On December 9, 2024 Silence Therapeutics plc ("Silence" or the "Company") (Nasdaq: SLN), a global clinical-stage company developing novel siRNA (short interfering RNA) therapies, reported additional results from the Phase 1 open label portion of the SANRECO study of divesiran, a siRNA targeting TMPRSS6, in patients with polycythemia vera (PV) were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in San Diego, California (Press release, Silence Therapeutics, DEC 9, 2024, View Source [SID1234648914]).

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"Additional divesiran data presented at ASH (Free ASH Whitepaper) continue to support a compelling profile in PV and highlight the broad potential of our siRNA platform to target both rare and common genetic diseases," said Craig Tooman, President and CEO at Silence. "Based on these very encouraging results, we are committed to advancing divesiran development as the first-in-class siRNA in PV and will prioritize our resources to ensure we are well positioned to progress this very promising program. To this end, we are pleased to have dosed the first subject in the Phase 2 portion of the SANRECO study, which is currently underway."

Initial results from the SANRECO Phase 1 study were presented in June 2024 and showed that all doses of divesiran substantially reduced phlebotomy frequency and lowered hematocrit (HCT) in 16 phlebotomy dependent PV patients regardless of baseline HCT levels. Additional data presented at ASH (Free ASH Whitepaper) further support those findings and included 19 PV patients with a combined history of 79 phlebotomies prior to enrolment. Following divesiran dosing, only five phlebotomies occurred during the 18-week treatment period – all were in patients who entered the study with high baseline HCT levels (over 45%). Two phlebotomies occurred in the 16-week follow-up period following the last administered dose.

Consistent with results reported in June, there was a sustained reduction in HCT during the treatment period and favorable effects on indices of iron metabolism. Hepcidin levels increased and were sustained within physiological levels in all dose groups, demonstrating consistent target engagement. Importantly, divesiran continues to be well tolerated to-date with no dose-limiting toxicities.

"PV patients could benefit from a novel treatment option that effectively manages their condition without causing serious adverse effects," said Marina Kremyanskaya, MD, PhD, Associate Professor of Medicine, Hematology and Medical Oncology, at the Icahn School of Medicine at Mount Sinai. "In the Phase 1 portion of the SANRECO study, divesiran substantially reduced the need for phlebotomy and lowered hematocrit levels following infrequent dosing in a range of PV patients. I’m particularly impressed by the long duration of effect and clean safety/tolerability profile. These data are very exciting and support further development of divesiran in PV."

The ASH (Free ASH Whitepaper) presentation is available on the Company’s website, linked here.

The Phase 1 portion of the SANRECO study has enrolled 21 patients and is ongoing until all patients complete follow-up which is expected to conclude in February 2025. Silence also announced today the first subject has been dosed in the Phase 2 portion of the SANRECO Study. Divesiran has FDA Fast Track and Orphan Drug designation in the US.

SANRECO Phase 1 Study Design

The Phase 1 portion of SANRECO is a 34-week, open-label study evaluating divesiran (3 mg/kg, 6 mg/kg and 9 mg/kg) administered subcutaneously every 6 weeks for four doses, with a 16-week follow-up period following the date of the last administered dose in 21 PV patients. Key inclusion criteria include a PV diagnosis and a history of requiring at least three phlebotomies in the last six months or five in the last year prior to screening. Patients are allowed to be on stable doses of cytoreductive agents. Given the exploratory nature of this Phase 1 study, both well-controlled patients—defined as those with HCT levels at 45% or less – as well as those with HCT levels greater than 45% at baseline on current standard of care treatment were enrolled.

