On June 10, 2022 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported positive initial data from its ongoing Phase 2 APEX clinical trial evaluating the selective KIT D816V inhibitor bezuclastinib in patients with advanced systemic mastocytosis (AdvSM) (Press release, Cogent Biosciences, JUN 10, 2022, View Source [SID1234615864]). The data are being presented today in a poster presentation at the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Congress in Vienna, Austria.

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"Advanced systemic mastocytosis is a severe, debilitating hematologic disorder and physicians and patients remain in search of more effective and better tolerated treatment options to fight this disease," said Daniel DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at the Dana-Farber Cancer Institute and APEX clinical trial investigator. "I am very impressed with the early, encouraging results presented today from the APEX study. If results like these can be shown in a larger set of patients with AdvSM, I believe bezuclastinib has the potential to help us take a big step forward in treating systemic mastocytosis patients."

"We are very excited to present initial clinical data from the APEX study of bezuclastinib in advanced systemic mastocytosis," said Andrew Robbins, Chief Executive Officer at Cogent Biosciences. "These results reinforce the hypothesis that a potent, selective KIT D816V inhibitor with limited CNS penetration has the potential to provide meaningful clinical activity to all systemic mastocytosis patients, without the tolerability challenges seen with other available treatment options. Based on these results, we expect to accelerate our timelines and investment and look forward to providing another APEX clinical update by the end of 2022, and to presenting SUMMIT clinical data in non-advanced systemic mastocytosis (NonAdvSM) patients in the first half of 2023."

Data from Ongoing Phase 2 APEX Clinical Trial

APEX is a global, open-label, multi-center, two-part Phase 2 clinical trial in patients with AdvSM evaluating the safety, efficacy, pharmacokinetic, and pharmacodynamic profiles of bezuclastinib. As of the data cutoff date of May 24, 2022, 11 patients had been treated in Part 1 at one of four dose levels

(50 mg BID, 100 mg BID, 200 mg BID or 400 mg QD). The median age of patients at study entry was 70 years (ranging from 48-87 years). Patients were enrolled with the following sub-types: two patients with aggressive systemic mastocytosis (ASM), eight patients with systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and one patient with mast cell leukemia (MCL). Two patients had received prior avapritinib and midostaurin treatment.

Initial Safety Data

As of the cutoff date, May 24, 2022, bezuclastinib was generally well-tolerated at all doses. The majority of adverse events were Grade 1/2 and seen in no more than one patient with one serious adverse event and no Grade 4 events reported. Grade 3 events reported as at least possibly related were anemia (1 patient), neutropenia (1 patient) and hypersensitivity/mediator flare (1 patient). There were no reported cases of periorbital/peripheral edema, cognitive effects or intracranial bleeding events, which have been associated with other KIT inhibitors. As of the cutoff date, all patients remained on study. Subsequently, one SM-AHN patient with chronic myelomonocytic leukemia (CMML) transformed to acute myeloid leukemia (AML) and discontinued participation in the trial.

Initial Clinical Activity Data

As of the data cutoff date of May 24, 2022, all 11 patients treated were evaluated for signs of clinical activity. Eight of 11 patients had been treated for at least two cycles, had available data from bone marrow biopsy, and were evaluated for additional endpoints Cycle 3 Day 1 (C3D1) evaluable.

11/11 patients achieved ≥50% reduction in serum tryptase levels by central assessment

89% median reduction in serum tryptase

Six of these patients achieved reduction to <20 ng/mL

8/8 patients (C3D1 evaluable) achieved ≥50% reduction in bone marrow mast cells by central review

Six of these patients achieved complete clearance of bone marrow mast cell aggregates

8/8 patients (C3D1 evaluable) demonstrated decreases in KIT D816V variant allele fraction (VAF) by droplet digital polymerase chain reaction (ddPCR)

All patients remained on treatment with treatment duration ranging from 0.5 – 4.8 months

Two patients enrolled had previously received and discontinued avapritinib for toxicity reasons (intracranial hemorrhage, thrombocytopenia). Both patients have demonstrated clinical outcomes consistent with the avapritinib-naïve patients, including similar magnitude reductions in serum tryptase.

