On December 9, 2024 Syndax Pharmaceuticals (Nasdaq: SNDX), a commercial-stage biopharmaceutical company developing an innovative pipeline of cancer therapies, reported additional positive data from the AUGMENT-101 trial of Revuforj (revumenib) in relapsed or refractory (R/R) mutant NPM1 (mNPM1) acute myeloid leukemia (AML) and the BEAT AML trial of revumenib in combination with venetoclax and azacitidine in newly diagnosed AML patients (Press release, Syndax, DEC 9, 2024, View Source [SID1234648918]). Revuforj is the Company’s oral, first-in-class menin inhibitor that is FDA approved for the treatment of relapsed or refractory (R/R) acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients one year and older.

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"These new data continue to highlight the exciting potential for Revuforj as both a monotherapy and in combination with other therapies," said Michael A. Metzger, Chief Executive Officer of Syndax. "The recent approval of Revuforj for R/R acute leukemia with a KMT2A translocation, coupled with the consistency of the results we have reported across KMT2Ar and mNPM1 within the different trials and populations, continues to bolster our confidence in its practice-changing and blockbuster potential."

Additional Results from R/R mNPM1 AML Patients in Pivotal Phase 2 Portion of AUGMENT-101

Syndax recently announced that the primary endpoint was met with a complete remission (CR) plus CR with partial hematological recovery (CRh) rate of 23% (15/64; 95% confidence interval [CI]: 14%, 36%; one-sided p-value =0.0014) in the protocol-defined efficacy population of 64 adults with R/R mNPM1 AML in the Phase 2 cohort of the AUGMENT-101 trial of revumenib (DCO: September 2024). The median duration of CR/CRh responses was 4.7 months at the time of the data cutoff with three patients remaining in response. Minimal residual disease (MRD) status was assessed in 14 of 15 patients who achieved CR/CRh, 64% (9/14) of whom were MRD negative. The overall response rate (ORR)1 was 47% (30/64). The safety profile observed with revumenib in the 84 patients enrolled in the cohort was consistent with previously reported data.

Syndax announced today additional results from the Phase 2 cohort of R/R mNPM1 AML patients in the AUGMENT-101 trial, including data generated from the protocol-defined efficacy population of 64 adults and a post-hoc efficacy analysis based on all patients who met the efficacy evaluable criteria.

Subgroup analyses from the Phase 2 protocol-defined R/R mNPM1 efficacy population (N=64) show that CR/CRh responses were observed across all major subgroups, including patients with multiple prior lines of therapy and prior venetoclax exposure, although the trial was not powered to evaluate differences among subgroups. The CR+CRh rate was 25% (4/16) among patients with 1 prior line of therapy, 20% (5/25) among patients with 2 prior lines of therapy, and 26% (6/23) among patients who had received three or more prior lines of therapy. The CR+CRh rate was 44% (7/16) among patients without prior venetoclax exposure and 17% (8/48) among patients with prior venetoclax exposure. Historically, AML patients who have failed prior treatment with venetoclax are unlikely to respond to subsequent therapy, with a CR rate of 6% reported for other targeted therapies after prior venetoclax therapy.2

Syndax also shared results from an expanded analysis of the R/R mNPM1 AML patients who enrolled into the Phase 2 cohort of AUGMENT-101. Among the 84 patients enrolled in the cohort, 77 met the efficacy evaluable criteria requiring patients to have blast counts >5% measured within 28 days prior to treatment and a centrally confirmed NPM1 mutation. In this expanded post-hoc efficacy analysis, 48% (37/77; 95% CI: 37%, 60%) achieved an overall response, and 26% (20/77; 95% CI: 17%, 37%) achieved a CR/CRh. The median duration of CR/CRh response was 4.7 months as of the September 2024 DCO. Minimal residual disease (MRD) status was assessed in 19 of 20 patients who achieved CR/CRh, 63% (12/19) of whom were MRD negative.