About PV

PV is a rare, myeloproliferative neoplasm – a type of blood cancer—characterized by the excessive production of red blood cells, often resulting in elevated hematocrit levels. Elevated hematocrit above 45-percent is associated with a four-times higher rate of death from cardiovascular or thrombotic events. PV is associated with a range of burdensome symptoms including fatigue, cognitive disturbance and pruritis and additionally, longer term can transform to myelofibrosis and Acute Myeloid Leukemia. The aim of treatment is to maintain hematocrit less than 45%, a level that is associated with a reduced incidence of thrombosis and CV-associated death. The current standard of care includes repeated phlebotomies to reduce hematocrit and/or cytoreductive agents to reduce red blood cell production. There are currently no approved therapies that specifically target red blood cells and hematocrit.

About Divesiran

Divesiran is Silence’s wholly owned siRNA product candidate developed from its proprietary mRNAi GOLD platform that "silences" TMPRSS6 expressed almost exclusively in the liver. TMPRSS6 is a negative regulator of hepcidin, the body’s master regulator of iron metabolism including its absorption, distribution, and storage. By silencing TMPRSS6 in PV patients, divesiran aims to increase hepcidin production and release by liver hepatocytes, leading to the restriction of iron to the bone marrow and, thus, reducing the excessive production of red blood cells, a process dependent on availability of iron.

On December 9, 2024 SELLAS Life Sciences Group, Inc. (NASDAQ: SLS) ("SELLAS" or the "Company"), a late-stage clinical biopharmaceutical company focused on the development of novel therapies for a broad range of cancer indications, reported additional data from the expansion cohorts in the Phase 2 trial of SLS009, a highly selective CDK9 inhibitor, in relapsed/refractory acute myeloid leukemia (r/r AML) (Press release, Sellas Life Sciences, DEC 9, 2024, View Source [SID1234648913]).

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"We are highly encouraged by the emerging data, which continue to show the potential of SLS009 to transform outcomes of these heavily pretreated AML patients," said Angelos Stergiou, MD, ScD h.c., President and Chief Executive Officer of SELLAS. "In the Cohort 3, the optimal dosing regimen of 30 mg BIW, in patients relapsed or refractory to venetoclax-based regimens, the median overall survival has not been reached but exceeds 7.7 months at latest follow-up, marking a significant milestone for patients in this setting, where the expected mOS is historically around 2.5 months. In addition, we are seeing more than 50% ORR to date in our expansion cohorts in patients with AML-myelodysplasia-related changes (AML-MRC) with ASXL1 mutation and mutations and cytogenic changes other than ASXL1, similar to the previously reported ORR in Cohort 3. We set up an aggressive threshold of 33% response rate before the trial started, and to date we achieved 56% in 5/9 evaluable patients. The rapid enrollment in the expansion cohorts further highlight the critical need for new treatments for our target patient population. These results support the potential of SLS009 to become an important new therapeutic option for this underserved patient population."

Key Highlights from the updated topline data:

As of December 4, 2024, data cutoff, 14 patients were enrolled in Cohort 3 and 14 in Cohort 4 and 5, of which 9 were evaluable at the time of analysis.
At latest follow-up, the mOS has not been reached yet but has exceeded 7.7 months in Cohort 3. This is particularly significant as the expected mOS for patients in this setting is typically 2.5 months.
In expansion cohorts 4 and 5, in patients with AML-myelodysplasia-related changes (AML-MRC) with ASXL1 mutation (cohort 4) and mutations and cytogenic changes other than ASXL1 (cohort 5) the ORR was 56% in 9 evaluable for efficacy patients.
SLS009 was well-tolerated with no new safety signals observed to date as the regimen remains safe in additional patients enrolled to date.
The Phase 2 clinical trial of SLS009 is an open-label, single-arm, multi-center study designed to evaluate the safety, tolerability, and efficacy of SLS009 in combination with venetoclax and azacitidine at two dose levels, 45 and 60 mg. In the 60 mg dose cohort patients were randomized into either a 60 mg dose once per week or a 30 mg dose two times per week. The trial was expanded to include two additional cohorts, one with ASXL1 mutated AML patients and one with patients with myelodysplasia-related molecular abnormalities other than ASXL1. In addition to response and survival analyses, the study aims to identify biomarkers for the target patient population and enrichment for further trials. For more information on the study, visit clinicaltrial.gov identifier NCT04588922.

