On December 5, 2020 AbbVie (NYSE: ABBV) reported new, updated results from the Phase 3 MURANO and CLL14 clinical trials evaluating VENCLEXTA/VENCLYXTO (venetoclax) fixed duration treatment combinations at the virtual 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (abstracts 125, 127, and 1310, respectively) (Press release, AbbVie, DEC 5, 2020, View Source [SID1234572218]). These findings add to the growing body of data supporting the use of VENCLEXTA/VENCLYXTO in first-line or previously treated chronic lymphocytic leukemia (CLL) patients.

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"MURANO and CLL14 provide a look at the benefits of fixed duration VENCLEXTA combinations in helping many patients to achieve sustained progression-free survival," said John Hayslip, M.D., M.S.C.R., executive medical director, AbbVie. "These responses reinforce that with VENCLEXTA/VENCLYXTO, it is possible for CLL patients to complete treatment and live longer without their disease progressing."

Data from the MURANO and CLL14 trials presented at ASH (Free ASH Whitepaper) reinforce that CLL patients who have relapsed or have not started treatment and receive a VENCLEXTA/VENCLYXTO regimen can experience long-lasting responses, even after stopping treatment, compared to standard of care treatment options.

MURANO Five-Year Analysis1
The results of the final, descriptive analysis of the MURANO trial (median follow-up of 59.2 months with all patients off VENCLEXTA/VENCLYXTO in combination with rituximab [VenR] treatment for at least three years; Abstract 125) demonstrated the following:

Investigator (INV)-assessed progression-free survival (PFS): Patients with relapsed or refractory (R/R) CLL on fixed duration VenR had a median PFS of 53.6 months (95% CI: 48.4-57.0) compared to 17.0 months (95% CI: 15.5-21.7) with bendamustine plus rituximab (BR; HR 0.19, 95% CI: 0.15-0.26).
Overall survival (OS): The OS estimate was 82.1% (95% CI: 76.4-87.8) with VenR compared to 62.2% (95% CI: 54.8-69.6) for BR (HR 0.40, 95% CI: 0.26-0.62), median not reached in either arm.
Minimal residual disease (MRD) status at completion of VenR treatment: Patients who achieved MRD-negativity without disease progression at the end of their treatment course had improved PFS and OS compared to patients with MRD. MRD refers to the small number of cancer cells that remain in the body after treatment. The number of remaining cells may be so small that they do not cause any physical signs or symptoms and often cannot even be detected through traditional methods.4
Consistent safety profile: The safety profile of the VenR combination is consistent with the known safety profile of each individual therapy alone. No new, serious safety issues were observed in the five-year MURANO updated analysis.
According to the Leukemia & Lymphoma Society, MRD refers to the small number of cancer cells that remain in the body after treatment.4 The number of remaining cells may be so small that they do not cause any physical signs or symptoms and often cannot even be detected through traditional methods, this is known as undetectable MRD (uMRD). Doctors use MRD/uMRD to measure the effectiveness of treatment and to predict which patients are at risk of relapse.

CLL14 Analyses2,3
Data from descriptive analyses of the Phase 3 CLL14 trial was also presented today evaluating the role of MRD measurements in clinical trials.

One analysis showed that patients with previously untreated CLL and co-existing medical conditions who had partial response (PR) after treatment with VENCLEXTA/VENCLYXTO in combination with obinutuzumab (Ven-Obi) had a similar outcome as patients with complete response (CR) when uMRD levels were achieved. These data suggest that patients on the VENCLEXTA/VENCLYXTO combination with uMRD levels and PR had longer PFS than patients with MRD and CR. This is significant because patients with CLL who show a PR to chemoimmunotherapy have a poorer prognosis than patients with CR.2 These results were not tested for statistical significance. (Abstract 1310)

The second analysis looked at clonal growth patterns – or how quickly cancer cells grow and spread – in patients treated within the CLL14 trial. The findings from the analysis shed light on which patient group may be at risk of relapsing despite initial MRD response.3 (Abstract 127)

The four-year, follow-up analysis showed an OS rate of 85.3% with Ven-Obi versus 83.1% with chlorambucil in combination with obinutuzumab (Obi-Clb; HR 0.85, 95% CI [0.54-1.35]; P=0.4929).

