On December 11, 2022 Aptose Biosciences Inc. ("Aptose") (NASDAQ: APTO, TSX: APS) reported a clinical update of its lead oral myeloid kinome inhibitor, tuspetinib (formerly HM43239), as responses continue to emerge from a Phase 1/2 trial, and from its oral, dual lymphoid and myeloid kinase inhibitor, luxeptinib (formerly CG-806) in an ongoing Phase 1a/b trial (Press release, Aptose Biosciences, DEC 11, 2022, View Source [SID1234625069]).

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Tuspetinib, a once daily oral agent designed to target FLT3, SYK, and JAK kinases but avoid targets that drive toxicities, safely delivered complete remissions (CR/CRh/CRi/CRp) as a monotherapy across four dose levels (40mg, 80mg, 120mg, and 160mg) in acute myeloid leukemia (AML) patients that previously had been failed by chemotherapy, Bcl-2 inhibitors, hypomethylating agents, competitor FLT3 inhibitors, and hematopoietic stem cell transplants. Data are being presented at the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting by lead investigator Naval G. Daver, M.D., Associate Professor in the Department of Leukemia at MD Anderson Cancer Center, showing tuspetinib delivers single agent responses in very ill and heavily pretreated relapsed or refractory AML patients of mutationally-defined populations, including those with AML harboring wild-type FLT3, ITD or TKD mutated FLT3, or mutated forms of NPM1, MLL,TP53, NRAS, KRAS, DNMT3A, RUNX1, various slicing factors, and other genes. "The welcome blend of safety and breadth of activity seen with tuspetinib in AML patients makes this an ideal candidate for combination therapy," remarked Dr. Daver.

As of October 6, 2022, 60 heavily pretreated relapsed/refractory AML patients were enrolled at multiple centers and treated at doses escalating from 20 mg to 200 mg, with further dose exploration at the 40 mg, 80 mg, 120 mg and 160 mg dose levels. Prior to Aptose licensing tuspetinib, Hanmi Pharmaceutical Company demonstrated complete remissions at the 80 mg dose level. As of January 1, 2022, Aptose assumed control of clinical trial activities and has demonstrated additional complete remissions at the 120 mg, 160 mg, and now the 40 mg dose levels. Many responders were bridged successfully to hematopoietic stem cell transplant (HSCT), while others not eligible for HSCT remained on tuspetinib with a durable response and no drug related myelosuppression even after months of continuous dosing.

The noteworthy safety and potency profile position tuspetinib, in both FLT3 mutated (FLT3+) and wildtype (FLT3-WT) AML patients, potentially to become the kinase inhibitor of choice to combine with venetoclax and hypomethylating agents to deliver high response rates without exacerbated myelosuppression or life-threatening toxicities and potentially to become the preferred agent for maintenance therapy to prevent relapse after HSCT or drug-induced complete remissions. Such roles can define the ultimate therapeutic success for patients and commercial success for tuspetinib.

"While the superior target and safety profile, and proven breadth of activity of tuspetinib compared to competitive compounds in development advocate for tuspetinib to participate in broader and more sizable commercial markets," said William G. Rice, Ph.D., Chairman, President, and Chief Executive Officer, "responses generated by tuspetinib in mutationally-defined populations of high unmet need may also provide accelerated approval opportunities."

