On June 9, 2023 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, pulmonary and cardiovascular 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 showing the potential of a research form of KER-050 ("RKER-050") to restore erythropoiesis in an animal model of myelofibrosis ("MF"), at the 28th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) ("EHA"), held in person and virtually June 8 through 15, 2023 (Press release, Keros Therapeutics, JUN 9, 2023, View Source [SID1234632613]). In addition, Keros announced preclinical data evaluating activin receptor-like kinase-2 ("ALK2") inhibition, as well as its combination with RKER-050, as potential treatment options for anemia of inflammation.

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"We are pleased to present additional data from our ongoing Phase 2 clinical trial of KER-050 in MDS patients at EHA (Free EHA Whitepaper) this year, which demonstrated durable hematological responses with longer-term treatment in a broad, lower-risk MDS patient population, including those with high transfusion burden," said Jasbir S. Seehra, Ph.D., President and Chief Executive Officer of Keros. "Additionally, we are excited to announce that we have recently expanded this trial to include two cohorts of MDS patients with iron overload, which will enable us to further explore the potential of KER-050 to reduce iron overload and improve iron utilization in MDS patients. Separately, we believe that we will have sufficient data from this trial at the end of this year that will allow us to begin the process of engaging with regulators on the design of a Phase 3 clinical trial."

Clinical Presentation

•KER-050 treatment improved markers of erythropoietic activity and hematopoiesis over six months which resulted in hematological responses across a broad, lower-risk MDS population

This ongoing, open-label, two-part, Phase 2 clinical trial is evaluating KER-050 in participants with very low-, low-, or intermediate-risk MDS. In Part 1, the dose escalation portion of the trial, enrollment 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 in Part 1 received KER-050 subcutaneously every 28 days for up to four cycles 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. In Part 2, the dose confirmation portion of the trial, an identical dosing schedule was followed, and patients initiated treatment at a starting dose of 3.75 mg/kg, the recommended Part 2 dose ("RP2D"), with the opportunity to dose escalate to 5.0 mg/kg or to down-titrate based on individual titration rules. Following completion of Part 1, eligible patients were given the opportunity to escalate up to the RP2D and receive long-term treatment with KER-050 for up to an additional 20 cycles ("Part 1 Extension").

As of April 3, 2023 (the "data cut-off date"), 25 patients from Part 1, including the Part 1 Extension, and 34 patients from Part 2, had received at least one dose of KER-050 at RP2D (collectively, the "safety population"). Of these patients, 37 had completed at least 24 weeks of treatment or discontinued as of the data cut-off date (the "evaluated RP2D patients"). Data for hematological response and markers of hematopoiesis were presented from exploratory analyses of these evaluated RP2D patients.

Of the 59 patients in the safety population, 71.2% (n=42/59) were RS positive while 28.8% (n=17/59) were non-RS. The safety population included 12 non-transfused ("NT"), 16 low transfusion burden ("LTB") and 31 high transfusion burden ("HTB") patients.

As of the data cut-off date, KER-050 was generally well tolerated by the 59 patients in the safety population. No patients had progressed to acute myeloid leukemia. There were two cases of fatal treatment-emergent adverse events ("TEAEs") in the trial (cardiac failure and myocardial infarction), each of which were determined to be unrelated to treatment. Four additional patients experienced TEAEs that led to discontinuation of treatment. One case was deemed treatment related (injection site reaction), and in three patients, the events were determined to be unrelated to treatment (dyspnea, chronic obstructive pulmonary disease and cardiac failure congestive (in one patient), and nodular melanoma). The most commonly reported TEAEs (in ≥15% of patients) were COVID-19, diarrhea, dyspnea, fatigue, nausea and nosebleeds (epistaxis).