Bezuclastinib Clinical Development

Based on the favorable initial safety and tolerability profile and clinical activity observed to date in the Phase 2 APEX clinical trial with bezuclastinib for AdvSM, Cogent will continue enrolling patients in Part 1 of APEX to determine a recommended dose for use in Part 2 of the trial. A pre-planned interim analysis is scheduled once approximately 28 patients have received at least two cycles of study treatment in Part 1. Cogent plans to present additional data from APEX by the end of 2022. In addition, Cogent continues to actively enroll patients in SUMMIT, a Phase 2 clinical trial with bezuclastinib for NonAdvSM, and PEAK, a registrational randomized, open-label, global, Phase 3 clinical trial in patients with imatinib-resistant Gastrointestinal Stromal Tumors (GIST). Cogent plans to present initial data from SUMMIT and lead-in data from PEAK in the first half 2023.

Conference Call Information & EHA (Free EHA Whitepaper) poster

Cogent will host a webcast today at 8:00 am ET to discuss today’s APEX results. The webcast will be accessible through the Investors and Media section of Cogent’s website at View Source Following the live webcast, an archived replay will also be available.

The APEX poster to be presented at EHA (Free EHA Whitepaper) is available to registered conference attendees as well as on the Cogent Biosciences website in the Posters and Publications section of www.cogentbio.com/research.

On June 10, 2022 Wugen, Inc., a clinical-stage biotechnology company developing a pipeline of off-the-shelf cell therapies to treat a broad range of hematological and solid tumor malignancies, reported that new preclinical data demonstrating the enhanced anti-tumor properties of WU-NK-101, Wugen’s lead memory natural killer (NK) cell therapy product (Press release, Wugen, JUN 10, 2022, View Source [SID1234615883]). The data elucidate the unique cytokine-induced memory-like (CIML) phenotype of WU-NK-101 and further support its clinical development for acute myeloid leukemia (AML) and a range of solid tumor indications. The findings will be presented during a poster session at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress in Vienna.

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"These data are foundational to our approach and confirm our development strategy as we advance WU-NK-101 for both AML and solid tumors," said Dan Kemp, Ph.D., President and Chief Executive Officer of Wugen. "Today’s presentation highlights key functional features of WU-NK-101: its unique CIML phenotype, enhanced metabolic fitness, and persistent cytotoxic activity, which is maintained even within the harsh immunosuppressive tumor microenvironment. Together, these data affirm our conviction in WU-NK-101 as a best-in-class allogeneic NK cell therapy. We are eager to continue development of WU-NK-101 and expect to advance into an initial clinical trial for patients with relapsed or refractory (r/r) AML followed by additional studies in solid tumor indications."

Today’s presentation highlighted the following:

WU-NK-101 cells have a unique CIML phenotype with improved activation, metabolic flexibility, and cytotoxicity compared to conventional natural killer cells (cNK).

In vivo activity of WU-NK-101 was confirmed in an AML THP-1 xenograft model, where both single- and multi-dose regimens effectively reduced tumor burden relative to vehicle controls. The data support a planned clinical trial of WU-NK-101 for patients with r/r AML.

WU-NK-101 also overcomes several limitations associated with NK cell therapy in solid tumors, with key features including enhanced metabolic fitness and adaptability and enhanced functionality in immunosuppressive TME conditions compared to cNK—functional characteristics supporting further development of WU-NK-101 in solid tumor indications.

The details of Wugen’s poster presentation at EHA (Free EHA Whitepaper) are as follows:

Title: WU-NK-101, An Allogeneic Memory NK Cell, for the Treatment of Relapse or Refractory (R/R) Acute Myeloid Leukemia (AML)
Session date and time: Friday, June 10, 2022, from 4:30 – 5:45 p.m. CEST
Abstract Number: P1426
Presenting Author: Jan Davidson-Moncada, M.D., Ph.D., Chief Medical Officer, Wugen

Additional meeting information can be found at www.ehaweb.org/congress.

