On April 14, 2023 AstraZeneca reported that it will present new data across its diverse, industry-leading Oncology pipeline and portfolio at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, 14 to 19 April 2023 (Press release, AstraZeneca, APR 14, 2023, View Source [SID1234630100]).

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Data from 70 presentations will be featured, including eight oral presentations, a plenary presentation of the AEGEAN Phase III trial of Imfinzi (durvalumab) based regimen in resectable non-small cell lung cancer (NSCLC), and the first disclosures of preclinical data for five novel molecules across the Company’s Antibody Drug Conjugate (ADC), Cell Therapy and Epigenetics scientific platforms.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "It’s exciting to see our strategy to attack cancer from multiple angles come to life at AACR (Free AACR Whitepaper) this year through data from our proprietary antibody drug conjugates, next generation cell therapies and epigenetics molecules. Furthermore, results from the AEGEAN trial show the potential of treating lung cancer patients early with Imfinzi before and after surgery which reinforces the importance of diagnosing lung cancer early."

Improving outcomes for patients with resectable lung cancer with Imfinzi
A late-breaking presentation of the AEGEAN Phase III trial results will highlight the potential of a novel Imfinzi-based treatment before and after surgery for patients with resectable early-stage (IIA-IIIB) NSCLC. AEGEAN has met its two primary endpoints, demonstrating improvements in event-free survival and pathologic complete response with Imfinzi in combination with neoadjuvant chemotherapy before surgery and as adjuvant monotherapy versus neoadjuvant chemotherapy alone followed by surgery.

Delivering the next wave of ADCs with proprietary platform
Two oral presentations will feature the first preclinical and translational results for AZD9592, a bispecific ADC designed to deliver targeted chemotherapy to cancer cells with a topoisomerase inhibitor 1 (TOP1i) warhead using the Company’s proprietary linker technology.

AZD9592 binds to two known oncogenic drivers: epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (cMET). These two drivers are often co-expressed in solid tumours including in NSCLC and head and neck squamous cell carcinoma (HNSCC). This is the Company’s first bispecific ADC to enter the clinic and shows a promising efficacy and safety profile in preclinical models, with evidence for DNA damage dependent tumour cell death as the mechanism of action.

In addition, the first preclinical results will be presented for another ADC, AZD5335, a promising therapeutic candidate for the treatment of certain ovarian cancers. This ADC has a folate receptor alpha (FRα) targeting antibody linked to a proprietary TOP1i warhead. A robust anti-tumour response is reported in FRα-expressing preclinical models that are resistant to another FRα ADC with a microtubule inhibitor warhead. In addition, AZD5335 is active in models with either high or low levels of target expression as detected by computational pathology.

Preclinical data for AZD8205, an ADC targeting B7-H4, will also be presented both as monotherapy and in combination with the PARP-1 selective inhibitor, AZD5305. Robust anti-tumour activity is evident in preclinical models across multiple B7-H4 positive tumour types, including ovarian and cholangiocarcinoma tumours, with combination therapy resulting in higher anti-tumour activity than monotherapy.

Building the next generation of cell therapies in solid tumours
In cell therapy, the first clinical data will be presented for C-CAR031, a novel transforming growth factor-beta (TGFβ) armoured Glypican 3 (GPC3) targeting chimeric antigen receptor T cell (CAR-T) therapy that is being investigated for liver cancer. Early results show it is well tolerated with promising anti-tumour activity seen with objective responses in several patients to date.

The CAR-T is based on AZD5851, a novel cell therapy that was designed by AstraZeneca, and is being developed and manufactured by Cellular Biomedicine Group (CBMG). AstraZeneca’s TGFβ armouring is designed to resist the immuno-suppressive tumour microenvironment and enhance the potential effectiveness of CAR-Ts in solid tumours.

In addition, the first preclinical data will be shared on AZD0754, a novel TGFβ armoured CAR-T targeting STEAP2, a protein commonly overexpressed in prostate cancer. This is the first cell therapy to be designed, manufactured and developed by AstraZeneca. The presentation will show encouraging preclinical safety data and supports future clinical development of this potential first-in-class CAR-T therapy.

First disclosure and preclinical data for an epigenetics molecule targeting PRMT5
Epigenetic therapy is one of AstraZeneca’s six core scientific areas of focus. The modality is the latest addition to the Company’s diverse portfolio, which is designed to attack cancer from multiple angles and redefine outcomes for patients with high unmet needs.