As of the data cut-off date, 51.4% (n=19/37) of the evaluated RP2D patients achieved an overall erythroid response over the first 24 weeks of treatment, which is defined as meeting one of the following two endpoints:

•Modified IWG 2006 Hematological improvement-erythroid ("HI-E"), which is defined as either:
◦a ≥ 1.5 g/dL mean increase in hemoglobin over any eight-week period on treatment compared with the eight-week period prior to Cycle 1, Day 1 in LTB and NT patients; or
◦a reduction by ≥ 4 RBC units transfused during any eight-week period on treatment, 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 evaluated RP2D patients, as of the data cut-off date, include:

•51.4% (n=19/37) of the evaluated RP2D patients achieved HI-E over an eight-week period during the first 24 weeks of treatment.
•42.3% (n=11/26) of the transfused RP2D patients receiving ≥ 2 RBC units at baseline achieved TI for at least eight weeks over the first 24 weeks of treatment. Of these 26 patients, 19 were RS positive and seven were non-RS.
◦42.1% (n=8/19) of these RS positive patients achieved TI for at least eight weeks over the first 24 weeks of treatment.
◦42.9% (n=3/7) of these non-RS patients achieved TI for at least eight weeks over the first 24 weeks of treatment.
•Of the transfused RP2D patients, 40.9% (n=9/22) of those who are HTB achieved TI for at least eight weeks during the first 24 weeks of treatment. Of these 22 patients, 17 were RS positive and five were non-RS.
◦35.3% (n=6/17) of these RS positive HTB patients achieved TI for at least eight weeks.
◦60.0% (n=3/5) of these non-RS HTB patients achieved TI for at least eight weeks.
•Of the 19 patients who achieved HI-E or TI during the first 24 weeks of treatment (the "HI-E or TI Responders"), 10 of them (52.6%) had ongoing response as of the data cutoff date.
◦The median duration of response for the HI-E or TI Responders was 42.4 weeks.

As of the data cut-off date, 44.1% (n=15/34) of the evaluated RP2D patients who had at least eight weeks of post-baseline platelet measurements exhibited sustained increases in platelet counts from baseline over at least eight weeks. Additionally, sustained increases in hemoglobin were observed over six months of treatment with KER-050 in the LTB and NT HI-E responders.

Additional data from the exploratory analysis of biomarkers of erythropoiesis and iron overload ("IO") were also presented, with data from the evaluated RP2D patients. Key observations from this analysis, as of the data cut-off date, are as follows:

•Soluble transferrin receptor levels generally increased with KER-050 treatment in HI-E or TI Responders, while ferritin levels generally decreased.
•As of the data cut-off date, 18 patients had baseline ferritin of >500 ng/mL. Of those 18 patients, eight (44.4%) had a maximum mean decrease of ≥250 ng/mL over any 12-week period during the first six months of treatment with KER-050, suggesting potential for KER-050 to reduce IO in the most impacted patients.

Based on these additional data, this trial has been expanded to include two cohorts of MDS patients with iron overload either with or without iron chelation, which would allow Keros to further evaluate the potential of KER-050 to reduce serum ferritin, an indicator of iron overload, in that MDS patient population.

Preclinical Presentations

•A modified activin receptor type II ligand trap RKER-050 restored erythropoiesis in a mouse model of myelofibrosis

RKER-050 was tested in a mouse model of advanced MF. Male MF mice with established anemia were administered either vehicle or 10 mg/kg of RKER-050 twice weekly for 12 weeks. Healthy male mice received only vehicle.

The vehicle-treated MF mice continued to exhibit a significant or trending decrease in RBC parameters, including RBCs, hemoglobin and hematocrit, compared to healthy controls. Relative to vehicle-treated MF mice, RKER-050-treated MF mice had a significant recovery of those RBC parameters, demonstrating that RKER-050 fully reversed anemia in this MF mouse model.

In the bone marrow, vehicle-treated MF mice showed a significant reduction in erythroid progenitors compared to healthy controls. Treatment with RKER-050 significantly increased certain erythroid progenitors in MF mice compared to vehicle-treated MF mice, suggesting bone marrow erythropoiesis was increased with RKER-050 treatment. Additionally, RKER-050-treated MF mice also had increased erythroid progenitors in the spleen compared to vehicle-treated MF mice, which may be due to the severe state of the disease-impacted bone marrow microenvironment in this MF mouse model.

Additionally, RKER-050 significantly reduced megakaryocyte progenitors in the bone marrow compared to the elevated levels observed in vehicle-treated MF mice, suggesting RKER-050 may positively influence the megakaryocyte lineage. However, platelets in the RKER-050-treated MF mice were not significantly increased compared to vehicle-treated MF mice at this advanced stage of disease.