Updated Data from BEAT-AML Trial of Revumenib in Combination with Venetoclax and Azacitidine in Newly Diagnosed AML Patients

Today the company announced an update from the Phase 1 BEAT-AML trial evaluating the combination of revumenib with venetoclax and azacitidine in newly diagnosed mNPM1 or KMT2A-rearranged (KMT2Ar) AML patients aged 60 years or older. The trial is being conducted as part of the Leukemia & Lymphoma Society’s Beat AML Master Clinical Trial. Today’s update builds on the BEAT AML data that was presented in June at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 Congress from 24 efficacy evaluable patients showing a composite complete remission (CRc) rate of 96% (23/24) as of a May 2024 data cutoff.

As of a November 2024 data cutoff, 46 newly diagnosed mNPM1 (n=37) or KMT2Ar (n=9) patients have been enrolled in BEAT AML across two dose levels of revumenib (113 mg q12 or 163 mg q12h with azoles) in combination with venetoclax and azacitidine. The median age of patients enrolled was 71 years (range: 60-92).

The efficacy evaluable population includes 37 patients across both dose levels with an ORR1 of 100% (37/37) and CRc rate of 95% (35/37). The rate of MRD negativity was 95% (35/37). 27% (10/37) of patients proceeded to hematopoietic stem cell transplant (HSCT).

Revumenib was generally well tolerated at both the 113 mg and 163 mg q12h dose in combination with venetoclax and azacitidine. In the safety population (N=46), 15% (7/46) of patients experienced differentiation syndrome with two (4%) Grade 3 or greater events. 43% (20/46) of patients experienced QTc prolongation with five (11%) Grade 3 or greater events. DS and QTc prolongations were self-limiting and did not cause any discontinuations. Analysis of the onset and extent of hematologic toxicities suggest a similar experience to what has been reported for the venetoclax/azacitidine doublet alone. Overall, there were no new or increased safety signals observed when revumenib was included in this triplet combination.

"These are very exciting data that highlight the potential for revumenib to enhance the responses typically observed with venetoclax/azacitidine in newly diagnosed patients with mNPM1 or KMT2Ar who are unfit to receive intensive chemotherapy," said Joshua F. Zeidner, M.D., Chief, Leukemia Research at the University of North Carolina, Lineberger Comprehensive Cancer Center. "These new data continue to show that revumenib has a safety profile that could enable it to be combined with venetoclax/azacitidine and, importantly, we are observing high rates of response and MRD negativity that underscore the potential for revumenib to become an integral component of frontline treatment for KMT2Ar and mNPM1 AML patients."

Enrollment in the expansion cohort is ongoing at both dose levels. The Company plans to initiate a pivotal trial with this combination in front-line newly diagnosed patients by year-end 2024.

Syndax Corporate Event

The new data described above, along with other data presented through today at the 66th ASH (Free ASH Whitepaper) Annual Meeting being held in San Diego, CA for both the Revuforj (revumenib) and Niktimvo (axatilimab-csfr) clinical programs, will be highlighted at the Company’s investor event on Monday, December 9, 2024 at 7:00 a.m. PT/10:00 a.m. ET. The live audio webcast and accompanying slides for the event may be accessed through the Events & Presentations page in the Investors section of the Company’s website or directly through the meeting link here.

For those unable to participate in the conference call or webcast for the event, a replay will be available on the Investors section of the Company’s website at www.syndax.com for a limited time.

About Revuforj (revumenib)

Revuforj (revumenib) is an oral, first-in-class menin inhibitor that is FDA approved for the treatment of relapsed or refractory (R/R) acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients one year and older.

Revumenib is in development for the treatment of R/R acute myeloid leukemia (AML) with a nucleophosmin 1 mutation (mNPM1). Positive pivotal data from the AUGMENT-101 trial in this population with revumenib as a monotherapy were recently reported. The Company expects to file a supplemental NDA filing for revumenib in R/R mNPM1 AML in the first half of 2025. Additionally, multiple trials of revumenib in combination with standard-of-care agents in mNPM1 AML or KMT2A-rearranged acute leukemia are ongoing across the treatment landscape, including in newly diagnosed patients.

