On October 24, 2023 Servier, a leader in oncology committed to bringing the promise of tomorrow to the patients we serve, reported that the U.S. Food and Drug Administration (FDA) has approved TIBSOVO (ivosidenib tablets) for the treatment of patients with isocitrate dehydrogenase 1 (IDH1)-mutated relapsed or refractory (R/R) myelodysplastic syndromes (MDS) (Press release, Servier, OCT 24, 2023, View Source [SID1234636307]). This is the fifth indication for TIBSOVO across IDH1-mutated cancers, and the first and only approved targeted therapy for people diagnosed with R/R MDS within this molecularly defined subset.

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"Servier is proud to lead the way in mutant IDH inhibition through continued innovations that support patients living with difficult and hard-to-treat cancers," said Arjun Prasad, Head of Commercial, Servier Pharmaceuticals. "As the first and only targeted therapy available for patients with IDH1-mutated relapsed or refractory myelodysplastic syndromes, today’s FDA approval for TIBSOVO reinforces our commitment to deliver significant advances in areas of high unmet need and bring the right treatment, to the right patient, at the right time."

The FDA approval of this indication is supported by a pivotal Phase 1, open-label study in IDH1-mutated R/R MDS patients (n=18) where a complete remission (CR) rate of 38.9% and objective response rate (ORR) of 83.3% were documented in patients treated with TIBSOVO. In addition, the median time to CR was 1.9 months (range: 1.0, 5.6). At the time of data cutoff, the median duration of CR had not been reached (range: 1.9, 80.8+*) and the median overall survival was 35.7 months (range: 3.7*, 88.7*). Additionally, of the nine patients who were transfusion dependent with red blood cells or platelets at baseline, 66.7% (n=6) became independent of transfusions during any ≥56-day post-baseline period. Overall, treatment-related adverse events were consistent with the known safety profile of TIBSOVO.

"The novel use of targeted therapy across IDH-mutated cancers has become a powerful therapeutic option for patients within this molecularly defined subset," said Amir Fathi, M.D., hematologist, medical oncologist, and expert in myeloid malignancies. "This new indication in IDH1-mutated relapsed or refractory myelodysplastic syndromes reinforces the importance of mutational testing to inform treatment decisions and potentially improve patient outcomes."

An estimated 16,000 people in the U.S. are diagnosed with MDS each year.1 Approximately 3.6% of MDS patients have an IDH1 mutation,2 which is considered an early "driver" mutation.3 For MDS patients with an IDH1 mutation, the prognosis has often been associated with worse overall outcomes and an increased risk of transformation to AML.

"This approval for TIBSOVO is welcome news for the MDS community," said Tracey Iraca, Executive Director, MDS Foundation. "Before today, there were no approved targeted therapies available to relapsed or refractory MDS patients harboring the IDH1-mutation. We want to thank the study participants, their families and caregivers, as well as the researchers at Servier and clinical investigators involved in this study for helping to bring a new treatment option to patients where there has been a significant unmet need."

"An MDS diagnosis is ambiguous. I remember feeling confused trying to make sense of my diagnosis, what having an IDH1-mutation meant, and what options were available for my treatment plan," said Susan, a patient living with IDH1-mutated MDS.** "The news of an FDA approval for a targeted therapy in IDH-1 mutated MDS has given me a tremendous sense of gratitude and provides hope to patients – like me – who are living with this disease. I want to thank everyone who played a role in this major step forward for the MDS community."

TIBSOVO was granted Breakthrough Therapy designation for the treatment of adult patients with R/R (MDS) with an IDH1 mutation and received Priority Review, which accelerated the review timeline and is granted to applications for medicines that, if approved, would provide significant improvements in the effectiveness or safety of the treatment, diagnosis, or prevention of serious conditions.4

The FDA also approved the Abbott RealTime IDH1 Assay as a companion diagnostic device to select patients for TIBSOVO.

* Denotes a censored observation.
**Last name withheld to protect privacy.

About the NCT02074839 Clinical Trial5
This Phase I, open-label multinational study evaluated the safety, tolerability, and clinical activity of ivosidenib in patients with relapsed or refractory myelodysplastic syndromes with an IDH1 mutation. The primary endpoint was complete remission (CR) plus partial remission (PR) rate and key secondary endpoints included duration of CR+PR, duration of transfusion independence, and time to transfusion independence.

About TIBSOVO (ivosidenib tablets)
TIBSOVO is a precision medicine that targets a specific type of mutation known as isocitrate dehydrogenase 1 (IDH1). TIBSOVO is approved in five indications globally, including approvals in the U.S., European Union, Australia, and China.