These results suggest that RKER-050 can promote erythropoiesis and reduce aberrant megakaryocyte progenitor proliferation in the bone marrow in this MF mouse model. Keros believes that KER-050 has the potential to treat patients with MF and other hematological diseases where ineffective hematopoiesis occurs.

•Combining ALK2 inhibition with a modified activin receptor IIA ligand trap provided additive benefits in resolving anemia in a mouse model of anemia of inflammation

This preclinical study evaluated whether RKER-050 combined with RKER-216, an investigational neutralizing antibody to ALK2, could ameliorate anemia in a mouse model of induced chronic kidney disease ("CKD") representative of anemia of inflammation ("AI").

To induce a model of CKD, mice were fed a diet containing 0.2% adenine and 40 ppm iron for five weeks. After AI was confirmed, CKD mice were treated with 3 mg/kg of RKER-216 or vehicle twice a week for four weeks. In a separate study, CKD mice received twice weekly treatment of 3 mg/kg of RKER-216 or vehicle in combination with once weekly treatment of 7.5 mg/kg of RKER-050 or vehicle for four weeks.

•RKER-216-treated CKD mice exhibited a >95% decrease in serum hepcidin, decreases in spleen iron retention and an increase in transferrin saturation compared to vehicle-treated CKD mice. RKER-216-treated CKD mice also showed improvements in hemoglobin and RBC production compared to vehicle-treated CKD mice. Taken together, these data suggest that the observed increase in iron availability resulting from the administration of RKER-216 may be sufficient for improving iron-restricted erythropoiesis in this AI model.
•While RKER-216 monotherapy improved hemoglobin and RBC levels in CKD mice relative to vehicle-treated CKD mice, combination treatment with RKER-050 resulted in a greater magnitude of increase in both hematological parameters. No significant differences in serum hepcidin, spleen iron, or transferrin saturation were observed between CKD mice receiving combination therapy or monotherapy.

By targeting ALK2 inhibition to suppress hepcidin, RKER-216 increased iron availability for erythropoiesis and partially rescued anemia in CKD mice. Separately, the combination of RKER-216 and RKER-050 maximized the hematologic recovery in this AI model, which supports the potential benefits of this combination therapy.

About the Ongoing Phase 2 Clinical Trial of KER-050 in Patients with MDS (NCT04419649)

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 erythroid stimulating agent.

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. The primary objective of Part 2 of this trial is confirmation of the safety and tolerability of the RP2D (3.75 mg/kg and 5.0 mg/kg). The secondary objectives of this trial are to evaluate the pharmacokinetics, pharmacodynamics and efficacy of KER-050.

Conference Call and Webcast Information

The Company will host a conference call and webcast today, June 9, 2023, at 8:00 a.m. Eastern time, to discuss updates to and additional data from its hematology franchise, including the additional results from the ongoing Phase 2 clinical trial of KER-050 presented at the 28th Annual Congress of EHA (Free EHA Whitepaper).

The conference call will be webcast live at View Source;tp_key=a5c7667d07. 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 MF.

On June 9, 2023 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:​HCM; HKEX:​13) reported that new and updated clinical data related to two novel investigational hematological malignancy therapies, HMPL-306 and amdizalisib, will be presented at the upcoming European Hematology Association (EHA) (Free EHA Whitepaper) ("EHA") Annual Meeting, taking place June 8-11, 2023 in Frankfurt, and the 17th International Conference on Malignant Lymphoma ("ICML") taking place June 13-17, 2023 in Lugano (Press release, Hutchison China MediTech, JUN 9, 2023, View Source [SID1234632612]).

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HMPL-306: first in human results

Title:

A phase 1 study of HMPL-306, a dual inhibitor of mutant isocitrate dehydrogenase (IDH) 1 and 2, in pts with relapsed/refractory myeloid hematological malignancies harboring IDH1 and/or 2 mutations

Lead Author:

Lijuan Hu, MD, Peking University People’s Hospital Graphic

Meeting:

EHA poster presentation

Session:

Myeloproliferative neoplasms – Clinical

Abstract # & Link:

Abstract #P539

Mutations in isocitrate dehydrogenase ("IDH") 1/2 are frequently identified in various cancers, such as acute myeloid leukemia ("AML"), cholangiocarcinoma, chondrosarcoma and glioma. Mutant IDHs cause accumulated 2-hydroxyglutarate, leading to blockage of cell differentiation, thereby inducing malignant transformation. Mutant IDH isoform switching, from mutant IDH1 to mutant IDH2 and vice versa, have been reported as a mechanism of acquired resistance to IDH inhibition in AML and cholangiocarcinoma, as well as cases initially carrying co-existing mutations.

