On June 10, 2022 ADC Therapeutics SA (NYSE: ADCT) reported that results from the ongoing pivotal Phase 2 clinical trial of camidanlumab tesirine (Cami) in relapsed or refractory (r/r) Hodgkin lymphoma (Press release, ADC Therapeutics, JUN 10, 2022, View Source [SID1234615854]). An overall response rate (ORR) of 70.1% and a complete response (CR) rate of 33.3% was observed with a median duration of response of 13.7 months for all responders in r/r Hodgkin lymphoma patients who were refractory or had relapsed after a median of 6 prior treatments, including brentuximab vedotin (BV) and a PD-1 blockade. The safety profile of Cami was substantially consistent with previously reported interim findings. The results will be presented today during an oral session at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress (EHA2022).

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The Phase 2 single-arm, multicenter, open-label clinical trial is evaluating Cami in 117 patients with r/r Hodgkin lymphoma who have received ≥3 prior lines of treatment (≥2 lines if ineligible for hematopoietic stem cell transplantation, HSCT). Patients received a median of 6 prior lines of systemic therapy.

Data to be presented at EHA (Free EHA Whitepaper)2022 by Carmelo Carlo-Stella, MD, Department of Biomedical Sciences, Humanitas University, and Department of Oncology and Hematology, IRCCS Humanitas Research Hospital in Milan, Italy, include:

·ORR of 70.1% and CR rate of 33.3% in patients with a median of 6 prior treatments

·Median duration of response (DOR) was 13.7 months and median progression-free survival (PFS) was 9.1 months; patients who achieved a CR had a median DOR of 14.5 months

·14 patients received HSCT following treatment with Cami

·The most common grade ≥3 treatment-emergent adverse events in ≥5% of patients were: thrombocytopenia (9.4%), anemia (8.5%), hypophosphatemia (7.7%), neutropenia (7.7%), maculopapular rash (6.8%) and lymphopenia (5.1%)

·8/117 patients developed Guillain-Barré syndrome/polyradiculopathy. GBS symptoms could be mitigated with careful medical intervention.

In addition, the following three posters will be presented at EHA (Free EHA Whitepaper)2022 today from 16:30 – 17:45 CEST / 10:30 a.m. – 11:45 a.m. EDT in Hall D:

·Health-Related Quality Of Life And Tolerability Of Loncastuximab Tesirine In High-Risk Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma Treated In A Phase 2 Clinical Trial (LOTIS 2)
Abstract Code: P1717

·Real-World Characteristics And Clinical Outcomes In Relapse/Refractory Diffuse Large B-Cell Lymphoma Patients Who Received Car-T Therapy
Abstract Code: P1182

·Real-World Characteristics And Clinical Outcomes In Relapse/Refractory Diffuse Large B-Cell Lymphoma Post Car-T Failure
Abstract Code: P1181

About Camidanlumab Tesirine (Cami)

Camidanlumab tesirine (Cami) is an antibody drug conjugate (ADC) comprised of a monoclonal antibody that binds to CD25 (HuMax-TAC, licensed from Genmab A/S), conjugated to the pyrrolobenzodiazepine (PBD) dimer payload, tesirine. Once bound to a CD25-expressing cell, Cami is internalized into the cell where enzymes release the PBD-based payload, killing the cell. This applies to CD25-expressing tumor cells and also to CD25-expressing Tregs. The intra-tumoral release of its PBD payload may also cause bystander killing of neighboring tumor cells, and PBDs have also been shown to induce immunogenic cell death. All of these properties of Cami may enhance immune-mediated anti-tumor activity.

Cami is being evaluated in a pivotal Phase 2 clinical trial in patients with relapsed or refractory Hodgkin lymphoma and a Phase 1b clinical trial as monotherapy and in combination with pembrolizumab in solid tumors.

On June 10, 2022 AbbVie (NYSE: ABBV) reported new data from Cohort 3 of its Phase 2 REFINE study of investigational navitoclax in combination with ruxolitinib in JAK inhibitor naïve patients with myelofibrosis (MF), a rare and difficult to treat blood cancer (Press release, AbbVie, JUN 10, 2022, View Source [SID1234615853]). These preliminary findings show spleen volume and symptomatic improvement in this cohort. These data are consistent with previously observed data from relapsed/refractory patients in Cohort 1a1 and will be shared in an oral presentation at the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress (Abstract #S197).2

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REFINE is a Phase 2 non-randomized open-label multi-cohort study evaluating the safety and efficacy of navitoclax alone or in combination with ruxolitinib in MF.