At AACR (Free AACR Whitepaper), the first preclinical data will be presented for the novel lead epigenetics molecule, AZ-PRMT5i-1, a potent methylthioadenosine phosphorylase (MTAP)-selective PRMT5 inhibitor with anti-tumour activity in MTAP-deleted tumours. Loss of the MTAP gene occurs across approximately 15% of all cancers, which provides an opportunity to use a biomarker selection strategy and also spare healthy tissue. The preclinical results demonstrate MTAP selectivity and promising anti-tumour activity.

Harnessing transformational technologies
Transformational technologies, including circulating tumour DNA (ctDNA), computational pathology, and data science and artificial intelligence (AI), underpin the success of progressing AstraZeneca’s pipeline. Several presentations at AACR (Free AACR Whitepaper) showcase the Company’s efforts to harness the power of these technologies to better understand complex cancer biology, identify and select patients for treatment and increase the probability of success in the clinic.

Key AstraZeneca presentations during AACR (Free AACR Whitepaper) 2023

Lead author

Abstract title

Presentation details

IO

Heymach, JV

CT005 – AEGEAN: A phase 3 trial of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC

Abstract #CT005

Plenary

Harnessing the Immune System in the Clinic

16 April 2023

14:45 – 15:00 ET

Iyer S

Immunomodulatory effects of ceralasertib in combination with durvalumab in NSCLC patients with progression on anti-PD-(L)1 treatment (HUDSON, NCT03334617)

Abstract #CT039

Clinical Trials Minisymposium

Novel Immunotherapy Combination Clinical Trials

18 April 2023

15:50 – 16:00 ET

ADCs

Gymnopoulos, M

First disclosure of AZD5335, a TOP1i-ADC targeting low and high FRα-expressing ovarian cancer with superior preclinical activity vs FRα-MTI ADC

Abstract #LB025 / 17

Poster

Late-Breaking Research: Experimental and Molecular Therapeutics 1

16 April 2023

13:30 – 17:00 ET

Comer, F

AZD9592: an EGFR-cMET bispecific antibody-drug conjugate (ADC) targeting key oncogenic drivers in non-small-cell lung cancer (NSCLC) and beyond

Abstract #5736

Minisymposium

New Tricks for Known Targets: Novel Approaches to Inhibit Oncogenic Signaling

18 April 2023

15:22 – 15:37 ET

McGrath, L

Evaluation of the relationship between target expression and in vivo anti-tumour efficacy of AZD9592, an EGFR/c-MET targeted bispecific antibody drug conjugate

Abstract #5737

Minisymposium

New Tricks for Known Targets: Novel Approaches to Inhibit Oncogenic Signaling

18 April 2023

15:37 – 15:52 ET

Cazes, A

Preclinical evaluation of a novel B7-H4-targeted antibody-drug conjugate AZD8205 as a single agent and in combination with novel PARP inhibitor and checkpoint blockade

Abstract #2947 / 25

Poster

Therapeutic Antibodies 2

17 April 2023

13:30 – 17:00 ET

Meric-Bernstam, F

TROPION-PanTumor03: Phase 2, multicenter study of datopotamab deruxtecan (Dato-DXd) as monotherapy and in combination with anticancer agents in patients (pts) with advanced/metastatic solid tumours

Abstract #CT058 / 16

Poster

Phase II and Phase III Clinical Trials in Progress

17 April 2023

9:00 – 12:30 ET

Bhavsar, D

Combination of T-DXd with the irreversible pan-HER TKI afatinib drives combination benefit in HER2-low gastric and lung tumours

Abstract #3999 / 22

Poster

Oncogenes and Tumour Suppressor Genes as Targets for Therapy 3

18 April 2023

9:00 – 12:30 ET

Wray, R.