Preclinical data presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (AACR 2023) demonstrated that HMPL-306 is a potent, durable, dual inhibitor of IDH1/2 mutation that crosses the blood brain barrier and affects pharmacodynamic ("PD") markers that lead to the differentiation of immature malignant cells to mature normal cells. It is being evaluated in clinical trials (NCT04272957, NCT04762602, NCT04764474).

This first-in-human, dose-escalation study data presents HMPL-306 in patients with relapsed/refractory myeloid hematological malignancies harboring IDH1 and/or IDH2 mutations. Based on PD, pharmaco­kinetic ("PK"), and preliminary clinical findings, a recommended Phase II dose was nominated for the dose expansion phase of the study.

Amdizalisib: updates from Phase Ib

Title:

Updated results from a phase 1b study of amdizalisib, a novel inhibitor of phospho­inositide 3-kinase-delta (PI3Kδ), in patients with relapsed or refractory lymphoma

Lead Author:

Junning Cao, MD, Fudan University Shanghai Cancer Center

Meeting:

ICML Publication

Session:

Phase I-II trials

Abstract #:

Abstract #653

Amdizalisib (HMPL-689) is a novel, selective and potent oral inhibitor targeting the isoform PI3Kδ. Amdizalisib’s PK properties are favorable with good oral absorption, moderate tissue distribution and low clearance in preclinical PK studies, suggesting a low risk of drug accumulation and drug-to-drug interaction. Because of its high target selectivity and optimal PK profile, amdizalisib has the potential to demonstrate an optimal benefit-risk profile in this class. Amdizalisib is currently being evaluated in a Phase II registration trial in relapsed or refractory follicular lymphoma ("FL") and marginal zone lymphoma ("MZL") as a single agent (NCT04849351), as well as in combination with tazemetostat (a methyl­trans­ferase inhibitor of EZH2) in patients with relapsed or refractory lymphoma in a Phase II study in China (NCT05713110).

Here we report updated results from a Phase Ib study of amdizalisib in patients with various subtypes of non-Hodgkin’s lymphoma ("NHL"). In this update, more mature data were available from the FL cohorts, at median follow-up duration of 22.1 months. Median duration of response ("DoR") and progression free survival ("PFS") were not reached for the 26 efficacy evaluable patients in the FL cohort. PFS and DoR from the MZL cohort were presented for the first time, at median follow-up duration of 20.3 months. Median DoR was not reached and median PFS was 26.8 months for the 16 efficacy evaluable patients in the MZL cohort. Safety data were reported from 153 patients with median exposure duration of 8.7 months. The most common treatment emergent adverse events (TEAEs) of Grade ≥3 (≥5%) were pneumonia (15.7%), neutrophil count decreased (12.4%), lipase increased (7.8%), and rash (5.9%). The treatment discontinuation rate due to adverse events was 11.8%.

On June 9, 2023 Elevation Oncology, Inc. (Nasdaq: ELEV), an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs, reported the pricing of an underwritten public offering of (i) 17,810,000 shares of its common stock and, in lieu of common stock to investors that so choose, pre-funded warrants to purchase up to an aggregate of 4,440,000 shares of common stock and (ii) accompanying warrants to purchase one share of common stock for each share of common stock or pre-funded warrant sold (Press release, Elevation Oncology, JUN 9, 2023, View Source;utm_medium=rss&utm_campaign=elevation-oncology-announces-pricing-of-50-million-public-offering [SID1234632611]). The combined offering price to the public of each share of common stock and accompanying warrant is $2.2500. The combined offering price to the public of each pre-funded warrant and accompanying warrant is $2.2499. The accompanying warrants have an exercise price of $2.25 per share, are exercisable immediately, and will expire five years following the date of issuance. All of the shares of common stock, pre-funded warrants and accompanying warrants are being offered by Elevation Oncology. Before deducting the underwriting discounts and commissions and other offering expenses, Elevation Oncology expects to receive total gross proceeds of approximately $50 million. The offering is expected to close on or about June 13, 2023, subject to the satisfaction of customary closing conditions.