"Current treatment options for myelofibrosis are limited and targeted toward controlling disease symptoms," said Mohamed Zaki, M.D., Ph.D., vice president and global head of oncology clinical development, AbbVie. "Together with pre-clinical findings, early results of this study demonstrating anti-fibrosis activity of navitoclax in combination with ruxolitinib are promising. Specifically, the data findings regarding reduction in spleen volume, symptoms and bone marrow fibrosis help support the further exploration of disease modification in myelofibrosis."

The results presented at EHA (Free EHA Whitepaper) 2022 were from a preliminary analysis of 32 JAK inhibitor naïve MF patients from Cohort 3 of the Phase 2 REFINE trial (NCT03222609).2 The primary endpoint was spleen volume reduction of ≥35 percent (SVR35) from baseline at week 24.2 Key secondary endpoints include ≥50 percent reduction in total symptom score (TSS50) at week 24, anemia response and BMF reduction.2

In the results, SVR35 was achieved by 63 percent of evaluable patients at week 24 (20/32) and by 78 percent at any time on treatment (25/32).2 At week 24, 41 percent (11/27) of evaluable patients with measurable baseline symptoms reached TSS50; notably, 67 percent of patients (18/27) met this endpoint at any time during the study.2 In this cohort, 35 percent of evaluable patients, with available fibrosis grade at baseline and during the study, (9/26) achieved reduction in BMF by ≥1 grade at any time during the study with three patients experiencing ≥2 grade reductions in BMF.2 Additionally, 40 percent of patients evaluable for anemia response (6/15) experienced improvement in anemia, a common clinical feature of MF.2

Preliminary safety analysis identified no new safety signals. Thirty-one (97 percent) patients reported one or more adverse event (AE).1 The most common Grade ≥3 AEs were thrombocytopenia (47 percent), anemia (34 percent), and neutropenia (25 percent).1 Seven patients (22 percent) reported experiencing serious AEs.1 Three patients (9 percent) experienced an AE leading to navitoclax discontinuation and three patients (9 percent) reported an AE leading to ruxolitinib discontinuation.2

"These data reinforce the importance of early intervention in myelofibrosis and the potential to achieve improved clinical outcomes," said Francesco Passamonti, Full Professor of Hematology, University of Insubria and Chief, Hematology, Varee Hospital. "These preliminary results show good responses to combination therapy with navitoclax that may continue to improve over time."

About Navitoclax
Navitoclax is an investigational, oral BCL-XL/BCL-2 inhibitor. The BCL-2 family of proteins are known regulators of the apoptosis pathway.3

Navitoclax is not approved by the U.S. Food and Drug Administration (FDA) or any Health Authority worldwide at this time. Its safety and efficacy are under evaluation as part of ongoing Phase 2 and registrational Phase 3 studies.

AbbVie has an extensive late-stage clinical trial program for investigational navitoclax that is currently enrolling. For more information about enrolling in a clinical trial, please visit us here.

About the REFINE Study
REFINE is a multi-cohort, Phase 2, randomized, open-label, multicenter study evaluating the tolerability and efficacy of navitoclax alone or when added to ruxolitinib in patients with myelofibrosis (MF).4 The primary outcome measure is the percentage of patients who achieve Spleen Volume Reduction of greater than or equal to 35 percent (SVR35) from baseline to Week 24. Secondary outcomes measures include percentage of participants achieving 50 percent reduction in Total Symptom Score from baseline to Week 24 and change in grade of bone marrow fibrosis assessed according to the European Consensus Grading System.

Data presented at EHA (Free EHA Whitepaper) 2022 include preliminary safety and efficacy results from Cohort 3 of REFINE (n=32). Patients in Cohort 3 had primary or secondary MF with splenomegaly and had not received JAK-2 therapy or BET inhibitors prior to enrollment. Data presented at EHA (Free EHA Whitepaper) 2022 are representative of data from Cohort 3 of the REFINE study as of February 7, 2022.

