Ribometrix Demonstrates Rapid Progress for eIF4E Program at San Antonio Breast Cancer Symposium

On December 8, 2023 Ribometrix, a biotechnology company developing small molecule therapeutics that modulate RNA biology, reported preclinical data supporting the potential of its eIF4E inhibitors in Estrogen Receptor-positive (ER+) breast cancer at the annual San Antonio Breast Cancer Symposium (SABCS), held December 5-9, 2023, in San Antonio, TX. This builds on analogous data announced last month in melanoma, providing further depth to the data supporting this target and Ribometrix’s portfolio of eIF4E-targeted small molecule inhibitors (Press release, Ribometrix, DEC 8, 2023, View Source [SID1234638333]).

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Ribometrix’s preclinical studies in ER+ breast cancer include evaluation of eIF4E inhibition via both monotherapy and in combination with standard-of-care (SoC) CDK4/6 inhibitors, which target key pro-oncogenic signaling pathways shared with eIF4E. Furthermore, eIF4E controls parts of the pathway that complement those targeted by CDK4/6 inhibition, suggesting additive benefit from combined therapy. All patients eventually develop resistance to CDK4/6 inhibitors, leaving a large unmet need and opportunity to restore tumor sensitivity to treatment and improve outcomes. Ribometrix expects to present additional data and select a development candidate in 2024.

"The data presented at SABCS reflect Ribometrix’s ability to efficiently translate the well-supported eIF4E target hypothesis into an RNA-modulating small molecule drug that has now achieved preclinical in vivo proof-of-concept in an additional tumor indication," said Michael Solomon, Ph.D., Chief Executive Officer of Ribometrix. "We are encouraged to see the added validation of eIF4E as an important mediator of pro-oncogenic signaling, this time in ER+ breast cancer, and the excellent emerging profiles of our eIF4E inhibitors. These data provide a strong foundation on which to build and refine the clinical development strategy for which eIF4E inhibition can ultimately have the greatest impact for patients."

Key takeaways from the presentation at SABCS include:

• Daily oral dosing of single agent Ribometrix eIF4E inhibitors shows anti-tumor efficacy in vivo with no signs of overt toxicity in an ER+ breast cancer tumor model

• Targeting ER+ breast cancer resistant to CDK4/6 inhibitors with a Ribometrix eIF4E inhibitor has the potential to mitigate drug resistance and restore sensitivity to standard of care (SoC) in a second line setting

• eIF4E inhibition with Ribometrix compounds potentiates cancer cell sensitivity to CDK4/6 inhibition, supporting a combination approach to improve SoC response durability in ER+ breast cancer

The data will be presented as a poster by Matthew Friedersdorf, Ph.D. and on display beginning today, December 8, 2023, at 12pm CT, at which time it will become available on the Ribometrix website.

About eIF4E
Eukaryotic translation initiation factor 4E (eIF4E), the main regulatory component of cap-dependent mRNA translation, selectively promotes pro-oncogenic protein synthesis in response to activation of multiple tumor signaling pathways. Interestingly, many pro-oncogenic signaling pathways require eIF4E activity to promote tumor growth. Clinically, eIF4E activity is elevated in many tumor indications and is typically associated with poor prognosis. Thus, targeting eIF4E has the potential to enhance anti-cancer activity when given in combination with standard-of-care (SoC). Additionally, eIF4E is also central to many resistance mechanisms, therefore eIF4E inhibition has the potential to overcome drug resistance and re-sensitize tumors to anti-cancer therapies. Ribometrix is developing eIF4E inhibitors as a promising therapeutic strategy to inhibit oncogene expression to enhance efficacy in combination with SoC and overcome resistance to targeted anti-cancer therapies.

ORIEN to Present Abstracts at 65th Annual ASH Meeting Utilizing Aster Insights’ Avatar Platform

On December 8, 2023 Aster Insights, the leading provider of scientific and clinical intelligence for oncology discovery, reported upcoming research presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper)’s (ASH) (Free ASH Whitepaper) 65th Annual Meeting, December 9-12 in San Diego, CA (Press release, Aster Insights, DEC 8, 2023, View Source [SID1234638349]).

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Three abstracts will be shared at this year’s ASH (Free ASH Whitepaper) meeting by Moffitt Cancer Center, which co-founded the Oncology Research Information Exchange Network (ORIEN) in 2006. The investigations all utilize patient data from Aster Avatar, the best-in-class, deepest multimodal dataset for discovery research in oncology.