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SVB Securities and TD Cowen are acting as joint bookrunning managers in the offering.

Elevation Oncology intends to use the net proceeds from the offering primarily to fund clinical development of its lead product candidate EO-3021, an antibody drug conjugate (ADC) that has been designed to selectively deliver a cytotoxic payload directly to cancer cells expressing Claudin 18.2, and other general corporate purposes.

The shares, pre-funded warrants and accompanying warrants are being offered by Elevation Oncology pursuant to a registration statement on Form S-3 previously filed and declared effective by the Securities and Exchange Commission (SEC). The offering was made only by means of a preliminary prospectus supplement and accompanying prospectus, which was filed on June 8, 2023, relating to and describing the terms of the offering. A final prospectus supplement and accompanying prospectus relating to this offering will be filed with the SEC. These documents may be obtained from: SVB Securities LLC, Attention: Syndicate Department, 53 State Street, 40th Floor, Boston, MA 02109, by telephone at (800) 808-7525, ext. 6105, or by email at [email protected]; or Cowen and Company, LLC, 599 Lexington Avenue, New York, NY 10022, by email at [email protected] or by telephone at (833) 297-2926. Electronic copies of the preliminary prospectus supplement and accompanying prospectus will also be available on the website of the SEC at View Source

This press release does not constitute an offer to sell or the solicitation of an offer to buy the securities, nor shall there be any sale of the securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of such state or other jurisdiction.

On June 9, 2023 Nucleai, reported a strategic collaboration with Mayo Clinic BioPharma Diagnostics to bring world-class digital pathology solutions, technologies, and services to support drug development and clinical practice (Press release, Debiopharm, JUN 9, 2023, View Source [SID1234632610]).

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This collaboration combines Nucleai’s AI-powered spatial biology technology with Mayo’s longitudinally annotated, multi-modal data sets, world-class lab services, and clinical diagnostic footprint.

On June 9, 2023 Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and CRISPR Therapeutics (Nasdaq: CRSP) reported that both pivotal trials for exagamglogene autotemcel (exa-cel) in patients with transfusion-dependent beta thalassemia (TDT) or severe sickle cell disease (SCD) met primary and key secondary endpoints at pre-specified interim analyses (Press release, CRISPR Therapeutics, JUN 9, 2023, View Source [SID1234632609]). The results are being presented at the Annual European Hematology Association (EHA) (Free EHA Whitepaper) Congress.

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"The updated results from both the TDT and SCD trials are remarkable and bring the promise of an autologous CRISPR/Cas9 gene-edited cell therapy one-step closer to patients who are waiting," said Carmen Bozic, M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer at Vertex.

"This analysis confirms the potential of exa-cel to render patients transfusion-independent or VOC-free, with significant improvement in their quality of life and physical performance," said Franco Locatelli, M.D., Ph.D., Professor of Pediatrics at the Sapienza University of Rome, Director of the Department of Pediatric Hematology and Oncology at Bambino Gesù Children’s Hospital. "This therapy offers the potential of a functional cure for patients with transfusion-dependent beta thalassemia or severe sickle cell disease along with a favorable safety profile."

New Data From Pre-Specified Interim Analyses in exa-cel Pivotal Trials

Both CLIMB-111 and CLIMB-121 met their primary endpoint and key secondary endpoint at the pre-specified interim analysis for each trial. These analyses evaluated the efficacy and safety of exa-cel in patients with TDT or SCD in the ongoing Phase 3 trials as well as in the long-term follow up trial CLIMB-131. The data shared are from 83 patients (48 with TDT and 35 with SCD) dosed with exa-cel with follow-up up to 43.7 months. All patients treated with exa-cel demonstrated clinical benefit, and these data continue to demonstrate the potentially transformative profile of exa-cel.

Efficacy of exa-cel in Patients With Transfusion-Dependent Beta Thalassemia

Of the 48 patients with TDT who had received exa-cel at the time of the analysis, more than half (58.3%) have genotypes associated with severe disease, beta-zero/beta-zero or other beta-zero-like severe genotypes. At the time of the data cut, 27 TDT patients were evaluable for the primary and key secondary endpoint.