Data included in the official EHA (Free EHA Whitepaper) 2022 Abstract Book are representative of data from Cohort 3 of the REFINE study as of October 4, 2021.

More information can be found on View Source (NCT03222609).

About Myelofibrosis
Myelofibrosis (MF) is a rare, difficult-to-treat blood cancer that results in excessive scar tissue formation (fibrosis) in the bone marrow. Patients living with MF experience symptoms such as an enlarged spleen, fatigue, weakness, and severe anemia, that are often debilitating and greatly impact quality of life. MF also carries a risk of transformation to more aggressive disease such as acute myeloid leukemia.4

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 June 10, 2022 AbbVie (NYSE: ABBV) reported five-year follow-up results from the Phase 3 CLL14 trial, finding that over 60 percent of patients with previously untreated chronic lymphocytic leukemia (CLL) who had received one-year fixed-duration combination treatment of VENCLYXTO/VENCLEXTA (venetoclax) plus obinutuzumab (GAZYVA) continued to show longer progression-free survival (PFS) and higher rates of undetectable minimal residual disease (MRD) after four years off treatment (Press release, AbbVie, JUN 10, 2022, View Source [SID1234615852]).1 The findings were presented at the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress (Abstract #S148).

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"Long-term data from the CLL14 trial show that the one-year fixed-duration combination regimen of venetoclax and obinutuzumab offers patients the possibility of four years of CLL treatment-free response without disease progression," said Mohamed Zaki, M.D., Ph.D., vice president and global head of oncology clinical development, AbbVie. "Since its approval, this chemotherapy-free combination option has helped transform the therapeutic landscape for CLL."

Data shows that after more than five years of median follow-up (65.4 months), PFS remained significantly superior among patients treated with the VENCLYXTO/VENCLEXTA and obinutuzumab combination compared to the chlorambucil and obinutuzumab chemotherapy regimen (n=432; median NR vs 36.4 months; hazard ratio [HR] 0.35 [95% CI 0.26-0.46], p<0.0001). The therapies were administered for a fixed-duration of 12 months for VENCLYXTO/VENCLEXTA in combination with six cycles of obinutuzumab. At five years after randomization, the estimated PFS rate after one-year fixed-duration treatment was 62.6 percent for the VENCLYXTO/VENCLEXTA-based combination compared to 27.0 percent for the chlorambucil combination 1 The improvement in PFS was maintained across all risk groups, including patients with TP53 mutation/deletion and unmutated IGHV status.1

Among the secondary endpoints, patients were assessed for MRD in peripheral blood and/or bone marrow, using next generation sequencing. Undetectable MRD (uMRD) was defined as less than one CLL cell being identified per 10,000 lymphocytes sampled. Four years after treatment completion, 18.1 percent of patients treated with the VENCLYXTO/VENCLEXTA-based combination still had uMRD compared to 1.9 percent of patients in the chlorambucil combination study arm.1

The estimated overall survival (OS) rate was 81.9 percent in the VENCLYXTO/VENCLEXTA-based combination and 77.0 percent in the chlorambucil combination group (HR 0.72 [0.48-1.09], p=0.12) at five years after randomization.1

No new safety signals were observed in the five-year follow-up analysis. The most frequently occurring serious adverse reactions (>=2%) in patients receiving the VENCLYXTO/VENCLEXTA-based combination were pneumonia, sepsis, febrile neutropenia, and tumor lysis syndrome.1

"Four years following treatment completion, we are pleased to report that approximately three out of five patients who received the fixed-duration combination treatment with venetoclax have remained progression free," said Othman Al-Sawaf, M.D., investigator in the CLL14 study, hematologist-oncologist at the University Hospital Cologne in Germany, and study physician at the German CLL Study Group. "Additionally, it is notable that the population of patients who received chlorambucil combination was observed to have slightly more than twice the rate of progression events, compared to the patients who received the venetoclax combination."

VENCLYXTO/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 CLL14 Phase 3 Trial3,4,5
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 VENCLYXTO/VENCLEXTA and obinutuzumab (n=216) versus obinutuzumab and chlorambucil (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 VENCLYXTO/VENCLEXTA 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 independent review committee.

Key secondary endpoints were rates of MRD in peripheral blood and bone marrow, overall and complete response rates, MRD in complete response in peripheral blood and bone marrow, and overall survival.