VENCLEXTA is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About the MURANO Trial5,6,7
A total of 389 patients with R/R CLL who had received at least one prior therapy were enrolled in the international, multicenter, open-label, randomized Phase 3 MURANO trial. The trial was designed to evaluate the efficacy and safety of VenR (n=194) compared with BR (n=195). The median age of patients in the trial was 65 years (range: 22 to 85).

The trial met its primary efficacy endpoint of INV-assessed PFS. At the time of the primary analysis, median PFS with VenR was not reached compared with 17.0 months for BR (HR: 0.17; 95% CI: 0.11- 0.25; p<0.0001). In the primary efficacy analysis, the median follow-up for PFS was 23.8 months (range: 0 to 37.4). Additional efficacy endpoints included independent review committee (IRC)-assessed PFS, INV- and IRC-assessed overall response rate (defined as complete response + complete response with incomplete marrow recovery + partial response + nodular partial response), OS and rates of MRD-negativity.

In patients with CLL receiving combination therapy with rituximab, the most frequent serious adverse reaction (AR; ≥5%) was pneumonia (9%). The most common ARs (≥20%) of any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), and nausea (21%). Fatal ARs that occurred in the absence of disease progression and within 30 days of the last venetoclax treatment and/or 90 days of the last rituximab were reported in 2% (4/194) of patients.

About the CLL14 Trial6,7,8
The prospective, multicenter, open-label, randomized Phase 3 CLL14 trial, which was conducted in close collaboration with the German CLL Study Group (DCLLSG), evaluated the efficacy and safety of a combined regimen of Ven-Obi (n=216) versus Obi-Clb (n=216) in previously untreated patients with CLL and coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance <70 mL/min). The therapies were administered for a fixed duration of 12 months for venetoclax in combination with six cycles of obinutuzumab. The trial enrolled 432 patients, all of whom were previously untreated according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Efficacy was based on PFS as assessed by an IRC.

Key secondary endpoints were MRD-negativity in peripheral blood and bone marrow, overall and complete response rates, MRD-negativity in complete response in peripheral blood and bone marrow, and OS.

In patients with CLL receiving combination therapy with obinutuzumab, serious ARs were most often due to febrile neutropenia and pneumonia (5% each). The most common ARs (≥20%) of any grade were neutropenia (60%), diarrhea (28%), and fatigue (21%). Fatal ARs that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection.

About VENCLEXTA/VENCLYXTO (venetoclax)
VENCLEXTA/VENCLYXTO (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLEXTA/VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.

VENCLEXTA/VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. VENCLEXTA/VENCLYXTO is approved in more than 50 countries, including the U.S.

Uses and Important VENCLEXTA (venetoclax) U.S. Safety Information7

Uses
VENCLEXTA is a prescription medicine used:

to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly diagnosed acute myeloid leukemia (AML) who:
are 75 years of age or older, or
have other medical conditions that prevent the use of standard chemotherapy.
It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information

What is the most important information I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water during treatment with VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects. When restarting VENCLEXTA after stopping for 1 week or longer, your healthcare provider may again check for your risk of TLS and change your dose.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased TLS.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.
Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

have kidney or liver problems.
have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
have a history of high uric acid levels in your blood or gout.
are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for at least 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment and for 1 week after the last dose of VENCLEXTA.
What should I avoid while taking VENCLEXTA?

You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Low white blood cell counts (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA and may pause dosing.
Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with VENCLEXTA. Your healthcare provider will closely monitor and treat you right away if you have a fever or any signs of infection during treatment with VENCLEXTA.
Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA.

The most common side effects of VENCLEXTA when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell counts; low platelet counts; low red blood cell counts; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of your arms, legs, hands, and feet.

The most common side effects of VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include nausea; diarrhea; low platelet count; constipation; low white blood cell count; fever with low white blood cell count; tiredness; vomiting; swelling of arms, legs, hands, or feet; fever; infection in lungs; shortness of breath; bleeding; low red blood cell count; rash; stomach (abdominal) pain; infection in your blood; muscle and joint pain; dizziness; cough; sore throat; and low blood pressure.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Call your doctor for medical advice about side effects.

You are encouraged to report side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you cannot afford your medication, contact genentech-access.com/patient/brands/venclexta for assistance.

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here.

