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Soligenix Submits Type A Meeting Request to U.S. FDA for HyBryte™ New Drug Application in the Treatment of Cutaneous T-Cell Lymphoma

On March 9, 2023 Soligenix, Inc. (Nasdaq: SNGX) (Soligenix or the Company), a late-stage biopharmaceutical company focused on developing and commercializing products to treat rare diseases where there is an unmet medical need, reported that the Company has submitted a Type A Meeting Request to the United States (U.S.) Food and Drug Administration (FDA) to discuss the contents of a refusal to file (RTF) letter previously issued by the FDA regarding the Company’s new drug application (NDA) for HyBryte (synthetic hypericin) in the treatment of early stage cutaneous T-cell lymphoma (CTCL), a rare cancer, where it has successfully demonstrated statistically significant results in a Phase 3 clinical trial (Press release, Soligenix, MAR 9, 2023, View Source [SID1234628462]). The Type A Meeting is expected to occur approximately 30 days from the FDA’s receipt of the meeting request.

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"Participating in a Type A meeting with the FDA will be an important next step towards enabling HyBryte’s advancement through the regulatory process," stated Christopher J. Schaber, PhD, President and Chief Executive Officer of Soligenix. "We believe the briefing package submitted with our request addresses the items raised in the RTF letter and will assist with discussions regarding the NDA. We will provide further update once the meeting has been scheduled with the FDA."

About HyBryte

HyBryte (research name SGX301) is a novel, first-in-class, photodynamic therapy utilizing safe, visible light for activation. The active ingredient in HyBryte is synthetic hypericin, a potent photosensitizer that is topically applied to skin lesions that is taken up by the malignant T-cells, and then activated by visible light approximately 24 hours later. The use of visible light in the red-yellow spectrum has the advantage of penetrating more deeply into the skin (much more so than ultraviolet light) and therefore potentially treating deeper skin disease and thicker plaques and lesions. This treatment approach avoids the risk of secondary malignancies (including melanoma) inherent with the frequently employed DNA-damaging drugs and other phototherapy that are dependent on ultraviolet exposure. Combined with photoactivation, hypericin has demonstrated significant anti-proliferative effects on activated normal human lymphoid cells and inhibited growth of malignant T-cells isolated from CTCL patients. In a published Phase 2 clinical study in CTCL, patients experienced a statistically significant (p=0.04) improvement with topical hypericin treatment whereas the placebo was ineffective. HyBryte has received orphan drug and fast track designations from the FDA, as well as orphan designation from the European Medicines Agency (EMA).

The recently published Phase 3 FLASH trial enrolled a total of 169 patients (166 evaluable) with Stage IA, IB or IIA CTCL. The trial consisted of three treatment cycles. Treatments were administered twice weekly for the first 6 weeks and treatment response was determined at the end of the 8th week of each cycle. In the first double-blind treatment cycle, 116 patients received HyBryte treatment (0.25% synthetic hypericin) and 50 received placebo treatment of their index lesions. A total of 16% of the patients receiving HyBryte achieved at least a 50% reduction in their lesions (graded using a standard measurement of dermatologic lesions, the CAILS score) compared to only 4% of patients in the placebo group at 8 weeks (p=0.04) during the first treatment cycle (primary endpoint). HyBryte treatment in the first cycle was safe and well tolerated.

In the second open-label treatment cycle (Cycle 2), all patients received HyBryte treatment of their index lesions. Evaluation of 155 patients in this cycle (110 receiving 12 weeks of HyBryte treatment and 45 receiving 6 weeks of placebo treatment followed by 6 weeks of HyBryte treatment), demonstrated that the response rate among the 12-week treatment group was 40% (p<0.0001 vs the placebo treatment rate in Cycle 1). Comparison of the 12-week and 6-week treatment groups also revealed a statistically significant improvement (p<0.0001) between the two groups, indicating that continued treatment results in better outcomes. HyBryte continued to be safe and well tolerated. Additional analyses also indicated that HyBryte is equally effective in treating both plaque (response 42%, p<0.0001 relative to placebo treatment in Cycle 1) and patch (response 37%, p=0.0009 relative to placebo treatment in Cycle 1) lesions of CTCL, a particularly relevant finding given the historical difficulty in treating plaque lesions in particular.

