On December 12, 2022 Asher Biotherapeutics, Inc., a biotechnology company focused on developing therapies to precisely engage specific immune cells to fight cancer, reported new preclinical data demonstrating proof-of-concept for cis-targeted cytokines as a novel strategy for enhancing chimeric antigen receptor T cell (CAR-T) engraftment, expansion, and functionality culminating in the delivery of improved anti-tumor activity (Press release, Asher Biotherapeutics, DEC 12, 2022, View Source [SID1234625183]). This data will be presented in a poster at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in New Orleans, Louisiana, December 10-13, 2022.

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"We are delighted to share new preclinical data with our cell therapy program, further highlighting the versatility of our cis-targeting cytokine platform, as well as its potential applicability across a range of hematologic malignancies and solid tumors," said Ivana Djuretic, Ph.D., Founder and Chief Scientific Officer of Asher Bio. "These data demonstrate our ability to selectively activate only CAR-T cells post-adoptive transfer and, as a result, to improve anti-tumor activity. We are particularly pleased to observe these results using two different cytokines, interleukin-2 (IL-2) and interleukin-21 (IL-21), which act through distinct, potentially complementary, mechanisms. Over time, our ability to deliver different, supportive cytokine signals could enable us to target a diverse set of cell therapies, including those based on T cell receptors, tumor-infiltrating lymphocytes, natural killer cells and regulatory T cells, to support the use of cell therapies in a diverse set of tumor types. We look forward to advancing this program as we aim to maximize the reach of our platform, with the goal of delivering better outcomes to cancer patients who remain underserved by existing therapeutic options."

CAR-T cell therapies have recently transformed the treatment of some hematological malignancies and are showing promise in solid tumors. In the clinic, the successful expansion and persistence of CAR-T cells has correlated with improved therapeutic outcomes, including durable complete responses and survival; in preclinical studies, the administration of IL-2 has been observed to enhance CAR-T engraftment, persistence and functionality. However, the clinical potential of utilizing existing IL-2 molecules in combination with CAR-T therapies is limited due to the severe toxicity of high dose IL-2 and the inadequate selectivity of existing engineered IL-2 variants, which expand multiple endogenous cell types in addition to the transferred CAR-T cells.

In order to overcome these challenges, Asher Bio developed two cis-targeted fusion molecules, one using IL-2 and the other using IL-21, which are designed to selectively activate CAR-T cells by recognizing an extracellular tag, while exhibiting minimal effects on non-engineered or endogenous cells. Both cis-targeted cytokine fusions are comprised of a targeting antibody directed against a tag expressed on the CAR-T surface, that is co-expressed with the CAR, and a cytokine mutein with attenuated binding to its cognate cytokine receptor.

In a poster titled, "Selective Support of CAR-T Cell Therapies by Cis-Targeted IL-2 or IL-21 Cytokines Results in Enhanced Anti-Tumor Activity," Asher Bio scientists and collaborators at the Perelman School of Medicine at the University of Pennsylvania presented preclinical in vitro and in vivo data that support the development of cis‑targeted cytokines directed by anti-tag antibodies as a promising approach to enhance CAR-T cell therapies. The data show:

– Cis-targeted IL-2 or IL-21 molecules targeting an exogenous tag selectively activated CAR‑T cells in vitro and enhanced anti-tumor activity and survival in vivo.
– CAR-T cell targeted IL-2 and IL-21 enhanced anti-tumor activity through distinct mechanisms.
– Cis-targeted cytokine therapies allowed for temporal control, while avoiding the negative pleiotropic effects associated with systemically administered wild-type cytokines.

The poster presentation will be available in the "Presentations and Posters" section of Asher Bio’s website: View Source

On December 12, 2022 Rocket Pharmaceuticals, a leading late-stage biotechnology company advancing an integrated and sustainable pipeline of genetic therapies for rare childhood disorders with high unmet need, reported positive clinical data from its lentiviral (LV)-based gene therapy programs at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place in New Orleans, Louisiana, from December 10-13 (Press release, Rocket Pharmaceuticals, DEC 12, 2022, View Source [SID1234625182]).

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Lentiviral-mediated Gene Therapy for Patients with Fanconi Anemia [Group A]: Updated Results from Global RP-L102 Clinical Trials

The poster presentation includes positive updated data (cut-off October 26, 2022) from the ongoing Phase 2 pivotal trial of RP-L102, Rocket’s ex vivo lentiviral gene therapy candidate for Fanconi Anemia (FA).