See VENCLYXTO full summary of product characteristics (SmPC) at View Source

Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Oncology
At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potentially breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world’s most widespread and debilitating cancers. As we work to have a remarkable impact on people’s lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit View Source

On December 5, 2020 Sierra Oncology, Inc. (SRRA), a late-stage biopharmaceutical company on a quest to deliver targeted therapies that treat rare forms of cancer, reported updated overall survival (OS) data for momelotinib in both JAKi-naïve and patients previously treated with ruxolitinib (Press release, Sierra Oncology, DEC 5, 2020, View Source [SID1234572217]). The data were presented in an oral presentation at the 2020 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting by Srdan Verstovsek, MD, PhD, Chief, Section for Myeloproliferative Neoplasms, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

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"Momelotinib’s unique mechanism of action—targeting JAK1, JAK2 and ACVR1—is translating to durability of activity and survival data consistent with its clinical and biologic profile," said Dr. Verstovsek. "Notably, momelotinib showed improved rates in transfusion independence and the duration thereof as well as overall survival, and that benefit was present regardless of whether or not the patient was previously treated with a JAK inhibitor."

"As the SIMPLIFY data sets continue to mature, we are seeing increasingly exciting outcomes in terms of overall survival, as well as myelofibrosis disease hallmarks, including splenic response and transfusion independence," said Barbara Klencke, MD, Chief Development Officer at Sierra Oncology. "We believe these data presented at the ASH (Free ASH Whitepaper) annual meeting, in combination with previously reported safety data, tell a truly innovative story for how momelotinib can fulfill an unmet need for intermediate and high-risk myelofibrosis patients who are not ideal candidates for currently approved therapies. We look forward to continuing enrollment in the Phase 3 MOMENTUM study to further highlight where momelotinib may be a preferred treatment option for patients and their physicians."

Robust Overall Survival and Sustained Efficacy Outcomes During Long Term Exposure to Momelotinib in JAK Inhibitor Naïve and Previously JAK Inhibitor Treated Intermediate/High Risk Myelofibrosis Patients (Abstract #54)

The SIMPLIFY-1 (S1) and SIMPLIFY-2 (S2) Phase 3 studies evaluated momelotinib (MMB) against ruxolitinib (S1) or best available therapy (S2) for a 24-week randomization treatment phase, followed by an opportunity for extended momelotinib treatment for all patients. Results based on a total 588 patients presented by Dr. Verstovsek include:

Robust OS was observed in both JAKi-naïve and previously ruxolitinib-treated patients
In S1, the median OS has not been reached in the MMB arm and 53.1 months in the control arm (HR=0.99, p=0.97)
In S2, the median OS was 34.3 months in originally MMB-randomized patients and 37.5 months in the BAT/RUXàMMB arm (HR=0.96, p=0.86), representing the best reported OS in this previously RUX-treated setting
Sustained transfusion independence was observed with extended MMB treatment
In S1, TI response at Week 24 was 67% in the MMB arm and 49% in the control arm (p<0.001). 40% of MMB-treated patients achieved a splenic response at any time during S1
The median duration of TI has not been reached after >3 years of follow up
In S2, TI response at Week 24 was 43% in the MMB arm and 21% in the control arm (p=0.001)
Compound safety was favorable for MMB with limited hematological toxicity and lack of cumulative toxicity
Patients were randomized 1:1 (S1) and 2:1 (S2) to receive MMB (200 mg QD) versus RUX (20 mg BID) or BAT (88.5% RUX/RUX+) for 24 weeks followed by extended momelotinib treatment. Both trials had primary endpoints of Splenic Response Rate and secondary endpoints of Total Symptom Score and Transfusion Independence Rate.

About Momelotinib

Momelotinib is a selective and orally bioavailable JAK1, JAK2 and ACVR1 inhibitor currently under investigation for the treatment of myelofibrosis. Myelofibrosis results from dysregulated JAK-STAT signaling and is characterized by constitutional symptoms, splenomegaly (enlarged spleen) and progressive anemia.

Momelotinib is currently under investigation in the MOMENTUM clinical trial, a global, randomized, double-blind Phase 3 study for symptomatic and anemic myelofibrosis patients. Top-line data are anticipated in H1 2022. The U.S. Food & Drug Administration has granted Fast Track designation for momelotinib.