The third (optional) treatment cycle (Cycle 3) was focused on safety and all patients could elect to receive HyBryte treatment of all their lesions. Of note, 66% of patients elected to continue with this optional compassionate use / safety cycle of the study. Of the subset of patients that received HyBryte throughout all 3 cycles of treatment, 49% of them demonstrated a positive treatment response (p<0.0001 vs patients receiving placebo in Cycle 1). Moreover, in a subset of patients evaluated in this cycle, it was demonstrated that HyBryte is not systemically available, consistent with the general safety of this topical product observed to date. At the end of Cycle 3, HyBryte continued to be well tolerated despite extended and increased use of the product to treat multiple lesions.

Overall safety of HyBryte is a critical attribute of this treatment and was monitored throughout the three treatment cycles (Cycles 1, 2 and 3) and the 6-month follow-up period. HyBryte’s mechanism of action is not associated with DNA damage, making it a safer alternative than currently available therapies, all of which are associated with significant and sometimes fatal, side effects. Predominantly these include the risk of melanoma and other malignancies, as well as the risk of significant skin damage and premature skin aging. Currently available treatments are only approved in the context of previous treatment failure with other modalities and there is no approved front-line therapy available. Within this landscape, treatment of CTCL is strongly motivated by the safety risk of each product. HyBryte potentially represents the safest available efficacious treatment for CTCL. With very limited systemic absorption, a compound that is not mutagenic and a light source that is not carcinogenic, there is no evidence to date of any potential safety issues.

The Phase 3 CTCL clinical study was partially funded by the National Cancer Institute via a Phase II SBIR grant (#1R44CA210848-01A1) awarded to Soligenix, Inc. In addition, the FDA awarded an Orphan Products Development grant to support the evaluation of HyBryte for expanded treatment in patients with early-stage CTCL, including in the home use setting. The grant, totaling $2.6 million over 4 years, was awarded to a prestigious academic institution that was a leading enroller in the Phase 3 FLASH study.

About Cutaneous T-Cell Lymphoma (CTCL)

CTCL is a class of non-Hodgkin’s lymphoma (NHL), a type of cancer of the white blood cells that are an integral part of the immune system. Unlike most NHLs which generally involve B-cell lymphocytes (involved in producing antibodies), CTCL is caused by an expansion of malignant T-cell lymphocytes (involved in cell-mediated immunity) normally programmed to migrate to the skin. These malignant cells migrate to the skin where they form various lesions, typically beginning as patches and may progress to raised plaques and tumors. Mortality is related to the stage of CTCL, with median survival generally ranging from about 12 years in the early stages to only 2.5 years when the disease has advanced. There is currently no cure for CTCL. Typically, CTCL lesions are treated and regress but usually return either in the same part of the body or in new areas.

CTCL constitutes a rare group of NHLs, occurring in about 4% of the approximate 700,000 individuals living with the disease. It is estimated, based upon review of historic published studies and reports and an interpolation of data on the incidence of CTCL that it affects over 25,000 individuals in the U.S., with approximately 3,000 new cases seen annually.

Prescient Therapeutics receives FDA orphan drug status for PTX-100 to treat T-cell lymphomas

On March 9, 2023 Prescient Therapeutics reported that it has secured an orphan drug designation from the US Food and Drug Administration (FDA) for its lead candidate PTX-100 for the treatment of T-cell lymphomas (TCLs) including cutaneous TCL (CTCL) (Press release, Prescient Therapeutics, MAR 9, 2023, View Source;utm_medium=rss&utm_campaign=prescient-therapeutics-receives-fda-orphan-drug-status-for-ptx-100-to-treat-t-cell-lymphomas [SID1234628461]).

TCLs are a group of lymphomas that develop when white blood cells (lymphocytes) grow out of control.

Collectively, TCLs represent an area of unmet, or poorly met, patient need, especially in people with relapsed or refractory disease.

Prescient separately received orphan drug designation for peripheral TCL (PTCL) in 2022, and then applied for CTCL to be designated as well.

The FDA has now granted a broader designation than Prescient requested, which encompasses all TCLs.

Orphan drug status
The FDA’s orphan drug designation program provides orphan status to drugs intended for the safe and effective treatment, diagnosis or prevention of rare diseases (defined as those affecting fewer than 200,000 people in the US).

The program provides benefits to incentivise drug development including seven years guaranteed market exclusivity from the granting of regulatory approval; and a waiver of Prescription Drug User Fee Act (PDUFA) fees, which had a value of over US$3.1 million in 2022.