About WU-NK-101

WU-NK-101 is a novel immunotherapy harnessing the power of memory natural killer (NK) cells to treat liquid and solid tumors. Memory NK cells are hyper-functional, long-lasting immune cells that exhibit enhanced anti-tumor activity and a cytokine-induced memory-like (CIML) phenotype. This rare cell population has a superior phenotype, proliferation capacity, and metabolic fitness that makes it better suited for cancer therapy than other NK cell therapies. Wugen is applying its proprietary MonetaTM platform to advance WU-NK-101 as a commercially scalable, off-the-shelf cell therapy for cancer. WU-NK-101 is currently in development for acute myelogenous leukemia (AML) and solid tumors.

On June 10, 2022 CTI BioPharma Corp. (Nasdaq: CTIC) reported two scientific poster presentations from the Company’s pacritinib clinical program at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Congress, being held in Vienna, Austria, June 9-12, 2022 (Press release, CTI BioPharma, JUN 10, 2022, View Source [SID1234615865]).

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"Our presentions today demonstrate that full dose pacritinib achieved higher response rates and a similar, manageable safety profile compared to lower-dose ruxolitinib in patients with myelofibrosis who have moderate or severe thrombocytopenia," said Adam Craig, President and Chief Executive Officer of CTI BioPharma. "As the commercial launch of VONJOTM (pacritinib) in the U.S. continues to exceed our expectations, we are pleased to highlight VONJO’s clinical value as a potential best in class treatment for patients with cytopenic myelofibrosis with platelet counts below 50 × 109/L."

Presentation materials will be available at ctibiopharma.com.

Retrospective Comparison of Patient Outcomes on Pacritinib Versus Ruxolitinib in Patients with Myelofibrosis and Thrombocytopenia (New)

Poster Number: P1069
Session Name: Poster session
Session Date: Friday, June 10, 2022
Presentation Time: 16:30 – 17:45 p.m. CEST (10:30 – 11:45 a.m. ET)
Presenter: Prof. Claire Harrison

Pacritinib is a novel JAK2/IRAK1 inhibitor approved by the U.S. Food and Drug Administration (FDA) for patients with myelofibrosis and thrombocytopenia. Unlike the JAK 1/2 inhibitor ruxolitinib, which must be dose-reduced or held in patients with thrombocytopenia, pacritinib has been studied at full dose regardless of platelet count. In this part of of the Phase 3 PERSIST-2 study, which focuses on retrospectively analyzing outcomes in patients treated with pacritinib versus ruxolitinib, patients were randomized 1:1:1 to pacritinib 200 mg twice daily (BID), pacritinib 400 mg once daily (QD) or best available therapy (BAT), with 45 percent of patients on BAT receiving ruxolitinib.

This analysis demonstrates overall and fatal adverse events occurred at similar rates on pacritinib versus ruxolitinib, as did bleeding events. Cardiac events occurred more commonly on pacritinib, though the difference was largely due to higher rates of grade 1 peripheral edema on pacritinib. There were lower rates of herpes zoster reactivation (n=0 vs. 1), pulmonary aspergilosis (n=1 vs. 0), deep venous thrombosis (n=0 vs. 1) and pulmonary embolism (n=1 vs. 0) on pacritinib and ruxolitinib, respectively. These results show that pacritinib, administered at the full dose of 200 mg BID, yielded higher response rates and a similar safety profile compared to lower-dose ruxolitinib, in patients with myelofibrosis who have moderate or severe thrombocytopenia.

Risk-Adjusted Safety Analysis of Pacritinib in Patients with Myelofibrosis (Encore)

Poster Number: P1068
Session Name: Poster session
Session Date: Friday, June 10, 2022
Presentation Time: 16:30 – 17:45 p.m. CEST (10:30 – 11:45 a.m. ET)
Presenter: Dr. Naveen Pemmaraju

Pacritinib is a novel JAK2/IRAK1 inhibitor that has shown significant activity in patients with myelofibrosis, including those with platelet counts <50 × 109/L. This safety analysis focuses on toxicities of interest for patients treated with pacritinib 200 mg twice daily (BID) and best available therapy (BAT), including ruxolitinib, on the Phase 3 PERSIST-2 and Phase 2 PAC203 studies. Because the average treatment duration was longer for patients on pacritinib 200 mg BID on PERSIST-2 and PAC203 compared to BAT on PERSIST-2, this analysis presents adverse events rates in these patients corrected for duration of exposure.