Revumenib was previously granted Orphan Drug Designation for the treatment of AML, ALL and acute leukemias of ambiguous lineage (ALAL) by the U.S. FDA and for the treatment of AML by the European Commission. The U.S. FDA also granted Fast Track designation to revumenib for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation and Breakthrough Therapy Designation for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Differentiation syndrome, which can be fatal, has occurred with Revuforj. Signs and symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and renal dysfunction. If differentiation syndrome is suspected, immediately initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation syndrome: Revuforj can cause fatal or life-threatening differentiation syndrome (DS). Symptoms of DS, including those seen in patients treated with Revuforj, include fever, dyspnea, hypoxia, peripheral edema, pleuropericardial effusion, acute renal failure, and/or hypotension. In clinical trials, DS occurred in 39 (29%) of 135 patients treated with Revuforj. DS was Grade 3 or 4 in 13% of patients and fatal in one. The median time to onset was 10 days (range 3-41 days). Some patients experienced more than 1 DS event. Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1%.

Reduce the white blood cell count to less than 25 Gi/L prior to starting Revuforj. If DS is suspected, immediately initiate treatment with systemic corticosteroids (e.g., dexamethasone 10-mg IV every 12 hours in adults or dexamethasone 0.25-mg/kg/dose IV every 12 hours in pediatric patients weighing less than 40 kg) for a minimum of 3 days and until resolution of signs and symptoms. Institute supportive measures and hemodynamic monitoring until improvement. Interrupt Revuforj if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids, or earlier if life-threatening symptoms occur such as pulmonary symptoms requiring ventilator support. Restart steroids promptly if DS recurs after tapering corticosteroids.

QTc interval prolongation: In the clinical trials, QTc interval prolongation was reported as an adverse reaction in 39 (29%) of 135 patients treated with Revuforj. QTc interval prolongation was Grade 3 in 12% of patients. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 8%, and the increase from baseline QTcF was greater than 60 msec in 18%. Revuforj dose reduction was required for 5% of patients due to QTc interval prolongation. QTc prolongation occurred in 16% of the 31 patients less than 17 years old, 33% of the 88 patients 17 years to less than 65 years old, and in 50% of the 16 patients 65 years or older.

Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to treatment with Revuforj. Perform an electrocardiogram (ECG) prior to initiation of Revuforj, and do not initiate Revuforj in patients with QTcF >450 msec. Perform an ECG at least once weekly for the first 4 weeks and at least monthly thereafter. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring may be necessary. Concomitant use with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.

Interrupt Revuforj if QTcF increases >480 msec and <500 msec, and restart Revuforj at the same dose twice daily after the QTcF interval returns to ≤480 msec
Interrupt Revuforj if QTcF increases >500 msec or by >60 msec from baseline, and restart Revuforj twice daily at the lower-dose level after the QTcF interval returns to ≤480 msec
Permanently discontinue Revuforj in patients with ventricular arrhythmias and in those who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.
Embryo-fetal toxicity: Revuforj can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Revuforj and for 4 months after the last dose of Revuforj.

ADVERSE REACTIONS
Fatal adverse reactions occurred in 4 (3%) patients who received Revuforj, including 2 with differentiation syndrome, 1 with hemorrhage, and 1 with sudden death.

Serious adverse reactions were reported in 99 (73%) patients. The most frequent serious adverse reactions (≥5%) were infection (24%), febrile neutropenia (19%), bacterial infection (17%), differentiation syndrome (12%), hemorrhage (9%), and thrombosis (5%).

The most common adverse reactions (≥20%) including laboratory abnormalities, were hemorrhage (53%), nausea (51%), phosphate increased (50%), musculoskeletal pain (42%), infection (41%), aspartate aminotransferase increased (37%), febrile neutropenia (35%), alanine aminotransferase increased (33%), parathyroid hormone intact increased (33%), bacterial infection (31%), diarrhea (30%), differentiation syndrome (29%), electrocardiogram QT prolonged (29%), phosphate decreased (25%), triglycerides increased (25%), potassium decreased (24%), decreased appetite (24%), constipation (23%), edema (23%), viral infection (23%), fatigue (22%), and alkaline phosphatase increased (21%).

DRUG INTERACTIONS
Drug interactions can occur when Revuforj is concomitantly used with:

Strong CYP3A4 inhibitors: reduce Revuforj dose
Strong or moderate CYP3A4 inducers: avoid concomitant use with Revuforj
QTc-prolonging drugs: avoid concomitant use with Revuforj. If concomitant use is unavoidable, obtain ECGs when initiating, during concomitant use, and as clinically indicated. Withhold Revuforj if the QTc interval is >480 msec. Restart Revuforj after the QTc interval returns to ≤480 msec.
SPECIFIC POPULATIONS
Lactation: advise lactating women not to breastfeed during treatment with Revuforj and for 1 week after the last dose.

