personalized Manufacture with T Cell Receptor

– 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.

https://www.marketscreener.com/ZIOPHARM-ONCOLOGY-INC-33865/news/Ziopharm-Oncology-Presents-Pre-Clinical-Data-Validating-ldquo-Rapid-Personalized-Manufacture-rdquo-29698404/

Agios Proof-of-Concept in Thalassemia Based on Preliminary Phase 2 Results

– Treatment with Mitapivat Induced Hemoglobin Increase of ≥1.0 g/dL in 7 of 8 Evaluable Patients –

– Safety Profile Consistent with Previously Published Phase 2 Data for Mitapivat in Patients with Pyruvate Kinase Deficiency –

– Additional Data for the Phase 2 Study of Mitapivat in Thalassemia to be Presented at a Medical Meeting in the First Half of 2020 –

– Company to Host ASH Investor Event and Webcast Monday, December 9 at 8:00 p.m. ET –

https://www.marketscreener.com/AGIOS-PHARMACEUTICALS-IN-13709228/news/Agios-Establishes-Proof-of-Concept-for-Mitapivat-in-Non-transfusion-dependent-Thalassemia-Based-on-P-29698407/

TG Therapeutics Presents on Leukemia Triple Combo Phase I/II at ASH19

100% overall response rate (ORR) in relapsed/refractory CLL patients treated with U2 (umbralisib + ublituximab) plus venetoclax at cycle 7 (n=13)

100% of patients (n=9) achieved undetectable MRD in the peripheral blood after 12 months of therapy and 78% achieved undetectable MRD in bone marrow and have stopped all therapy

No patients have progressed to date

Investor and analyst event to be held on Monday, December 9, 2019 at 7:30 PM ET at the Hyatt Regency Orlando featuring a fireside chat with leading clinical investigators

https://www.marketscreener.com/TG-THERAPEUTICS-INC-13314736/news/TG-Therapeutics-Announces-Oral-Presentation-of-Umbralisib-Ublituximab-and-Venetoclax-Triple-Combina-29698406/

Karyopharm Presents XPOVIO® (Selinexor) and Eltanexor Data at ASH19

— Once-Weekly Oral Selinexor in Combination with Weekly Kyprolis® and Low Dose Dexamethasone Demonstrates 71% Overall Response Rate, Including a Complete Response Rate of 21%, in Patients with Heavily Pretreated, Kyprolis-Naïve Multiple Myeloma —

— All Oral Regimen of Once-Weekly Selinexor with Revlimid® and Low Dose Dexamethasone Achieves High Response Rates in Patients with Newly Diagnosed Multiple Myeloma —

— STORM Study Patients Treated with Selinexor Achieved Survival Advantage Over Matched Patients from the MAMMOTH Study Who Were Treated with Other Anti-Myeloma Agents —

— Single-Agent Oral Eltanexor Shows Encouraging Activity in Elderly Patients with Higher-Risk Myelodysplastic Syndrome —

https://www.marketscreener.com/KARYOPHARM-THERAPEUTICS-I-14825950/news/Karyopharm-Presents-XPOVIO-Selinexor-and-Eltanexor-Data-at-the-American-Society-of-Hematology-201-29698409/

Oncopeptides promising Phase 2 combo myeloma study at ASH

Oncopeptides AB (Nasdaq Stockholm: ONCO) will today present updated data from the ongoing Phase 2 ANCHOR (OP-104) triple combination study at the ASH Annual Meeting 2019. In the data presented, melflufen and dexamethasone demonstrated positive efficacy in combination with daratumumab or bortezomib in patients with relapsed/refractory multiple myeloma (RRMM). Preclinical data supporting clinical development of melflufen in AL amyloidosis will also be presented for the first time.