RP-L102 conferred phenotypic correction in at least six of 10 evaluable patients with ≥12 months of follow-up as demonstrated by increased resistance to mitomycin-C (MMC) in bone marrow (BM)-derived colony forming cells, concomitant genetic correction and hematologic stabilization.
A seventh patient has displayed evidence of progressively increasing genetic correction as demonstrated by peripheral blood and BM vector copy numbers (VCNs), with recent development of MMC resistance and indicators of hematologic stability after 36 months of follow-up.
The primary endpoint has been achieved, based on a trial protocol in which statistical and clinical significance requires a minimum of five patients to attain increased MMC resistance at least 10% above baseline at two or more timepoints and concomitant evidence of genetic correction and clinical stabilization.
The safety profile of RP-L102 has been highly favorable, and the treatment, administered without any cytotoxic conditioning, has been well tolerated. No signs of bone marrow dysplasia, clonal dominance or insertional mutagenesis related to RP-L102 have been observed.
As previously disclosed, one patient experienced a Grade 2 transient infusion-related reaction, which resolved; one patient with confirmed engraftment developed a T-cell lymphoblastic lymphoma that was conclusively determined by the investigator, sponsor and the independent data monitoring committee to be related to FA (a cancer predisposition syndrome) and unrelated to RP-L102 gene therapy.
Based on the positive efficacy and safety data from the Phase 2 pivotal FA trial, Rocket anticipates regulatory filing in the second half of 2023.
Lentiviral-mediated Gene Therapy for Adults and Children with Severe Pyruvate Kinase Deficiency: Results from an Ongoing Global Phase 1 Study

The poster presentation includes positive updated data (cut-off October 26, 2022) from two adult patients with significant anemia who were treated with RP-L301, Rocket’s ex vivo lentiviral gene therapy candidate for Pyruvate Kinase Deficiency (PKD).

At 24 months post-infusion, both patients have robust and sustained efficacy demonstrated by normalized hemoglobin (from baseline levels in the 7.0-7.5 g/dL range), improved hemolysis parameters, independence from red blood cell transfusions and improved quality of life both reported anecdotally and as documented via formal quality of life assessments.
The safety profile appears highly favorable, with no RP-L301-related serious adverse events through 24 months post-infusion in both adult patients.
Insertion site analyses in peripheral blood and bone marrow in both adult patients up to 12 months post-RP-L301 demonstrated highly polyclonal patterns and there has been no evidence of insertional mutagenesis.
Adult and pediatric enrollment is completed in the Phase 1 study. Phase 2 pivotal trial initiation is anticipated in 2023.
Interim Results from an Ongoing Phase 1/2 Study of Lentiviral-mediated Ex-vivo Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I

The poster presentation includes previously disclosed top-line data at three to 24 months of follow-up after RP-L201 infusion for all patients and overall survival data for seven patients at 12 months or longer after infusion. RP-L201 is Rocket’s ex vivo lentiviral gene therapy candidate for severe Leukocyte Adhesion Deficiency-I (LAD-I).

Observed 100% overall survival at 12 months post-infusion via Kaplan Meier estimate and a statistically significant reduction in all hospitalizations, infection- and inflammatory-related hospitalizations and prolonged hospitalizations for all nine LAD-I patients with three to 24 months of available follow-up. Data also shows evidence of resolution of LAD-I-related skin rash and restoration of wound repair capabilities.
The safety profile of RP-L201 has been highly favorable in all patients with no RP-L201-related serious adverse events to date. Adverse events related to other study procedures, including busulfan conditioning, have been previously disclosed and consistent with the safety profiles of those agents and procedures.
Based on the positive efficacy and safety data from the Phase 2 pivotal LAD-I trial, Rocket has initiated discussions with the FDA and anticipates regulatory filing in the first half of 2023.
About Fanconi Anemia