In the U.S., TIBSOVO is approved for the treatment of adults with IDH1-mutant relapsed or refractory AML and in monotherapy or in combination with azacitidine for adults with newly diagnosed IDH1-mutant AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy, as monotherapy for the treatment of adult patients with IDH1-mutant relapsed or refractory MDS, and for patients with previously treated IDH1-mutated cholangiocarcinoma.

Servier has granted CStone a co-exclusive license for the development and an exclusive license agreement for the commercialization of TIBSOVO in Mainland China, Taiwan, Hong Kong, Macao and Singapore.

For more information about TIBSOVO in the U.S., please visit www.tibsovo.com.

About Myelodysplastic Syndromes
Myelodysplastic Syndromes (MDS) are disorders in which progenitor (stem) cells do not mature into healthy blood cells.6 In the U.S., approximately 16,000 new cases of MDS are reported each year.1 Approximately 3.6% of MDS patients have an IDH1 mutation,2 which is considered an early "driver" mutation.3 For MDS patients with an IDH1 mutation, the prognosis has often been associated with worse overall outcomes and in an increased risk of transformation to AML. Prior to the approval of TIBSOVO, there were no approved targeted therapies for this molecularly defined subset.

On October 24, 2023 IDEAYA Biosciences, Inc. (Nasdaq: IDYA) reported the pricing of an underwritten public offering of common stock and pre-funded warrants (Press release, Ideaya Biosciences, OCT 24, 2023, View Source [SID1234636306]). IDEAYA is selling 5,000,000 shares of common stock and pre-funded warrants to purchase 319,150 shares of common stock in the offering. The shares of common stock are being sold at a public offering price of $23.50 per share, before underwriting discounts and commissions, and the pre-funded warrants are being sold at a public offering price of $23.4999 per pre-funded warrant. The exercise price of the pre-funded warrants is $0.0001 per share. In addition, IDEAYA has granted the underwriters a 30-day option to purchase up to an additional 797,872 shares of its common stock at the public offering price per share, before underwriting discounts and commissions. The aggregate gross proceeds to IDEAYA from this offering are expected to be approximately $125,000,000, before deducting underwriting discounts and commissions and other offering expenses, and excluding the exercise of any pre-funded warrants. The offering is expected to close on or about October 27, 2023, subject to the satisfaction of customary closing conditions.

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J.P. Morgan, Goldman Sachs & Co. LLC, Jefferies and RBC Capital Markets are acting as joint book-running managers for the offering.

The securities described above are being offered by IDEAYA pursuant to an automatically effective shelf registration statement on Form S-3 that was previously filed with the U.S. Securities and Exchange Commission, or the SEC. The offering is being made only by means of a written prospectus and prospectus supplement that form a part of the registration statement, copies of which may be obtained, when available, by request from: J.P. Morgan, by mail at J.P. Morgan Securities LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, or by telephone at 866-803-9204, or by email at [email protected]; Goldman Sachs & Co. LLC by mail at Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, NY 10282, or by telephone at 866-471-2526, or by email at [email protected]; Jefferies, by mail at Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, New York, NY 10022, or by telephone at 877-547-6340 or 877-821-7388, or by email at [email protected]; or RBC Capital Markets, by mail at RBC Capital Markets, LLC, Attention: Equity Capital Markets, 200 Vesey Street, 8th Floor, New York, NY 10281, or by telephone at 877-822-4089, or by email at [email protected].

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

On October 24, 2023 Cellectis (the "Company") (Euronext Growth: ALCLS – NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies, reported that they will be showcasing pre-clinical data on its program of gene therapy for HSPC as well as comprehensive analysis of TALE-BE editing determinants at the European Society of Gene and Cell Therapy (ESGCT) 30th annual congress that will take place on October 24-27, 2023 in Brussels, Belgium (Press release, Cellectis, OCT 24, 2023, View Source [SID1234636305]).