Improving Treatment Outcomes: A Digital Solution for Remote Patient Monitoring of Stomatitis for Patients receiving Dato-DXd

Abstract #LB143 / 7

Poster

Late-Breaking Research: Population Sciences

17 April 2023

13:30 – 17:00 ET

Cell Therapy

van Dyk, D

Antitumour activity of AZD0754, a dnTGFbR2 armored STEAP2 targeted CAR-T therapy, in preclinical models of prostate cancer

Abstract #LB085 / 1

Poster

Late-Breaking Research: Immunology 1

17 April 2023

9:00 – 12:30 ET

Zhang, Q

First report of preliminary safety, efficacy, and pharmacokinetics of C-CAR031 (GPC3-specific TGFBRIIDN CAR-T) in patients with advanced HCC

Abstract #CT097 / 5

Poster

First-in-Human Phase I Clinical Trials 1

17 April 2023

13:30 – 17:00 ET

Epigenetics

Smith, JM

Identification of a novel series of MTAP-selective PRMT5 inhibitors, and first disclosure of AZ-PRMT5i-1

Abstract #3088 / 1

Poster

Targeted Drug Design and Development for Cancer Therapy

17 April 2023

13:30 – 17:00 ET

Lynch, J

AZ-PRMT5i-1: A potent MTAP-selective PRMT5 inhibitor with pharmacodynamic and monotherapy anti-tumour activity in MTAP-deleted tumours

Abstract #6272 / 10

Poster

Epigenetics

19 April 2023

9:00 – 12:30 ET

TDR1

Zhi Peng

A Multicenter Phase II Study of Savolitinib in Patients with MET-Amplified Gastroesophageal Junction Adenocarcinomas or Gastric Cancer

Abstract # CT152

Phase II Clinical Trials 1

17 April 2023

13:30 – 17:00 ET

ctDNA

Labrousse, P

The evolution of MRD assays; moving beyond the tumour-informed bespoke NGS panel

Abstract #LB293 / 6

Poster

Late-Breaking Research: Clinical Research 3

19 April 2023

9:00 – 12:30 ET

Russell, H

Evaluation of a tumour informed MRD assay with contrived breast cancer samples

Abstract #3384 / 27

Poster

Liquid Biopsies: Circulating Nucleic Acids and Circulating Tumour Cells 3

17 April 2023

13:30 – 17:00 ET

Munugalavadla V

Utility of ctDNA-based targeted methylation MRD assay for hematological malignancies

Abstract #3369 / 12

Poster

Liquid Biopsies: Circulating Nucleic Acids and Circulating Tumour Cells 3

17 April 2023

13:30 – 17:00 ET

Hartmaier, R

Baseline and on-treatment plasma-based genomics as a predictor of outcomes in SAVANNAH: savolitinib + osimertinib in EGFRm MET overexpressed/amplified NSCLC post-osimertinib

Abstract #LB294 / 7

Poster

Late-Breaking Research: Clinical Research 3

19 April 2023

9:00 – 12:30 ET

Data Science & AI

Arango G

Translating state-of-the-art deep learning predictions of IO treatment efficacy to clinical practice

Abstract #5359 / 8

Poster

Artificial Intelligence and Machine/Deep Learning 1

18 April 2023

13:30 – 17:00 ET

Arango G

Enhancing the utilization of deep learning to predict patient response in small immunotherapy cohorts using real world data

Abstract #1174

Minisymposium

Advancing Cancer Research Through an International Cancer Registry: AACR (Free AACR Whitepaper) Project GENIE Use Cases

16 April 2023

15:36 – 15:51 ET

Nikolau N

Improving survival prediction using flexible late fusion machine learning framework for multi-omics data integration

Abstract #5395 / 11

Poster

Artificial Intelligence and Machine/Deep Learning 2

18 April 2023

13:30 – 17:00 ET

Arango G

Improved identification of CHIP mutations from cell free DNA without matched normal samples using machine learning

Abstract #5360 / 9

Poster

Artificial Intelligence and Machine/Deep Learning 1

18 April 2023

13:30 – 17:00 ET

Ellen JG

Autoencoder-based multimodal prediction of survival for non-small cell lung cancer

Abstract #5373 / 22

Poster

Artificial Intelligence and Machine/Deep Learning 1

18 April 2023

13:30 – 17:00 ET

Computational Pathology

Potdevin, G

A first assessment of CD8-PET/CT with 89-Zr-Crefmirlimab as predictive biomarker for response to standard of care immunotherapy in patients with solid tumours

Abstract #3577 / 2

Poster

PET, MRI, and CT Imaging

18 April 2023

9:00 – 12:30 ET

Brieu, N

A unified computational pathology method to quantify HER2 expression from raw IHC and IF images in breast cancer

Abstract #5388 / 4

Poster

Artificial Intelligence and Machine/Deep Learning 2

18 April 2023

13:30 – 17:00 ET

On April 14, 2023 Merus N.V. (Nasdaq: MRUS) (Merus, the Company, we, or our), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported the publication of an abstract for a poster presentation of early clinical data on the bispecific antibody petosemtamab in advanced gastric/esophageal adenocarcinoma (GEA) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 taking place in Orlando, Florida April 14-19, 2023 (Press release, Merus, APR 14, 2023, View Source [SID1234630099]).