Fanconi Anemia (FA) is a rare pediatric disease characterized by bone marrow failure, malformations and cancer predisposition. The primary cause of death among patients with FA is bone marrow failure, which typically occurs during the first decade of life. Allogeneic hematopoietic stem cell transplantation (HSCT), when available, corrects the hematologic component of FA, but requires myeloablative conditioning. Graft-versus-host disease, a known complication of allogeneic HSCT, is associated with an increased risk of solid tumors, mainly squamous cell carcinomas of the head and neck region. Approximately 60-70% of patients with FA have a Fanconi Anemia complementation group A (FANCA) gene mutation, which encodes for a protein essential for DNA repair. Mutations in the FANCA gene leads to chromosomal breakage and increased sensitivity to oxidative and environmental stress. Increased sensitivity to DNA-alkylating agents such as mitomycin-C (MMC) or diepoxybutane (DEB) is a ‘gold standard’ test for FA diagnosis. Somatic mosaicism occurs when there is a spontaneous correction of the mutated gene that can lead to stabilization or correction of a FA patient’s blood counts in the absence of any administered therapy. Somatic mosaicism, often referred to as ‘natural gene therapy’ provides a strong rationale for the development of FA gene therapy because of the selective growth advantage of gene-corrected hematopoietic stem cells over FA cells.

About Pyruvate Kinase Deficiency

Pyruvate kinase deficiency (PKD) is a rare, monogenic red blood cell disorder resulting from a mutation in the PKLR gene encoding for the pyruvate kinase enzyme, a key component of the red blood cell glycolytic pathway. Mutations in the PKLR gene result in increased red cell destruction and the disorder ranges from mild to life-threatening anemia. PKD has an estimated prevalence of 4,000 to 8,000 patients in the United States and the European Union. Children are the most commonly and severely affected subgroup of patients. Currently available treatments include splenectomy and red blood cell transfusions, which are associated with immune defects and chronic iron overload. Recently, mitapivat, an oral enzyme activator, was approved for use in the least severely-afflicted adult patients (those who are not transfusion-dependent and do not have mutations known to cause severe disease).

RP-L301 was in-licensed from the Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD).

About Leukocyte Adhesion Deficiency-I

Severe Leukocyte Adhesion Deficiency-I (LAD-I) is a rare, autosomal recessive pediatric disease caused by mutations in the ITGB2 gene encoding for the beta-2 integrin component CD18. CD18 is a key protein that facilitates leukocyte adhesion and extravasation from blood vessels to combat infections. As a result, children with severe LAD-I are often affected immediately after birth. During infancy, they suffer from recurrent life-threatening bacterial and fungal infections that respond poorly to antibiotics and require frequent hospitalizations. Children who survive infancy experience recurrent severe infections including pneumonia, gingival ulcers, necrotic skin ulcers, and septicemia. Without a successful bone marrow transplant, mortality in patients with severe LAD-I is 60-75% prior to the age of 2 and survival beyond the age of 5 is uncommon. There is a high unmet medical need for patients with severe LAD-I.

Rocket’s LAD-I research is made possible by a grant from the California Institute for Regenerative Medicine (Grant Number CLIN2-11480). The contents of this press release are solely the responsibility of Rocket and do not necessarily represent the official views of CIRM or any other agency of the State of California.

On December 12, 2022 10:00 Atara Biotherapeutics, a leader in T-cell immunotherapy, leveraging its novel allogeneic Epstein-Barr virus (EBV) T-cell platform to develop transformative therapies for patients with cancer and autoimmune diseases, reported updated interim analysis and safety results from its Phase 3 multicenter ALLELE study investigating tabelecleucel (tab-cel) for the treatment of relapsed/refractory (r/r) Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV+ PTLD) following solid organ transplant (SOT) or hematopoietic cell transplant (HCT) (Press release, Atara Biotherapeutics, DEC 12, 2022, View Source [SID1234625181]).

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The Phase 3 ALLELE study findings, along with updated efficacy and safety data from two single-center, open-label studies as well as a multicenter expanded access program investigating tab-cel including patients with Epstein-Barr virus positive leiomyosarcomas (EBV+ LMS), were featured among four poster presentations at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting taking place December 10-13, 2022, in New Orleans.

"The updated efficacy and safety results of the Phase 3 ALLELE study including additional patients and longer follow-up are consistent with the transformative potential of tab-cel in EBV+ PTLD patients with no approved treatment options available," said Jakob Dupont, MD, Head of Global Research & Development at Atara. "Similar to EBV+ PTLD, patients with EBV+ LMS face a poor prognosis with limited treatment options, underscoring the significant need for effective and safe new therapeutic options. We report exciting new data that suggest tab-cel may provide a clinical benefit in these hard-to-treat patients with LMS and, together with other EBV-driven diseases like PTLD, represent the potential of tab-cel to transform the lives of thousands of patients across multiple indications and geographies."