Prescient managing director Steven Yatomi-Clarke welcomed the designation of PTX-100 in treating all TLCs.

"We are delighted to be granted Orphan Drug Designation by the FDA, and we have been pleasantly surprised to receive a designation that was broader than our request," he said.

"This now confers the certainty of seven years of market exclusivity for PTX-100 in a broader range of diseases with unmet or poorly met clinical need."

First-in-class compound
PTX-100 is a first in class compound with the ability to block the geranylgeranyl transferase-1 (GGT-1) cancer growth enzyme.

It disrupts oncogenic Ras pathways by inhibiting the activation of Rho, Rac and Ral circuits in cancer cells, leading to apoptosis (or death) of the cells.

PTX-100 is believed to be the only GGT-1 inhibitor in the world in clinical development and has demonstrated safety and early clinical activity in a phase 1 study and recent PK/PD basket study of haematological and solid malignancies.

The drug is now in a phase 1b expansion cohort study in T-cell lymphomas, where it has shown encouraging efficacy signals and safety.

Novel domain inhibitor
Prescient’s other targeted therapy PTX-200 is a novel PH domain inhibitor designed to stop a tumour survival pathway known as Akt, which plays a key role in the development of breast and ovarian cancers, as well as leukaemia.

Unlike other drug candidates which target Akt inhibition, PTX-200 has a novel mechanism of action which specifically inhibits Akt without non-specific kinase inhibition effects.

It is currently in a phase 1b/2 trial in relapsed and refractory acute myeloid leukaemia, where it has resulted in four remissions to date.

PTX-200 has previously generated encouraging results in trials relating to HER2-negative breast cancer and recurrent or persistent platinum-resistant ovarian cancer.

CEL-SCI’s Multikine Phase 3 Cancer Study Shows 43% Survival Extension

On March 9, 2023 CEL-SCI Corporation (NYSE American: CVM) reported new data from its pivotal Phase 3 study, the largest study ever conducted in newly diagnosed locally advanced squamous cell carcinoma of the head and neck (SCCHN) (Press release, Cel-Sci, MAR 9, 2023, View Source [SID1234628460]). A poster presentation titled "Leukocyte Interleukin Injection (LI) immunotherapy followed by radiotherapy extends overall survival (OS) in treatment naïve locally advanced primary squamous cell carcinoma of the head & neck: the IT-MATTERS Study" was delivered by Eyal Talor, Ph.D., CEL-SCI’s Chief Scientific Officer on March 8, 2023 at the 10th European Congress on Head & Neck Oncology (ECHNO) in Lisbon, Portugal.

CEL-SCI plans to submit a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) and other regulatory agencies for approval of Multikine* (Leukocyte Interleukin, Injection) in the treatment of newly diagnosed SCCHN in patients deemed at lower risk for recurrence (LR), as defined by National Comprehensive Cancer Network (NCCN) guidelines, representing a patient population of about 210,000 annual cases globally. The new data presented is very important because it focuses exclusively on the patient population (n=352) from the IT-MATTERS study for which CEL-SCI is seeking regulatory marketing approval, for locally advanced primary head and neck cancer patients scheduled to receive radiotherapy, but not chemotherapy, after surgery.

Per the NCCN guidelines, these LR patients typically are recommended to receive only radiotherapy following surgery. The recommended treatment for higher risk for recurrence (HR) patients is concurrent chemoradiotherapy (chemotherapy and radiotherapy at the same time) after surgery. In the IT-MATTERS study, 44 patients who were determined to be higher risk for recurrence following surgery should have been administered chemoradiotherapy, but received only radiotherapy, and were included in the survival analysis of the IT-MATTERS study initially performed. A more accurate representation of the survival of the intended LR patient population treated with Multikine would have been obtained had the analysis been performed by excluding these 44 patients. At the ECHNO 2023 Congress, we present study data demonstrating the survival and death rate advantages of the patients treated with Multikine over control in the LR population who received only radiotherapy (n=352) following surgery.

Key study findings for the intended Multikine patient population who received radiotherapy, as recommended by NCCN guidelines, following surgery include:

The overall survival advantage accelerated and increased over time, with the benefit of adding Multikine+CIZ to the treatment regimen as compared to Standard of Care (SOC) alone increasing from 2.8% at 3 years (36 months), to 8.3% at 4 years (48 months), to 15.6% at 5 years (60 months), with a 49.7% survival for control vs. 65.3% for the Multikine treated group at 5 years.