The schedule of presentations and highlights include:

Rafael Renatino-Canevarolo, PhD, Ex Vivo Mathematical Myeloma Advisor (EMMA) – a Clinical, Molecular, and Phenotypic Platform to Tailor Personalized Therapeutic Strategies for Multiple Myeloma (abstract 2280)
Presentation time: Saturday, December 9, 2023, 5:30 PM-7:30 PM

Examining the impact of a state-of-the-art platform for clinical-informed decisions, research advancement, and preclinical compound testing called the "Ex Vivo Mathematical Myeloma Advisor" (EMMA) on drug discovery and understanding of drug interaction for multiple myeloma patients.

Praneeth Reddy Sudalagunta, PhD, Selinexor Disrupts Epigenetic Programing and Modulates Immunogenicity in Multiple Myeloma (abstract 3301)
Presentation time: Sunday, December 10, 2023, 6:00 PM-8:00 PM

Investigating the cellular mechanisms of Selinexor (SELI) resistance leading to an immunogenic cell state.

Ciara L. Freeman, PhD, MSc, FRCPC, MRCP, Single Cell RNA Sequencing of Sequential Samples before and after BCMA-Directed CAR-T Reveal Features Associated with Non-Durable Response, Exhausted T-Cells and Decreased Expression of Genes Encoding Key Surface Targets in Particular in Patients with Extramedullary Disease (abstract 3304)
Presentation time: Sunday, December 10, 2023, 6:00 PM-8:00 PM

Longitudinal single cell analysis to identify factors associated with response, or therapeutic failure, to FDA approved anti-B-cell maturation antigen (BCMA) directed CAR-T cell therapy.

"ASH is a unique opportunity to demonstrate the impactful discoveries resulting from ORIEN and Aster Insights’ discovery solutions," said Anand Shah, MD, Aster Insights CEO. "This year, we are proud to showcase our collaborative work with Moffitt Cancer Center’s scientists that continues to push the envelope of multiple myeloma research and patient care."

AMGEN HIGHLIGHTS HEMATOLOGY PORTFOLIO AT ASH 2023

On December 8, 2023 Amgen (NASDAQ:AMGN) reported the presentation of new data from its blood cancer portfolio and pipeline at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place from Dec. 9-12 in San Diego (Press release, Amgen, DEC 8, 2023, View Source [SID1234638318]).

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"Data at this year’s ASH (Free ASH Whitepaper) meeting illustrate the expanding potential of our innovative hematology medicines, BLINCYTO and KYPROLIS, as well as our commitment to providing additional treatment options with our biosimilar eculizumab," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "As the pioneer of T-cell engager technology and building on nearly a decade of real-world experience, we continue to advance our first-in-class BiTE molecule, BLINCYTO, into earlier lines of treatment where we have seen encouraging data in patients living with acute lymphoblastic leukemia."

Abstracts are available on the ASH (Free ASH Whitepaper) website.

Key Abstracts and Presentation Times:

Amgen Sponsored Abstracts

KYPROLIS (carfilzomib)

Real-World Outcomes for Relapsed or Refractory Multiple Myeloma Patients Treated with Lenalidomide and Daratumumab Sparing Triplet Regimens: A United States Retrospective Cohort Study
Abstract #4705, Session #652, Monday, December 11 from 6:00 – 8:00 p.m. PT
Eculizumab (investigational biosimilar ABP 959 candidate to SOLIRIS)

Efficacy of Parallel and Crossover Analysis As Well As Pharmacokinetic Similarity Were Confirmed between ABP 959 and Eculizumab Reference Product in Patients with PNH
Abstract #4092, Session #508, Monday, December 11 from 6:00 – 8:00 p.m. PT
Investigator Sponsored Studies

BLINCYTO (blinatumomab)