Highlights of Updated Tuspetinib Data

In addition to 5 CRc and 1 PR reported at ASH (Free ASH Whitepaper) 2021, 4 new CRc and 3 new PR have been generated thus far during 2022.
New responses during 2022 were achieved with 160 mg,120 mg, 80 mg, and 40 mg
Among efficacy evaluable patients treated with 80 mg, 120 mg, or 160mg, the following response rates were achieved:
FLT3+ 8 of 21 (38.1%)
FLT3-WT 4 of 21 (19%), plus additional CRi since data cutoff date
FLT3+ with prior FLT3i 3 of 11 (27.3%)
FLT3+/NPM1+ 4 of 6 (66.7%)
FLT3+/NPM1+/DNMT3A+ 3 of 4 (75%)
N/K-RAS+ 3 of 8 (37.5%)
Significant bone marrow leukemic blast reductions were observed broadly in FLT3+ and FLT3 wildtype patients across multiple dose levels, comparable to reported gilteritinib data, but in more heavily pre-treated relapsed and refractory AML patients (waterfall chart available on Aptose website).
Vignettes of patient experiences highlight the potency and breadth of tuspetinib to deliver complete remissions among several mutationally-defined populations with a diversity of adverse mutations.
Tuspetinib continued to show a favorable safety profile with only mild AEs and no DLTs up to 160 mg per day, and no drug discontinuations from drug related toxicity.
No drug related SAE, drug related deaths, differentiation syndrome
No drug related AE of QT prolongation
No DLT through 160 mg level – one DLT of muscle weakness at 200 mg (not rhabdomyolysis)
No observed muscle destruction – no AE of elevated creatinine phosphokinase (CPK)
Avoids many of the typical toxicities observed with other tyrosine kinase inhibitors
Aptose has identified a safe therapeutic range with a broad therapeutic window, spanning the dose levels of 40, 80, 120 and 160 milligrams.
For the APTIVATE expansion trial that has initiated patient enrollment, Aptose has selected 120 mg as the initiating single agent expansion dose and 80 mg as the initiating dose selected for combination with venetoclax. The trial is designed to confirm activity through patient enrichment of specific mutationally defined AML populations, including FLT3-mutant patients who have been failed by a prior FLT3 inhibitor, as supported by fast-track designation and a significant response rate to date.
More detail on the data is available on the presentations page of the Aptose website here.

Aptose also provided an update of the luxeptinib clinical program:

Luxeptinib Key Highlights

Luxeptinib is an oral, first-in-class FLT3 and BTK kinase inhibitor in Phase 1 a/b clinical studies for the treatment of myeloid hematologic malignancies. This small molecule demonstrates potent inhibition of wild type and all mutant forms of FLT3 (including internal tandem duplication, or ITD, and mutations of the receptor tyrosine kinase domain and gatekeeper region) and cures animals of AML in the absence of toxicity in murine leukemia models.

Just recently, a CR was achieved with a diffuse large B-cell lymphoma (DLBCL) patient at the end of Cycle 22 with 900mg BID of the original G1 formulation. Previously, an MRD-negative CR was reported with a R/R AML patient receiving 450mg BID of the original G1 formulation. Collectively, these findings demonstrate luxeptinib is active against AML as well as lymphoid malignancies.
The original G1 formulation of luxeptinib was hampered by poor absorption. The new "G3" formulation was designed and developed for more rapid absorption (early Tmax), more efficient absorption (use lower doses), longer retention (longer t1/2), and greater accumulation (higher steady state levels).
The new G3 formulation this year was tested as a single dose in 20 patients from a Phase 1 clinical program of luxeptinib. Modeling of the pharmacokinetic (PK) properties of G3 predicts steady-state plasma exposure from continuous dosing with 50 mg of G3 (every 12 hours, Q12h) should be comparable to that of 900 mg of the original G1 formulation Q12h, representing up to an 18-fold improvement in bioavailability with G3.
Aptose recently announced dosing of the first patient with continuous dosing of the G3 formulation (50 mg BID) in an ongoing Phase 1a/b clinical trial in patients with relapsed or refractory AML. A second patient now has initiated continuous dosing with the G3 formulation.
The G3 formulation may result in greater exposures of luxeptinib and additional responses in these difficult-to-treat patient populations.
Aptose expects that 9-15 patients will determine if G3 is safe and achieves desired exposures to deliver clinical responses.
As announced prior, Aptose will be holding a conference call and data review today:

Aptose Corporate Update Details

Date & Time: Sunday, Dec 11, 2022, 10:00 AM EST

Participant Webcast Link: Link

Participant Dial-in:

Toll Free Investors Dial: 1-877-407-9039

Toll/International Investors Dial: 1-201-689-8470

Conference ID: 13734698

The slides will be available on Aptose’s website here and the webcast of the presentation will be archived shortly after the conclusion of the event at the link above.

On December 11, 2022 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported interim results from the Phase III HAVEN 7 study (Press release, Genentech, DEC 11, 2022, View Source [SID1234625056]). The study shows Hemlibra (emicizumab-kxwh) achieved meaningful bleed control with a favorable safety profile in infants (up to 12 months) with severe hemophilia A without factor VIII inhibitors: 77.8% of participants did not have any bleeds that required treatment and 42.6% did not have any treated or untreated bleeds at all. These results help support the use of Hemlibra in this population, in which it is already approved in many countries around the world. The new data were presented at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in New Orleans from December 10-13, 2022.