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The data will be presented in three posters:

Intronic editing enables lineage specific expression of therapeutics relevant for HSPC gene therapy (Poster N°646)

Presenter: Eduardo Seclen, Senior Scientist & Team Leader, Gene Editing

Date/Time: Wednesday October 25th from 18:15 to 19:30 and Thursday October 26th from 19:30 to 20:30

Intronic editing enables lineage specific expression of therapeutics relevant for HSPC gene therapy.
TALEN-mediated intron editing of the CD11b locus results in the lineage-specific expression of a reporter transgene in myeloid cells, with negligible expression in HSPC or other cellular subsets in vitro and in vivo.
We believe this intron editing approach could be disruptive in HSPC gene therapy and brain delivery of multiple therapeutics.
TALEN editing coupled to non-viral DNA delivery enables efficient correction of sickle cell mutation with minimal transcriptional changes and low level of HBB KO (Poster N°380)

Presenter: Julien Valton, VP, Gene Therapy

Date/Time: Wednesday October 25th from 18:15 to 19:30 and Thursday October 26th from 19:30 to 20:30

Using a combination of scRNA sequencing and multiple genomic read out methodologies, we demonstrate that the mutant HBB gene can be efficiently corrected in HSPCs by TALEN-mediated gene editing coupled to non-viral gene delivery (ssODN) with a low risk of generating β-thalassemic RBCs.
TALEN-mediated HBB editing coupled to non-viral gene delivery (ssODN) in SCD patients’ HSPCs led to a lower activation of p53 response compared to viral gene delivery (AAV), preserves the transcriptomic profile of edited HSPCs in vitro and their engraftment capacity in vivo.
Comprehensive analysis of TALE-BE editing determinant (Poster N°667)

Presenter: Maria Feola, Scientist III, Manager, Gene Editing

Date/Time: Wednesday October 25th from 17:00 to 18:15 and Thursday October 26th from 20:30 to 21:30

The robustness and versatility of genome engineering strategies we developed allowed us to gain in-depth insight of TALE-BE editing rules in cellulo and further highlighted that the composition surrounding the TC to be edited could strongly impact editing efficiencies. Therefore, educated choice of the TALE-BE architecture and positioning on DNA could either prevent target sequence limitations (increasing targetable sequence space) or decrease, if not eliminate, bystander editing within the editing window, allowing for more precise genome editing outcomes.
We believe that the knowledge presented will help ensure that genome editing-based strategies are skillfully designed to minimize the risk of potential genotoxic events, overall expanding the potential of TALE-BE for nuclear and mitochondrial therapeutic cell engineering.

On October 24, 2023 TransCode Therapeutics, Inc. (NASDAQ: RNAZ), the RNA oncology company committed to more effectively treating cancer using RNA therapeutics, reported preliminary results with its lead therapeutic candidate, TTX-MC138, in the first patient enrolled in its Phase 0 clinical trial aimed at demonstrating delivery of TTX-MC138 to metastatic cancer, including metastases beyond those found in the liver (Press release, TransCode Therapeutics, OCT 24, 2023, View Source [SID1234636304]). These preliminary data showed that radioactivity consistent with accumulation of TTX-MC138 was detected by noninvasive imaging in the regions of the metastatic lesions previously identified by fluorodeoxyglucose (FDG)/positron emission tomography (PET) (FDG/PET). In addition, radiolabeled TTX-MC138 had pharmacokinetic behavior consistent with that expected based on non-clinical IND-enabling studies. The patient tolerated the dosing with no reported adverse reactions. Metabolite analysis indicated circulation of intact radiolabeled TTX-MC138 for more than 20 hours, equivalent to that predicted by Drug Metabolism and Pharmacokinetics (DMPK) modelling, and that the drug candidate analyzed in the blood was identical to that of the manufactured drug candidate, demonstrating in vivo stability. Complete analysis of data from this first patient is in process and will be included in the final report for all patients enrolled in the study.

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TransCode’s Chief Technology Officer, Zdravka Medarova, PhD, commented, "We believe these preliminary clinical data support our thesis that TTX-MC138 can be delivered successfully to metastatic lesions for the potential treatment of metastatic cancer. Preclinical evidence pointing towards miRNA-10b’s critical role in metastatic progression across a number of major cancer types suggests that inhibition of miRNA-10b in patients with advanced disease could have a dramatic impact on their disease."

The Phase 0 trial is an open-label, single-center, microdose study intended to demonstrate delivery of the radiolabeled version of TTX-MC138 to radiographically-confirmed metastases in subjects with advanced solid tumors. Up to 12 subjects may be enrolled in this clinical study, each of which is expected to receive a single microdose of radiolabeled TTX-MC138 followed by positron emission tomography/magnetic resonance imaging (PET-MRI) and blood analyses. The trial is intended to quantify the amount of TTX-MC138 delivered to metastatic lesions, especially beyond the liver, and the pharmacokinetics of the therapeutic candidate in those patients. The trial is intended to yield important data regarding TTX-MC138 delivery to clinical metastases that could inform dose selection and frequency, for further clinical development. The trial is not intended to demonstrate a therapeutic effect.