Chemotherapy-Free Combination of Blinatumomab and Ponatinib in Adults With Newly Diagnosed Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: Updates From a Phase II Trial
Abstract #2827, Session #612, Sunday, December 10 from 6:00 – 8:00 p.m. PT
Phase II Study of Low-Intensity Chemotherapy (Mini-Hyper-CVD) and Ponatinib Followed by Blinatumomab and Ponatinib in Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Abstract #2868, Session #614, Sunday, December 10 from 6:00 – 8:00 p.m. PT
Assessment of Outcomes of Consolidation Therapy By Number of Cycles of Blinatumomab Received in Newly Diagnosed Measurable Residual Disease Negative Patients with B-Lineage Acute Lymphoblastic Leukemia: In the ECOG-ACRIN E1910 Randomized Phase III National Clinical Trials Network Trial*
Abstract #2877, Session #614, Sunday, December 10 from 6:00 – 8:00 p.m. PT
Phase 2 Trial of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, With or Without Blinatumomab, in Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia
Abstract #2878, Session #614, Sunday, December 10 from 6:00 – 8:00 p.m. PT
Pediatric Patients with High-Risk B-Cell ALL in First Complete Remission May Benefit from Less Toxic Immunotherapy with Blinatumomab – Results from Randomized Controlled Phase 3 Trial AIEOP-BFM ALL 2017
Abstract #825, Session #614, Monday, December 11 from 2:45 – 4:15 p.m. PT
Dose Reduced Chemotherapy in Sequence with Blinatumomab for Newly Diagnosed Older Patients with Ph/BCR::ABL Negative B-Precursor Adult Lymphoblastic Leukemia (ALL): Preliminary Results of the GMALL Bold Trial
Abstract #964, Session #614, Monday, December 11 from 4:30 – 6:00 p.m. PT
Updated Results from a Phase II Study of Hyper-CVAD, with or without Inotuzumab Ozogamicin, and Sequential Blinatumomab in Patients with Newly Diagnosed B-cell Acute Lymphoblastic Leukemia
Abstract #4245, Session #614, Monday, December 11 from 6:00 – 8:00 p.m. PT
Comparison between Dasatinib-Blinatumomab Vs Ponatinib-Blinatumomab Chemo-Free Strategy for Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia Patients. Preliminary Results of the Gimema ALLL2820 Trial
Abstract #4249, Session #614, Monday, December 11 from 6:00 – 8:00 p.m. PT
*E1910 is sponsored by National Cancer Institute (NCI), part of the National Institutes of Health, and conducted by the NCI Funded National Clinical Trial Network.

KYPROLIS (carfilzomib)

Carfilzomib-Lenalidomide-Dexamethasone (KRd) Vs. Lenalidomide-Dexamethasone (Rd) in Newly Diagnosed Fit or Intermediate-Fit Multiple Myeloma Patients Not Eligible for Autologous Stem-Cell Transplantation (Phase III EMN20 Trial): Analysis of Sustained Undetectable Minimal Residual Disease (MRD)
Abstract #205, Session #653, Saturday, December 9 from 2:00 – 3:30 p.m. PT
Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone Induction and Consolidation with Tandem Transplant in High-Risk Newly Diagnosed Myeloma Patients: Final Results of the Phase 2 Study IFM 2018-04
Abstract #207, Session #653, Saturday, December 9 from 2:00 – 3:30 p.m. PT
GEM2017FIT Trial: Induction Therapy with Bortezomib-Melphalan and Prednisone (VMP) Followed By Lenalidomide and Dexamethasone (Rd) Versus Carfilzomib, Lenalidomide and Dexamethasone (KRd) Plus/Minus Daratumumab (D), 18 Cycles, Followed By Consolidation and Maintenance Therapy with Lenalidomide and Daratumumab: Phase III, Multicenter, Randomized Trial for Elderly Fit Newly Diagnosed Multiple Myeloma (NDMM) Patients Aged between 65 and 80 Years
Abstract #209, Session #653, Saturday, December 9 from 2:00 – 3:30 p.m. PT
Results of the Phase III Randomized Iskia Trial: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Lenalidomide-Dexamethasone As Pre-Transplant Induction and Post-Transplant Consolidation in Newly Diagnosed Multiple Myeloma Patients
Abstract #4, Plenary Scientific Session, Sunday, December 10 from 2:00 – 4:00 p.m. PT
About BLINCYTO (blinatumomab)
BLINCYTO is a BiTE (bispecific T-cell engager) immuno-oncology therapy that targets CD19 surface antigens on B cells. BiTE molecules fight cancer by helping the body’s immune system detect and target malignant cells by engaging T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. By bringing T cells near cancer cells, the T cells can inject toxins and trigger cancer cell death (apoptosis). BiTE immuno-oncology therapies are currently being investigated for their potential to treat a wide variety of cancers.

BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration and is approved in the U.S. for the treatment of:

CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and pediatric patients.
relapsed or refractory CD19-positive B-cell precursor ALL in adults and pediatric patients.
In the European Union (EU), BLINCYTO is indicated as monotherapy for the treatment of:

adults with Philadelphia chromosome-negative CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL). Patients with Philadelphia chromosome-positive B-precursor ALL should have failed treatment with at least 2 tyrosine kinase inhibitors (TKIs) and have no alternative treatment options.
adults with Philadelphia chromosome-negative CD19 positive B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.
pediatric patients aged 1 year or older with Philadelphia chromosome-negative CD19 positive B-precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.
pediatric patients aged 1 year or older with high-risk first relapsed Philadelphia chromosome-negative CD19 positive B-precursor ALL as part of the consolidation therapy.
BLINCYTO IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO and treat with corticosteroids as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications
BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in 15% of patients with R/R ALL and in 7% of patients with MRD-positive ALL. The median time to onset of CRS is 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Closely monitor and advise patients to contact their healthcare professional for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome, and hemophagocytic histiocytosis/macrophage activation syndrome. If severe CRS occurs, interrupt BLINCYTO until CRS resolves. Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS.

Neurological Toxicities: Approximately 65% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO treatment and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache and tremor. Severe, life–threatening, or fatal neurological toxicities occurred in approximately 13% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.

Infections: Approximately 25% of patients receiving BLINCYTO in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.

Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.

Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.

Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.

Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase, and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.

Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.

Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.

Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).

Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.

Benzyl Alcohol Toxicity in Neonates: Serious adverse reactions, including fatal reactions and the "gasping syndrome", have been reported in very low birth weight (VLBW) neonates born weighing less than 1500 g, and early preterm neonates (infants born less than 34 weeks gestational age) who received intravenous drugs containing benzyl alcohol as a preservative. Early preterm VLBW neonates may be more likely to develop these reactions, because they may be less able to metabolize benzyl alcohol.

Use the preservative-free preparations of BLINCYTO where possible in neonates. When prescribing BLINCYTO (with preservative) for neonatal patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative), other products containing benzyl alcohol or other excipients (e.g., ethanol, propylene glycol) which compete with benzyl alcohol for the same metabolic pathway.

Monitor neonatal patients receiving BLINCYTO (with preservative) for new or worsening metabolic acidosis. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known. The BLINCYTO 7-Day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL.

Embryo-Fetal Toxicity: Based on its mechanism of action, BLINCYTO may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO and for 48 hours after the last dose.
Adverse Reactions

The most common adverse reactions (≥ 20%) are pyrexia, infusion-related reactions, infections (pathogen unspecified), headache, neutropenia, anemia, and thrombocytopenia.
Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).
INDICATIONS

BLINCYTO (blinatumomab) is indicated for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adult and pediatric patients.
BLINCYTO is indicated for the treatment of relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients.
Please see BLINCYTO full Prescribing Information, including BOXED WARNINGS.

About BiTE Technology
BiTE (bispecific T-cell engager) technology is a targeted immuno-oncology platform that is designed to engage patient’s own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells to eliminate detectable cancer. The BiTE immuno-oncology platform has the potential to treat different tumor types through tumor-specific antigens. The BiTE platform has a goal of leading to off-the-shelf solutions, which have the potential to make innovative T cell treatment available to all providers when their patients need it. Amgen is advancing more than a dozen BiTE molecules across a broad range of hematologic malignancies and solid tumors, further investigating BiTE technology with the goal of enhancing patient experience and therapeutic potential. To learn more about BiTE technology, visit View Source

About KYPROLIS (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.1 KYPROLIS has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.2 In some cells, KYPROLIS can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.1,2

Since its first approval in 2012, more than 285,000 patients worldwide have received KYPROLIS. KYPROLIS is approved in the U.S. for the following:

for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with
Lenalidomide and dexamethasone; or
Dexamethasone; or
Daratumumab and dexamethasone.
Daratumumab and hyaluronidase-fihj and dexamethasone; or
Isatuximab and dexamethasone
as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
KYPROLIS is also approved in Algeria, Argentina, Australia, Bahrain, Belarus, Brazil, Canada, Chile, Colombia, Ecuador, Egypt, European Union, Hong Kong, India, Israel, Japan, Jordan, Kazakhstan, Kuwait, Lebanon, Macao, Malaysia, Mexico, Morocco, New Zealand, Oman, Peru, Philippines, Qatar, Russia, Saudi Arabia, Serbia, Singapore, S. Africa, S. Korea, Switzerland, Taiwan, Thailand, Turkey and United Arab Emirates.