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"Hemophilia can substantially reduce quality of life for those affected, starting at infancy, which is especially distressing for parents and caregivers. We continue to explore Hemlibra’s potential benefits to a broad range of people with hemophilia A."

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The burden of severe hemophilia A in infants and on their parents and caregivers is significant. The World Federation of Hemophilia treatment guidelines consider the standard of care in hemophilia to be regular prophylaxis initiated at a young age, as studies have shown that early prophylaxis improves long-term outcomes, while reducing the risk of intracranial hemorrhage. However, for many infants with hemophilia A, prophylaxis is not started until after the first year of life because of the high treatment burden. Hemlibra provides a flexible treatment option that can be administered subcutaneously from birth at different dosing frequencies.

"These initial results support the benefit of starting Hemlibra from birth given that early preventative treatment is essential in infants," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "Hemophilia can substantially reduce quality of life for those affected, starting at infancy, which is especially distressing for parents and caregivers. We continue to explore Hemlibra’s potential benefits to a broad range of people with hemophilia A."

HAVEN 7 is a Phase III, multi-center, open-label study evaluating the efficacy, safety, pharmacokinetics and pharmacodynamics of Hemlibra in infants with severe hemophilia A without factor VIII inhibitors. The results of this interim analysis, which included data from 54 participants, showed that 77.8% of participants (n=42) did not have any bleeds which required treatment, while 42.6% (n=23) did not have any treated or untreated bleeds at all. There were no treated spontaneous bleeds in any participants, and all treated bleeds were traumatic. A total of 77 bleeds occurred in 31 participants (57.4%); 88.3% were traumatic. Mean model-based annualized bleeding rate (ABR) at the time of interim analysis was 0.4 (95% CI: 0.23–0.65) for treated bleeds.

Hemlibra’s safety profile was consistent with previous studies, with no new safety signals observed. Nine people (16.7%) reported a Hemlibra-related adverse event (AE), all of which were local injection site reactions. Eight participants (14.8%) reported 12 serious AEs, unrelated to Hemlibra. There were no deaths, thromboembolic events or cases of thrombotic microangiopathy, reinforcing Hemlibra’s favorable safety profile. No intracranial hemorrhages occurred.

Primary analysis will be conducted at 52 weeks. The study also has an additional seven-year follow-up period to collect long-term data such as safety and joint health outcomes, further building upon our understanding of the benefit of Hemlibra in this population.

EUHASS Database and ATHN 7 Study

Genentech also presented data from the European Haemophilia Safety Surveillance (EUHASS) database and the prospective observational ATHN 7 study at ASH (Free ASH Whitepaper) 2022. Data from EUHASS, which collects real-world safety data on treatments for inherited disorders, showed the safety profile of Hemlibra in people with hemophilia A was favorable and consistent with clinical trial data. Data from ATHN 7, exploring the efficacy of Hemlibra in women with hemophilia A, showed two of the three female participants had no bleeds; the third had one treated bleed associated with a dental procedure and one untreated bleed associated with menses. Ongoing evaluation is vital to further understand the safety and efficacy profile of Hemlibra in this rare and under-represented population.

Hemlibra is approved as a treatment for people with hemophilia A with factor VIII inhibitors in more than 110 countries worldwide, and for people without factor VIII inhibitors in more than 100 countries worldwide. It has been studied in one of the largest clinical trial programs in people with hemophilia A with and without factor VIII inhibitors, including eight Phase III studies.

About Hemlibra

Hemlibra is a bispecific factor IXa- and factor X-directed antibody. It is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for hemophilia A patients. Hemlibra is a prophylactic (preventative) treatment that can be administered by an injection of a ready-to-use solution under the skin (subcutaneously) once weekly, every two weeks or every four weeks. Hemlibra was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed globally by Chugai, Roche and Genentech.

Hemlibra U.S. Indication

Hemlibra is a prescription medicine used for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children, ages newborn and older, with hemophilia A with or without factor VIII inhibitors.

Important Safety Information

What is the most important information to know about Hemlibra?

Hemlibra increases the potential for blood to clot. People who use activated prothrombin complex concentrate (aPCC; Feiba) to treat breakthrough bleeds while taking Hemlibra may be at risk of serious side effects related to blood clots.