On December 5, 2020 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company focused on the development of precision medicines for the treatment of cancer, reported preliminary clinical data from KOMET-001, an ongoing Phase 1/2A clinical trial of the Company’s oral, potent and selective menin inhibitor, KO-539, including single-agent activity in genetically defined subgroups of patients with relapsed or refractory acute myeloid leukemia (AML) (Press release, Kura Oncology, DEC 5, 2020, View Source [SID1234572216]).

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These data are being presented during an oral session at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition. A copy of the presentation is available on Kura’s website at www.kuraoncology.com/pipeline/publications.

"The preliminary first-in-human data generated by KO-539 for the treatment of patients with relapsed or refractory AML is encouraging," said Eunice Wang, M.D., Chief of the Leukemia Service at Roswell Park Comprehensive Cancer Center and principal investigator of the trial. "In addition to a favorable safety and tolerability profile, we have observed evidence of biologic activity in each dose-escalation cohort treated to date. I am delighted to observe evidence of clinical activity in patients with diverse genetic backgrounds, including patients with NPM1 mutations. The preliminary clinical data for KO-539 suggest it has the potential to be effective for multiple genetically defined AML subgroups of high unmet need."

As of the data cutoff on November 2, 2020, the first-in-human, open-label, multicenter trial enrolled 12 patients with relapsed or refractory AML, of whom eight were evaluable for efficacy. Patients were enrolled into four dose cohorts: 50 mg, 100 mg, 200 mg and 400 mg. KO-539 was administered orally, on a once-daily schedule in continuous 28-day cycles. These patients were heavily pretreated and received a median of three prior lines of therapy (range 2-7). Clinical or biological activity was reported in six of the eight efficacy-evaluable patients, including:

An NPM1 mutant patient with DNMT3A and KMT2D co-mutations achieved a complete remission (CR) with no measurable residual disease. The patient entered the trial following seven prior lines of therapy and remains on KO-539 after three cycles.

A second NPM1 mutant patient with FLT3-ITD, TET2 and CUX1 co-mutations achieved a morphological leukemia-free state (MLFS) following four prior lines of therapy. Both NPM1 mutant patients were dosed at 200 mg.

A patient with SETD2 and RUNX1 co-mutations achieved a CR after two cycles and was dose-escalated from 100 mg to 200 mg on cycle seven after blast counts were observed to increase. The patient experienced clinical benefit for more than six months prior to disease progression.

A patient with a KMT2A/MLL rearrangement had a marked decrease in hydroxyurea requirements and attained peripheral blood count stabilization at the 50 mg starting dose.
Notably, the clinical activity observed across patients was not correlated with concomitant treatment with CYP3A4 inhibitors. This is supported by drug pharmacokinetic studies in patients, which showed that KO-539 metabolism appears to be unaffected by co-administration of CYP3A4 inhibitors.

Four patients were not evaluable for efficacy as of the data cutoff, including an NPM1 mutant patient and a DNMT3A mutant patient with CUX1, ASXL1, IDH2, CBL, U2AF1 and RUNX1 co-mutations in the 400 mg cohort and a KMT2A/MLL-r patient in the 200 mg cohort.

Continuous daily dosing of KO-539 has been well tolerated and with a manageable safety profile to date. There have been no drug discontinuations due to treatment-related adverse events (AEs) and no evidence of QTc prolongation or other clinically significant EKG changes. Treatment related AEs (grade ≥ 3) have included pancreatitis, increased lipase, decreased neutrophil count, tumor lysis syndrome and deep venous thrombosis.

Kura expects to determine a maximum tolerated dose and/or a recommended Phase 2 dose in the first quarter of 2021, at which point the Company intends to advance into expansion cohorts in NPM1-mutant AML and KMT2A/MLL-rearranged AML, selected patient populations where KO‑539 has the potential to demonstrate pronounced clinical benefit.

"We are pleased to see encouraging evidence of biologic and clinical activity from KO-539 in the preliminary data, particularly in these heavily pretreated AML patients who were enrolled without genetic selection in the dose-escalation portion of this trial," said Stephen Dale, M.D., Chief Medical Officer of Kura Oncology. "We are also encouraged by the clinical activity observed in cytogenetically normal patients with various co-mutations whose activity may be implicated by the upstream menin-KMT2A/MLL interaction, and believe these patients may represent a potential third expansion cohort. Meanwhile, we continue to explore options to broaden the opportunity for KO-539 in the treatment of acute leukemias, as well as in combination with chemotherapy and targeted therapies to support advancement to earlier lines of therapy."