On December 9, 2024 Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL), a commercial stage biotechnology company focused on hematologic disorders and cancer, reported initial data from its ongoing Phase 1b study evaluating R2891, an oral prodrug of R835, a potent and selective dual inhibitor of IRAK1 and IRAK4, in patients with relapsed or refractory (R/R) lower-risk myelodysplastic syndrome (LR-MDS) (Press release, Rigel, DEC 9, 2024, View Source [SID1234648912]). The data is being presented today by Dr. Guillermo Garcia-Manero (Poster #: 4595) at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held December 7-10, in San Diego, California and virtually.

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"Elderly patients with transfusion dependent LR-MDS have few effective treatment options. We are encouraged by the safety and tolerability profile demonstrated by R289 thus far, and by the first evidence of hematologic responses, namely transfusion independence, observed," said Lisa Rojkjaer, M.D, Rigel’s chief medical officer. "The promising initial safety and efficacy data, together with the recent Fast Track designation from the FDA, underscores the potential of R289 as a new treatment option for these patients."

Rigel’s open-label, Phase 1b study of R289 is enrolling patients with lower-risk MDS who are R/R to prior therapies (NCT05308264). The primary objective of the study is to assess the safety and tolerability of R289 with secondary objectives to assess preliminary efficacy of R289 and characterize its pharmacokinetic profile.

Key highlights from the interim data as of October 25, 2024, include:

22 patients were enrolled. The median age was 76; the median number of prior therapies was 3 (range: 1-8); 73% and 77% of patients had received a hypomethylating agent or luspatercept, respectively; and 73% of patients were high transfusion burden (HTB) at baseline.
The median time on therapy was 4.6 months (range: 0.9-22.4 months). R289 was generally well-tolerated in this heavily pretreated LR-MDS patient population, the majority of whom were HTB. The most common treatment emergent adverse events (in ≥20% of patients) were diarrhea and fatigue (each n=6, 27%), and chills, nausea and pruritus (all n=5, 23%), which were all Grade 1/2. The most frequent Grade 3/4 adverse events (AEs) were anemia, platelet count decreased, pneumonia and alanine aminotransferase (ALT) increased (all n=2,9%). One patient discontinued study drug due to hyperuricemia (not drug related) and a second patient discontinued study due to Grade 3 aspartate aminotransferase (AST)/Grade 4 ALT increase (drug related).
R835 exposure increased with increasing R289 dose. At doses ≥500 mg QD (once daily), R835 plasma concentrations at steady state in some patients were ≥ those correlating with 50% or 90% lipopolysaccharide-induced cytokine inhibition previously observed in a healthy volunteer study.
For the 18 efficacy evaluable patients (≥1 dose of R289 with ≥1 efficacy assessment), hematologic responses occurred in 40% (4/10) of evaluable transfusion dependent patients receiving R289 doses ≥500 mg QD. Red blood cell (RBC)-transfusion independence (RBC-TI) ≥8 weeks was achieved by three patients (1 at 500 mg QD and 2 at 750 mg QD); two HTB patients achieved RBC-TI >24 weeks. The median duration of RBC-TI was 29 weeks (range 12.7-51.9 weeks).
One HTB patient receiving 500 mg QD achieved a minor hematologic improvement-erythroid (HI-E) response, with a 64% reduction in RBC transfusions compared to baseline.
Additional supporting data:

The patients achieving RBC-TI had peak hemoglobin increases exceeding 2.0 g/dL compared to baseline.
There were no RBC-TI/HI-E responses in evaluable transfusion dependence patients receiving R289 doses of 250 mg QD and 250 mg BID.
R289 was recently granted Fast Track designation by the U.S. Food and Drug Administration for the treatment of patients with previously-treated transfusion dependent LR-MDS.