This risk-adjusted analysis demonstrates that the safety profile of pacritinib 200 mg BID is comparable to BAT. In particular, rates of bleeding were not elevated on pacritinib 200 mg BID compared to BAT, both overall and in patients with PLT <50 x 109/L. Rates of fatal events, thrombosis, major adverse cardiac events (MACE) and non-melanoma skin cancer were higher on ruxolitinib than pacritinib. These results indicate that pacritinb 200 mg BID may represent a full-dose therapeutic option for patients with myelofibrosis, including those with thrombocytopenia.

About VONJO (pacritinib)
Pacritinib is an oral kinase inhibitor with activity against wild type Janus Associated Kinase 2 (JAK2), mutant JAK2V617F form and FMS-like tyrosine kinase 3 (FLT3), which contribute to signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Myelofibrosis is often associated with dysregulated JAK2 signaling. Pacritinib has higher inhibitory activity for JAK2 over other family members, JAK3 and TYK2. At clinically relevant concentrations, pacritinib does not inhibit JAK1. Pacritinib exhibits inhibitory activity against additional cellular kinases (such as CSF1R and IRAK1), the clinical relevance of which is unknown.

VONJO is indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. This indication is approved under accelerated approval based on spleen volume reduction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Important VONJO Safety Information
Hemorrhage:
Serious (11%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <100 × 109/L. Serious (13%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <50 × 109/L. Grade ≥3 bleeding events (defined as requiring transfusion or invasive intervention) occurred in 15% of patients treated with VONJO compared to 7% of patients treated on the control arm. Due to hemorrhage, VONJO dose-reductions, dose interruptions, or permanent discontinuations occurred in 3%, 3%, and 5% of patients, respectively.

Avoid use of VONJO in patients with active bleeding and hold VONJO 7 days prior to any planned surgical or invasive procedures. Assess platelet counts periodically, as clinically indicated. Manage hemorrhage using treatment interruption and medical intervention.

Diarrhea:
VONJO causes diarrhea in approximately 48% of patients compared to 15% of patients treated on the control arm. The median time to resolution in VONJO-treated patients was 2 weeks. The incidence of reported diarrhea decreased over time with 41% of patients reporting diarrhea in the first 8 weeks of treatment, 15% in Weeks 8 through 16, and 8% in Weeks 16 through 24. Diarrhea resulted in treatment interruption in 3% of VONJO-treated patients. None of the VONJO-treated patients reported diarrhea that resulted in treatment discontinuation. Serious diarrhea adverse reactions occurred in 2% of patients treated with VONJO compared to no such adverse reactions in patients in the control arm.

Control pre-existing diarrhea before starting VONJO treatment. Manage diarrhea with antidiarrheal medications, fluid replacement, and dose-modification. Treat diarrhea with anti–diarrheal medications promptly at the first onset of symptoms. Interrupt or reduce VONJO dose in patients with significant diarrhea despite optimal supportive care.

Thrombocytopenia:
VONJO can cause worsening thrombocytopenia. VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre–existing moderate to severe thrombocytopenia (platelet count <100 × 109/L). VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre–existing severe thrombocytopenia (platelet count <50 × 109/L).

Monitor platelet count prior to VONJO treatment and as clinically indicated during treatment. Interrupt VONJO in patients with clinically significant worsening of thrombocytopenia that lasts for more than 7 days. Restart VONJO at 50% of the last given dose once the toxicity has resolved. If toxicity recurs hold VONJO. Restart VONJO at 50% of the last given dose once the toxicity has resolved.

Prolonged QT interval:
VONJO can cause prolongation of the QTc interval. QTc prolongation of >500 msec was higher in VONJO-treated patients than in patients in the control arm (1.4% vs 1%). QTc increase from baseline by 60 msec or higher was greater in VONJO-treated patients than in control arm patients (1.9% vs 1%). Adverse reactions of QTc prolongation were reported for 3.8% of VONJO-treated patients and 2% of control arm patients. No cases of torsades de pointes were reported.