Virtual Investor Event

Kura’s management will host a virtual investor event at 2:00 p.m. ET / 11:00 a.m. PT today, December 5, 2020, to provide a review of KO-539 following the oral presentation of preliminary clinical data at the ASH (Free ASH Whitepaper) Annual Meeting. The event will feature members of the Kura management team along with two of the investigators from the KOMET-001 clinical trial, Dr. Eunice Wang and Dr. Ghayas Issa. A live video webcast of the event will be available in the Investors section of Kura’s website at www.kuraoncology.com, with an archived replay available shortly after the conclusion of the event.

About Acute Myeloid Leukemia

AML is the most common acute leukemia in adults and begins when the bone marrow makes abnormal myeloblasts (white blood cells), red blood cells or platelets. Despite the many available treatments for AML, prognosis for patients remains poor, especially in the relapsed/refractory setting. More than 50% of patients with AML who achieve a CR after induction therapy relapse within one to three years, and less than 10% of those with relapsed/refractory AML are alive at three years. Prognosis is poor in patients with KMT2A rearrangements and in those with co-mutations that may include NPM1.

About KOMET-001

KOMET-001 (Kura Oncology Menin Inhibitor Trial) is a Phase 1/2A clinical trial to determine the safety, tolerability and recommended Phase 2 dose of KO-539 in patients with refractory or relapsed AML. A planned expansion phase in specific genetic subgroups, including NPM1 mutant AML and KMT2A/MLL rearranged AML, is expected to further evaluate anti-leukemic activity and tolerability of KO-539. Additional information about KOMET-001 can be found at kuraoncology.com/clinical-trials-komet.

About KO-539

KO-539 is a novel, once-daily, oral investigational drug candidate targeting the menin-KMT2A/MLL protein-protein interaction for treatment of genetically defined AML patients with high unmet need. In preclinical models, KO-539 inhibits the KMT2A/MLL protein complex and has downstream effects on HOXA9/MEIS1 expression. KO-539 has received Orphan Drug Designation from the U.S. Food and Drug Administration for the treatment of AML.

On December 5, 2020 Intellia Therapeutics, Inc. (NASDAQ:NTLA), reported that new preclinical data in support of NTLA-5001, the company’s wholly owned Wilms’ Tumor 1 (WT1)-directed T cell receptor (TCR)-T cell therapy candidate for the treatment of acute myeloid leukemia (AML), at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place virtually from December 5-8, 2020 (Press release, Intellia Therapeutics, DEC 5, 2020, View Source [SID1234572215]). NTLA-5001 capitalizes on how natural T cells recognize and respond to tumors. The target, WT1, is highly overexpressed in AML, a cancer of the blood and bone marrow that is often fatal despite existing treatments (NIH SEER Cancer Stat Facts: Leukemia – AML). The new preclinical data being presented today highlight the faster expansion and superior function of T cells manufactured by Intellia’s proprietary approach, compared to a standard genome editing process. Specifically, NTLA-5001’s lead TCR-T cells resulted in significantly higher anti-tumor activity in mouse models of acute leukemias than that observed in mice treated with cells engineered using the standard process.

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"NTLA-5001 is the first potential CRISPR-based cancer treatment engineered using Intellia’s proprietary process. Based on our preclinical results, we believe our process will result in a pipeline of safer and more efficacious oncological products, with reduced manufacturing time and, importantly, reduced vein-to-vein time, compared to currently available approaches. Showing in vivo efficacy in acute leukemia mouse models, as presented today at ASH (Free ASH Whitepaper), is extremely encouraging and an important steppingstone to entering the clinic next year," said Intellia President and Chief Executive Officer John Leonard, M.D. "In our first-in-human trial, we plan to establish the safety and activity that will enable us to move quickly to a pivotal investigation of NTLA-5001 for the treatment of AML, which is the most common type of acute leukemia in adults."