In patients with CLL receiving venetoclax combination therapy with obinutuzumab, serious adverse reactions (ARs) were most often due to febrile neutropenia and pneumonia (5 percent each). The most common ARs (≥20 percent) of any grade were neutropenia (60 percent), diarrhea (28 percent), and fatigue (21 percent). 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 percent (4/212) of patients, most often from infection.

About VENCLYXTO (venetoclax)

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. VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.

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. Venetoclax is approved in more than 80 countries, including the U.S.

Indication and Important VENCLYXTO (venetoclax) EU Safety Information4

Indications

Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).

Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the treatment of CLL:

In the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
In the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.

Contraindications

Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumour lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as Venclyxto efficacy may be reduced.

Special Warnings & Precautions for Use

Tumour Lysis syndrome, including fatal events, has occurred in patients when treated with Venclyxto. For CLL and AML, please refer to the indication-specific recommendations for prevention of TLS in the Venclyxto summary of product characteristic (SmPC).

Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS. The risk of TLS is a continuum based on multiple factors, including comorbidities. Venclyxto poses a risk for TLS at initiation and during the dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venclyxto and at each dose increase.

Neutropenia (grade 3 or 4) has been reported. Complete blood counts should be monitored throughout the treatment period.

In patients with AML, neutropenia (grade 3 or 4) is common before starting treatment. The neutrophil counts can worsen with Venetoclax in combination with a hypomethylating agent. Neutropenia can recur with subsequent cycles of therapy. Dose modification and interruptions for cytopenias are dependent on remission status.

For CLL and AML, please refer to the indication-specific recommendations for dose modifications for toxicities in the Venclyxto SmPC.

Serious infections including sepsis with fatal outcome have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections should receive prompt treatment including antimicrobials and dose interruption or reduction as appropriate.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions

In CLL and AML CYP3A inhibitors may increase Venclyxto plasma concentrations.

In CLL, at initiation and dose-titration phase, Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, please refer to the recommendations for dose modifications in the Venclyxto SmPC.

In AML, please refer to the AML-specific recommendation for dose modifications for potential interactions with CYP3A inhibitors, in the VENCLYXTO SmPC.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease Venclyxto plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions

CLL

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab or rituximab were neutropenia, diarrhoea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (>=2%) were pneumonia and febrile neutropenia.

Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax in combination with obinutuzumab or rituximab in the CLL14 and Murano studies, respectively. In the monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions.

Dosage reductions due to adverse reactions occurred in 21% of patients treated with the combination of venetoclax and obinutuzumab in CLL14, in 15% of patients treated with the combination of venetoclax and rituximab in Murano, and in 14% of patients treated with venetoclax in the monotherapy studies. The most common adverse reaction that led to dose interruptions was neutropenia.

AML

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in combination with azacitidine or decitabine in the VIALE-A and M14-358, respectively, were thrombocytopenia, neutropenia, febrile neutropenia, nausea, diarrhoea, vomiting, anaemia, fatigue, pneumonia, hypokalaemia, and decreased appetite, haemorrhage, dizziness/syncope, hypotension, headache, abdominal pain, and anaemia.

The most frequently reported serious adverse reactions (≥5%) in patients receiving venetoclax in combination with azacitidine were febrile neutropenia, pneumonia, sepsis and haemorrhage. In M14-358, the most frequently reported serious adverse reactions (≥5%) were febrile neutropenia, pneumonia, bacteraemia and sepsis.

Discontinuations due to adverse reactions occurred in 24% of patients treated with venetoclax in combination with azacitidine in the VIALE-A study, and 26% of patients treated with venetoclax in combination with decitabine in the M14-358 study, respectively.

Dosage reductions due to adverse reactions occurred in 2% of patients in VIALE-A, and in 6% of patients in M14-358. Venetoclax dose interruptions due to adverse reactions occurred in 72% and 65% of patients, respectively. The most common adverse reaction that led to dose interruption (>10%) of Venetoclax in VIALE-A, were febrile neutropenia, neutropenia, pneumonia, and thrombocytopenia. The most common adverse reactions that led to dose interruption (≥5%) of venetoclax in M14-358 were febrile neutropenia, neutropenia/neutrophil count decreased, pneumonia, platelet count decreased, and white blood cell count decreased.