Overall Conclusions – ANCHOR Poster Presentation

· Patients in the ANCHOR study had a median of two prior lines of therapy. All patients were refractory to at least one agent.
· For melflufen and dexamethasone in combination with daratumumab (n=33) the overall response rate (ORR) was 76% with a median progression-free survival (PFS) of 14.3 months.
· 70% of the patients were still progression-free at the time of the data cut.
· For melflufen and dexamethasone in combination with bortezomib (n=6) the ORR was 67%.
· Responses improved with continued therapy for both combinations.
· Both combinations were well tolerated and the grade 3 and 4 Adverse Events (AE) were primarily hematologic.

https://www.marketscreener.com/ONCOPEPTIDES-AB-PUBL-34091154/news/Oncopeptides-publ-presents-promising-data-from-the-Phase-2-ANCHOR-combination-study-in-patients-wi-29698411/

Verma: We’ve strengthened Medicare for seniors – Don’t let others tear it apart

As Medicare’s Open Enrollment period draws to a close this week, the experience for seniors in the program has never been better. The Trump administration has made historic strides in strengthening and protecting Medicare.

Our approach – to restore Washington, D.C. to its proper role as a facilitator of patient-centered markets, rather than a hindrance to them – has had amazing results.

We have torn down needless government barriers to innovation and ingenuity, and as the president’s recent Medicare executive order indicates, we are just getting started.

The result of our efforts has been an infusion of new Medicare options, and – most importantly – lower costs for seniors accompanied by better benefits.

Nevertheless, it remains true that Medicare faces solvency issues within the next decade. Foolish demands for “Medicare-for-all” threaten the fiscal sustainability of the program, while squandering the many advances this administration has made.

Take Medicare Advantage. Policies adopted under the Trump administration have cleared the runway for nearly 1,200 new Medicare Advantage plan options since 2018, bringing costs down for seniors through increased competition.

Medicare Advantage premiums will decline to an average of $23, a 14 percent decrease from last year. For some plans, the decrease is as high as 80 percent. Premiums have not been this low since 2007.

Medicare Part D has experienced the same price plunge as well, with prescription drug plan premiums decreasing by over 13 percent since 2017. Combined with the lower Medicare Advantage premiums, beneficiaries are saving over $2.65 billion since 2017.

What’s more, this reduced price tag has actually accompanied an expansion in benefits that will keep seniors healthy and independent, such as home modifications like wheelchair ramps. Those with chronic conditions increasingly have access to plans that can cover home meal delivery, pest control and transportation to the grocery store.

At the same time, the drive to tear down burdensome government barriers has also expanded access to innovative new treatments that can cure diseases.

Innovation has even made accessing the care seniors need more convenient for them. New telehealth benefits that allow seniors to text or video chat with their doctor – rather than having to travel – are a boon for seniors in rural areas, and new methods of receiving vital drugs at home are making life easier for seniors and their caregivers.

And that’s just the tip of the iceberg: new tools with which to search and compare Medicare health and prescription drug plans, innovative methods to find affordable prescription drugs, improved access to Medicare data, and much more are revolutionizing this vital program for America’s seniors.

The president’s recent executive order on Medicare is a powerful illustration of the bold future he sees for the program.  Its provisions will result in lower costs, higher quality, and a flurry of innovation – providing sorely needed security for America’s seniors.

As this administration continues to build on our existing Medicare successes, our efforts will necessarily have a profound ripple effect on the health care system as a whole.

The animating principle behind our successful efforts is this: Medicare should be strengthened for seniors – the people to whom these benefits were promised in the first place.

Advocates of “Medicare-for-all” propose a different principle, one that ultimately jeopardizes seniors’ access to high-quality health care. As “Medicare-for-all” gathers momentum in certain circles, America faces a fork in the road: do we continue to strengthen this fundamental benefit for many of our most vulnerable fellow citizens – seniors – or do we shunt them aside in favor of pipe dreams like “Medicare-for-All” that will ruin the program for everyone? The Trump administration firmly stands for the first option.

The Trump administration has strengthened Medicare, but serious problems persist. It is both irresponsible and callous to endanger the health of our nation’s elderly by reneging on our promise to them.

We should build on the Trump administration’s Medicare successes – not torch them altogether.

https://www.foxbusiness.com/healthcare/medicare-seema-verma-seniors