24/27 (88.9%) achieved the primary endpoint of transfusion-independence for at least 12 consecutive months (TI12) and the secondary endpoint of transfusion-independence for at least 6 consecutive months (TI6) with a mean weighted hemoglobin of at least 9 g/dL (95% CI: 70.8%, 97.6%; P<0.0001). Mean duration of transfusion-independence was 20.5 months with a maximum of 40.7 months.
Of the 3 patients who did not achieve TI12, one patient has since stopped transfusions and has been transfusion-free for 2.9 months; the remaining 2 patients have had substantial reductions (80% and 96%) in transfusion volume from baseline.
Increases in total hemoglobin occurred early within the first few months and were maintained over time. In the analysis of all patients who received exa-cel, mean total hemoglobin was ≥11g/dL at Month 3 and ≥12g/dL from Month 6 onward with pancellular distribution of fetal hemoglobin.
Mean proportion of edited BCL11A alleles was stable over time in bone marrow and peripheral blood indicating successful permanent editing in the long-term hematopoietic stem cells.
Patients also had clinically significant improvements in patient-reported outcomes.

Efficacy of exa-cel in Patients With Severe Sickle Cell Disease

Of the 35 patients with SCD who had received exa-cel at the time of the analysis, 17 patients were evaluable for the primary and key secondary endpoint at the time of the data cut.

16/17 (94.1%) achieved the primary endpoint of freedom from vaso-occlusive crises (VOCs) for at least 12 consecutive months (VF12) (95% CI: 71.3%, 99.9%; P=0.0001). Mean duration of VOC-free was 18.7 months, with a maximum of 36.5 months. 17/17 (100%) achieved the key secondary endpoint of being free from hospitalizations related to VOCs for at least 12 consecutive months (HF12) (95% CI: 80.5%, 100.0%; P<0.0001).
The one patient who did not achieve VF12 did achieve HF12 and has a complex set of comorbidities, including a history of chronic pain.
One patient who achieved VF12 had a VOC 22.8 months following exa-cel infusion in the setting of a parvovirus infection. This patient has since fully recovered from the infection and been VOC-free.
Increases in fetal hemoglobin and total hemoglobin occurred early, within the first few months, and were maintained over time. In the analysis of all patients who received exa-cel, mean fetal hemoglobin was more than 30% of total hemoglobin by Month 3 and was then maintained at approximately 40.0% through follow-up, with pancellular distribution.
Mean proportion of edited BCL11A alleles was stable over time in bone marrow and peripheral blood, indicating successful permanent editing in the long-term hematopoietic stem cells.
Patients also had clinically significant improvements in patient-reported outcomes.

Safety of exa-cel in All Patients

The safety profile of exa-cel was generally consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant. All patients engrafted neutrophils and platelets after exa-cel infusion.

As previously reported, two TDT patients had serious adverse events (SAEs) considered related to exa-cel. One patient had three SAEs considered related to exa-cel: hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and headache, and one SAE of idiopathic pneumonia syndrome that was considered related to both exa-cel and busulfan. All four SAEs occurred in the context of HLH in the peri-engraftment period and have resolved. One patient had SAEs of delayed neutrophil engraftment and thrombocytopenia, both of which were considered related to exa-cel and busulfan, and both SAEs have resolved. Among the 35 patients with SCD, there were no SAEs considered related to exa-cel.

Also as previously reported, one adult patient with SCD developed pneumonia and respiratory failure following SARS-CoV-2 infection, resulting in death. The investigator assessed the events as not related to exa-cel. There were no other deaths or discontinuations, and there have been no malignancies in either study.

These data will be shared as outlined below:

Abstract S270 will be an oral presentation entitled "Transfusion Independence and Elimination of Vaso-Occlusive Crises After Exagamglogene Autotemcel For Transfusion-Dependent Βeta-Thalassemia and Severe Sickle Cell Disease," on Sunday, June 11 at 11:30 CEST. This presentation will include updated pivotal trial data from patients treated with exa-cel in CLIMB-111 and CLIMB-121 and followed in CLIMB‑131. This abstract was chosen for the media briefing program.