Avoid use of VONJO in patients with a baseline QTc of >480 msec. Avoid use of drugs with significant potential for QTc prolongation in combination with VONJO. Correct hypokalemia prior to and during VONJO treatment. Manage QTc prolongation using VONJO interruption and electrolyte management.

Major Adverse Cardiac Events (MACE):
Another Janus associated kinase (JAK)-inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with VONJO particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.

Thrombosis:
Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated.

Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.

Secondary Malignancies:
Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding non-melanoma skin cancer (NMSC) (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with VONJO, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

Risk of Infection:
Another JAK-inhibitor has increased the risk of serious infections (compared to best available therapy) in patients with myeloproliferative neoplasms. Serious bacterial, mycobacterial, fungal and viral infections may occur in patients treated with VONJO. Delay starting therapy with VONJO until active serious infections have resolved. Observe patients receiving VONJO for signs and symptoms of infection and manage promptly. Use active surveillance and prophylactic antibiotics according to clinical guidelines.

Interactions with CYP3A4 Inhibitors or Inducers:
Co-administration of VONJO with strong CYP3A4 inhibitors or inducers is contraindicated. Avoid concomitant use of VONJO with moderate CYP3A4 inhibitors or inducers.

Drug interruptions due to an adverse reaction occurred in 27% patients who received VONJO 200 mg twice daily compared to 10% of patients treated with BAT. Dosage reductions due to an adverse reaction occurred in 12% of patients who received VONJO 200 mg twice daily compared to 7% of patients treated with BAT. Permanent discontinuation due to an adverse reaction occurred in 15% of patients receiving VONJO 200 mg twice daily compared to 12% of patients treated with BAT.

Please visit View Source for full Prescribing Information and the Medication Guide.

About Myelofibrosis
Myelofibrosis is bone marrow cancer that results in formation of fibrous scar tissue and can lead to thrombocytopenia and anemia, weakness, fatigue and an enlarged spleen and liver. Within the United States, there are approximately 21,000 patients with myelofibrosis, 7,000 of which have severe thrombocytopenia (defined as blood platelet counts of less than 50 x109/L). Severe thrombocytopenia is associated with poor survival and high symptom burden and can occur as a result of disease progression or from drug toxicity with other JAK2 inhibitors, such as JAKAFI and INREBIC.

On June 10, 2022 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies, reported the publication of clinical data across multiple programs at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress, being held June 9-12, 2022 (Press release, Autolus, JUN 10, 2022, View Source [SID1234615884]).

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Autolus will hold a conference call on Monday June 13 2022 at 7:30 am EST / 12:30 pm BST, which will include participation from; Dr. Steven Horwitz, M.D., Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center; Dr. Kate Cwynarski, Chair UK T cell Lymphoma Group, Consultant Hematologist, University College London Hospital; and Autolus’ management team.

"We are excited to be presenting this first clinical data for two new product candidates, AUTO4 with its unique targeting approach for T cell lymphoma and AUTO1/22 a dual targeting CAR T product for the treatment of children with ALL," said Dr. Christian Itin, CEO of Autolus. "With obe-cel progressing towards pivotal data in the FELIX trial in adult patients with ALL, we are pleased to show obe-cel’s broader utility in B-NHL patients, mirroring the high level of activity and well manageable safety profile we have seen in previous trials."

"This year’s EHA (Free EHA Whitepaper) is an important meeting for Autolus with four presentations providing updates from ongoing clinical studies," said Dr. Martin Pule, Chief Scientific Officer of Autolus. "In an oral presentation we will present AUTO4 clinical data for the first time. These data suggest that AUTO4 has the potential to become an important therapeutic option for patients with T cell lymphoma. In a second presentation, we will present our finding from clinical testing of AUTO1/22. These data show that AUTO1/22 can induce remission in children with B-ALL, including in those whose disease was not successfully treated with commercial CAR T product. Further, data suggest that AUTO1/22 can prevent antigen escape. In two additional presentations, we demonstrate incremental obe-cel data in B-NHL and B-CLL, as well as some early data in PCNSL. Obe-cel continues to have consistent safety and efficacy data across these indications."