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Petosemtamab, or MCLA-158, is a human IgG1 Biclonics designed to bind to cancer cells expressing epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5).

Petosemtamab is in clinical development in the expansion part of a phase 1/2 open-label, multicenter trial in advanced solid tumors, including advanced GEA.

Although petosemtamab has demonstrated promising clinical activity among pretreated gastric/esophageal adenocarcinoma (GEA) patients having EGFR gene amplification and/or overexpression, the Company has decided to pause further clinical exploration of the GEA cancer cohort at this time. The Company plans to prioritize investigating petosemtamab in head and neck squamous cell carcinoma, in view of the strong clinical activity observed in this cohort.

Information and observations from the cohort of GEA patients treated in the phase 1/2 trial include:

As of an October 24, 2022 data cutoff date, 14 previously treated GEA patients (pts) were treated with petosemtamab 1500 mg (IV) every two weeks
Patient Population:
Median age was 63 (range of 40-80); 79% were male
Median prior lines of systemic therapy was 3 (range 1-4); including platinum-based chemotherapy (36% of pts) and checkpoint inhibitors (14%)
14 pts were evaluable for efficacy, receiving ≥2 treatment cycles (≥8 weeks) with ≥1 post-baseline tumor assessment or experiencing early progressive disease
Antitumor activity among the 14 pts:
1 pt with tumor EGFR protein overexpression and gene copy number amplification (CNA) showed a confirmed sustained partial response (67% tumor reduction; response ongoing after 24 cycles);
3 pts had stable disease (1 with EGFR overexpression and gene CNA; 2 not evaluable for IHC), with tumor reductions of 2%, 17%, and 40%.
Petosemtamab continues to demonstrate a manageable safety profile:
Of 78 pts treated at the recommended phase 2 dose of 1500 mg every two weeks (escalation and all expansion cohorts), the most frequent AEs regardless of causality (all grades/G3-4) were rash (33%/0%), hypotension (26%/6%), dyspnea (26%/4%), nausea (26%/1%), dermatitis acneiform (24%/1%), blood magnesium decreased (19%/5%), erythema (19%/0%), diarrhea (19%/0%); IRRs (composite term) were reported in 74%/21% of pts, mostly at the first infusion, and all resolved. 5 pts (6%) discontinued treatment due to IRRs on Day 1.
Presentation Details:
Title: MCLA-158 (petosemtamab), an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced gastric/esophageal adenocarcinoma (GEA)
Session: Phase II Clinical Trials 1
Date: Monday, April 17, 2023
Time: 1:30 – 5:30 p.m. ET
Poster #: 18
Abstract #: CT156

The abstract can be found on the conference website.

About Petosemtamab 
Petosemtamab, or MCLA-158, is a bispecific Biclonics low-fucose human full-length IgG1 antibody targeting the epidermal growth factor receptor (EGFR) and the leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5). Petosemtamab is designed to exhibit three independent mechanisms of action including inhibition of EGFR-dependent signaling, LGR5 binding leading to EGFR internalization and degradation in cancer cells, and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activity.

On April 14, 2023 Merus N.V. (Nasdaq: MRUS) (Merus, the Company, we, or our), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported the publication of an abstract for a plenary session oral presentation of interim clinical data on the bispecific antibody petosemtamab in previously treated head and neck squamous cell carcinoma (HNSCC) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 taking place in Orlando, Florida April 14-19, 2023 (Press release, Merus, APR 14, 2023, View Source [SID1234630098]).

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Petosemtamab, or MCLA-158, is a human IgG1 Biclonics designed to bind to cancer cells expressing epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5).