The hazard ratio was 0.70 (95% CI: [0.49 – 1.00]) which represents a 43% survival extension.

Progression free survival was 8.4% higher at 5 years for patients treated with Multikine+ CIZ+SOC as compared to patients treated with SOC control alone.

16.5% of these patients were early tumor responders, including complete tumor responders (confirmed by pathology at surgery), following the 3-week treatment with Multikine as compared to 0% responders of patients who were treated with SOC alone.

Multikine patients who had an early tumor response had significantly improved survival. Their death rate was only 15.6% vs. 48.7% death rate for the control patients.

Even the patients who did not have an early tumor response had a better survival than did the control group patients, with a 43.8% death rate vs. 48.7% death rate for control.

"Our pivotal study, the largest ever of its kind in head and neck cancer, continues to produce impressive data that demonstrate Multikine’s ability to improve outcomes and extend survival for newly diagnosed patients who have not had the benefit of a new treatment in decades," stated CEL-SCI CEO, Geert Kersten. "These data are presented at the world’s leading scientific peer-reviewed conferences, underscoring Multikine’s potential as we work toward an FDA marketing approval submission."

Imfinzi significantly improved event-free survival in AEGEAN Phase III trial for patients with resectable non-small cell lung cancer

On March 9, 2023 AstraZeneca reported Positive high-level results from a planned interim analysis of the AEGEAN Phase III, placebo- controlled trial showed that treatment with Imfinzi (durvalumab) in combination with neoadjuvant chemotherapy before surgery and as adjuvant monotherapy after surgery demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS) versus neoadjuvant chemotherapy alone followed by surgery for patients with resectable early-stage (IIA-IIIB) non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, MAR 9, 2023, View Source [SID1234628457]).

Results from the final pathologic complete response (pCR) and major pathologic response (mPR) analyses were consistent with previously announced positive results. The trial will continue as planned to assess key secondary endpoints including disease-free survival (DFS) and overall survival (OS).

Each year there are an estimated 2.2 million people diagnosed with lung cancer globally with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.1-3 Approximately 25-30% of all patients with NSCLC are diagnosed early enough to have surgery with curative intent.4-5 However, only around 56-65% of patients with Stage II disease will survive for five years.6 This decreases to 41% for patients with Stage IIIA and 24% for patients with Stage IIIB disease, reflecting a high unmet medical need.6

John V. Heymach, MD, PhD. Professor and Chair Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, said: "Treating patients early with durvalumab both before and after surgery delivers a significant and clinically meaningful benefit in resectable non-small cell lung cancer, where new options are urgently needed to offer patients the best chance of long-term survival. The AEGEAN results provide compelling evidence that this novel durvalumab regimen can drive improved outcomes in this curative-intent setting."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Patients with resectable non-small cell lung cancer face unacceptably high rates of recurrence, despite treatment with chemotherapy and surgery. We have shown that adding Imfinzi both before and after surgery significantly increased the time patients live without recurrence or progression events. We will continue to follow patients for overall survival."

Imfinzi was well tolerated and no new safety concerns were observed in the neoadjuvant and adjuvant settings. Further, adding Imfinzi to neoadjuvant chemotherapy was consistent with the known profile for this combination and did not increase complications or adverse events, or compromise patients’ ability to undergo surgery versus chemotherapy alone.

These data will be presented at a forthcoming medical meeting and shared with global health authorities.

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in development for patients with lung cancer. In addition to these results, the Company is also announcing today that Tagrisso (osimertinib) met a secondary endpoint of OS in the ADAURA Phase III trial in early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) NSCLC after complete tumour resection with curative intent.

Notes

Lung cancer
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer (SCLC).2 The majority of NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis.4-5 Early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition.7-8

For patients with resectable tumours, the majority eventually develop recurrence despite complete tumour resection and adjuvant chemotherapy.9

AEGEAN
AEGEAN is a randomised, double-blind, multi-centre, placebo-controlled global Phase III trial evaluating Imfinzi as perioperative treatment for patients with resectable Stage IIA-IIIB (Eighth Edition AJCC Cancer Staging Manual) NSCLC, irrespective of PD-L1 expression. Perioperative therapy includes treatment before and after surgery, also known as neoadjuvant/adjuvant therapy. In the trial, 802 patients were randomised to receive a 1500mg fixed dose of Imfinzi plus chemotherapy or placebo plus chemotherapy every three weeks for four cycles prior to surgery, followed by Imfinzi or placebo every four weeks (for up to 12 cycles) after surgery. Patients with known EGFR or ALK genomic tumour aberrations were excluded from the primary efficacy analyses.