"As clinicians, we are always searching for new strategies to address unmet needs in aggressive blood cancers," said Dr. Steven Horwitz, M.D., Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York. "T Cell Lymphomas are particularly challenging, and I’ve been following Dr. Pule’s strategy of CAR T targeting based on the mutually exclusive expressions of TRBC1 or TRBC2 with great interest. Any advance in bringing new effective therapies to patients with T cell lymphomas is of great importance."

Data presentations:

Title: Safety and preliminary efficacy findings of AUTO4, a TRBC1-targetting CAR, in relapsed/refractory TRBC1 positive selected T Cell Non-Hodgkin Lymphoma
Session Title: Gene therapy and cellular immunotherapy – Clinical 2
Session date and time: Saturday, June 11, 2022 16:30 – 17:45 CEST
Session room: Hall Strauss 1-2
Final Abstract Code: S261
Presenting Author: Kate Cwynarski
Conclusions: As of April 26 2022, 10 patients with TRBC1-positive r/r T-cell lymphoma (Peripheral T-cell lymphoma Not Otherwise Specified (PTCL-NOS), Angioimmunoblastic T-cell lymphoma (AITL), Anaplastic Large cell lymphoma (ALCL)) have been treated with AUTO4 in a Phase I dose escalation trial. Three patients had prior stem cell transplantation. After lymphodepletion with Flu/Cy, patients received either 25, 75, 225 or 450 x 106 CAR T cells. AUTO4 demonstrated a tolerable safety profile, with no patient experiencing any dose limiting toxicities, and no neurotoxicity/immune effector cell-associated neurotoxicity (ICANS) and no Grade 3 or higher infections. CRS was only seen at the highest dose level of 450 x 106 CAR T cells (Grade 3 in 1 patient; Grade 1-2 in 3 patients). As of 26 April 2022, 9 patients were evaluable for efficacy. At the highest dose level 3 of the 3 patients dosed achieved a complete metabolic remission (CMR) at 1 month. 2 of these patients remain in ongoing CMR by PET-CT at Month 3 and 6 respectively, whilst the 3rd relapsed at 3 months.
Title:Dual antigen targeting with co-transduced CD19/22 CAR T cells for relapsed/refractory ALL (AUTO1/22)
Session Title: Gene therapy and cellular immunotherapy – Clinical 1
Session date and time: Saturday, June 11, 2022 11:30 – 12:45 CEST
Session room: Hall Strauss 1-2
Final Abstract Code: S259
Presenting Author: Sara Ghorashian
Conclusions: As of May 27 2022, in 11 treated patients, we have reproducibly generated a product that is balanced in CD19 and CD22 CAR expression, with predominance of dual CAR T cells and having a mostly central memory phenotype. To date and in Kymriah-ineligible patients, AUTO1/22 has demonstrated a favorable safety profile. There have been no incidences of severe CRS, and one Grade 4 ICANS which was indistinguishable from chemotherapy-related leukoencephalopathy. We have seen excellent CAR T expansion, with only 4 patients losing CAR T persistence at the last follow up. Overall, 9 out of 11 patients achieved complete response, and there were 2 non-responders. Notably, 2 out of 3 patients with CD19-ve disease achieved complete response demonstrating the efficacy of the CD22 CAR. Two patients relapsed with CD19+CD22+ disease, a further patient had emergence of molecular MRD and all these events were associated with lack of CAR T Cell persistence. No antigen negative relapses were seen in responding patients. At a median follow up of 8.7 months, 6 of 9 responding patients were in MRD-negative complete remission (1-12 months) and the median duration of b-cell aplasia has not been reached.
Title: Safety and efficacy findings of AUTO1, a fast off-rate CD19 CAR, in relapsed/refractory Primary CNS Lymphoma
Session Title: Poster session
Session date and time: Friday, June 10, 2022 – 16:30 – 17:45 CEST
Final Abstract Code: P1460
Presenting Author: Claire Roddie
Conclusions: Excellent AUTO1 expansion was observed in the peripheral blood by qPCR, with persistence in all treated patients at last follow-up. No grade >/=3 CRS was observed using IV or I-VEN AUTO1 administration. Two cases of grade 3 ICANS were reported following IV infusion. In the first case the patient had several neurological deficits that evolved despite ICANS treatment and were compatible with progressive PCNSL, as confirmed with the month 1 MRI scan. The second case was a patient whose neurological deficits improved with steroids/anakinra. Encouraging response rates were observed: of 6 patients evaluable for efficacy following IV AUTO1, the ORR was 4/6 (67%), with 2 CRs and 2 PRs. These four responding patients are without disease progression at last follow up. Two patients died from progressive PCNSL on study. Longer follow-up is needed and enrolment of additional patients is ongoing.
Title: Safety and efficacy findings of AUTO1, a fast off-rate CD19 CAR, in relapsed/refractory B-Cell Non-Hodgkin’s Lymphoma (B-NHL), and chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL)
Session Title: Poster session
Session date and time: Friday, June 10, 2022 – 16:30 – 17:45 CEST
Final Abstract Code: P1459
Presenting Author: Claire Roddie
Conclusions: AUTO1 continues to display a favorable safety profile with no ICANS or Grade ≥ 3 CRS. Long term persistence of AUTO1 in the peripheral blood was demonstrated by qPCR. Of the 20 patients evaluable for efficacy, the overall response rate was 18/20 (90%). In the B-NHL cohorts the CRR was 16/17 (94%) (FL: 7/7, MCL: 3/3, DBCL: 6/7). In the CLL cohort a best response of a PR was achieved in 2/3 patients, notably both achieved MRD-negativity in their marrow and both remain in PR at 10 and 6 months respectively. Of the responding MCL, DLBCL, FL and CLL patients, 17/18 (94%) are without disease progression at last follow-up. One MCL patient relapsed six months following treatment and 1 FL patient died in CR from COVID-19. Longer follow-up and enrolment of additional MCL, FL, DLBCL and CLL patients is ongoing.
Conference Call
Management will host a conference call and webcast on June 13, 2022 at 7:30 am ET/12:30 pm BST to discuss the EHA (Free EHA Whitepaper) data. To listen to the webcast and view the accompanying slide presentation, please go to the events section of Autolus’ website.