Special Populations

Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined.

For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.

Venclyxto may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See Venclyxto (venetoclax) SmPC at www.ema.europa.eu. 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 June 10, 2022 Keros Therapeutics, Inc. ("Keros" or the "Company") (Nasdaq: KROS), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel treatments for patients suffering from hematological and musculoskeletal disorders with high unmet medical need, reported that it presented additional data from its ongoing Phase 2 clinical trial of KER-050 in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes ("MDS"), as well as preclinical data on the differentiated mechanism of action of KER-050 and its activity on multiple stages of thrombopoiesis, at the 27th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) ("EHA"), held in person and virtually June 9 through 17, 2022 (Press release, Keros Therapeutics, JUN 10, 2022, View Source [SID1234615851]). In addition, Keros announced preclinical data evaluating ALK2 inhibition as a potential treatment option for anemia of inflammation.

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"We believe the additional data from our ongoing Phase 2 clinical trial of KER-050 in MDS patients continues to support the potential of KER-050 as a treatment for multilineage cytopenias, and are pleased to present at EHA (Free EHA Whitepaper) this year," said Jasbir S. Seehra, Ph.D., President and Chief Executive Officer of Keros. "Additionally, we are excited to announce that we have recently initiated dosing for Part 2 of the trial, at a starting dose of 3.75 mg/kg, with an opportunity for patients to dose escalate to 5.0 mg/kg based on individual titration rules, following the Safety Review Committee recommendation for this trial."

Clinical Presentation

A Phase 2, open-label, ascending dose study of KER-050 for the treatment of anemia in patients with very low, low, or intermediate risk myelodysplastic syndromes
This ongoing, open-label, two-part, multiple ascending dose Phase 2 clinical trial is evaluating KER-050 in participants with very low-, low-, or intermediate-risk MDS who either have or have not previously received treatment with an erythroid stimulating agent ("ESA"). Enrollment for Part 1 was balanced approximately one-to-one between patients that did not have ring sideroblasts ("non-RS") and patients that have ring sideroblasts ("RS positive"). Patients received KER-050 subcutaneously every 28 days for up to four cycles during Part 1 of the trial, at the following dose levels: Cohort 1, 0.75 mg/kg; Cohort 2, 1.5 mg/kg; Cohort 3, 2.5 mg/kg; Cohort 4, 3.75 mg/kg; and Cohort 5, 5.0 mg/kg.

As of April 3, 2022 (the "data cut-off date"), 31 patients in Cohorts 1 through 5 had received at least one dose of KER-050. Of these, 27 patients in Cohorts 1 through 5 had completed eight weeks of treatment and evaluation as of the data cut-off date (the "evaluable patients"). The 27 evaluable patients were comprised of five non-transfused ("NT"), six low transfusion burden ("LTB"), and 16 high transfusion burden ("HTB") patients. Two of the transfused LTB patients required <2 red blood cell ("RBC") units at baseline. Of the 20 LTB and HTB patients that required ≥2 RBC units at baseline, eight were non-RS and 12 were RS positive.

As of the data cut-off date, 51.9% (n=14/27) of the evaluable patients achieved an overall erythroid response, which is defined as meeting one of the following two endpoints:

IWG 2006 Hematological improvement-erythroid ("HI-E"), which is defined as either:
a ≥ 1.5 g/dL increase in hemoglobin for eight weeks in LTB and NT patients; or
a reduction by ≥ 4 RBC units transfused during any eight-week period during the trial, compared with the eight-week period prior to Cycle 1, Day 1 in HTB patients.
Transfusion independence ("TI") for at least eight weeks in transfusion-dependent patients who required ≥ 2 RBC units transfused at baseline.
Additional data from the evaluable patients in Cohorts 1 through 5 of the trial, as of the data cut-off date, include:

46.2% (n=12/26) of the evaluable population achieved HI-E over an eight-week period.
45.0% (n=9/20) of the transfused patients receiving ≥ 2 RBC units at baseline achieved TI for at least eight weeks. Of these 20 patients, 12 were RS positive and eight were non-RS.
50.0% (n=6/12) of these RS positive patients achieved TI for at least eight weeks.
37.5% (n=3/8) of these non-RS patients achieved TI for at least eight weeks.
43.8% (n=7/16) of the HTB patients achieved TI for at least 8 weeks.
In addition, sustained increases in platelets were observed in HTB patients achieving HI-E or TI, which supports the potential of KER-050 as a treatment for multilineage cytopenias in difficult-to-treat HTB patients. Increases in reticulocytes and serum soluble transferrin receptor levels, as well as decreases in serum ferritin, were also observed in HTB patients. Together, these exploratory pharmacodynamic data suggest an improvement in erythropoiesis.