NTLA-5001 is being developed using Intellia’s proprietary process to treat AML patients regardless of the genetic subtype of a patient’s leukemia. Intellia plans to submit an Investigational New Drug (IND) application or equivalent for NTLA-5001 in the first half of 2021, subject to the impact of the COVID-19 pandemic, with the first-in-human trial planned to evaluate safety and activity in patients with persistent or recurrent AML who have previously received first-line therapies. Additional efforts are underway to evaluate the potential use of NTLA-5001 to treat WT1-positive solid tumors.

Presentation Details

Title: "NTLA-5001, a T Cell Product Candidate with CRISPR-Based Targeted Insertion of a High-Avidity, Natural, WT1-Specific TCR, Shows Efficacy in In Vivo Models of AML and ALL"
Publication Number: 1435
Session Name: 703. Adoptive Immunotherapy: Poster I
Presenting Author: Birgit Schultes, Ph.D., vice president of Intellia’s Cell Therapy group

With Intellia’s proprietary T cell engineering process, CRISPR/Cas9 in combination with adeno-associated virus (AAV) is used to insert a WT1-directed TCR in locus, while eliminating the expression of the endogenous TCRs. Benefits of Intellia’s approach include the following:

Intellia’s proprietary T cell engineering process enables multiple, sequential gene edits and is a significant improvement over standard engineering processes commonly used to introduce proteins and nucleic acids into cells.
Sequential editing maintains high T cell viability and may result in safer T cell products because treated cells have minimal levels of translocations, similar to unedited cells, and do not cause graft-versus-host disease (GvHD).
The observed faster T cell expansion with favorable T cell memory phenotype could lead to a reduced vein-to-vein time and better T cell persistence in patients, respectively.
T cells engineered using Intellia’s proprietary process to express the lead TCR to the WT137-45 epitope are efficacious, durable and safe in vivo in gold-standard mouse models of AML and acute lymphocytic leukemia (ALL). In collaboration with Chiara Bonini’s team at IRCCS Ospedale San Raffaele (OSR), the AML mouse model was developed using patient-derived primary AML blasts. WT1-specific T cell administration inhibited tumor growth more significantly and durably in blood, bone marrow and spleen than T cells edited using an industry standard electroporation process. Researchers additionally used an aggressive ALL model in immunocompromised mice engineered to express T cell-supporting cytokines at levels comparable to those in patients post-conditioning regimen, or post-lymphodepletion. In the ALL model, WT1-specific T cells also bestowed significant tumor control.

The presentation can be found here, on the Scientific Publications & Presentations page of Intellia’s website.

On December 5, 2020 Novartis reported analyses from two separate trials with Kymriah (tisagenlecleucel) in patients with certain advanced lymphomas. In the interim analysis of the investigational Phase II ELARA study, Kymriah led to a complete response (CR) in 65% of patients with relapsed or refractory (r/r) follicular lymphoma (FL) and an overall response rate (ORR) of 83% after at least three months of follow-up (Press release, Novartis, DEC 5, 2020, View Source [SID1234572214]). These patients continued to relapse or have refractory disease despite exposure to numerous lines of therapy (median four prior lines of therapy [range 2-13]) prior to Kymriah infusion1. The second analysis – a 40-month median follow-up from the Phase II JULIET trial – reported that the two-year progression-free survival (PFS) rate was 33% in patients with r/r diffuse large B-cell lymphoma (DLBCL), an important finding given these patients have limited treatment options that provide durable responses2. The JULIET study continued to show the effectiveness and well-characterized safety profile of Kymriah for these patients. These results were presented today during the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper).

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"For people who have follicular lymphoma that continues to relapse or does not respond after treatment with many lines of therapy, response to therapy becomes less likely with each additional treatment," said Nathan H. Fowler, MD, Department of Lymphoma and Myeloma, Division of Cancer Medicine at MD Anderson Cancer Center. "We are encouraged by these interim results from the ELARA trial, as there is a great need for potentially definitive options and an alternative to stem cell transplant. We look forward to continuing to learn more about how Kymriah may provide benefit for these patients."

In the interim analysis of the investigational ELARA clinical trial, in which 52 patients were evaluable for efficacy with a median follow-up of 9.9 months, Kymriah led to responses for the majority of patients treated. Specifically, after at least three months of follow-up, 65% (99.5% CI, 45.1-82.4) of patients achieved a complete response, meeting the primary endpoint. The overall response rate was 83% (95% CI, 69.7-91.8). For those who had a complete response, the vast majority (90%) sustained responses for six months or more.

