Venetoclax in transplant conditioning shows promise in myeloid cancers

For patients with high-risk myeloid cancers undergoing a donor stem cell transplant, adding the targeted drug venetoclax to a reduced-intensity drug regimen prior to transplant is safe and does not impair the ability of the donor cells to take root in recipients’ bodies, a study led by Dana-Farber Cancer Institute researchers suggests. The study will be presented today at the 61st American Society of Hematology (ASH) Annual Meeting.

The findings provide support for the use of venetoclax prior to transplant as a way to increase the chances of transplant success in this group of patients, said Jacqueline S. Garcia, MD, physician in the Adult Leukemia Program at Dana-Farber and first author of the study.

While a donor stem cell transplant can cure myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), patients whose tumor cells carry certain genetic mutations or chromosomal abnormalities have a high risk of relapsing after transplant. A variety of approaches to lowering the chance of relapse are under study. One involves using venetoclax, which prompts cancer cell death by blocking the BCL-2 protein, as part of the conditioning regimen patients receive in preparation for a donor stem cell transplant.

The new study focused on patients who underwent reduced-intensity conditioning regimens, which use lower, less toxic doses of chemotherapy and radiation therapy. While such regimens kill fewer cancer cells than traditional “myeloablative” treatments, they are milder on the body and are used in patients over age 60.

“In previous research, we have shown that adding venetoclax to leukemia drugs produces a very large increase in anti-leukemia activity,” Garcia remarked. “We hypothesized that venetoclax would promote the anti-leukemic effect of conditioning chemotherapy and therefore reduce the risk of relapse without producing undue toxicity.”

The study involved nine patients with high-risk AML or MDS who were recommended for a donor stem cell transplant. In a phase I clinical trial, they received venetoclax along with the chemotherapy drugs fludarabine and busulfex as a conditioning regimen and then underwent a donor stem cell transplant.

“We found that venetoclax can be safely added to standard reduced-intensity conditioning without impeding the ability of donor neutrophils [a type of white blood cell] to engraft,” Garcia stated.

Because patients are just six months removed from transplant, it is too early to know if the new regimen reduced the chance of relapse, Garcia noted, but the fact that the donor cells have engrafted – evidenced by patients’ blood counts – is an encouraging sign. There has not been a signal of toxicity in excess of what is expected with standard reduced-intensity conditioning, including rates of graft-versus-host disease. To further minimize the potential for relapse, the trial is under an amendment to allow trial participants to receive post transplant maintenance therapy of low dose venetoclax and the chemotherapy drug azacytidine.

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The presentation was scheduled for Session 721, Abstract 258, on Saturday, Dec. 7, at 3:15 p.m. EST, in Room W331, Level 3 of the Orange County Convention Center.

Complete details on Dana-Farber’s activities at ASH are available online here.

https://www.eurekalert.org/pub_releases/2019-12/dci-uov120519.php

ASH to Highlight Advances, Science Behind Them

Science and data that have fueled the rapidly evolving field of hematology figure prominently in the program for the 2019 American Society of Hematology (ASH) meeting, which begins here today.

The largest hematology conference in the world, ASH will host more than 25,000 attendees from 115 countries. The program includes almost 5,000 research abstracts, 1,000 of which were selected for presentation at oral sessions.

“This really is just a great, grand meeting of the minds,” said chair of the ASH communications committee, Aaron Gerds, MD, of the Cleveland Clinic.

The meeting begins with a day of continuing education programming, covering all aspects of hematology. Industry-sponsored satellite symposia feature some of the leaders in their respective fields, offering insights into key clinical issues and ongoing research and development. Afternoon scientific workshops introduce attendees to current science and emerging scientific concepts that will provide the basis for future clinical advances.

Abstract presentations begin early Saturday and continue through mid-day Tuesday.

Developments in the field of CAR T-cell therapy will continue to figure prominently in the key scientific presentations.

