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.

On October 24, 2023 Palatin Technologies, Inc. (NYSE American: PTN) ("Palatin" or the "Company"), a biopharmaceutical company developing first-in-class medicines based on molecules that modulate the activity of the melanocortin receptor system, reported that it has entered into a definitive agreement with an institutional investor for the issuance and sale of an aggregate of 2,358,491 shares of its common stock (or common stock equivalents in lieu thereof), at a purchase price of $2.12 per share of common stock (or common stock equivalents in lieu thereof) (Press release, Palatin Technologies, OCT 24, 2023, View Source [SID1234636302]). Palatin has also agreed to issue in a private placement warrants to purchase up to an aggregate of 2,358,491 shares of common stock at an exercise price of $2.12 per share. The warrants will be issued upon receiving stockholder approval, or earlier if such approval is not necessary, will become exercisable on the six months anniversary of the closing date and will expire on the date that is five and a half years after the closing date.

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H.C. Wainwright & Co. is acting as exclusive placement agent for the offering.

The closing of the offering is expected to occur on or about October 24, 2023, subject to the satisfaction of customary closing conditions. The gross proceeds from the offering are expected to be approximately $5 million. Palatin intends to use the net proceeds of this offering for general corporate purposes.

The securities described above (excluding the warrants and the shares of common stock underlying the warrants) are being offered by Palatin pursuant to a shelf registration statement on Form S-3 (File No. 333-262555) that was previously filed with the Securities and Exchange Commission ("SEC") on February 7, 2022 and subsequently declared effective on September 26, 2022. The securities are being offered only by means of a prospectus, including a prospectus supplement, forming a part of the effective registration statement. A final prospectus supplement and accompanying base prospectus relating to, and describing the terms of, the offering will be filed with the SEC and will be available on the SEC’s website at www.sec.gov. Electronic copies of the final prospectus supplement and the accompanying base prospectus relating to the offering, when available, may also be obtained by contacting H.C. Wainwright & Co., LLC, at 430 Park Ave., New York, New York 10022, by telephone at (212) 856-5711, or by email at [email protected].

The warrants described above will be issued in a private placement under Section 4(a)(2) of the Securities Act of 1933, as amended (the "Securities Act"), and Regulation D promulgated thereunder and, along with the shares of common stock underlying such warrants, will not be registered under the Securities Act, or applicable state securities laws. Accordingly, the warrants and underlying shares of common stock, upon issuance, may not be offered or sold in the United States except pursuant to an effective registration statement or an applicable exemption from the registration requirements of the Securities Act and such applicable state securities laws.

On October 24, 2023 Orphelia Pharma, a pharmaceutical company dedicated to the development and marketing of pediatric and orphan medicines, reported the filing of a centralized Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for KIZFIZO, the first oral liquid formulation of temozolomide (Press release, ORPHELIA Pharma, OCT 24, 2023, View Source;utm_medium=rss&utm_campaign=orphelia-pharma-files-eu-marketing-authorization-application-for-kizfizo [SID1234636301]).

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KIZFIZO (temozolomide oral suspension, 40 mg/ml), known as Ped-TMZ or KIMOZO during its clinical development and ongoing early access programs, is designed specifically for use in the treatment of children with relapsed or refractory neuroblastoma, oncology indications with a very poor prognosis. This oral suspension, which is taste-masked, was developed for children : it allows a precise dose to be administered orally or via a nasogastric tube in a small volume. Orphelia Pharma has been developing KIZFIZO in collaboration with Gustave Roussy, the leading European cancer center, for the last six years.

"We take great pride in having developed this new pediatric medicine," said Laurent Martin, chief pharmaceutical affairs officer at Orphelia Pharma. "KIZFIZO fills an unmet medical need for a drinkable temozolomide medication in the treatment of relapsed or refractory neuroblastoma. This formulation aims to avoid the use of
non-age-appropriate dosage forms mixed with a drink or food, which may expose caregivers to a cytotoxic molecule without full control of the dose actually delivered to the patient."

"The application for a drug marketing authorization of KIZFIZO is excellent news for the children living with cancer and their families. It underscores Gustave Roussy’s commitment to playing a leading role in the development of medicines for children and curing all of them in the future," said Prof. Fabrice Barlesi, CEO of Gustave Roussy.
The pharmacokinetics of KIZFIZO in children have been evaluated in TEMOkids, a European multicenter population pharmacokinetic acceptability and safety study in pediatric patients in need of temozolomide (NCT04610736).

Efficacy and safety data for temozolomide in relapsed or refractory neuroblastoma submitted in the application includes in particular :

BEACON-Chemo, a sub-analysis of the chemotherapy arms of the BEACON study, a prospective randomized phase II study in refractory or relapsed neuroblastoma. This study was sponsored by Birmingham University (UK)
Retro-TMZ, a multicenter descriptive, retrospective study, assessing the efficacy and tolerability of temozolomide in children with refractory or relapsed neuroblastoma. This study was conducted by Gustave Roussy (France)
About KIZFIZO 40 mg/ml

KIZFIZO (temozolomide oral suspension, 40 mg/ml) is a ready-to-use oral liquid pediatric formulation of temozolomide developed for use in the treatment of relapsed or refractory neuroblastoma, which carry a very poor prognosis. This age-adapted and taste-masked formulation delivers an accurate dose in a small volume,
while avoiding drug handling and caregiver exposure to temozolomide. It is the result of a collaboration between the pharmacists and clinicians at Gustave Roussy hospital and the development team at Orphelia Pharma.
In March 2022, KIZFIZO was granted Early Access Authorization (Autorisation d’Accès Précoce) by the French authorities, for the treatment of refractory and relapsed neuroblastoma as monotherapy or in combination with irinotecan or topotecan.
KIZFIZO has received Orphan Drug Designation (ODD) from the EMA and the FDA, the formulation is covered by granted patents and pending applications in Europe and the US.

About neuroblastoma
Neuroblastoma is the most common extracranial cancer in early childhood, with approximately 900 new cases diagnosed per year in the European Union. It almost exclusively affects children under five, with a median age at diagnosis of 18 months. Neuroblastoma has a wide diversity of clinical outcomes, which is reflected in the risk stratification. Approximately 40% of patients have the high-risk disease and often face a poor response to first line induction therapy or later relapse. There remains a high unmet need for relapsed or refractory neuroblastoma patients and the best therapeutic strategy is still an intensive area of research. Temozolomide is the standard chemotherapy and is therefore an essential part of the treatment armamentarium for these patients.