The call may also be accessed by dialing (866) 679-5407 for U.S. and Canada callers or (409) 217-8320 for international callers. Please reference conference ID: 6594553. After the conference call, a replay will be available for one week. To access the replay, please dial (855) 859-2056 for U.S. and Canada callers or (404) 537-3406 for international callers. Please reference conference ID: 6594553.

On June 10, 2022 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported the presentation of novel findings on biomarker development for IRAK4 inhibitor emavusertib, collaborative work from the University of Florida in primary CNS lymphoma (pCNSL), and clinical data from the TakeAim Leukemia and TakeAim Lymphoma studies at the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Hybrid Congress currently taking place in Vienna, Austria and online until June 12, 2022 (Press release, Curis, JUN 10, 2022, View Source [SID1234615866]).

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"We are delighted to share with our colleagues in Europe our findings regarding IRAK4’s previously undescribed localization in the nucleus of cancer cells. It appears that when IRAK4 is found in the nucleus with active NF-kB proteins p50 and p65, using a technique which we refer to as ‘triple staining,’ this triple nuclear presence is associated with better responses to emavusertib," said James Dentzer, President and Chief Executive Officer of Curis.

"Also at EHA (Free EHA Whitepaper) this year, collaborative work by Dr. Duane Mitchell’s team at the University of Florida is being presented on the potential role of emavusertib in treating pCNSL, including data on one patient who achieved a complete response following previous treatment with ibrutinib," Mr. Dentzer continued. "And finally, in addition to this foundational work on IRAK4 biology, we are presenting data from our TakeAim Lymphoma and TakeAim Leukemia studies as we continue to spread the word on IRAK4 and the utility of inhibiting this important target to our European colleagues."