"We are excited by these data demonstrating clinically meaningful efficacy and durability of petosemtamab in previously treated head and neck cancer. We are looking forward to sharing additional details at the AACR (Free AACR Whitepaper) clinical trials plenary session and on our upcoming investor call," said Dr. Andrew Joe, Chief Medical Officer at Merus.

Petosemtamab (MCLA-158: EGFR x LGR5 Biclonics): Solid Tumors
Enrollment continues in dose expansion in the phase 1/2 trial, including in combination with Keytruda (pembrolizumab)

Petosemtamab is in clinical development in the expansion part of a phase 1/2 open-label, multicenter trial in advanced solid tumors, including previously treated head and neck squamous cell carcinoma (HNSCC). The Company also initiated a cohort investigating petosemtamab in combination with Keytruda in patients with untreated HNSCC, designed to evaluate safety and clinical activity in this population.

Plenary Session Oral Presentation: Clinical activity of MCLA-158 (petosemtamab), an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell cancer (HNSCC)

The oral presentation will include updated interim data from the ongoing phase 1/2 clinical trial and will be presented by the Principal Investigator, Dr. Ezra EW Cohen, Moores Cancer Center, UC San Diego Health.

The abstract provides information and observations from the ongoing phase 1/2 trial, including:

As of a November 28, 2022 data cutoff date, 49 previously treated HNSCC patients (pts) were treated with petosemtamab 1500 mg IV every two weeks
Patient Population:
Median age was 63 (range of 31-77); 78% were male
Median prior lines of systemic therapy was 2 (range 1-4); including anti-PD-1/PD-L1 in 96% of pts, platinum-based chemotherapy in 92% of pts; 2 pts received prior cetuximab
Most frequent primary tumor locations were oropharynx (35%), oral cavity (31%), and larynx (16%)
42 pts were evaluable for efficacy, receiving ≥2 treatment cycles (≥8 weeks) with ≥1 post-baseline tumor assessment or experiencing early progressive disease:
Antitumor activity among the 42 pts:
Overall responses rate (ORR) was 35.7% (15/42), by RECIST 1.1 per investigator assessment including 1 complete response (ongoing after 18 months), 12 partial responses (PRs), and 2 unconfirmed PRs with treatment ongoing at the data cutoff
Median duration of response (DOR) was 6.0 months (95%CI=3.3-not calculable) and median progression-free survival was 5.0 months (95%CI=3.2-6.8) with 17 pts continuing on therapy at the data cutoff
Petosemtamab continued to demonstrate a manageable safety profile:
Of 78 pts treated at the recommended phase 2 dose of 1500 mg every two weeks (escalation and all expansion cohorts), the most frequent AEs regardless of causality (all grades/G3-4) were rash (33%/0%), hypotension (26%/6%), dyspnea (26%/4%), nausea (26%/1%), dermatitis acneiform (24%/1%), blood magnesium decreased (19%/5%), erythema (19%/0%), diarrhea (19%/0%); IRRs (composite term) were reported in 74%/21% of pts, mostly at the first infusion, and all resolved. 5 pts (6%) discontinued treatment due to IRRs on Day 1.
Presentation Details:
Title: Clinical activity of MCLA-158 (petosemtamab), an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell cancer (HNSCC)
Session Category: Clinical Trials Plenary Session
Session: Promising Novel Antitumor Strategies in Early Phase Clinical Trials
Date: Monday, April 17, 2023
Time: 10:15 a.m. – 12:15 p.m. ET
Presentation #: CT012

Regulatory Update

Merus met with the U.S. Food and Drug Administration (FDA) in an end-of-phase meeting to discuss interim results from the previously treated HNSCC cohort of the petosemtamab phase 1/2 trial. The FDA recognized recurrent or metastatic HNSCC represents an area of unmet medical need, and provided clear recommendations for the path to potential registration.

Based on the strong clinical data and discussions with the FDA, Merus believes a randomized clinical trial in previously treated (2L/3L) or untreated (front-line) HNSCC may support a possible registration. Additionally, Merus believes a randomized registration trial in HNSCC with an overall response rate endpoint could potentially support accelerated approval and the overall survival results from the same study could potentially verify its clinical benefit to support regular approval. The Company plans to continue to acquire data to confirm a suitable dose for future randomized clinical trials.

