On April 14, 2025 Cue Biopharma, Inc. (Nasdaq: CUE), a clinical-stage biopharmaceutical company developing a novel class of therapeutic biologics to selectively engage and modulate disease-specific T cells for the treatment of cancer and autoimmune disease, reported the pricing of an underwritten public offering of (i) 13,530,780 shares of its common stock and accompanying common stock warrants to purchase an aggregate of 3,382,695 shares of common stock and, (ii) to certain investors in lieu of common stock, pre-funded warrants to purchase 11,469,216 shares of common stock and accompanying common stock warrants to purchase an aggregate of 2,867,304 shares of common stock (Press release, Cue Biopharma, APR 14, 2025, View Source [SID1234651914]). Each share of common stock and accompanying common stock warrant are being sold together at a combined public offering price of $0.79, and each pre-funded warrant and accompanying common stock warrant are being sold together at a combined public offering price of $0.789. The aggregate gross proceeds of the offering are expected to be approximately $20 million, before deducting underwriting discounts and commissions and other offering expenses. Each pre-funded warrant will have an exercise price of $0.001 per share, will be exercisable immediately and will be exercisable until all of the pre-funded warrants are exercised in full. Each common stock warrant will have an exercise price of $0.79 per share, will be exercisable immediately and will expire five years from the date of issuance. The offering is expected to close on or about April 16, 2025, subject to satisfaction of customary closing conditions. All of the securities are being offered by Cue Biopharma.

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Oppenheimer & Co. Inc. is acting as sole book-running manager for the offering. Newbridge Securities Corporation is acting as co-manager for the offering.

A shelf registration statement on Form S-3 (File No. 333-271786) relating to the securities to be offered in the public offering was filed with the Securities and Exchange Commission (the "SEC") on May 9, 2023 and declared effective on May 26, 2023. The offering was made only by means of a prospectus supplement and accompanying prospectus that form a part of the registration statement. A preliminary prospectus supplement relating to and describing the terms of the offering has been filed with the SEC and may be obtained for free by visiting the SEC’s website at www.sec.gov. A final prospectus supplement relating to the offering will be filed with the SEC. When available, copies of the preliminary prospectus supplement and final prospectus supplement relating to the offering may also be obtained by contacting: Oppenheimer & Co. Inc., Attention: Syndicate Prospectus Department, 85 Broad Street, 26th Floor, New York, New York 10004, by telephone at (212) 667-8055, or by email at [email protected].

This press release does 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 jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On April 14, 2025 Can-Fite BioPharma Ltd. (NYSE American: CANF) (TASE: CANF), a biotechnology company developing a pipeline of proprietary small molecule drugs targeting oncological and inflammatory diseases, reported financial results and clinical updates for the year ended December 31, 2024 (Press release, Can-Fite BioPharma, APR 14, 2025, View Source [SID1234651907]).

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Clinical & Development Milestones Achieved

Namodenoson Drug Candidate:

Liver Cancer – A patient, who initially had an overall survival time of 8 years, currently treated with Namodenoson in a compassionate use program in the former Can-Fite Phase II study has evidenced a complete cure manifested by the disappearance of all metastases, normal liver function and good quality of life. In addition, the Company has found that Namodenoson has protective effects on top of the anti-cancer activity that was presented at the 2025 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium and also published in European Society of Medicine Journal entitled: "The Neuro- Cardio- and Hepato- Protective Effects of Namodenoson are Mediated by Adiponectin". The article presents compelling preclinical and clinical data demonstrating Namodenoson’s potent anti-ischemic, anti-inflammatory, anti-fibrotic, and anti-toxicity effects across multiple body tissues, including the liver, central nervous system and cardiovascular system. The study highlights Namodenoson’s ability to increase adiponectin levels, a key cytokine known to drive multi-organ protective effects. Importantly, the manuscript underscores Namodenoson’s dual role as both an anti-cancer therapy and a protective agent for normal tissues, setting it apart from conventional chemotherapy and other oncology treatments with significant toxicity.