Pregnancy and testing: Revuforj can cause fetal harm when administered to a pregnant woman. Verify pregnancy status in females of reproductive potential within 7 days prior to initiating Revuforj.

Pediatric: monitor bone growth and development in pediatric patients.

Geriatric: compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years and older.

Infertility: based on findings in animals, Revuforj may impair fertility. The effects on fertility were reversible.

To report SUSPECTED ADVERSE REACTIONS, contact Syndax Pharmaceuticals at 1-888-539-3REV or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

On December 9, 2024 Star Therapeutics, a clinical stage biotechnology company discovering and developing best-in-class antibodies, reported interim clinical data from VIVID 2 (VGA039 Investigation in Von Willebrand Disease), a Phase 1 single ascending dose (SAD) study of VGA039 in Von Willebrand Disease (VWD) patients (Press release, Star Therapeutics, DEC 9, 2024, View Source [SID1234648917]). VGA039 is an investigational monoclonal antibody that targets Protein S to restore balance in blood clotting, as a universal hemostatic therapy for numerous bleeding disorders. It is potentially the first subcutaneous therapy that addresses all types of VWD and has a convenient dosing regimen. The VGA039 clinical data is being presented at the annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) on December 7-10, in San Diego, California.

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The interim clinical data in VIVID 2 from three VWD patients with high bleeding rates showed that a subcutaneous dose of VGA039 was associated with substantial reductions in annualized bleed rate (ABR) in line with currently approved VWD prophylaxis therapies. In the interim VIVID 2 data, VGA039 sustained multi-week therapeutic concentrations following a single subcutaneous dose, in contrast to currently approved VWD prophylaxis therapies that require multiple intravenous (IV) infusions every week. These VWD patients had high bleeding rates with ABRs greater than 50 bleeds per year.

"Drug innovation for VWD has lagged behind advancements in treatments for other bleeding disorders, like hemophilia. VGA039 offers a promising breakthrough as a subcutaneous therapy, potentially transforming care for VWD patients by reducing their high treatment burden," said Dr. Nicholetta Machin of the Hemophilia Center of Western Pennsylvania and University of Pittsburgh. "The interim clinical data is particularly encouraging, showing significant bleed reduction in VWD patients with high baseline bleeding rates."

Interim clinical data from VIVID 2 (Phase 1 SAD study in VWD patients)

The interim clinical data from VIVID 2 reported in the poster presentation at ASH (Free ASH Whitepaper) 2024 describe results in VWD patients who received a 3.0 or 4.5 mg/kg dose of VGA039 administered subcutaneously and evaluated over 8 weeks, including the following highlights:

In the seven VWD patients evaluated for safety, pharmacodynamic (PD) and pharmacokinetic (PK) activity, VGA039 was safe and well-tolerated with no injection site reactions observed. VGA039 demonstrated pharmacokinetics and pharmacodynamics that support convenient, prophylactic subcutaneous dosing.
Therapeutic concentrations of VGA039 were sustained for approximately 4 weeks following a single subcutaneous 4.5 mg/kg dose.
VGA039 showed PD activity across all types of VWD patients, including Type 1, Type 2 and Type 3.
In three VWD patients (a Type 2M and two Type 3) with high historic bleeding rates, a single subcutaneous 4.5 mg/kg dose of VGA039 resulted in 75% to 88% reductions in annualized bleeding rate (ABR). These reductions are consistent with those observed in clinical trials of approved VWD prophylactic therapies that require multiple IV infusions every week.
"These initial results showing a significant reduction of bleeds in VWD patients highlight the exciting prospects ahead for VGA039. We are keenly aware of the unmet need of VWD patients and are working to bring the first potential subcutaneous therapy for patients with all types of VWD," said Gary Patou, MD, Chief Medical Officer of Star Therapeutics. "Based on the positive results, we are moving ahead with our plans to begin a multi-dose study with VGA039 in early 2025."