Poster #: 4595
Title: R289, a Dual IRAK 1/4 Inhibitor, in Patients with Relapsed/Refractory (R/R) Lower-Risk Myelodysplastic Syndrome (LR-MDS): Initial Results from a Phase 1b Study
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster III
Time: Monday, December 9, 2024, 6:00pm to 8:00pm PT
Location: Halls G-H (San Diego Convention Center)

About R289
R289 is a prodrug of R835, an IRAK1/4 dual inhibitor, which has been shown in preclinical studies to block inflammatory cytokine production in response to toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) family signaling. TLRs and IL-1Rs play a critical role in the innate immune response and dysregulation of these pathways can lead to various inflammatory conditions. Chronic stimulation of both these receptor systems is thought to cause the pro-inflammatory environment in the bone marrow responsible for persistent cytopenias in lower-risk MDS patients.

On December 9, 2024 PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) ("PureTech" or the "Company"), a clinical-stage biotherapeutics company dedicated to changing the lives of patients with devastating diseases, reported data from the dose escalation phase of its ongoing Phase 1b trial evaluating LYT-200, a first-in-class anti-galectin-9 monoclonal antibody, in patients with relapsed or refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) at the 2024 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California (Press release, PureTech Health, DEC 9, 2024, View Source [SID1234648911]).

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LYT-200 is currently being evaluated both as a monotherapy and in combination with the standard-of-care venetoclax and hypomethylating agents (HMA) for patients whose disease is relapsed/refractory to at least one line of prior treatment. It targets galectin-9, a glycan-binding protein that is significantly upregulated in AML and MDS and plays a key role in disease development, progression, immune interference and drug resistance. Initial results show a favorable safety profile across both arms and all dose levels with no dose limiting toxicities, as well as evidence of response, hematological improvement and sustained disease management.

"Relapsed/refractory acute myeloid leukemia is one of the most dire cancer diagnoses, with 50% of patients non-responsive to or relapsing after initial treatment and a median survival time of less than six months,[2]" said Luba Greenwood, J.D., Entrepreneur-in-Residence at PureTech who is leading the Gallop Oncology work. "We are encouraged to see that LYT-200 achieved responses as well as long-term disease stabilization in heavily pre-treated patients, and we look forward to progressing LYT-200 as a critical therapeutic option with the potential to treat most AML patients."

In the monotherapy arm, patients received LYT-200 at five dose levels (2.0 mg/kg to 16.0 mg/kg). Across all dose levels, LYT-200 induced clinical benefit and responses in heavily pre-treated, relapsed/refractory AML/MDS patients, even in those with complex cytogenetics and mutations such as KRAS, NRAS, BRAF as well as patients previously fully refractory to standard of care. Out of 22 evaluable patients who received monotherapy, 59% achieved stable disease or better with two partial responses. The mean duration on treatment is greater than two months, which exceeds the standard overall survival of approximately 1.7 months in venetoclax/HMA-refractory patients.[3]

When administered in combination with venetoclax/HMA, results demonstrate that LYT-200 may enhance the efficacy of standard-of-care therapies, even in relapsed or refractory patients. In the combination arm, patients received LYT-200 across three dose levels (4.0 mg/kg to 12.0 mg/kg) with venetoclax/HMA. Out of 15 evaluable patients who received combination therapy, 80% achieved stable disease or better, with two experiencing complete responses and one patient achieving a morphologic leukemia free state (MLFS).1 The combination regimen has also demonstrated clinical benefit in patients with KRAS/NRAS mutations and the mean duration on treatment up until the point of data cut-off is greater than two months.

"Galectin-9 is an essential driver of both disease proliferation and immune suppression in AML that has not yet been addressed therapeutically," said Aleksandra Filipovic, M.D., Ph.D., Head of Oncology at PureTech. "LYT-200 represents a novel approach for treating AML via a two-gear mode of action that kills cancer cells directly via apoptosis and DNA damage, as well as by re-activating central anti-cancer effectors of the immune system. We are excited by these Phase 1 data that demonstrate the transformative potential of this dual mechanism of LYT-200, both as a single agent and in combination with existing standard-of-care treatments."