In the ongoing Phase 3 ALLELE study, 43 patients — 14 HCT recipients and 29 SOT recipients — were treated with tab-cel and were included in the analysis. Patients received a median of 2 cycles (range: 1-6) of tab-cel. The median age of evaluable patients for both SOT and HCT was 48.5 years (3.2–81.5) who had received a median of 1 (range: 1-5) prior systemic treatments. Responses per clinical and radiographic assessment were measured by independent oncologic response adjudication (IORA) assessment.

Results as of November 2021 data cutoff showed:

An objective response rate (ORR) of 51.2% (22/43) was observed for both HCT and SOT groups (95% CI: 35.5, 66.7), 51.7% (15/29) for patients following SOT (95% CI: 32.5, 70.6) and 50.0% (7/14) for HCT patients (95% CI: 23.0, 77.0) with a best overall response of Complete Response (CR; 27.9%; n=12; n=6, SOT, n=6, HCT) or Partial Response (PR; 23.3%; n=10; n=9, SOT, n=1, HCT).
The median time to response (TTR) in all patients was 1.0 month (range: 0.7-4.7) and median duration of response (DOR) in 22 responders was 23.0 months (95% CI: 6.8, not estimable [NE]), with 12/22 responders having a DOR >6 months.
Median overall survival (OS) of 18.4 months (95% CI: 6.9, NE) in all patients, 16.4 months in SOT (95% CI: 5.0, NE) and not yet reached in HCT (95% CI: 5.7, NE).
One-year survival rates were 61.1% (95% CI: 43.7, 74.5), 56.2% in SOT (95% CI: 34.6, 73.2) and 70.1% in HCT (95% CI: 38.5, 87.6).
Patients responding to tab-cel had longer one-year survival compared to the non-responders, with a one-year survival rate of 84.4% (95% CI: 58.9, 94.7) versus 34.8% (95% CI: 14.6, 56.1) for non-responders.
In addition, Atara presented updated efficacy and safety data investigating the potential of tab-cel in patients with EBV+ LMS who have received at least one therapy. EBV+ LMS is a rare, aggressive, and potentially fatal solid tumor that responds poorly to radiation and chemotherapy. Among 18 patient-treatments, median age was 8.9 years (range: 3–35) and 44.4% of patients were male.

Results showed:

A clinical benefit rate (CR, PR, and stable disease) of 77.8% (14/18) (95% CI: 56.6, 96.2), and ORR of 22.2% (95% CI: 6.4, 47.6; PR in all cases) was observed. Median follow-up for all patients was 18.9 months (95% CI: 1.5, 109.3).
The estimated median OS was 77.4 months (95% CI:18.0, NE) and the median progression-free survival (PFS) was 12.5 months (95% CI: 5.5, NE).
Median DOR was 6.2 months (95% CI: 4.8, NE) with a one-year DOR rate of 37.5% (95% CI: 1.1, 80.8). The one-year survival rate was 86.7% (95% CI: 56.4, 96.5) and the estimated two-year survival rate was 78.0% (95% CI: 45.5, 92.5).
In both the ALLELE and LMS studies, tab-cel was well tolerated and the safety profile consistent with previous data. There was no evidence of tumor flare reaction, infusion reactions, cytokine release syndrome, transmission of infectious diseases, and no events of graft versus host disease (GvHD) or organ rejection related to tab-cel.

In separate posters, Atara also presented the methodology of using T-cell receptor β (TCRβ) sequencing to identify allogeneic cell product clones post-infusion and data confirming the absence of clinical manifestation of immunogenicity following tab-cel administration in patients enrolled in the ALLELE study.

Poster Presentation Details:

Title: New and Updated Results from a Multicenter, Open-Label, Global Phase 3 Study of Tabelecleucel (Tab-cel) for Epstein–Barr Virus-Positive Post-Transplant Lymphoproliferative Disease (EBV+ PTLD) Following Allogeneic Hematopoietic Cell (HCT) or Solid Organ Transplant (SOT) after Failure of Rituximab or Rituximab and Chemotherapy (ALLELE)

Presenting Author: Kris Michael Mahadeo, MD, MPH, MD Anderson Cancer Center, Houston, TX
Date & Time: Monday, December 12, 2022, 6-8 p.m. CST / 5-7 p.m. PST
Abstract Number: 4658
Poster Session: 705. Cellular Immunotherapies: Late Phase and Commercially Available Therapies: Poster III
Location: Ernest N. Morial Convention Center, Hall D
Title: Updated Efficacy and Safety of Tabelecleucel in Patients with Epstein-Barr Virus-Positive (EBV+) Leiomyosarcomas (LMS)