KYPROLIS IMPORTANT SAFETY INFORMATION

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of administration.
Monitor patients for signs or symptoms of cardiac failure or ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse reactions until recovery, and consider whether to restart at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate.
For patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment prior to starting treatment with KYPROLIS and remain under close follow-up with fluid management.
Acute Renal Failure

Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency (including renal failure) have occurred. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred. Patients with a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly, and withhold until resolved.
Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart based on a benefit/risk assessment.
Dyspnea

Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart based on a benefit/risk assessment.
Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed, some fatal. Control hypertension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart based on a benefit/risk assessment.
Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed. Provide thromboprophylaxis for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
For patients using hormonal contraception associated with a risk of thrombosis, consider an alternative method of effective contraception during treatment.
Infusion-Related Reactions

Infusion-related reactions, including life-threatening reactions, have occurred. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration. Premedicate with dexamethasone to reduce the incidence and severity of infusion-related reactions.
Hemorrhage

Fatal or serious cases of hemorrhage have been reported. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.
Thrombocytopenia

KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Monitor platelet counts frequently during treatment. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have occurred. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome, have occurred. Monitor for signs and symptoms of TTP/HUS. Discontinue if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS. If PRES is suspected, discontinue and evaluate with appropriate imaging. The safety of reinitiating KYPROLIS is not known.
Progressive Multifocal Leukoencephalopathy (PML)

Cases of PML, including fatal cases, have occurred. In addition to KYPROLIS, other contributary factors may include prior or concurrent use of immunosuppressive therapy. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue and initiate evaluation for PML including neurology consultation.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients

In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse reactions was observed in patients in the KMP arm. KMP is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.
Embryo-fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Females of reproductive potential should use effective contraception during treatment with KYPROLIS and for 6 months following the final dose. Males of reproductive potential should use effective contraception during treatment with KYPROLIS and for 3 months following the final dose.
Adverse Reactions

The most common adverse reactions in the combination therapy trials: anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia.
The most common adverse reactions in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.
Please see accompanying full Prescribing Information.

INDICATIONS

KYPROLIS (carfilzomib) is indicated in combination with dexamethasone, or with lenalidomide plus dexamethasone, or with daratumumab plus dexamethasone, or with daratumumab plus hyaluronidase-fihj plus dexamethasone, or with isatuximab plus dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
KYPROLIS is indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

Rigel Pharmaceuticals and MD Anderson Announce Strategic Alliance to Advance REZLIDHIA® (Olutasidenib) in AML and Other Cancers

On December 8, 2023 Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) and The University of Texas MD Anderson Cancer Center (MD Anderson) reported a multi-year strategic development collaboration to expand the evaluation of REZLIDHIA (olutasidenib) in acute myeloid leukemia (AML) and other hematologic cancers (Press release, Rigel, DEC 8, 2023, View Source [SID1234638334]).

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The alliance brings together MD Anderson’s clinical research expertise with Rigel’s differentiated targeted molecule. Under the strategic collaboration, Rigel and MD Anderson will evaluate the potential of olutasidenib to treat newly diagnosed and relapsed or refractory (R/R) patients with AML, higher-risk myelodysplastic syndromes (MDS), and advanced myeloproliferative neoplasms (MPN), in combination with other agents. The collaboration will also support the evaluation of olutasidenib as monotherapy in lower-risk MDS and as maintenance therapy in post-hematopoietic stem cell transplant patients.

"We are excited to enter into this strategic alliance with the exceptional team at MD Anderson to evaluate REZLIDHIA as a potential therapy for a broad range of IDH1-mutant cancers," said Raul Rodriguez, Rigel’s president and CEO. "We believe REZLIDHIA has the potential to become a standard of care for patients in urgent need of new hematology-oncology therapies. We look forward to a close collaboration with MD Anderson to advance this as a new therapeutic option for more patients."