Pancreatic Cancer – Namodenoson has been granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) for the indication of pancreatic cancer, one of the most aggressive malignancies. The designation as an orphan drug will provide, among others, potential for market exclusivity for seven years after approval and several and regulatory advantages (View Source). In addition, the Company initiated a Phase IIa clinical trial in patients with advanced pancreatic adenocarcinoma (NCT06387342). The Phase IIa study is a multicenter open-label trial in patients with advanced pancreatic adenocarcinoma whose disease has progressed on at least first-line therapy. The trial is evaluating the safety, clinical activity and pharmacokinetics (PK) of Namodenoson in this patient population. Recently, the FDA approved compassionate use treatment of a U.S.-based pancreatic cancer patient with its anti-cancer drug Namodenoson.

Anti-Obesity – Namodenoson was granted a patent for its use as an anti-obesity drug by the U.S. patent office. The patent application (No. 17/309,952) entitled, "An A3 adenosine receptor ligand for use for achieving a fat loss effect", has been accepted by the U.S. Patent Office, was issued in February 2024 and expires in 2042.

The patent application covers methods of treating obese patients by administering Namodenoson in an oral formulation. In addition, the Company was also granted a patent application (No.2020205042) for the anti-obesity indication by the Australian Patent Office, which expires in 2040.

Piclidenoson Drug Candidate:

Psoriasis – Can-Fite initiated a pivotal phase 3 psoriasis study of its oral drug, Piclidenoson, with the FDA and the European Medicines Agency (EMA). The study will enroll patients with moderate to severe plaque psoriasis. Patient enrolment will be initiated in Europe, with the U.S. and Canada expected to follow.

Lowe Syndrome – Can-Fite recently entered into the clinical development of implementing Piclidenoson into the treatment of the rare genetic disease, Lowe Syndrome. A Phase II design has been completed and preparatory work is being undertaken to initiate the study that will be conducted by Dr. Franchesca Emma from the Division of Nephrology, Bambino Gesù Children’s Hospital – IRCCS Rome Italy. The Phase II open-label study will enroll 5 patients that will be treated twice daily with 3 mg Piclidenoson for 12 months. The study’s primary end point will be the efficacy of Piclidenoson in increasing 99mTc-DMSA renal uptake.

Canine Osteoarthritis – Can-Fite partnered with Vetbiolix for the development of Piclidenoson for canine osteoarthritis and successfully concluded a clinical study in dogs with osteoarthritis who were treated orally with Piclidenoson for a period of a few months. The arthritis market for companion animals was estimated by Coherent Market Insights to be $3.8 Billion in 2023 and is expected to grow to $6.3 Billion by 2030. Can-Fite and Vetbiolix model that Piclidenoson has the potential to capture up to 6% of this opportunity, with peak worldwide sales of $445 Million by 2034. Under the agreement, Can-Fite is entitled to receive a 15% royalty on worldwide sales in this indication. This means that Can-Fite’s upfront and royalties on sales upon regulatory approval for veterinary use is projected to be $325 million in the aggregate over the next decade assuming a 2029 launch. In addition, Vetbiolix is initiating an advanced clinical study in dogs with osteoarthritis, utilizing oral daily treatment with Piclidenoson. Expected registration of Piclidenoson for this indication is anticipated to be in 2029.

Financial Results

Revenues for the year ended December 31, 2024 were $0.67 million, a decrease of $0.07 million, or 9.3%, compared to $0.74 million for the year ended December 31, 2023. The decrease in revenues was mainly due to the recognition a lower portion of advance payments received under distribution agreements that the Company previously entered into, offset by a recognition of advance payment received under the license agreement with Vetbiolix.

Research and development expenses for the year ended December 31, 2024 were $5.75 million, a decrease of $0.23 million, or 3.8%, compared to $5.98 million for the year ended December 31, 2023. Research and development expenses for the year ended December 31, 2024 comprised primarily of expenses associated with the completion of the Phase 3 study of Piclidenoson for the treatment of psoriasis and two ongoing studies for Namodenoson: a Phase 3 study in the treatment of advanced liver cancer and a Phase 2b study for MASH. The decrease is primarily due to a decrease in expenses associated with Piclidenoson.