Pharmacodynamic assessments of treated patients, using gene and protein analyses of patient cells, validate the LYT-200 dual mode of action, and reveal AML cellular pathways as well as specific immune cell types which may be most critical for response.

Based on these data, LYT-200 will continue development in relapsed/refractory AML/MDS towards a Phase 2 clinical trial. PureTech previously announced that it intends to advance LYT-200 via its Founded Entity, Gallop Oncology.

About LYT-200

LYT-200 is a fully human IgG4 monoclonal antibody targeting a foundational oncogenic and immunosuppressive protein, galectin-9, for the potential treatment of hematological malignancies and locally advanced metastatic solid tumors, including head and neck cancers, with otherwise poor survival rates. A wide variety of preclinical data support the potential clinical efficacy of LYT-200 and the importance of galectin-9 as a target and suggest a potential opportunity for biomarker development. PureTech has presented data demonstrating high expression of galectin-9 across various solid tumor types and blood cancers and has found that, in several cancers, galectin-9 levels correlate with shorter time to disease relapse and poor survival. Preclinical work also demonstrates single mechanistic and anti-tumor efficacy of LYT-200 in multiple animal and patient-derived tumor cell models. For example, LYT-200 outperforms anti-PD-1 in preclinical models as a single agent. LYT-200 also synergizes with anti-PD-1 in activating CD4 and CD8 T cells in in vivo cancer models. LYT-200 is currently being evaluated in two ongoing Phase 1/2 adaptive design trials for the potential treatment of AML/MDS and head and neck cancers.

On December 9, 2024 Orna Therapeutics, a biotechnology company dedicated to designing and delivering a new class of circular RNA medicines and unprecedented lipid nanoparticle (LNP) delivery solutions for oncology and autoimmune diseases, reported a poster highlighting new preclinical data that demonstrates the potential of its in vivo panCAR platform for the treatment of B cell mediated diseases at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting taking place in San Diego from December 7-10, 2024 (Press release, Orna Therapeutics, DEC 9, 2024, View Source [SID1234648910]).

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Orna’s lead LNP candidate, demonstrated effective delivery of oRNA cargo to 60% of splenic T cells and 84% of peripheral blood T cells in non-human primates (NHPs). When paired with an oRNA cargo, the Company’s LNP demonstrated up to ~70% delivery of an anti-CD20 CAR to NHP T cells and human T cells in vitro and maintained expression over 72 hours. A single dose of the anti-CD20 panCAR resulted in a 95% reduction in NHP B cells, with sustained depletion (82%) observed 7 days after dosing.

"Our panCAR approach combining a synthetic, circular coding RNA platform oRNA and proprietary immunotropic LNP holds the potential to deliver an entirely novel class of in vivo CAR therapies that eliminate lengthy patient cell processing and lymphodepletion regimens," said Joe Bolen, Ph.D., Chief Scientific Officer for Orna. "The data presented today at ASH (Free ASH Whitepaper) further validate our hypothesis, demonstrating our ability to effectively deliver oRNA cargo and achieve robust and sustained B cell depletion in NHPs, highlighting the potential of our work in advancing our in vivo CAR therapies across both cancer and autoimmune diseases towards the clinic."

Additional key findings are as follows:

In cytotoxicity assays, both the anti-CD20 CAR and an anti-CD19 CAR construct killed human B lymphoblast cell lines in vitro.
In vivo, both the anti-CD19CAR and anti-CD20 CAR oRNAs showed significant B cell depletion that manifested as a 75-80% reduction in B cells in peripheral blood, spleen, and bone marrow at 24 hours. This effect was sustained for 7 days after dosing in peripheral blood and bone marrow.