REZLIDHIA is a potent, selective, oral, small-molecule inhibitor of mutated IDH1 (mIDH1)1 designed to bind to and inhibit mIDH1 to reduce 2-hydroxyglutarate levels and restore normal cellular differentiation of myeloid cells. REZLIDHIA is approved by the Food and Drug Administration (FDA) for the treatment of adult patients with R/R AML with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

"Based on its differentiated profile and compelling clinical data to date, REZLIDHIA has the potential, beyond its currently approved indication, to benefit patients with various cancers where mutant IDH1 is thought to play a role," said Courtney DiNardo, M.D., professor of Leukemia. "We look forward to collaborating with Rigel to conduct in-depth studies that will determine the broader potential of REZLIDHIA in these patient populations."

Rigel and MD Anderson will jointly lead all clinical development efforts, which will be overseen by a joint steering committee. Rigel will provide $15 million in time-based milestone payments and study material over the five-year collaboration. Rigel will retain all rights to its programs under the collaboration.

About AML
Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow that affects myeloid cells, which normally develop into various types of mature blood cells. AML occurs primarily in adults and accounts for about 1 percent of all adult cancers. The American Cancer Society estimates that in the United States alone, there will be about 20,380 new cases, most in adults, in 2023.2

Relapsed AML affects about half of all patients who, following treatment and remission, experience a return of leukemia cells in the bone marrow.3 Refractory AML, which affects between 10 and 40 percent of newly diagnosed patients, occurs when a patient fails to achieve remission even after intensive treatment.4 Quality of life declines for patients with each successive line of treatment for AML, and well-tolerated treatments in relapsed or refractory disease remain an unmet need.

About REZLIDHIA
INDICATION
REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS
Differentiation Syndrome
REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dose interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence.

Hepatotoxicity
REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity. One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin.

Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity.

ADVERSE REACTIONS
The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis.

DRUG INTERACTIONS

Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers.
Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information. If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
LACTATION
Advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose.

GERIATRIC USE
No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Compared to patients younger than 65 years of age, an increase in incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age.

HEPATIC IMPAIRMENT
In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome.

Click here for Full Prescribing Information, including Boxed WARNING.

To report side effects of prescription drugs to the FDA, visit www.fda.gov/medwatch or call 1-800-FDA-1088 (800-332-1088).

REZLIDHIA is a registered trademark of Rigel Pharmaceuticals, Inc.

Updated clinical safety and efficacy data for iOnctura’s roginolisib presented at ESMO Immuno-Oncology Congress 2023

On December 8, 2023 iOnctura, a clinical-stage biotech developing selective cancer therapies against targets that play critical roles in multiple tumor survival pathways, reported clinical results for roginolisib, a first-in-class oral allosteric modulator of PI3Kδ, presented at the ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress 2023 in Geneva (Press release, iOnctura, DEC 8, 2023, View Source [SID1234638350]).

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Roginolisib is in development for solid and hematologic malignancies including uveal melanoma, a rare cancer of the eye. The poster presentation titled ‘Safety and clinical efficacy of Roginolisib (IOA-244), the first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ)’ demonstrated that roginolisib continues to be well tolerated over long periods of treatment and continues to show a favourable trend in overall survival exceeding the overall survival previously reported with immune checkpoint inhibitors.

Mass cytometry data showed treatment with roginolisib led to an increase in activated anti-cancer CD8+ T-cells and natural killer (NK) cells, increased interferon signalling and a decrease in cancer-promoting Regulatory T-cells. This shifts the balance of the immune system enabling a more-effective attack on cancer. Boosting of antitumoral immunity was observed in patients with long-term disease control after roginolisib treatment but not patients with progressive disease.

An exploratory analysis from a patient with uveal melanoma outlined the potential of radiomics, an advanced AI driven analysis of imaging data, as a way of tracking changes in cancer lesions over time in addition to standard RECIST measurements.

Overall, these findings are consistent with prior studies in pre-clinical models and support the development of roginolisib in uveal melanoma and other malignancies with immune suppressed conditions.

Catherine Pickering, Chief Executive Officer of iOnctura, said: "These safety and clinical efficacy data demonstrate iOnctura’s progression of roginolisib. Our first-in-class allosteric modulator of PI3Kδ continues to show a favourable trend in overall survival and is well tolerated over very long periods of treatment, now up to 38 months in patients with uveal melanoma. An exploratory readout also shows that patients who respond well to roginolisib, with prolonged stabilisation of their disease, exhibit signs of an activated immune system better able to fight the tumor. We eagerly anticipate a final clinical readout in 2024."