Additional ASH (Free ASH Whitepaper) posters and session details

Star Therapeutics is also presenting three other posters at ASH (Free ASH Whitepaper) 2024, including two posters with analyses of large real-world VWD patient data sets highlighting the significant disease burden and unmet treatment need in VWD.

The posters describe data from more than 50,000 diagnosed and treated VWD patients in a large US claims dataset.
VWD patients experienced high disease burden with bleeding comorbidities, including anemia, heavy menstrual bleeding, nosebleeds, gastrointestinal bleeds, and joint bleeds, sometimes requiring blood transfusions.
There still remains a disparity in VWD treatment with low prophylaxis use, likely due to the high treatment burden of currently available therapies, supporting the need for less frequent treatment options for VWD patients.
The Star Therapeutics posters are presented at ASH (Free ASH Whitepaper) today, December 9, at 6:00 to 8:00 p.m. PT in Hall G/H of the San Diego Convention Center, with the following details:

3981: A Phase 1a Study of VGA039, a Protein S-Targeting Monoclonal Antibody, in Individuals with Von Willebrand Disease Demonstrates Concentration-Dependent Increases in Thrombin Generation for Reducing Bleeding
3980: Diagnosis and Disease Burden of Von Willebrand Disease in a Large US Population Based-Dataset
3978: Disparities in Real-World Treatment Patterns Among Patients with Von Willebrand Disease in a Large US Population-Based Dataset
3982: Factor VIII Coagulant Activity (FVIII:C) As an Independent Predictor of Bleeding across Different Subtypes of Von Willebrand Disease (VWD)
About the VIVID Clinical Program

The VIVID multinational clinical program is a platform multi-phase protocol for the development of VGA039 in Von Willebrand disease (VWD). Patient bleeding is quantified by the number of bleeding events per year or annualized bleeding rate (ABR). For the Phase 1 study, VIVID 2 is the single ascending dose study in VWD patients (NCT05776069).

On December 9, 2024 Sonnet BioTherapeutics Holdings, Inc. (NASDAQ:SONN) (the "Company" or "Sonnet"), a clinical-stage company developing targeted immunotherapeutic drugs, reported that the results of SON-1010 at the highest dose have been formally evaluated by the Safety Review Committee in the Phase 1 SB101 clinical trial of SON-1010 (IL12-FHAB) in adult patients with advanced solid tumors. SB101 is the Company’s open-label, adaptive-design dose-escalation study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SON-1010 administered to patients with advanced solid tumors (Press release, Sonnet BioTherapeutics, DEC 9, 2024, View Source [SID1234648915]). The study has enrolled 24 subjects to date. Primary outcome measures for the study were to evaluate the safety and tolerability of SON-1010 and establish the MTD. Additionally, the Company announced the release of a "What This Means" segment to discuss the data which is now available here.

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SON-1010 is the Company’s proprietary version of recombinant human interleukin-12 (rhIL-12), configured using genetic fusion to Sonnet’s Fully Human Albumin Binding (FHAB) platform, which extends the half-life and bioactivity of the IL-12 component due to binding native albumin in the serum and also targets the tumor microenvironment (TME) by strong binding to gp60 and Secreted Protein Acidic and Rich in Cysteine (SPARC).

"We are encouraged by this topline safety data generated to date in our Phase 1 study. Given the history of safety concerns with rhIL-12 in its first human trials over 25 years ago, it is exciting to see higher doses of SON-1010 demonstrating minimal toxicity, which is likely due to its unique biodistribution and albumin binding profile, with delivery to and retention in the tumor microenvironment," said Richard Kenney, M.D., Sonnet’s Chief Medical Officer. "We may finally be able to realize the promising antitumor effect that has been associated with this cytokine in preclinical models for decades. The IFNγ response, which is considered to be important for anti-tumor control, has been robust but controlled with a much longer return to baseline. While the clinical benefit we have been seeing during dose escalation has been reassuring, the PR at the highest dose is particularly important, as this suggests that there may be a synergistic effect in combination with checkpoint inhibitors and/or chemotherapy."