Presenting Author: Lauren S. Jiménez-Kurlander, MD, Boston Children’s Hospital/Dana Farber Cancer Institute, Boston, MA
Date & Time: Sunday, December 11, 2022, 6-8 p.m. CST / 5-7 p.m. PST
Abstract Number: 3349
Poster Session: 705. Cellular Immunotherapies: Late Phase and Commercially Available Therapies: Poster II
Location: Ernest N. Morial Convention Center, Hall D
Title: Utilizing TCRseq to Detect Tabelecleucel, an Allogeneic Epstein-Barr Virus (EBV)-Specific T-Cell Therapy, Post-Infusion

Presenting Author: Fiona Ruiz, PhD, Atara Biotherapeutics, Thousand Oaks, CA
Date & Time: Saturday, December 10, 2022, 5:30-7:30 p.m. CST / 4:30-6:30 p.m. PST
Abstract Number: 2169
Poster Session: 803. Emerging Tools, Techniques and Artificial Intelligence in Hematology: Poster I
Location: Ernest N. Morial Convention Center, Hall D
Title: Exploring the Impact of Humoral Immunogenicity with Tabelecleucel for the Treatment of EBV+ PTLD Following HCT and SOT

Presenting Author: Tassja J. Spindler, Atara Biotherapeutics, Thousand Oaks, CA
Date & Time: Sunday, December 11, 2022, 6-8 p.m. CST / 5-7 p.m. PST
Abstract Number: 3351
Poster Session: 705. Cellular Immunotherapies: Late Phase and Commercially Available Therapies: Poster II
Location: Ernest N. Morial Convention Center, Hall D
About Tabelecleucel

Tabelecleucel (tab‐cel) is an allogeneic, EBV-specific T-cell immunotherapy which targets and eliminates EBV-infected cells in an HLA-restricted manner. Tab-cel has been granted Breakthrough Therapy Designation for the treatment of rituximab-refractory EBV-associated lymphoproliferative disease (LPD) by the U.S. Food and Drug Administration (FDA) and has orphan drug designation in the U.S. Tabelecleucel received PRIME designation by the European Medicines Agency (EMA) for the treatment of patients with EBV-associated PTLD in the allogeneic hematopoietic stem cell transplant (HCT) setting who have failed on rituximab and has orphan drug designation in the EU.

On December 12, 2022 Amphera B.V., a late-stage biotechnology company developing MesoPher cell therapy to treat cancer, reported topline results from both the phase II Reactive trial and the phase II/III DENIM trial (Press release, Amphera, DEC 12, 2022, View Source [SID1234625179]).

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In the phase II Reactive trial, patients with resected pancreatic cancer who had completed standard-of-care chemotherapy received 3 bi-weekly injections of Amphera’s MesoPher dendritic cell therapy and booster injections at 4 and 7 months.

The Reactive trial met the primary endpoint with topline safety and efficacy data from two cohorts of in total 38 patients demonstrating a statistically significant 2-year Recurrence Free Survival of 60%. The results from the first cohort of 10 patients have been published in the European Journal of Cancer1. Based on these results, a 2nd cohort of 28 patients was fully enrolled. As established in all MesoPher trials, the safety profile is excellent.

Prof Casper van Eijck, Principal Investigator of the Reactive trial:

We are thrilled by the promising results of the Reactive trial. These results exceed expectations for this group of patients compared to the best current treatments. A 60% 2-year recurrence free survival after surgical resection truly is an exceptional outcome. Further randomized clinical research with MesoPher in pancreatic cancer is a likely next step. In addition, we have seen that MesoPher induces a T cell response against the tumour of patients, which could explain the efficacy, although pancreatic cancer is known as a cold tumour.

In the DENIM trial, mesothelioma patients with stable disease or better after platin-pemetrexed chemotherapy received either MesoPher maintenance treatment or best supportive care (BSC). The dosing scheme was identical to the Reactive trial. The DENIM trial confirmed MesoPher’s excellent safety profile and MesoPher induced a robust T-cell response. The immune response did not translate into clinical benefit, and consequently the primary endpoint of an improvement of Overall Survival (OS) was not met.