“CAR T-cells have captured the imagination of physicians, scientists, and patients, mainly for their incredible efficacy in treating B-cell malignancies,” said ASH secretary Robert Brodsky, MD, of Johns Hopkins School of Medicine in Baltimore. “But there have been a number of drawbacks. One is the time and expense required to generate patient-specific CAR T cells. Only about two thirds of patients enrolled in clinical trials of CAR T cells will actually receive the treatment, as many times the disease will progress during the time it takes to produce the cells. Toxicity has been another issue.”

Several abstracts at ASH will feature strategies to overcome some of the limitations of CAR T-cell therapy. Examples of the research that will be presented include an off-the-shelf CAR NK cell for B-cell malignancies, clinical data from a trial of CAR T-cell therapy directed against B-cell maturation antigen (BCMA) in relapsed/refractory multiple myeloma, and a bispecific CAR T cell therapy targeting BCMA and CD38 in relapsed/refractory myeloma.

The Presidential Plenary Session will include data on mosunetuzumab, a monoclonal antibody that has induced complete remission in patients with poor-prognosis non-Hodgkin’s lymphoma that is resistant to or has relapsed after CAR T-cell therapy. A high response rate and persistence were observed in a difficult-to-treat population, including patients whose disease was refractory to CAR T-cell therapy, said Brodsky.

In the area of venous thromboembolism (VTE), the program includes several potentially practice-changing studies, said ASH president Roy Silverstein, MD, of Medical College of Wisconsin in Milwaukee. A trial of an oral formulation of rivaroxaban for VTE prevention in children demonstrated equivalent efficacy with low molecular weight heparin. The oral formulation facilitated administration and acceptance and will likely become a new standard of care for children with VTE, said Silverstein.

Another study evaluated the common practice of adding aspirin without an apparent indication to a direct oral anticoagulant (DOAC) for patients with atrial fibrillation or VTE. The results showed similar rates of recurrent thrombosis or stroke in patients who received DOACs alone or with aspirin, but aspirin-treated patients had more clinically relevant, nonmajor bleeding events.

“This is an example of less is more,” said Silverstein. “It will provide good evidence to our community practitioners that when starting a DOAC for nonvalvular atrial fibrillation or venous thrombosis, patients should not also receive aspirin unless there is a clear indication, such as a recent stenting or coronary disease.”

A number of sessions will address the issue of inclusiveness in medicine. Examples include a comprehensive evaluation of data on stem-cell transplantation for multiple myeloma, showing that older and younger patients derive similar benefit. Older patients who did worse tended to receive less-than-optimal dosing of melphalan, a pretransplant conditioner.

“The results suggest we are under-referring patients for bone marrow transplant on the basis of age alone and perhaps undertreating the ones who are referred,” said Silverstein. “This is a very important abstract that gets to the point that age as a number is probably not adequate as an exclusion or inclusion in clinical trials.”

A study of “real-world” experience with CAR T-cell therapy showed that older patients did well on the therapy and had a lower rate of healthcare resource utilization.

The late-breaking abstract session on Tuesday will include an entire lineup of potentially practice-changing studies, said Brodsky. The studies include a randomized phase III trial showing the superiority of blinatumomab (Blincyto) versus chemotherapy as post-induction therapy for children, adolescents, and young adults in first relapse of B-acute lymphoblastic leukemia; inhibition of C1s with monoclonal antibody sutimlimab in patients with cold agglutinin disease; a randomized, placebo-controlled phase III trial of an oral formulation of azacitidine for patients with acute myeloid leukemia in first remission; and a randomized trial demonstrating the superiority of adding daratumumab (Darzalex) to carfilzomib (Kyprolis) and dexamethasone versus carfilzomib and dexamethasone in relapsed/refractory myeloma.

The 2019 ASH meeting will continue until Tuesday afternoon.

https://www.medpagetoday.com/meetingcoverage/ashhematology/83760

US eyes faster launch for biosimilars in North American trade pact

Biosimilars could be brought to market much quicker in North America if a Trump administration proposal makes it into a new US-Canada-Mexico (USMCA) trade pact, according to press reports.