General and administrative expenses were $3.04 million for the year ended December 31, 2024, an increase of $0.09 million, or 3.1%, compared to $2.95 million for the year ended December 31, 2023. The increase is primarily due to higher public relations expenses. The Company expects that general and administrative expenses will remain at the same level through 2025.

Financial income, net for the year ended December 31, 2024, aggregated $0.25 million, compared to $0.56 million for the year ended December 31, 2023. The decrease in financial income, net was mainly due to a decrease in interest from deposits.

Net loss for the year ended December 31, 2024, was $7.88 million, compared with a net loss of $7.63 million for the same period in 2023. The increase in net loss for the year ended December 31, 2024, is considered immaterial.

As of December 31, 2024, Can-Fite had cash and cash equivalents and short term deposits of $7.88 million as compared to $8.90 million as of December 31, 2023. The decrease in cash during the year ended December 31, 2024 is due to the ongoing operations of the Company.

The Company’s consolidated financial results for the year ended December 31, 2024 are presented in accordance with US GAAP Reporting Standards.

More detailed information can be found in the Company’s Annual Report on Form 20-F for the fiscal year ended December 31, 2024, a copy of which has been filed with the Securities and Exchange Commission (SEC). The Annual Report, which contains the Company’s audited consolidated financial statements, can be accessed on the SEC’s website at View Source as well as via the Company’s investor relations website at View Source The Company will deliver a hard copy of its Annual Report, including its complete audited consolidated financial statements, free of charge, to its shareholders upon request to Can-Fite Investor Relations at 26 Ben Gurion Street, Ramat Gan, 5257346, Israel or by phone at +972-3-9241114.

CONSOLIDATED BALANCE SHEETS
U.S dollars in thousands (except for share and per share data)

December 31,
2024 2023
ASSETS
CURRENT ASSETS:
Cash and cash equivalents $ 4,825 $ 4,278
Short term deposits 3,057 4,625
Prepaid expenses and other current assets 1,095 986
Short-term investment 5 19
Total current assets 8,982 9,908
NON-CURRENT ASSETS:
Operating lease right of use assets 111 52
Property, plant and equipment, net 27 29
Total non-current assets 138 81
Total assets $ 9,120 $ 9,989
CONSOLIDATED BALANCE SHEETS
U.S dollars in thousands (except for share and per share data)

December 31,
2024 2023
LIABILITIES AND SHAREHOLDERS’ EQUITY
CURRENT LIABILITIES:
Trade payables $ 618 $ 427
Current maturity of operating lease liability 53 27
Deferred revenues 405 622
Other accounts payable 976 944
Total current liabilities 2,052 2,020
NON-CURRENT LIABILITIES:
Long – term operating lease liability 51 13
Deferred revenues 1,581 1,713
Total long-term liabilities 1,632 1,726
CONTINGENT LIABILITIES AND COMMITMENTS
SHAREHOLDERS’ EQUITY:
Ordinary shares of no-par value – Authorized: 10,000,000 and 5,000,000,000 shares at December 31, 2024 and December 31, 2023; Issued and outstanding: 2,983,181,793 and 1,359,837,393 shares as of December 31, 2024 and December 31, 2023 - -
Additional paid-in capital 170,670 163,597
Accumulated other comprehensive income 1,127 1,127
Accumulated deficit (166,361 ) (158,481 )
Total shareholders’ equity 5,436 6,243
Total liabilities and shareholders’ equity $ 9,120 $ 9,989
CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS
U.S dollars in thousands (except for share and per share data)

Year ended December 31,
2023 2022
Revenues $ 674 $ 743
Research and development expenses (5,757 ) (5,983 )
General and administrative expenses (3,047 ) (2,955 )
Operating loss (8,130 ) (8,195 )
Total financial income, net 250 561
Net loss (7,880 ) (7,634 )
Basic and diluted net loss per share (0.00 ) (0.01 )
Weighted average number of ordinary shares used in computing basic and diluted net loss per share 2,175,926,512 1,278,333,912