In the earlier IND-enabling studies conducted in non-human primates (NHP), TTX-MC138 demonstrated long circulation and tissue distribution consistent with hepatic clearance. Data from the NHP study were incorporated into a DMPK model, intended to model the pharmacokinetics and tissue distribution of TTX-MC138 in humans. The model predicted circulation and tissue distribution in humans consistent with results from TransCode’s nonclinical studies in which numerous complete regressions of metastatic disease were observed.

TTX-MC138 consists of an iron oxide nanocarrier conjugated to a nucleic acid specifically designed to inhibit the oncogenic RNA, microRNA-10b. MiRNA-10b has been described as the master regulator of cancer progression in a number of advanced solid tumors. TransCode believes that TTX-MC138 has the potential to become a treatment for many of these cancers. Administration of TTX-MC138 has demonstrated complete regression of metastatic disease in a number of mouse models of pancreatic and breast cancer. In addition, TTX-MC138 was successfully delivered and demonstrated bioactivity in a case study of spontaneous feline mammary carcinoma.

"Our Phase 0 trial involves a single microdose of radiolabeled TTX-MC138 followed by noninvasive PET-MRI imaging and metabolite analysis. Given the similarities between humans and non-human primates relative to anatomy, physiology, and molecular biology, we anticipated results in trial patients comparable to those observed in the DMPK model based on our NHP studies, as evidenced by the preliminary data we announced today," added Michael Dudley, Chief Executive Officer of TransCode.

This study was done in collaboration with Andreas Varkaris, MD, PhD, an attending physician and investigator for the Termeer Center for Targeted Therapies at Massachusetts General Hospital and the principal investigator of TransCode’s study.

On October 24, 2023 Syndax Pharmaceuticals (Nasdaq: SNDX), a clinical-stage biopharmaceutical company developing an innovative pipeline of cancer therapies, reported that the Company will submit a New Drug Application (NDA) for revumenib in relapsed or refractory (R/R) KMT2Ar acute leukemia, including acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), under the U.S. Food and Drug Administration (FDA) Real-Time Oncology Review (RTOR) program. Revumenib is the Company’s highly selective oral menin inhibitor (Press release, Syndax, OCT 24, 2023, View Source [SID1234636303]).

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During the Company’s pre-NDA meeting, the FDA indicated that it would review the revumenib NDA submission for adult and pediatric KMT2Ar acute leukemia under the Oncology Center of Excellence RTOR Program. Inclusion in the RTOR program follows the previously announced FDA Breakthrough Therapy Designation (BTD) for the same indication and recent positive topline data from the AUGMENT-101 pivotal trial in R/R KMT2Ar acute leukemia. Syndax plans to initiate the NDA submission imminently and expects to complete the submission by year-end 2023.

"On the heels of announcing positive pivotal data earlier this month, we are delighted the FDA has agreed to review the application under the RTOR program, underscoring the urgent unmet need and the substantial improvement over available therapies that revumenib may offer to this underserved patient population," said Michael A. Metzger, Chief Executive Officer of Syndax. "Working with the FDA, we designed an innovative strategy to bring revumenib to the broadest population of KMT2Ar patients – adults and pediatrics, AML and ALL – as rapidly as possible. Syndax is in an excellent position to launch revumenib and axatilimab, two first- and best-in-class agents, in 2024 and deliver on multiple key milestones."

"Relapsed or refractory KMT2Ar acute leukemia patients have a particularly poor prognosis, and no drugs are approved for this difficult to treat disease," said Eytan M. Stein, M.D., Chief, Program for Drug Development in Leukemia, Department of Medicine at Memorial Sloan Kettering Cancer Center and Principal Investigator in the AUGMENT-101 trial. "Revumenib’s clinical profile allowed 25% of the patients in the pivotal AUGMENT-101 trial to proceed to potentially curative transplant, which compares very favorably to the historical rate of <5% in this population.1 Based on these results, long-term post-transplant maintenance is now potentially an option which represents an important paradigm shift for how physicians treat patients with KMT2Ar R/R acute leukemias."

Data from the AUGMENT-101 pivotal trial in R/R KMT2Ar acute leukemia will serve as the basis for the NDA submission under the RTOR program. AUGMENT-101 is a Phase 1/2 open-label trial designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of revumenib as a monotherapy. As previously reported, the AUGMENT-101 R/R KMT2Ar cohort was stopped early for efficacy following a protocol-defined interim analysis based on achieving its primary endpoint of complete remission (CR) or a CR with partial hematological recovery (CRh) rate. These results demonstrated that revumenib monotherapy provided significant clinical benefit including deep, durable molecular remissions with a high proportion of patients proceeding to potentially curative transplant and re-starting revumenib therapy as maintenance. Revumenib was well tolerated, consistent with the Company’s earlier data.