Curis scientists have discovered previously unknown nuclear accumulation of IRAK4 selectively in acute myeloid leukemia (AML) cells whereas nuclear IRAK4 was not detectable in mature myeloid cells (#2609). IRAK4 nuclear accumulation is significantly correlated with NF-kB activation in bone marrow samples from de novo AML patients and in AML cell lines. The detection of IRAK4 and NF-kB (phospho-p50 and phospho-p65) using nuclear staining of blasts in AML bone marrow samples was defined as ‘triple-positive,’ and patients whose cells did not stain for the nuclear presence of any of the three markers were termed ‘triple-negative.’ Treatment with emavusertib led to a significant decrease in bone marrow blast count in AML patients whose bone marrow sample was triple-positive, whereas no significant decrease in bone marrow blast count was detected in triple-negative cases. The goal of the Company’s biomarker work is to develop a companion diagnostic for emavusertib that is broadly applicable and is intended to identify the patients most likely to benefit from emavusertib treatment.

Research from Curis collaborators at the University of Florida in pCNSL (#2715) show that, in a patient treated on the TakeAim Lymphoma study in the combination arm following a previous ibrutinib containing regimen, the combination of emavusertib and ibrutinib resulted in a complete response. The team also observed that IRAK-4 and NF-kB proteins have elevated expression levels in human pCNSL. Further, in preclinical work, the team showed that emavusertib achieves therapeutically relevant concentrations in brain parenchyma and shows single-agent activity in an aggressive model of pCNSL.

Also presented at the EHA (Free EHA Whitepaper) meeting were previously presented data from the TakeAim Leukemia (#3975) and TakeAim Lymphoma (#3875) studies. TakeAim Leukemia is being orally presented, and TakeAim Lymphoma is the subject of a poster at the meeting. The data from these studies were also presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting last week in Chicago.
About Emavusertib (CA-4948)
Emavusertib is an IRAK4 kinase inhibitor and IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with cancer. TLRs and the IL-1R family signal through the adaptor protein MYD88, which results in the assembly and activation of IRAK4, initiating a signaling cascade that induces cytokine and survival factor expression mediated by the NF-κB protein complex. Additionally, third parties have recently discovered that the long form of IRAK4 (IRAK4-L) is oncogenic and preferentially expressed in over half of patients with AML and MDS. The overexpression of IRAK4-L is believed to be driven by a variety of factors, including specific spliceosome mutation such as SF3B1 and U2AF1. In addition to inhibiting IRAK4, emavusertib was also designed to inhibit FLT3, a known oncologic driver, which may provide additional benefit in patients with AML and MDS.

About TakeAim Lymphoma
The TakeAim Lymphoma study (NCT03328078) is a Phase 1/2 open-label, dose escalation, dose expansion clinical trial investigating emavusertib as monotherapy and in combination with ibrutinib in patients with R/R hematologic malignancies, such as non-Hodgkins’s lymphoma and other B cell malignancies. After dose escalation in both monotherapy and combination therapy to determine the recommended Phase 2 dose (RP2D), we plan to expand four cohorts for combination treatment: marginal zone lymphoma, activated b-cell diffuse large b-cell lymphoma, primary CNS lymphoma, and patients developing adaptive resistance to ibrutinib monotherapy. The goals of the study are to determine several parameters including safety, maximum tolerated dose (MTD), RP2D and signals of activity.

About TakeAim Leukemia
The TakeAim Leukemia study (NCT04278768) is a Phase 1/2 dose escalation and dose expansion study examining emavusertib use as both monotherapy and in combination with azacitidine or venetoclax in patients with R/R AML or high risk MDS. After dose escalation in both monotherapy and combination therapy to determine the recommended Phase 2 dose, we plan to expand five cohorts: monotherapy in AML patients with spliceosome and FLT3 mutations, monotherapy in patients with MDS and spliceosome mutations and combination therapy with azacitidine or venetoclax in patients without spliceosome or FLT3 mutations. The goals of the study are to determine several parameters including safety, maximum tolerated dose (MTD), RP2D and signals of activity.