In the AEGEAN trial, the primary endpoints were pCR, defined as no viable tumour in the resection specimen (including lymph nodes) following neoadjuvant therapy, and EFS, defined as the time from randomisation to an event like tumour recurrence, progression precluding definitive surgery, or death. Key secondary endpoints were mPR, defined as residual viable tumour of less than or equal to 10% in the resected primary tumour following neoadjuvant therapy, DFS, OS, safety and quality of life. The final pathologic response analyses were performed after all patients had the opportunity for surgery and pathology assessment per the trial protocol. The trial enrolled participants in 264 centres in more than 25 countries including in the US, Canada, Europe, South America and Asia.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial.

Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage SCLC based on the CASPIAN Phase III trial. In an exploratory analysis in 2021, updated results from the CASPIAN trial showed Imfinzi plus chemotherapy tripled patient survival at three years versus chemotherapy alone. Additionally, Imfinzi is approved in combination with a short course of Imjudo (tremelimumab) and chemotherapy for the treatment of metastatic NSCLC in the US, EU and Japan based on the POSEIDON Phase III trial.

In addition to its indications in lung cancer, Imfinzi is also approved in combination with chemotherapy in locally advanced or metastatic biliary tract cancer in the US, EU, Japan and several other countries; in combination with Imjudo in unresectable hepatocellular carcinoma in the US, EU and Japan; and in previously treated patients with advanced bladder cancer in several countries.

Since the first approval in May 2017, more than 150,000 patients have been treated with Imfinzi.

AstraZeneca has several ongoing registrational trials focused on testing Imfinzi in earlier stages of lung cancer, including in resectable NSCLC (ADJUVANT BR.31) and unresectable NSCLC (PACIFIC-2, 4, 5, 8 and 9), and in limited-stage SCLC (ADRIATIC).

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal (GI) cancers, ovarian cancer, endometrial cancer and other solid tumours.

Astellas and Seagen Announce China’s National Medical Products Administration Accepts Biologics License Application for Enfortumab Vedotin in Certain Patients with Locally Advanced or Metastatic Urothelial Cancer

On March 9, 2023 Astellas Pharma Inc. (TSE:4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq: SGEN) reported that the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) has accepted the Biologics License Application (BLA) for enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial cancer (la/mUC) who received prior treatment with a PD-1/L1 inhibitor and platinum-based chemotherapy (Press release, Astellas, MAR 9, 2023, View Source [SID1234628456]).

"In China, there were nearly 86,000 new cases of bladder cancer in 2020, and we are working with the NMPA to seek approval for enfortumab vedotin for patients with advanced stage disease," said Ahsan Arozullah, M.D., M.P.H., Senior Vice President and Head of Development Therapeutic Areas, Astellas. "Enfortumab vedotin has become a second- and third-line treatment option for many patients around the world with previously treated locally advanced or metastatic urothelial cancer, and an approval in China may bring this therapy to those patients."

The BLA submission for enfortumab vedotin is based on data from the EV-203 study (NCT04995419), a single-arm, open-label, multicenter Phase 2 study of enfortumab vedotin in Chinese patients with la/mUC who previously received a PD-1/L1 inhibitor and platinum-based chemotherapy. Results showed that EV-203 met its primary endpoint, showing statistical significance in objective response rate (ORR) by independent review committee (IRC) for patients treated with enfortumab vedotin alone compared to historical controls. Efficacy and pharmacokinetic data from the study are in line with global data, and EV-203 is a bridging study to EV-301, a Phase 3 randomized study that has supported global registrations of enfortumab vedotin, and EV-201 Cohort 1.

Please see Important Safety Information, including BOXED WARNING, at the end of this press release for further safety information regarding enfortumab vedotin including serious skin reactions.

Enfortumab vedotin alone and in combination with other therapies is the subject of a robust clinical development program aimed at addressing unmet medical needs across the continuum of urothelial cancer and in other solid tumors.