These serious side effects include:

Thrombotic microangiopathy (TMA), a condition involving blood clots and injury to small blood vessels that may cause harm to one’s kidneys, brain, and other organs
Blood clots (thrombotic events), which may form in blood vessels in the arm, leg, lung, or head
Patients should talk to their doctor about the signs and symptoms of these serious side effects, which can include

Confusion
Stomach, chest, or back pain
Weakness
Nausea or vomiting
Swelling, pain, or redness
Feeling sick or faint
Decreased urination
Swelling of arms and legs
Yellowing of skin and eyes
Eye pain, swelling, or trouble seeing
Fast heart rate
Numbness in your face
Headache
Shortness of breath
Coughing up blood
If patients experience any of these symptoms during or after treatment with Hemlibra, they should get medical help right away.

Patients should carefully follow their healthcare provider’s instructions regarding when to use an on demand bypassing agent or factor VIII, and the dose and schedule to use for breakthrough bleed treatment. If aPCC (Feiba) is needed, patients should talk to their healthcare provider in case they feel they need more than 100 U/kg of aPCC (Feiba) total.

Patients’ bodies may make antibodies against Hemlibra, which may stop Hemlibra from working properly. Patients should contact their healthcare provider immediately if they notice that Hemlibra has stopped working for them (e.g., increase in bleeds).

The most common side effects of Hemlibra include: injection site reactions (redness, tenderness, warmth, or itching at the site of injection), headache, and joint pain. These are not all of the possible side effects of Hemlibra. Patients can speak with their healthcare provider for more information.

What else should patients know about Hemlibra?

Patients should see the detailed "Instructions for Use" that comes with Hemlibra for information on how to prepare and inject a dose of Hemlibra, and how to properly throw away (dispose of) used needles and syringes.

Patients should stop taking their prophylactic bypassing therapy the day before they start Hemlibra
Patients may continue taking their prophylactic factor VIII for the first week of Hemlibra
Hemlibra may interfere with laboratory tests that measure how well blood is clotting and create an inaccurate result. Patients should speak with their healthcare provider about how this may affect their care.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Patients should only use Hemlibra for the condition it was prescribed. Patients should not give Hemlibra to other people, even if they have the same symptoms that they have. It may harm them.

Patients should tell their healthcare provider about all the medicines they take, including prescription medicines, over-the-counter medicines, vitamins, or herbal supplements. Patients should keep a list of them to show their healthcare provider and pharmacist.

Before using Hemlibra, patients should tell their healthcare provider about all of their medical conditions, including if they are pregnant, plan to become pregnant, are breastfeeding, or plan to breastfeed.

Since Hemlibra was tested in males, there is no information on whether Hemlibra may impact an unborn baby or breast milk. Females who are able to become pregnant should use birth control during treatment.

Side effects may be reported to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. Side effects may also be reported to Genentech at (888) 835-2555.

Please see Important Safety Information, including Serious Side Effects, as well as the Hemlibra full Prescribing Information and Medication Guide.

About hemophilia A

Hemophilia A is an inherited, serious disorder in which a person’s blood does not clot properly, leading to uncontrolled and often spontaneous bleeding. Hemophilia affects around 20,000 people in the United States, with hemophilia A being the most common form and approximately 50-60% of people living with a severe form of the disorder.

People with hemophilia A either lack or do not have enough of a clotting protein called factor VIII. In a healthy person, when a bleed occurs, factor VIII brings together the clotting factors IXa and X, which is a critical step in the formation of a blood clot to help stop bleeding. Depending on the severity of their disorder, people with hemophilia A can bleed frequently, especially into their joints or muscles. These bleeds can present a significant health concern as they often cause pain and can lead to chronic swelling, deformity, reduced mobility and long-term joint damage.

A serious complication of treatment is the development of inhibitors to factor VIII replacement therapies. Inhibitors are antibodies developed by the body’s immune system that bind to and block the efficacy of replacement factor VIII, making it difficult, if not impossible, to obtain a level of factor VIII sufficient to control bleeding.

On December 11, 2022 Kite, a Gilead Company (Nasdaq: GILD), reported results from one of the largest real-world analyses of patients who received CAR T-cell therapy assessing the impact of time from leukapheresis to infusion ("vein-to-vein" time) for Yescarta (axicabtagene ciloleucel) in adult patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) (Press release, Kite Pharma, DEC 11, 2022, View Source [SID1234625055]). The analysis reported shorter vein-to-vein times associated with improved outcomes in patients treated with Yescarta, adjusted for key prognostic factors. Data were presented on December 11, during the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Abstract #3345).