Safety results from this analysis of the ELARA trial suggest there was no emergence of new safety signals for Kymriah in the 97 patients evaluable for safety. No patients experienced grade 3/4 CRS, as defined by the Lee Scale, and any grade CRS occurred in 49% of patients (29% grade 1; 20% grade 2). To treat CRS, 15% of patients required tocilizumab and 3% required steroids. One percent of patients experienced grade 3/4 NEs and any grade NEs occurred in 9% of patients. Median time to CRS and severe NE onset was four and 8.5 days respectively, with respective median time to resolution of four and two days. All neurological and CRS events resolved with appropriate management. Three patients died from progressive disease and no deaths were treatment-related. Kymriah was administered in the outpatient setting for 18% of patients in the ELARA trial1.

Results from the primary analysis of the ELARA study, with data from 90 patients followed up for at least 6 months, will be presented at an upcoming medical meeting.

"Novartis is dedicated to continuing to explore the safety and efficacy of Kymriah for patients with advanced blood cancers who do not achieve long-term remissions despite multiple prior lines of therapy," said John Tsai, MD, Head of Global Drug Development and Chief Medical Officer, Novartis. "As we go deeper with our research in CAR-T cell therapies, these new analyses showcase the potential to rewrite cancer survival in patients with certain advanced lymphomas."

New updated efficacy results from pivotal JULIET clinical trial

New updated efficacy results from a 40-month median follow-up analysis demonstrated continued durable responses for patients with r/r DLBCL treated with Kymriah in the JULIET trial (n=115). Among the 61 patients who responded to treatment, the relapse-free probability was 60% at 24 and 36 months; median DOR was not reached (95% CI, 10-not estimable [NE])3. Two-year progression-free survival rate was 33% 2. Survival probability at 24 and 36 months was 40% and 36%, respectively. Importantly, no new safety signals were observed after more than three years of long-term follow-up observation3.

"Before the availability of Kymriah, long-term responses to treatment for those living with relapsed or refractory DLBCL were rare," said Ulrich Jaeger, MD, Medical University of Vienna, Vienna, Austria. "With these results from the JULIET trial, including biomarker analysis to better define patient subgroups who may benefit the most from CAR-T cell therapy, we are providing further evidence that Kymriah may be a definitive option for some patients. Additionally, with no new safety signals observed, physicians can continue to confidently refer their patients to certified centers to be treated with Kymriah."

The relationship between biomarkers, such as baseline Myc overexpression in tumors and tumor microenvironment (TME) characteristics, and response to Kymriah was also assessed in this analysis. Outcomes were better for those with negative Myc expression compared to those who had Myc overexpression, which leads to an unfavorable immunosuppressive TME with a restricted T-cell response. These results are consistent with historical outcomes for patients with Myc- and Myc+ expression4. Analyses to further identify biomarkers for response to CAR-T cell therapy are ongoing.

More information about Novartis activities at ASH (Free ASH Whitepaper) can be found on the Novartis 2020 ASH (Free ASH Whitepaper) Annual Meeting virtual portal.

About Follicular Lymphoma
Follicular lymphoma, the second most common form of non-Hodgkin lymphoma (NHL), is an indolent lymphoma, and represents approximately 22% of NHL cases5,6. Despite new treatments that improve overall survival, FL is regarded as an incurable malignancy with a relapsing and remitting pattern7,8. Throughout the lifetime of a patient with relapsing FL, they may be exposed to a median of five lines of prior treatment, with an upper range of 12 lines9,10. Although patients in third or later line treatment for FL have multiple systemic therapies available, the efficacy of these regimens drops off rapidly in later lines5. Additionally, because of this relapsing and remitting pattern, patients who are refractory to treatment or quickly relapse may exhaust available treatment options8.

About the ELARA trial
ELARA is a Phase II, single-arm, multicenter, open-label trial investigating the efficacy and safety of Kymriah in adult patients with r/r FL. This international trial has enrolled patients from over 30 sites in 12 countries worldwide. The primary endpoint is CRR based on best response by central review (Lugano 2014 criteria). Patients evaluable for efficacy had measurable disease at infusion and more than six months of follow-up from infusion or discontinued early. After infusion, disease assessments were performed every three months. Secondary endpoints include overall response rate, duration of response, progression-free survival, overall survival and safety.

