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Syndax to Initiate NDA Submission of Revumenib in Relapsed/Refractory KMT2Ar Acute Leukemia Under FDA’s Real-Time Oncology Review Program

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.

Palatin Announces $5 Million Registered Direct Offering

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.

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.

Orphelia Pharma files EU marketing authorization application for KIZFIZO®

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]).

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.

Corporate presentation

On October 24, 2023 Lipocine presented its corporate presentation (Presentation, Lipocine, OCT 24, 2023, View Source [SID1234636300]).

Immatics Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for ACTengine® IMA203 TCR-T Monotherapy

On October 24, 2023 Immatics N.V. (NASDAQ: IMTX, "Immatics"), a clinical-stage biopharmaceutical company active in the discovery and development of T cell-redirecting cancer immunotherapies, reported that its IMA203 TCR-T program has received Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA Center for Biologics Evaluation and Research (CBER) in multiple relapsed and/or refractory HLA-A*02:01-positive and PRAME-expressing cancers, including cutaneous melanoma, uveal melanoma, endometrial carcinoma, synovial sarcoma, and ovarian cancer. IMA203 is a TCR-T cell therapy targeting PRAME, a protein frequently expressed in a large variety of solid tumors (Press release, Immatics, OCT 24, 2023, View Source [SID1234636299]).

"The FDA RMAT designation for multiple indications underscores the broad potential of IMA203 and the benefits it may provide for advanced-stage solid tumor patients. This is an important regulatory milestone and a recognition of our clinical development progress for this program," said Cedrik Britten, Chief Medical Officer of Immatics. "The close support from the FDA resulting from the RMAT status enhances our efforts to accelerate bringing IMA203 to cancer patients by enabling real-time discussions on patient populations, trial design and CMC."

Established under the 21st Century Cures Act, RMAT designation is a dedicated program designed to expedite the development and review processes for promising pipeline products, including cell therapies, that includes all the benefits of Fast Track and Breakthrough designation programs. An investigational cell therapy is eligible for RMAT designation if it meets the definition of regenerative medicine therapy, it is intended to treat, modify, reverse, or cure a serious or life-threatening disease; and preliminary clinical evidence indicates that the therapy has the potential to address unmet medical needs for that disease. Advantages of the RMAT designation include early interactions with the FDA that may be used to discuss potential surrogate or intermediate endpoints for accelerated approval and potential ways to satisfy post-approval requirements, potential priority review of the biologics license application (BLA) and other opportunities to expedite development and review.

Based on publicly available information1, it is the Company’s understanding that this is the first time that FDA has granted a RMAT designation for an oncology drug candidate for more than two solid tumor indications. As of Sep 30, 2023, the U.S. FDA has received at least 238 requests for RMAT designations and granted 922.

About IMA203 and target PRAME
ACTengine IMA203 T cells are directed against an HLA-A*02:01-presented peptide derived from preferentially expressed antigen in melanoma (PRAME), a protein frequently expressed in a large variety of solid cancers, thereby supporting the program’s potential to address a broad cancer patient population. Immatics’ PRAME peptide is present at a high copy number per tumor cell and is homogeneously and specifically expressed in tumor tissue. The peptide has been identified and characterized by Immatics’ proprietary mass spectrometry-based target discovery platform, XPRESIDENT. Through its proprietary TCR discovery and engineering platform XCEPTOR, Immatics has generated a highly specific T cell receptor (TCR) against this target for its TCR-based cell therapy approach, ACTengine IMA203.

ACTengine IMA203 TCR-T is currently being evaluated in three ongoing Phase 1b dose expansion cohorts in last-line patients: Cohort A IMA203 GEN1 monotherapy, Cohort B IMA203 in combination with an immune checkpoint inhibitor (deprioritized) and Cohort C IMA203CD8 GEN2 monotherapy, where IMA203 engineered T cells are co-transduced with a CD8αβ co-receptor.

About ACTengine
ACTengine is a personalized cell therapy approach for patients with advanced solid tumors. The patient’s own T cells are genetically engineered to express a novel, proprietary TCR directed against a defined cancer target. The modified T cells are then reinfused into the patient to attack the tumor. The approach is also known as TCR-engineered cell therapy (TCR-T). All Immatics’ ACTengine product candidates can be rapidly manufactured utilizing a proprietary manufacturing process designed to enhance T cell engraftment and persistence in vivo.

The ACTengine T cell products are manufactured at the Evelyn H. Griffin Stem Cell Therapeutics Research Laboratory in collaboration with UTHealth.