As of the data cut-off date, KER-050 was observed to be generally well-tolerated in the 31 patients in Cohorts 1 through 5 who had received at least one dose of KER-050. No drug-related serious adverse events or dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events were dyspnea, fatigue, anemia, diarrhea, headache and nausea. Treatment-related adverse events were reported in five patients, which were mild or moderate in severity. No patients developed acute myeloid leukemia. Four patients withdrew from the trial prior to completing treatment with KER-050, one due to death deemed unrelated to study drug, one due to withdrawn consent and two due to unrelated treatment-emergent adverse events.

Following recommendation by the Safety Review Committee, dosing for Part 2 of the trial was initiated at a starting dose of 3.75 mg/kg, with an opportunity for patients to dose escalate to 5.0 mg/kg based on individual titration rules.

Preclinical Presentations

RKER-050, a novel inhibitor of TGF-β superfamily signaling, induced platelet production in healthy mouse megakaryocytes
Administration of a research form of KER-050 ("RKER-050") increased differentiation of early- and late-stage megakaryocyte precursors and increased platelet count:

Healthy mice treated with a single 10 mg/kg dose of RKER-050 had an increase in platelet numbers at 12 hours, 37 days and 51 days after administration compared to vehicle-treated mice (p ≤0.001, p ≤0.05 and p ≤0.01, respectively). At 14 days and 91 days after administration, counts normalized back to vehicle control levels, demonstrating a phasic response on thrombopoiesis. Taken together, these data suggest that RKER-050 may be affecting thrombopoiesis at multiple stages, including platelet formation and megakaryocyte progenitor renewal.
Keros also analyzed CD41+ cells, which are megakaryocyte precursors, from the bone marrow of healthy mice at 12 hours post-treatment in order to investigate the potential effects of RKER-050 on early stages of thrombopoiesis. An increase in the CD41+ cells was observed compared to vehicle-treated mice (p ≤0.01), as well as an increase in higher levels of ploidy at 24 hours post-treatment, indicating that RKER-050 increased differentiation of megakaryocyte precursors towards the later stages of maturation.
Keros also demonstrated that inhibition of activin A with a neutralizing antibody increased production of platelets. Similarly, treatment with RKER-050 increased platelet production. These data are consistent with these treatments acting to inhibit negative regulators of thrombopoiesis and shift the balance towards increased bone morphogenic protein ("BMP") signaling which promotes thrombopoiesis. These data support that RKER-050 promoted megakaryocyte maturation potentially by blocking inhibitory transforming growth factor-beta ("TGF-β") ligands, such as activin A, in this preclinical model.
Overall, these data support that KER-050 has the potential to treat thrombocytopenia, including in patients with MDS and myelofibrosis.

ALK2 inhibition lowered hepcidin and liberated spleen iron for erythropoiesis in anemia of inflammation
Hepcidin, the key regulator of iron absorption and recycling, can be regulated by the BMP-SMAD and IL-6-STAT3 signaling pathways in normal and inflammatory conditions. To understand whether and how ALK2 inhibition decreases hepcidin in inflammation, healthy mice were dosed with 3 mg/kg KTI-m216, an investigational neutralizing antibody to the ALK2 receptor, or vehicle for one hour, followed by a 1 mg/kg dose of lipopolysaccharide ("LPS") or phosphate buffered saline ("PBS") for six hours. Serum IL-6 was induced in the vehicle-LPS and KTI-m216-LPS mice, compared to respective PBS controls, indicating that a model of acute inflammation was induced.

Serum hepcidin was increased by LPS to a similar extent in the vehicle- and KTI-m216-treated mice, compared to the respective vehicle-PBS and KTI-m216-PBS controls. However, KTI-m216-LPS mice had a 69% reduction in absolute serum hepcidin compared to vehicle-LPS controls. These data indicate that KTI-m216 inhibited the BMP-SMAD signaling in this preclinical model and is potentially sufficient for hepcidin reduction in inflammation.