Citing people familiar with the matter, the Wall Street Journal says the US government is considering a reduction in the protections from competition for biologic drugs detailed in the USMCA from 10 years to five, to try to win support for the deal from Democrats in Congress.

Biologics have 12 years’ market exclusivity in the US, but the current wording of the trade agreement would reduce that to 10.

For comparison, Canada currently has eights years’ protection and Mexico five, so under the current wording patients would have to wait longer for biosimilars in the latter two countries.

Democrats and other groups have argued for the duration of the additional protection to be reduced to to allow cheaper copies of reference biologic drugs to get to market more quickly, as that would help cut spending on medicines by healthcare systems in all three countries.

Some have also argued for the provision to be dropped altogether, with the three countries retaining the status quo on biologics protection.

Companies that produce biosimilars in the US are also pushing for the reduction of course. The Association of Accessible Medicines – which represents generic and biosimilar manufacturers – argues that passing the USMCA with a five-year provision would prevent a biopharma monopoly from being expanded beyond the US and lower prescription drug prices for America’s patients.

Trump is keen to get the USMCA passed, as he has pledged a series of trade deals to boost the US economy in the build-up to the Presidential election next year. USMCA was agreed in principle by the US, Canada and Mexico a year ago, but still needs to be ratified by Congress.

The governments of Mexico and Canada would clearly need to agree any changes to the biologics’ exclusivity provisions in the trade deal if they do make it into the document.

Trump signed the USMCA in November 2018, shortly before the Democrats took control of the House of Representatives in the midterms. The shift in power has held up the treaty, which is the successor the North American Free Trade Agreement (NAFTA).

Last week, top Democrat Nancy Pelosi said that discussions with US Trade Representative (USTR) Robert Lighthizer were getting closer to an accord that could allow the USMCA to be tabled for a vote, with a few ‘wrinkles’ – such as enforcement of the provisions – still to be worked out.

US eyes faster launch for biosimilars in North American trade pact; reports

Takeda to develop home hemophilia bleeding risk test with Enzyre

Takeda is teaming up with the Dutch testing firm Enzyre to develop an at-home diagnostic device that will help people with hemophilia determine their own coagulation status.

Enzyre will receive funding from the Japanese drugmaker to refine its existing technology, with the goal of building a platform that will allow patients to share test results with their care teams over a smartphone.

“Diabetics have long been able to individually manage their disease through home glucose measurement, and we are determined to make this the case for those living with hemophilia,” Enzyre CEO Dirk Pollet said in a statement.

Patients with the rare genetic disorder lack sufficient levels of blood-clotting proteins, such as the factor VIII protein. With about 400,000 hemophilia patients worldwide, many receive treatment at home and only meet with their physicians annually.

“We are delighted to have Takeda on board as our development partner,” added Waander van Heerde, Enzyre’s chief scientific officer. “Next to their financial support, they also bring a wealth of knowledge on the treatment of hemophilia.”

Regular measures of coagulation status and the blood’s ability to clot can help caregivers manage a patient’s risk of excessive and dangerous bleeding or conversely developing clots within blood vessels.

“I hope in the near future we will be able to offer patients and their caregivers an easier, more innovative solution to manage hemophilia at home, while helping the healthcare team provide more holistic, personalized care to their patients,” said Alvaro Herreros, head of Takeda’s rare hematology and neuroscience franchises.

Earlier this year, Takeda was saddled with a $155 million bill over patent infringement, payable to its hemophilia rival Bayer—stemming from a December 2016 lawsuit initially filed by the German pharma against Shire’s Baxalta unit.

Following its $59 billion takeover of Shire—which included Baxalta’s Adynovate recombinant hemophilia treatment, the focus of Bayer’s patent suit—the first half of Takeda’s current fiscal year saw its rare disease business decline, with revenues dropping 11% year over year.