In Q2 2020, the FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation to Kymriah in r/r FL, based on preliminary results from the ELARA trial. RMAT designation is intended to expedite the development and review of Kymriah as a regenerative therapy for this underserved patient population. Kymriah also has Orphan Drug designation from the FDA for this indication.

About the JULIET Trial
JULIET was the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL. JULIET, led by researchers at the University of Pennsylvania, enrolled patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including Austria, France, Germany, Italy, Norway and the Netherlands.

About Kymriah
Kymriah is the first-ever FDA-approved CAR-T cell therapy, and the first-ever CAR-T to be approved in two distinct indications. It is a one-time treatment designed to empower patients’ immune systems to fight their cancer. Kymriah is currently approved for the treatment of r/r pediatric and young adult (up to 25 years of age) acute lymphoblastic leukemia (ALL), and r/r adult DLBCL11.

About Novartis Commitment to Oncology Cell & Gene
Novartis has a mission to reimagine medicine by bringing curative cell & gene therapies to patients worldwide. Novartis has a deep CAR-T pipeline and ongoing investment in manufacturing and supply chain process improvements. With active research underway to broaden the impact of cell and gene therapy in oncology, Novartis is going deeper in hematological malignancies, reaching patients with other cancer types and evaluating next-generation CAR-T cell therapies that focus on new targets and utilize new technologies.

Novartis was the first pharmaceutical company to significantly invest in pioneering CAR-T research and initiate global CAR-T trials. Kymriah, the first approved CAR-T cell therapy, developed in collaboration with the Perelman School of Medicine at the University of Pennsylvania, is the foundation of Novartis’ commitment to CAR-T cell therapy. Kymriah is currently approved for use in at least one indication in 27 countries and at more than 270 certified treatment centers, with the ambition for further expansion to help fulfill the ultimate goal of bringing CAR-T cell therapy to every patient in need.

The Novartis global CAR-T manufacturing footprint spans seven facilities, across four continents. This comprehensive, integrated footprint strengthens the flexibility, resilience and sustainability of the Novartis manufacturing and supply chain. Commercial and clinical trial manufacturing is now ongoing at Novartis-owned facilities in Stein, Switzerland, Les Ulis, France and Morris Plains, New Jersey, USA, as well as at the contract manufacturing sites at Fraunhofer-Institut for cell therapy and immunology (Fraunhofer-Institut für Zelltherapie und Immunologie) facility in Leipzig, Germany, and now FBRI in Kobe, Japan. Manufacturing production at Cell Therapies in Australia and Cellular Biomedicine Group in China is forthcoming.

Kymriah (tisagenlecleucel) US Important Safety information
Kymriah may cause side effects that are severe or life-threatening, such as Cytokine Release Syndrome (CRS) or Neurological Toxicities. Patients with CRS may experience symptoms including difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their healthcare provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, Kymriah is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Kymriah REMS.

Serious allergic reactions, including anaphylaxis, may occur after Kymriah infusion. Kymriah can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their healthcare provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenia), where one or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s healthcare provider will do blood tests to check all of their blood cell counts after treatment with Kymriah. Patients should be advised to tell their healthcare provider right away if they get a fever, are feeling tired, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with Kymriah, and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with Kymriah. Patients should tell their healthcare provider about their treatment with Kymriah before receiving a live virus vaccine.

After treatment with Kymriah, patients will be monitored lifelong by their healthcare provider, as they may develop secondary cancers or recurrence of their cancer.

Patients should not drive, operate heavy machinery, or do other dangerous activities for eight weeks after receiving Kymriah because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.

Some of the most common side effects of Kymriah are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, dizziness/lightheadedness, and headache. However, these are not all of the possible side effects of Kymriah. Patients should talk to their healthcare provider for medical advice about side effects.

Prior to a female patient starting treatment with Kymriah, their healthcare provider may do a pregnancy test. There is no information available for Kymriah use in pregnant or breast-feeding women. Therefore, Kymriah is not recommended for women who are pregnant or breast feeding. Patients should talk to their healthcare provider about birth control and pregnancy.

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving Kymriah, patients should be advised that some commercial HIV tests may cause a false-positive test result. Patients should also be advised not to donate blood, organs, or tissues and cells for transplantation after receiving Kymriah.