The unexpected outcome of the DENIM trial can be attributed to two main factors. The majority of patients were already progressive before or during the first 3 bi-weekly injections, as evidenced by the CT scan performed after the third injection. As such, the first injections were administered too late, as MesoPher cannot exert its effects in progressive patients. Only a small proportion of patients received the full MesoPher treatment. In addition, both arms performed well with a median OS around 18 months after randomization, potentially due to the second-line therapy with checkpoint inhibitors.

On December 12, 2022 Syros Pharmaceuticals, a leader in the development of medicines that control the expression of genes, reported a peer-reviewed publication of results from its completed biomarker-directed Phase 2 trial of tamibarotene in combination with azacitidine in newly diagnosed patients with acute myeloid leukemia (AML) who are not eligible for standard intensive chemotherapy (Press release, Syros Pharmaceuticals, DEC 12, 2022, View Source [SID1234625177]). These findings support Syros’ ongoing evaluation of tamibarotene for the treatment of AML and myelodysplastic syndrome (MDS) patients with RARA overexpression. The paper, titled "Targeting RARA Overexpression with Tamibarotene, a Potent and Selective RARα Agonist, is a Novel Approach in AML," was published online in Blood Advances on December 7, 2022 at View Source

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"We are excited to see a high CR rate and a rapid onset of response in newly diagnosed unfit AML patients with RARA overexpression treated with a combination of tamibarotene plus azacitidine. The biomarker test successfully identified AML patients positive for RARA overexpression who were enriched for response to tamibarotene and azacitidine relative to those patients who were negative for RARA overexpression. This observation further demonstrates that the activity of tamibarotene is dependent on the biology of RARA overexpression. In addition, the combination was generally well tolerated and provides the potential for a novel targeted treatment approach for patients with AML," said Stéphane de Botton, M.D., Head of Acute Myeloid Malignancies at Institut Gustave Roussy and a clinical investigator in the Phase 2 trial of tamibarotene.

"With approximately 30% of AML patients and 50% of HR-MDS patients positive for RARA overexpression, tamibarotene has the potential to contribute to a new frontline treatment paradigm for large, targeted patient populations," said David A. Roth, M.D., Chief Medical Officer at Syros. "These data, including the high CR rate in patients with low blast count AML, informed our ongoing SELECT-MDS-1 Phase 3 trial in newly diagnosed HR-MDS patients and SELECT-AML-1 Phase 2 trial in newly diagnosed unfit AML patients, from which we reported encouraging data from the safety lead-in portion at the ASH (Free ASH Whitepaper) Annual Meeting on December 10th."

In the SY-1425-201 trial, a total of 51 patients at 12 sites in the U.S. and France were enrolled into the newly diagnosed unfit AML cohort that evaluated the combination of tamibarotene plus azacitidine. Patients were screened with a novel blood-based clinical trial assay used to prospectively identify those with RARA overexpression. Based on RARA expression levels, each patient was classified as positive for RARA overexpression (22 patients) or negative for RARA overexpression (29 patients). Both groups were enrolled and treated with 28-day treatment cycles, including azacitidine dosed daily on Days 1 to 7, followed by oral tamibarotene dosed twice daily on Days 8 to 28.

A total of 18 patients with RARA overexpression were response evaluable and exhibited an overall response rate (ORR) of 67% (12/18), CR/CRi rate of 61% (9 CR, 2 CRi), CR rate of 50% and morphological leukemia-free state of 5% (one patient). Median time to initial composite complete remission for patients with RARA overexpression was 1.2 months and median duration of composite complete remission was 10.8 months (95% CI: 2.9, NE). Importantly, in patients with low blast count AML, which is similar to HR-MDS, data showed a 67% (4/6) CR rate. In the patients without RARA overexpression, the response rates were consistent with treatment with azacitidine alone. Additionally, correlative analyses of RARA expression levels identified an association of RARA overexpression with a monocytic gene expression signature that may be associated with resistance to venetoclax. These data also informed the strategy of evaluating the triplet combination of tamibarotene, venetoclax and azacitidine in the ongoing SELECT-AML-1 trial.

Importantly, the tamibarotene plus azacitidine combination was generally well tolerated in the patients treated. The rates of myelosuppression were comparable to azacitidine monotherapy in this population suggesting no added hematologic toxicity from tamibarotene when used in combination with azacitidine. The majority of non-hematologic adverse events (AEs) were low grade.