In October, Takeda CEO Christophe Weber cited competitive pressure in hemophilia as one of the causes. Formerly Shire’s flagship hemophilia A treatment, and now Takeda’s third best-selling product, Advate sales alone dropped 16% following the fast growth of Roche’s Hemlibra.

https://www.fiercebiotech.com/medtech/takeda-to-develop-home-hemophilia-bleeding-risk-test-enzyre

Xenon Updates on Partnered Neurology Pipeline Programs at Epilepsy Society

Overview of Clinical Stage XEN901 and Related Patient Survey to be Presented in the “Genetic Epilepsies – Updates in the Science and Diagnosis” Exhibit in Room 318-319 on Sunday, December 8^th

Pre-Clinical Work Suggests Selective Sodium Channel Inhibitors that Reduce Action Potential Firing in Excitatory Neurons, While Sparing Inhibitory Interneurons, May Provide Promising Drug Profile

https://www.marketscreener.com/XENON-PHARMACEUTICALS-INC-18411162/news/Xenon-Pharmaceuticals-Provides-Updates-on-Partnered-Neurology-Pipeline-Programs-at-the-2019-American-29697480/

Fate Phase 1 Data on 1st Universal Off-the-shelf NK Cell Cancer Immunotherapy

No Morphologic Evidence of Leukemia and Complete Neutrophil Recovery Observed in First Patient Treated with FT516 Monotherapy for AML following First Dosing Cycle

No Dose-limiting Toxicities or FT500-related SAEs Reported in First 12 Patients Treated with FT500 for Advanced Solid Tumors

Favorable FT500 Phase 1 Safety, Tolerability and Immunogenicity Profile Validates Novel Multi-dose Treatment Paradigm for Off-the-shelf, iPSC-derived NK Cell Products

Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, announced initial clinical data for its FT516 and FT500 off-the-shelf, iPSC-derived natural killer (NK) cell product candidates.

“The safety, tolerability, and immunogenicity data from the Phase 1 dose-escalation stage of FT500, the first-ever cell therapy derived from a clonal master induced pluripotent stem cell line to undergo clinical investigation in the U.S., provide compelling evidence that multiple doses of iPSC-derived NK cells can be delivered off-the-shelf and administered without patient matching,” said Wayne Chu, M.D., Vice President of Clinical Development of Fate Therapeutics. “Additionally, initial clinical observations with FT516 are very encouraging, as an assessment of the first AML patient’s bone marrow at Day 42 following three once-weekly doses of FT516 demonstrated anti-leukemia activity and hematopoietic recovery.”

https://www.marketscreener.com/FATE-THERAPEUTICS-INC-14297698/news/Fate-Therapeutics-Announces-Clinical-Data-from-Landmark-Phase-1-Studies-of-First-ever-Universal-Off-29697461/

Corvus Preclinical, Initial Phase 1/1b Lymphoma Data at Hematology Meet

Corvus Pharmaceuticals, Inc. (Nasdaq: CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of precisely targeted oncology therapies with biomarker patient enrichment selection, announced initial results from its Phase 1/1b trial of CPI-818, the Company’s ITK-inhibitor. The early clinical data from the study demonstrated specific target engagement by CPI-818. The results were presented in a poster at the American Society of Hematology (ASH) 61st Annual Meeting 2019 in Orlando, Florida, taking place December 7-10, 2019.

“We are excited to report the first clinical experience with CPI-818, our selective covalent ITK inhibitor designed to address T-cell lymphomas, a category of hematologic cancers with great need for novel therapeutic options,” said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. “The results show that CPI-818 achieved specific and sustained target occupancy and we look forward to continuing the dose escalation portion of the study to identify an optimum dose. In addition to T-cell lymphomas, we believe CPI-818 may have applications in other immune mediated diseases.  Overall, our team is now advancing three candidates in clinical trials for a wide range of cancers, and each of our programs remains on track with enrollment and progress towards next data milestones.”

https://www.marketscreener.com/CORVUS-PHARMACEUTICALS-I-26786329/news/Corvus-Pharmaceuticals-Presents-Preclinical-and-Initial-Clinical-Data-from-the-Phase-1-1b-Trial-of-C-29697497/