To induce a model of chronic kidney disease ("CKD"), mice were fed a diet containing 0.2% adenine and 40 ppm iron for six to seven weeks. CKD mice developed characteristics of anemia of inflammation ("AI"), including decreased hemoglobin, increased serum IL-6 and hepcidin, decreased serum iron and increased tissue iron retention, compared to mice on a control diet. After AI was confirmed, CKD mice received twice weekly treatment with 3 mg/kg of KTI-m218, an investigational neutralizing antibody to the ALK2 receptor, or vehicle for three weeks, while continuing the adenine diet. In a separate experiment, the CKD mice received twice weekly treatment with 3 mg/kg of KTI-m218 or vehicle for nine days, while on an adenine diet with 3 ppm iron.

KTI-m218-treated CKD mice on the continued adenine and 40 ppm iron diet exhibited a reversal of the CKD-related changes, including decreased serum hepcidin, increased serum iron, reduction in spleen iron and increased hemoglobin compared to vehicle-treated CKD mice. Similar responses were observed in the KTI-m218-treated CKD mice on the adenine and 3 ppm iron diet, which supports that the increased iron in KTI-m218-treated CKD mice was mostly from the spleen, rather than diet.

These data suggest that ALK2 inhibition-mediated hepcidin suppression was sufficient to improve erythropoiesis by liberating iron from the recycling pathway in a mouse model of AI. Accordingly, Keros believes that targeting ALK2 inhibition could potentially treat anemia resulting from CKD and other acute and chronic inflammatory diseases.

About the Ongoing Phase 2 Clinical Trial of KER-050 in Patients with MDS

Keros is conducting an open label, two-part, multiple ascending dose Phase 2 clinical trial to evaluate KER-050 in participants with very low-, low-, or intermediate-risk MDS who either have or have not previously received treatment with an ESA.

The primary objective of this trial is to assess the safety and tolerability of KER-050 in participants with MDS that are RS positive or non-RS. Confirmation of the safety and tolerability of the selected dose levels is the primary objective of Part 2 of this trial. The secondary objectives of this trial are to evaluate the pharmacokinetics, pharmacodynamics and efficacy of KER-050. Keros expects to report additional data from this trial by the end of 2022.

Conference Call and Webcast Information

The Company will host a conference call and webcast today, June 10, 2022, at 8:00 a.m. Eastern time, to discuss the additional results from the ongoing Phase 2 clinical trial of KER-050 presented at the 27th Annual Congress of EHA (Free EHA Whitepaper).

The conference call will be webcast live at View Source;tp_key=c785623d12. The live teleconference may be accessed by dialing (877) 405-1224 (domestic) or (201) 389-0848 (international). An archived version of the call will be available in the Investors section of the Keros website at View Source for 90 days following the conclusion of the call.

About KER-050

Keros’ lead protein therapeutic product candidate, KER-050, is an engineered ligand trap comprised of a modified ligand-binding domain of the transforming growth factor-beta receptor known as activin receptor type IIA that is fused to the portion of the human antibody known as the Fc domain. KER-050 is being developed for the treatment of low blood cell counts, or cytopenias, including anemia and thrombocytopenia, in patients with myelodysplastic syndromes, or MDS, and in patients with myelofibrosis.

On June 9, 2022 Ancora Biotech reported Lightspeed Venture Partners and S.R. One have co-led a $60million series A round for Ancora Biotech LLC, which housesthree bispecific antibodies spun out from TeneoBio Inc (Press release, Ancora Biotech, JUN 9, 2022, View Source [SID1234618882]). Ancora will advance TNB-486, a bispecific T cell engagertargeting CD19 and CD3 that is in Phase I testing for B cellcancers; TNB-738, an anti-CD38 enzyme inhibitor formetabolic disorders currently in a study in healthy volunteers;and an HBsAg x CD3 bispecific for HBV. Amgen Inc.(NASDAQ:AMGN) paid $900 million up front for TeneoBiolast year. AbbVie Inc. (NYSE:ABBV) had previously boughtanother of the asset-focused biotech’s programs.

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