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"These real-world data further clarify the positive impact that shorter vein-to-vein time can have on patient outcomes," said Frederick L. Locke, MD, Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center. "Additional studies must be conducted to further understand the impact of vein-to-vein time on treatment outcomes in the context of other prognostic features such as requirement for bridging therapy and tumor burden. It is important for both community oncologists seeking a CAR T consult and cell therapists to understand the potential impact of lost time when seeking the best possible CAR T result for their patients."

In the pivotal clinical trials of the three commercially available CAR T-cell therapies for LBCL, Yescarta has reported shorter median vein-to-vein wait times from leukapheresis to infusion.

"As the leader in cell therapy, it’s important that we understand all of the factors that can contribute to the best possible outcomes for patients," said Chris McDonald, SVP, Global Head of Technical Operations, Kite. "We’re continuing to invest in technical advances to reduce times even further. I am hopeful studies like this will prompt improvements in the health care delivery system to reduce lost time for patients leading up to apheresis."

This new real-world use analysis assessed Yescarta patients between October 2017 and August 2020 using the Center for International Blood and Marrow Transplant Research (CIBMTR) Research Database, the post marketing registry of commercial patients prescribed Yescarta. Among all patients in the analysis (n=1,383 treated across 78 U.S. authorized treatment centers), the overall median vein-to-vein time for Yescarta was 27 days, inclusive of apheresis, both pre- and post-manufacturing transport, manufacturing time, and hospital scheduling and readiness including patient pre-conditioning prior to receiving their CAR T treatment. Kite’s manufacturing time for Yescarta in the U.S. is a median of seven days from start of cell enrichment to harvest, with an overall 16-day turnaround time (Leukapheresis to Product Release).

Shorter vein-to-vein time from the same analysis was associated with a favorable complete response (CR) rate and overall survival (OS). With a median follow-up of 24.2 months, for patients with less than 28 days or 28-39 days of vein-to-vein time, CR rates were 60% or 61%, respectively in contrast to a CR rate of 50% among patients with vein-to-vein time of 40 or more days. OS rate at 24 months was 53% among patients with vein-to-vein time up to 39 days versus 38% among patients with 40 or more days vein-to-vein time.

Similar rates of Grade ≥3 cytokine release syndrome (CRS), Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged neutropenia were observed regardless of vein-to-vein time. Patients with shorter vein-to-vein time had reduced risk of thrombocytopenia. ICANS of any grade may be higher among patients with vein-to-vein time less than 28 days but most were resolved by 21 days from onset regardless of vein-to-vein time.

CAR T-cell therapies are one-time treatments individually made starting from a patient’s own white blood cells, called T-cells. The cells are removed through leukapheresis and sent to Kite’s specialized manufacturing facilities where they are modified with a Chimeric Antigen Receptor (CAR). Once an individual therapy is created for a patient, the cells are carefully checked, preserved, packed and sent back to the hospital to be infused back into the patient. Over 11,000 patients have been treated with Kite’s CAR T-cell therapies globally through more than 300 authorized treatment centers around the world, including 117 of the leading cancer hospitals in the U.S.

About LBCL

In the United States and globally, LBCL is the most common type of non-Hodgkin lymphoma (NHL). In the United States, more than 18,000 people are diagnosed with LBCL each year. About 30-40% of patients with LBCL will need second-line treatment, as their cancer will either relapse (return) or become refractory (not respond) to initial treatment.

About Yescarta

Please see full US Prescribing Information, including BOXED WARNING and Medication Guide.

YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.
Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on the response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed.
YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.
CYTOKINE RELEASE SYNDROME (CRS)

CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including ≥ Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and the median duration was 6 days (range: 1-27 days) for patients with iNHL.

Key manifestations of CRS (≥ 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing ≥ Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of all patients with NHL receiving YESCARTA, including ≥ Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range: 1-133 days) and the median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including ≥ Grade 3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days. Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities (≥ 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41), and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities, 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in a higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset of and decrease the duration of CRS.

Monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS

Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained in the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS

Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS

Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL; ≥ Grade 3 infections occurred in 17% of patients, including ≥ Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. ≥ Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA

B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES

Secondary malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with an unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-1 included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with an unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with an unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

About the CIBMTR

The Center for International Blood and Marrow Transplant Research is a nonprofit research collaboration between the National Marrow Donor Program (NMDP)/Be The Match, in Minneapolis, and the Medical College of Wisconsin, in Milwaukee. The CIBMTR collaborates with the global scientific community to increase survival and enrich quality of life for patients. The CIBMTR facilitates critical observational and interventional research through scientific and statistical expertise, a large network of centers, and a unique database of long-term clinical data for more than 600,000 people who have received hematopoietic cell transplantation and other cellular therapies. Learn more at cibmtr.org.

On December 11, 2022 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that new and updated data for its first-in-class anti-CD79b antibody-drug conjugate Polivy (polatuzumab vedotin-piiq) were presented at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, December 10-13 (Press release, Genentech, DEC 11, 2022, View Source [SID1234625054]). Data from the POLARIX study support the potential benefit of Polivy in combination with Rituxan (rituximab), cyclophosphamide, doxorubicin and prednisone (R-CHP) to improve outcomes for people with previously untreated diffuse large B-cell lymphoma (DLBCL).

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"These updated POLARIX data indicate the potential benefits that this Polivy based-regimen could bring to people living with this aggressive type of lymphoma, and demonstrate our commitment to developing new treatment options."

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"Too many patients with diffuse large B-cell lymphoma see their cancer relapse or progress after initial treatment. This highlights the need to improve on a standard-of-care that has remained unchanged for the last two decades," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "These updated POLARIX data indicate the potential benefits that this Polivy based-regimen could bring to people living with this aggressive type of lymphoma, and demonstrate our commitment to developing new treatment options."

After a median follow up of three years, progression-free survival (PFS) data continued to show a statistically significant reduction in the risk of disease worsening or death with Polivy plus R-CHP compared with Rituxan plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP; [hazard ratio (HR) 0.76; 95% confidence interval (CI): 0.60-0.97]). After a median follow-up of 39.7 months, overall survival (OS) data was immature with few events in each arm and remained similar between Polivy plus R-CHP and R-CHOP (HR 0.94; 95% CI: 0.67-1.33; p=0.73). In the longer follow-up analysis, no new safety signals were identified.

Health-related quality of life (HRQoL) data from the POLARIX study were also presented, showing that most patients with previously untreated DLBCL receiving Polivy plus R-CHP or R-CHOP reported clinically meaningful improvements in lymphoma symptoms after the first cycle of treatment across both arms (82.3% and 81.3% of patients, respectively). Improvements in fatigue and physical functioning were similar with Polivy plus R-CHP versus R-CHOP, with 74.8% versus 68.2% of patients reporting improvements in fatigue and 42.4% versus 39.6% of patients reporting clinically meaningful improvements in physical functioning at any time point. Reported improvements were sustained during and after first-line therapy, up to the 24-month follow-up. This HRQoL analysis of the POLARIX study demonstrates that these patient-reported outcomes are not compromised with improved PFS, highlighting the potential of Polivy to help manage the burden of DLBCL.

The need for more effective treatments for patients with previously untreated DLBCL was underscored in an economic analysis of the total cost of care in relapsed or refractory (R/R) DLBCL. The study evaluated healthcare costs and resources in the second-line setting and beyond, and found that total healthcare costs increased with each additional line of treatment. Separately, an analysis of the POLARIX study also presented at ASH (Free ASH Whitepaper) showed that over the next ten years, Polivy plus R-CHP has the potential to reduce the number of patients receiving second-line treatment by 27% compared to R-CHOP, potentially improving the chance of a positive outcome for more patients and significantly reducing the overall treatment burden of DLBCL.

Based on the pivotal data from the POLARIX study, more than 50 countries have approved Polivy in combination with R-CHP for the treatment of adult patients with previously untreated DLBCL, including the EU, Japan and, most recently, Canada. The company’s supplemental Biologics License Application was accepted by the U.S. Food and Drug Administration, and a decision is expected by April 2, 2023. Polivy is currently approved in more than 80 countries and regions worldwide, including in the U.S. and Europe, as a readily available, fixed-duration treatment option for R/R DLBCL in combination with bendamustine and Rituxan, after at least two prior therapies.

Genentech continues to explore areas of unmet need where Polivy has the potential to deliver additional benefit, including in ongoing studies investigating combinations of Polivy with CD20xCD3 T-cell engaging bispecific antibodies, mosunetuzumab and glofitamab, including the Phase III SUNMO study in combination with mosunetuzumab, and with Rituxan in combination with gemcitabine and oxaliplatin in the Phase III POLARGO study.