All enrolled patients have had advanced solid tumors. The final 1200 ng/kg dose-escalation cohort was increased in size to 6 patients to enhance the assessment of PK and PD at the MTD. The SB101 trial employed a ‘desensitizing’ first dose of 300 ng/kg to take advantage of the known tachyphylaxis with rhIL-12, with the intention of minimizing toxicity and allowing for higher maintenance doses. No dose-limiting toxicities or related serious adverse events (SAE) have occurred to date. The safety and toxicity profile that has developed is typical for a Phase 1 oncology trial, with the majority of adverse events (AEs) being reported as mild. All AEs seen to date have been transient, with no evidence of cytokine release syndrome. Of the 24 patients dosed to date, 17 (71%) had SD at the first follow-up CT, 12 of whom were progressing at study entry. 10 of the 21 evaluable patients (48%) remained stable at four months, suggesting SON-1010 clinical benefit, and one of those patients in the highest dose cohort, who has clear cell sarcoma, had a PR with a 45% reduction in tumor size by RESIST criteria. As previously disclosed, one patient in the first dose cohort with endometrial sarcoma who was progressing at study entry had evidence of improvement after 11 months, with smaller tumors and complete resolution of ascites. This patient later progressed at 23 months and started chemotherapy.

"This topline safety data release on our lead program is a significant milestone for Sonnet’s clinical development. We have now successfully completed dose escalation in our first trial with SON-1010 and are pleased to see a partial response in one patient at the highest dose, in addition to clinical benefit in almost half of the evaluable patients," said Pankaj Mohan, Ph.D., Sonnet Founder and Chief Executive Officer. "Safety of this extended PK version of IL-12 has been within expected levels and the comparison with dosing in healthy volunteers provided strong evidence of tumor targeting in humans. We have used this trial to establish the MTD and will continue to follow the patients currently being treated to assess longer-term safety and tumor responses. Sonnet is currently seeking partnership opportunities to help support later stage development of SON-1010."

For more information about the Phase 1 SB101 trial in adult patients with advanced solid tumors visit www.clinicaltrials.com and reference identifier NCT05352750.

SON-1010 is also being evaluated in a Phase 1b/2a dose-escalation and proof-of-concept study (SB221) in combination with SON-1010 and atezolizumab (in collaboration with Genentech, a member of the Roche Group), which is focused on platinum-resistant ovarian cancer (PROC) (NCT05756907). Enrollment remains ongoing and an update on safety at the MTD in that trial is expected in Q1 2025.

About SON-1010

SON-1010 is a candidate immunotherapeutic recombinant drug that links unmodified single-chain human IL-12 with the albumin-binding domain of the single-chain antibody fragment A10m3. This was selected to bind albumin both at normal pH, as well as at the acidic pH typically found in the TME. The FHAB technology targets tumor and lymphatic tissue, providing a mechanism for dose sparing and an opportunity to improve the safety and efficacy profile of not only IL-12, but a variety of potent immunomodulators that can be linked using the platform. Interleukin-12 can orchestrate a robust immune response to many cancers and pathogens. Given the types of proteins induced in the TME, such as the Secreted Protein and Rich in Cysteine (SPARC) and glycoprotein 60 (GP60), several types of cancer such as non-small cell lung cancer, melanoma, head and neck cancer, sarcoma, and some gynecological cancers are particularly relevant for this approach. SON-1010 is designed to deliver IL-12 to local tumor tissue, turning ‘cold’ tumors ‘hot’ by stimulating IFNγ, which activates innate and adaptive immune cell responses and increases the production of Programed Death Ligand 1 (PD-L1) on tumor cells.

About the Phase 1 SB101 Trial

This first-in-human study is primarily designed to evaluate the safety of multiple ascending doses of SON-1010 in cancer patients and is being conducted at several sites across the United States. While the optimal dose is unknown at this stage, the potential to target tumors, the extended PK mechanism, and our preclinical data suggest the therapeutic dose may be lower compared to native human IL-12. The study, utilizing a standard 3+3 oncology design in at least five cohorts, should establish the MTD using subcutaneous injections of SON-1010 every 3 to 4 weeks. The primary endpoint explores the safety and tolerability of SON-1010, with key secondary endpoints intended to measure PK, PD, immunogenicity, and anti-tumor activity. This study will form the basis for potential combinations with other types of immunotherapies and the future development of bispecific candidates using the FHAB platform.

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.