In addition, three health economics abstracts from Vertex have been accepted for poster presentation on Friday, June 9 at 18:00 CEST.

Abstract P1452 is entitled "Mortality and Clinical Complications Among Patients With Transfusion-Dependent Beta-Thalassemia in Italy."
Abstract P1447 is entitled "Mortality and Clinical Complications Among Patients With Sickle Cell Disease With Recurrent Vaso-Occlusive Crises in Italy."
Abstract P1464 is entitled "Clinical Complications Among Patients With Transfusion-Dependent Beta-Thalassemia in Germany."

About exagamglogene autotemcel (exa-cel)

Exa-cel is an investigational, autologous, ex vivo CRISPR/Cas9 gene-edited cell therapy that is being evaluated for patients with SCD or TDT, in which a patient’s own hematopoietic stem cells are edited to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. The elevation of HbF by exa-cel has the potential to reduce or eliminate painful and debilitating VOCs for patients with SCD and alleviate transfusion requirements for patients with TDT. Earlier results from these ongoing trials were published in The New England Journal of Medicine in January of 2021 and presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Congress in 2022.

Exa-cel has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the U.S. FDA for both TDT and SCD. The FDA has accepted the Biologics License Applications (BLAs) for exa-cel and assigned Prescription Drug User Fee Act (PDUFA) action dates of December 8, 2023, for SCD and March 30, 2024, for TDT.

In the EU, exa-cel has been granted Orphan Drug Designation from the European Commission, as well as Priority Medicines (PRIME) designation from the European Medicines Agency (EMA), for both SCD and TDT. In the U.K., exa-cel has also been granted an Innovation Passport under the Innovative Licensing and Access Pathway (ILAP) from the Medicines Healthcare products Regulatory Agency (MHRA). In Europe, the Marketing Authorization Applications (MAAs) for exa-cel were submitted in December 2022 and validated by the EMA and MHRA in January 2023.

About CLIMB-111 and CLIMB-121

The ongoing Phase 1/2/3 open-label trials, CLIMB-111 and CLIMB-121, are designed to assess the safety and efficacy of a single dose of exa-cel in patients ages 12 to 35 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now closed for enrollment. Patients will be followed for approximately two years after exa-cel infusion. Each patient will be asked to participate in CLIMB-131, a long-term follow-up trial.

About CLIMB-131

The ongoing long-term, open-label trial, CLIMB-131, is designed to evaluate the safety and efficacy of exa-cel in patients who received exa-cel in CLIMB-111, CLIMB-121, CLIMB-141, CLIMB-151 or CLIMB-161. The trial is designed to follow participants for up to 15 years after exa-cel infusion.

About CLIMB-141 and CLIMB-151

The ongoing Phase 3 open-label trials, CLIMB-141 and CLIMB-151, are designed to assess the safety and efficacy of a single dose of exa-cel in patients ages 2 to 11 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now open for enrollment and currently enrolling patients ages 5 to 11 years with the plan to extend to ages 2 to less than 5 years at a later date. Each trial will enroll approximately 15 patients. Patients will be followed for approximately two years after infusion. Each patient will be asked to participate in CLIMB-131, a long-term follow-up trial.

About CLIMB-161

The ongoing Phase 3b trial, CLIMB-161, is to support expansion of our manufacturing footprint after initial potential approval and launch. This trial will enroll approximately 12 patients with either TDT or with SCD, characterized by recurrent VOCs, ages 12 to 35 years. Patients will be followed for approximately one year after infusion. Each patient will be asked to participate in CLIMB-131, a long-term follow-up trial.

About the Gene-Editing Process in These Trials

Patients who enroll in these trials will have their own hematopoietic stem and progenitor cells collected from peripheral blood. The patient’s cells will be edited using the CRISPR/Cas9 technology. The edited cells, exa-cel, will then be infused back into the patient as part of an autologous hematopoietic stem cell transplant (HSCT), a process which involves a patient being treated with myeloablative busulfan conditioning. Patients undergoing HSCT may also encounter side effects (ranging from mild to severe) that are unrelated to the administration of exa-cel. Patients will initially be monitored to determine when the edited cells begin to produce mature blood cells, a process known as engraftment. After engraftment, patients will continue to be monitored to track the impact of exa-cel on multiple measures of disease and for safety.