About RTOR

RTOR provides a more efficient review process for oncology drugs to ensure that safe and effective treatments are available to patients as early as possible, while improving review quality and engaging in early iterative communication with the applicant. Specifically, it allows for close engagement between the sponsor and the FDA throughout the submission process and it enables the FDA to review individual sections of modules of a drug application rather than requiring the submission of complete modules or a complete application prior to initiating review.2 From the start of the program in 2018, 22 original applications (including sNDAs and NDAs) have been reviewed under the RTOR Program, resulting in 19 U.S. drug approvals while 3 are still being reviewed. Additional information about RTOR can be found at: View Source

About Revumenib

Revumenib is a potent, selective, small molecule inhibitor of the menin-KMT2A binding interaction that is being developed for the treatment of KMT2A-rearranged, also known as mixed lineage leukemia rearranged or MLLr, acute leukemias including ALL and AML, and NPM1-mutant AML. Revumenib was granted Orphan Drug Designation by the FDA and European Commission for the treatment of patients with AML, and Fast Track designation by the FDA for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation. Revumenib was granted BTD by the FDA for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement. Syndax plans to initiate the NDA submission for KMT2Ar acute leukemia under the Oncology Center of Excellence Review RTOR Program imminently and expects to complete the submission by year-end 2023.

About the AUGMENT-101 trial

AUGMENT-101 is a Phase 1/2 open-label trial designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of orally administered revumenib. The Phase 1 dose escalation portion of AUGMENT-101 included two cohorts based on concomitant treatment with a strong CYP3A4 inhibitor. Arm A enrolled patients not receiving a strong CYP3A4 inhibitor, while Arm B enrolled patients receiving a strong CYP3A4 inhibitor. The Phase 2 pivotal portion of AUGMENT-101 has enrolled R/R patients across the following trial populations: patients with NPM1-mutant AML, patients with KMT2Ar AML, and patients with KMT2Ar ALL. Following the receipt of Breakthrough Therapy designation from the FDA for revumenib for the treatment of R/R acute leukemia harboring a KMT2A rearrangement, regardless of age or tumor type, and based on discussions with the FDA, the Company decided to pool data from the AUGMENT-101 cohorts enrolling R/R KMT2Ar AML and R/R KMT2Ar ALL. Based on the Independent Data Monitoring Committee (IDMC) recommendation at the protocol pre-specified interim analysis, the Company is stopping the trial to further accrual in the KMT2A cohorts. The trial continues to enroll R/R patients with mNPM1 AML and expects to complete enrollment of this cohort by year-end. The primary endpoint for each of the cohorts is efficacy as measured by complete remission rate (CR + CRh) per protocol, with secondary endpoints including duration of response (DOR) and overall survival (OS).

About KMT2A (MLL) Rearranged Acute Leukemia

Rearrangements of the KMT2A (mixed lineage leukemia or MLL) gene give rise to KMT2Ar acute leukemia that is known to have a poor prognosis, with less than 25% of adult patients surviving past five years. KMT2A genes produce fusion proteins that require interaction with the protein called menin to drive leukemic cancer growth. Disruption of the menin-KMT2Ar interaction has been shown to halt the growth of KMT2Ar leukemic cells.

KMT2Ar acute leukemia can phenotypically appear as AML, ALL, or mixed phenotype acute leukemia (MPAL) and is routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques. The median overall survival (OS) after standard of care first-line treatment, including intensive chemotherapy and transplant, is less than one year and the majority of patients suffer relapse within five years. Most R/R patients treated with second-line therapy relapse within the first year. With third line treatment or beyond, only a small percentage of patients achieve complete remission (CR), and the median OS is less than three months. There are currently no approved therapies indicated for KMT2A- rearranged acute leukemia.

About NPM1-Mutant Acute Myeloid Leukemia

NPM1-mutant AML, which is distinguished by mutations in the NPM1 gene that drive the leukemic phenotype, is the most common type of cytogenetically normal adult AML and represents approximately 30% of all adult AML cases. This subtype of AML has a five-year overall survival rate of approximately 50%. Similar to KMT2A- rearranged acute leukemia, NPM1-mutant AML is highly dependent on the expression of specific developmental genes shown to be negatively impacted by inhibitors of the menin-KMT2A interaction. NPM1-mutant AML is routinely diagnosed through currently available screening techniques. There are currently no approved therapies indicated for NPM1-mutant AML.