On April 14, 2025 UroGen Pharma Ltd. (Nasdaq: URGN), a biotech company dedicated to developing and commercializing innovative solutions that treat urothelial and specialty cancers, reported that data on investigational drug UGN-102 (mitomycin) for intravesical solution, JELMYTO (mitomycin) for pyelocalyceal solution and UGN-301 (zalifrelimab) will be presented at the American Urological Association (AUA) 2025 Annual Meeting being held in Las Vegas, Nevada from April 26-29 (Press release, UroGen Pharma, APR 14, 2025, View Source [SID1234651908]).

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"We are thrilled to present the 18-month DOR data on UGN-102, along with additional data on JELMYTO and our investigational drug UGN-301 (zalifrelimab) an anti-CTL4 antibody in development for the treatment of recurrent non-muscle invasive bladder cancer, at the AUA Annual Meeting," said Mark Schoenberg, Chief Medical Officer, UroGen. "These data highlight the potential of our portfolio to offer significant advancements in the treatment of urothelial cancers."

Key details of UGN-102, JELMYTO and UGN-301 abstracts accepted by AUA:

UGN-102

Abstract Title

Presentation Details

Presenter

Treatment of recurrent low-grade intermediate-risk non-muscle invasive bladder cancer with UGN-102: ongoing results from a single-arm, open-label, phase 3 trial (ENVISION)

Podium Oral Presentation:

Abstract ID: PD12 – Galileo 1001

Saturday, April 26, 2025

3:30 PM – 5:30 PM

Dr. Sandip Prasad

Patient-reported side-effect burden for patients with low-grade intermediate-risk non-muscle invasive bladder cancer receiving treatment with UGN-102 (UGN-102 Integrated PROs)

Moderated Poster – MP15

Marco Polo 703

Sunday, April 27, 2025

9:30 AM – 11:30 AM

Dr. Charles Peyton

Treatment of low-grade intermediate-risk non-muscle invasive bladder cancer with UGN-102: long-term outcomes of the (OPTIMA II LT study)

Moderated Poster – MP15 –

Marco Polo 703

Sunday, April 27, 2025

9:30 AM – 11:30 AM

Dr. Neal Shore

JELMYTO

Long-term outcomes of treatment of recurrent or new-onset low-grade upper tract urothelial carcinoma with UGN-101, a mitomycin reverse thermal gel (OLYMPUS LT)

Interactive poster – IP12 – Casanova 501

Sunday, April 27, 2025

1:00 PM – 3:00 PM (IP12)

Dr. Brian Hu

UGN-301

Treatment of recurrent non-muscle invasive bladder cancer with UGN-301 (zalifrelimab): results of a phase 1 dose-escalation study (UGN-301-MONO)

Interactive Poster – IP02 – Marco Polo 701

Saturday, April 26, 2025

7:00 AM – 9:00 AM

Dr. Jay Raman

UroGen is a Founders’ Circle Sponsor of the AUA Innovation Nexus Conference
UroGen’s President and Chief Executive Officer, Liz Barrett, will participate in a Showcase Panel discussion on April 25, alongside exciting urology startups that span the globe and are developing products—devices, artificial intelligence platforms, diagnostic tests, etc.—covering a variety of urologic issues such as prostate and bladder cancer, kidney injuries, fertility testing, nocturnal enuresis, overactive bladder, and interstitial cystitis. Liz will also take part in the Founders’ Circle Awards Presentation.