"Based on our end-of-phase meeting with the FDA, we believe we have optionality in our development path for petosemtamab in head and neck squamous cell carcinoma and are excited to continue investigation of this important new potential therapy for patients," said Bill Lundberg, M.D., President, Chief Executive Officer at Merus. "I’m proud of the progress we are making towards our ambition to become a fully integrated US product company."

The abstract can be found on the conference website.

Company Conference Call and Webcast Information
Merus will hold a conference call and webcast for investors on April 17, 2023 at 6:30 p.m. ET. A replay will be available after the completion of the call in the Investors and Media section of our website for a limited time.

Date & Time: April 17, 2023 at 6:30 p.m. ET
Webcast link: Available on our website
Dial-in: Toll Free: 1 (800) 715-9871 / International: 1 (646) 307-19631
Conference ID: 4032258

About Petosemtamab
Petosemtamab, or MCLA-158, is a bispecific Biclonics low-fucose human full-length IgG1 antibody targeting the epidermal growth factor receptor (EGFR) and the leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5). Petosemtamab is designed to exhibit three independent mechanisms of action including inhibition of EGFR-dependent signaling, LGR5 binding leading to EGFR internalization and degradation in cancer cells, and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activity.

On April 14, 2023 TransCode Therapeutics, Inc. (NASDAQ: RNAZ) ("TransCode" or the "Company"), the RNA Oncology Company committed to more effectively treating cancer using RNA therapeutics, reported that it has entered into a Common Stock Purchase Agreement (the "Agreement") with White Lion Capital, LLC ("White Lion Capital") an investor in the glioblastomas / oncology sector (Press release, TransCode Therapeutics, APR 14, 2023, View Source [SID1234630095]). The Agreement provides the Company with the right to sell White Lion Capital up to approximately $1.08 million of its common stock until May 31, 2023, subject to certain limitations and conditions. The Company intends to use the net proceeds from the transaction for working capital and general corporate purposes.

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The shares of common stock described above will be offered by the Company pursuant to a "shelf" registration statement on Form S-3 (File No. 333-268764) previously filed with the Securities and Exchange Commission (the "SEC") on December 13, 2022, and declared effective by the SEC on December 16, 2022. The offering of the shares of common stock will be made only by means of a prospectus, including a prospectus supplement, forming a part of the effective registration statement. Electronic copies of the final prospectus supplement and accompanying prospectus were filed with the SEC and may be obtained on the SEC’s website at View Source

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 April 14, 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 convened a Type A Meeting with the United States (U.S.) Food and Drug Administration (FDA) (Press release, Soligenix, APR 14, 2023, View Source [SID1234630094]). During the Type A Meeting, representatives of the Company and the FDA discussed 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 sodium) in the treatment of early stage cutaneous T-cell lymphoma (CTCL), a rare cancer, where it successfully demonstrated statistically significant results in a Phase 3 clinical trial (Study HPN-CTCL-01; also referred to as the FLASH study).

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In order to accept an NDA filing for HyBryte, the FDA is requiring positive results from a second clinical study in addition to the Phase 3, randomized, double-blind, placebo-controlled FLASH study previously conducted in this orphan indication. The FDA indicated that it is open to engaging in protocol discussions regarding the second clinical study. Based on the feedback, the Company has decided to collaboratively engage in discussions with the FDA in order to define the protocol and evaluate the feasibility of conducting the additional clinical trial.

"While we are very disappointed by this delay, Soligenix and its clinical investigators remain committed to working with the FDA and advancing HyBryte to market for patients suffering with CTCL," stated Christopher J. Schaber, PhD, President and Chief Executive Officer of Soligenix. "The Phase 3 FLASH study was the largest double-blind, randomized, placebo-controlled clinical trial ever conducted in the CTCL population. While we are surprised that the FDA did not accept our submitted NDA for filing and review, it was very clear that the FDA’s thinking has evolved in evaluating CTCL therapies since our initial protocol discussions on Study HPN-CTCL-01 and that another Phase 3 study will be required to support an NDA for HyBryte. During the Type A meeting, we discussed elements of protocol design for the additional confirmatory study and look forward to collaborating with the FDA to advance these discussions as quickly as possible to have a reasonable study design to meet the FDA’s requirements."

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 sodium, 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 phototherapies 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 (Fluorescent Light Activated Synthetic Hypericin) study 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.