About the POLARIX Study

POLARIX [NCT03274492] is an international Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy, safety and pharmacokinetics of Polivy (polatuzumab vedotin-piiq) plus Rituxan (rituximab), cyclophosphamide, doxorubicin and prednisone (R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in people with previously untreated diffuse large B-cell lymphoma (DLBCL). Eight-hundred and seventy-nine patients were randomized 1:1 to receive either Polivy plus R-CHP plus a vincristine placebo for six cycles, followed by rituximab for two cycles; or R-CHOP plus a Polivy placebo for six cycles, followed by two cycles of rituximab. The primary outcome measure is progression-free survival (PFS) as assessed by the investigator using the Lugano Response Criteria for malignant lymphoma. POLARIX is being conducted in collaboration with The Lymphoma Study Association (LYSA) and The Lymphoma Academic Research Organisation (LYSARC). Other clinical investigators from around the world also participated in the trial.

About Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin’s lymphoma (NHL), accounting for about one in three cases of NHL. DLBCL is an aggressive (fast-growing) type of NHL. While it is generally responsive to treatment in the frontline, as many as 40% of people will relapse or have refractory disease, at which time salvage therapy options are limited and survival is short. Approximately 150,000 people worldwide are estimated to be diagnosed with DLBCL each year.

About Polivy (polatuzumab vedotin-piiq)

Polivy is a first-in-class anti-CD79b antibody-drug conjugate (ADC). The CD79b protein is expressed specifically in the majority of B cells, an immune cell impacted in some types of non-Hodgkin’s lymphoma (NHL), making it a promising target for the development of new therapies. Polivy is designed to bind to CD79b on B cells and destroys them through the delivery of an anti-cancer agent, which is thought to minimize the effects on normal cells. Polivy is being developed by Genentech using Seagen ADC technology and is currently being investigated for the treatment of several types of NHL.

Polivy U.S. Indication

Polivy is a prescription medicine used with other medicines, bendamustine and a rituximab product, to treat diffuse large B-cell lymphoma in adults who have progressed after at least two prior therapies.

The accelerated approval of Polivy is based on a type of response rate. There are ongoing studies to confirm the clinical benefit of Polivy.

Important Safety Information

Possible serious side effects

Everyone reacts differently to Polivy therapy, so it’s important to know what the side effects are. Some people who have been treated with Polivy have experienced serious to fatal side effects. A patient’s doctor may stop or adjust a patient’s treatment if any serious side effects occur. Patients must contact their healthcare team if there are any signs of these side effects.

Nerve problems in arms and legs: This may happen as early as after the first dose and may worsen with every dose. If a patient already has nerve pain, Polivy may make it worse. The patient’s doctor will monitor for signs and symptoms, such as changes in sense of touch, numbness or tingling in hands or feet, nerve pain, burning sensation, any muscle weakness, or changes to walking patterns
Infusion-related reactions: A patient may experience fever, chills, rash, breathing problems, low blood pressure, or hives within 24 hours of the infusion
Infections: Patients should contact their healthcare team if they experience a fever of 100.4°F or higher, chills, cough, or pain during urination. Also, a patient’s doctor may give medication before giving Polivy, which may prevent some infections, and monitor blood counts throughout treatment with Polivy. Treatment with Polivy can cause severe low blood cell counts
Rare and serious brain infections: A patient’s doctor will monitor the patient closely for signs and symptoms of these types of infections. Patients should contact their doctor if they experience confusion, dizziness or loss of balance, trouble talking or walking, or vision changes
Tumor lysis syndrome: Caused by the fast breakdown of cancer cells. Signs include nausea, vomiting, diarrhea, and lack of energy
Potential harm to liver: Some signs include tiredness, weight loss, pain in the abdomen, dark urine, and yellowing of the skin or the white part of the eyes. Patients may be at higher risk if they already have liver problems or are taking other medication
Side effects seen most often

The most common side effects during treatment were:

Low blood cell counts (platelets, red blood cells, white blood cells)
Nerve problems in arms and legs
Tiredness or lack of energy
Diarrhea
Nausea
Fever
Decreased appetite
Infections
Polivy may not be for everyone. A patient should talk to their doctor if they are:

Pregnant or may be pregnant: Data have shown that Polivy may harm an unborn baby
Planning to become pregnant: Women should avoid getting pregnant while taking Polivy. Women should use effective contraception during treatment and for at least 3 months after their last Polivy treatment. Men taking Polivy should use effective contraception during treatment and for at least 5 months after their last Polivy treatment
Breastfeeding: Women should not breastfeed while taking Polivy and for at least 2 months after the last dose
These may not be all the side effects. Patients should talk to their healthcare provider for more information about the benefits and risks of Polivy treatment.

Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the full Prescribing Information for additional Important Safety Information.

On December 11, 2022 Incyte (Nasdaq:INCY) reported that new research detailing the development and mechanism of action of INCA033989, an Incyte-discovered, investigational novel anti-mutant calreticulin (CALR)-targeted monoclonal antibody (Press release, Incyte, DEC 11, 2022, View Source [SID1234625053]). Pre-clinical data indicate that INCA033989 can alter disease course by reducing mutant CALR allele burden and thus may be an efficacious and safe treatment in patients with myelofibrosis (MF) and essential thrombocythemia (ET). This research was featured in the Plenary Scientific Session (Abstract #6. Session: Hematology Disease Topics & Pathways: Research, Diseases, Therapies, Myeloid Malignancies) at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, held December 10-13, 2022, in New Orleans and virtually1.

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"Diseases like myelofibrosis and essential thrombocythemia are often difficult to understand and treat, and unique approaches are necessary to develop effective and safe therapies"

"As a pioneer in the field of myeloproliferative neoplasms (MPNs), having brought the first FDA-approved treatment to patients, we are excited to have the opportunity to share details of our latest research," said Dash Dhanak, Ph.D., Executive Vice President and Chief Scientific Officer, Incyte. "We continue to apply our deep understanding of the complex biology of MPNs to expand treatment options for patients and the work on INCA033989 presented today reflects our progress toward this goal. We look forward to continuing to advance the development of this potential new treatment and to initiating clinical trials for INCA033989 next year."

CALR mutations are responsible for disease development in approximately 25-35%2,3 of patients with MF and ET – two common types of MPNs. INCA033989 binds with high affinity to mutant CALR and inhibits oncogenesis, the process of cells becoming cancerous, in cells expressing this oncoprotein. As described in our presentation, INCA033989 potently antagonizes CALR oncogenic function, resulting in selective inhibition of JAK/STAT signaling only in CALR-mutated cells with no effect on normal, non-oncogenic cells. This selectivity of action with INCA033989 results in the specific killing of tumor cells harboring the mutation and is suggestive of the potential to alter the course of disease in patients with CALR-mutant MF and ET.

"Diseases like myelofibrosis and essential thrombocythemia are often difficult to understand and treat, and unique approaches are necessary to develop effective and safe therapies," said Srdan Verstovsek, M.D., Ph.D., Professor of Medicine, Department of Leukemia, University of Texas MD Anderson Cancer Center. "As a leader in the field, Incyte is uniquely positioned to develop novel medicines for these rare blood cancers, and this research provides strong rationale for the continued investigation and clinical advancement of INCA033989 – a novel treatment approach that targets CALR mutations."

More information regarding the congress and the more than 50 abstracts from Incyte’s oncology portfolio being featured at the meeting is available on the ASH (Free ASH Whitepaper) website: View Source

About Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are a closely related group of blood cancers in which the bone marrow functions abnormally. The bone marrow is where the body’s blood cells are made. MPNs are progressive blood cancers that can strike anyone at any age, but they are more common in older adults. Estimates of the prevalence of MPNs vary, but analysis of claims data suggests there may be as many as 200,000 people in the U.S. living with the most prevalent MPNs: myelofibrosis, polycythemia vera or essential thrombocythemia4.

About LIMBER

Incyte is a leader in the discovery and development of therapies for patients with myeloproliferative neoplasms (MPNs) and graft-versus-host disease (GVHD). The Leadership In MPNs and GVHD BEyond Ruxolitinib (LIMBER) program is designed to evaluate multiple monotherapy and combination strategies to improve and expand treatments for patients with MPNs and GVHD. The program currently has three key areas of focus: development of a new, once-daily formulation of ruxolitinib; ruxolitinib-based combinations with new targets such as PI3Kδ, BET and ALK2; and new therapeutic options such as mutant CALR.