The AUA Innovation Nexus is a powerful forum to advance urologic discovery to solutions that improve patient care and save lives. Register here: View Source

About UGN-102
UGN-102 (mitomycin) for intravesical solution is an innovative drug formulation of mitomycin, currently in Phase 3 development for the treatment of recurrent LG-IR-NMIBC. Utilizing UroGen’s proprietary RTGel technology, a sustained release, hydrogel-based formulation, UGN-102 is designed to enable longer exposure of bladder tissue to mitomycin, thereby enabling the treatment of tumors by non-surgical means. UGN-102 is delivered to patients using a standard urinary catheter in an outpatient setting by a trained healthcare professional. UroGen completed the submission of the rolling new drug application (NDA) for UGN-102 in August 2024, ahead of schedule. The FDA accepted the NDA for UGN-102 and assigned a Prescription Drug User Free Act (PDUFA) goal date of June 13, 2025.

About Non-Muscle Invasive Bladder Cancer (NMIBC)
In the U.S., bladder cancer is the second most common urologic cancer in men. LG-IR-NMIBC represents approximately 23,000 newly diagnosed bladder cancer patients each year and an estimated 59,000 recurrences annually among patients diagnosed in previous years. Bladder cancer primarily affects older populations with increased risk of comorbidities, with the median age of diagnosis being 73 years. Guideline recommendations for the management of NMIBC include trans-urethral resection of bladder tumor (TURBT) as the standard of care. Up to 70 percent of NMIBC patients experience at least one recurrence and LG-IR-NMIBC patients are even more likely to recur and face repeated TURBT procedures.

About JELMYTO
JELMYTO (mitomycin) for pyelocalyceal solution is a mitomycin-containing reverse thermal gel containing 4 mg mitomycin per mL gel indicated for the treatment of adult patients with LG-UTUC. It is recommended for primary treatment of biopsy-proven LG-UTUC in patients deemed appropriate candidates for renal-sparing therapy. JELMYTO is a viscous liquid when cooled and becomes a semi-solid gel at body temperature. The drug slowly dissolves over four to six hours after instillation and is removed from the urinary tract by normal urine flow and voiding. It is approved for administration in a retrograde manner via ureteral catheter or antegrade through nephrostomy tube. The delivery system allows the initial liquid to coat and conform to the upper urinary tract anatomy. The eventual semisolid gel allows for chemoablative therapy to remain in the collecting system for four to six hours without immediately being diluted or washed away by urine flow.

About UGN-301
UGN-301 is our investigational, in-licensed, anti-CTLA-4 monoclonal antibody (zalifrelimab), prepared with reverse-thermal hydrogel for intravesical administration into the bladder. Intravesical administration of UGN-301 is designed to increase drug concentrations in the bladder without significant systemic exposure, potentially diminishing the systemic toxicity associated with CTLA-4 blockade.

UroGen is evaluating UGN-301 as a monotherapy and as combination therapy for the intravesical treatment of high-grade NMIBC. UroGen is evaluating UGN-301, in a multi-arm Phase 1 study of UGN-301 as monotherapy and in combination with other agents.

On April 14, 2025 SynOx Therapeutics Limited ("SynOx"), a late-stage clinical biopharmaceutical company developing of emactuzumab for Tenosynovial Giant Cell Tumours (TGCT), reported that the United States Food and Drug Administration (FDA) has granted Fast Track Designation (FTD) to emactuzumab for the treatment of TGCT patients that are not amenable to or who would not benefit from surgery (Press release, SynOx Therapeutics, APR 14, 2025, View Source [SID1234651909]). Emactuzumab, a potentially best-in-class CSF-1 receptor (CSF-1R) inhibiting monoclonal antibody, is currently being evaluated in the TANGENT study, a global, multi-centre, randomized, double-blind, placebo-controlled registrational Phase 3 trial.

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TGCT is a rare, non-malignant but aggressively growing tumour of the synovium, tendon sheaths and bursa membranes primarily located in knee, hip, and ankle joints and caused by excessive production of CSF-1. It is a chronically debilitating disease for patients causing loss of function of the affected joints, as well as pain, stiffness and limited range of motion. Receipt of FTD for TGCT was supported by data from Phase 1/2 clinical studies demonstrating rapid, robust tumour reduction and durable response combined with a manageable safety profile. Emactuzumab has also previously received Orphan Medicinal Project designation from the European Medicines Agency.

"The granting of FTD for emactuzumab in TGCT highlights the devastating toll that this disease has on patients, as well as the critical need that remains for new treatment options," said Elyse Seltzer, M.D., Chief Medical Officer of SynOx Therapeutics. "Based on our clinical work to date, we believe that emactuzumab has significant potential to address key patient needs by offering an effective, short-course treatment with rapid onset and a durable response that allows individuals suffering from TGCT to better manage their disease and move forward with their lives. We look forward to completing the ongoing TANGENT study and progressing emactuzumab toward potential commercialization."

On April 14, 2025 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 interim results from the ongoing open-label, investigator-initiated study (IIS) evaluating extended HyBryte (synthetic hypericin) treatment for up to 54 weeks in patients with early-stage cutaneous T-cell lymphoma (CTCL) (Press release, Soligenix, APR 14, 2025, View Source [SID1234651910]). Following 18 weeks of treatment, 75% of patients achieved "Treatment Success," reinforcing HyBryte as a potentially safe and fast-acting therapy for this chronic and underserved cancer.

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The IIS is sponsored by Ellen Kim, MD, Director, Penn Cutaneous Lymphoma Program, Vice Chair of Clinical Operations, Dermatology Department, and Professor of Dermatology at the Hospital of the University of Pennsylvania who was a leading enroller in the Phase 3 FLASH (Fluorescent Light Activated Synthetic Hypericin) study and is the Principal Investigator for the confirmatory Phase 3 FLASH2 study for the treatment of early-stage CTCL. To date, nine patients have been enrolled and treated with HyBryte over a time period of up to 54 weeks in the IIS, with all data for the Week 18 timepoint now complete. Consistent with the Phase 3 trials, Treatment Success is predefined as a greater than or equal to 50% improvement in the cumulative mCAILS (modified Composite Assessment of Index Lesion Severity) score compared to Baseline. Of the eight patients who could be evaluated through Week 18, six (75%) had a Treatment Success. The 18-week treatment window is the same window that is being evaluated in the FLASH2 double-blind, placebo-controlled, randomized study that is currently enrolling patients. This rapid response is a distinct advantage of HyBryte therapy, with many other therapies used in CTCL taking up to six to 12 months to generate a clinically meaningful treatment response. Of these eight evaluable patients through Week 18, four have gone on to complete the 54-week treatment with an average maximum improvement in mCAILS score of 85%, three are still on treatment and one dropped out (due to logistical issues). HyBryte appears to be safe and well tolerated in all patients.

"The complete response rates observed, including three patients achieving a complete response on this study to date, as well as the consistent treatment response and safety profile across multiple HyBryte clinical studies, has been exciting to see," noted Dr. Kim, Principal Investigator of the IIS. "In the first Phase 3 FLASH study, HyBryte was shown to be efficacious with a benign safety profile compared to the current therapies of steroids, chemotherapeutics and ultraviolet light in this chronic orphan disease. With limited treatment options, especially in the early stages of their disease, CTCL patients are often searching for alternative treatments. In our study funded by the U.S. Food and Drug Administration (FDA), initial results evaluating the expanded use of HyBryte in a "real world" treatment setting remain very promising, further supporting and extending results from the previous positive Phase 2 and 3 clinical trials. It also provides further confidence to the potential responses we can expect to see in the confirmatory Phase 3 placebo-controlled FLASH2 study. We look forward to continuing to work with the FDA to complete the IIS while we participate in the confirmatory 18-week FLASH2 study."

"We are pleased with these recent study results, giving patients an opportunity to access the therapy in an open-label setting," stated Christopher J. Schaber, PhD, President and Chief Executive Officer of Soligenix. "CTCL is an incredibly difficult to treat orphan disease and remains an area of unmet medical need with a very limited number of safe and effective therapies. Following the initial Phase 3 FLASH study, which demonstrated the safety and efficacy of shorter courses of HyBryte therapy, we are pleased to see that continuing treatment for longer time periods is resulting in the anticipated improved outcomes for patients. The majority of patients show a strong treatment response by Week 18, a noticeable advantage over other therapies that may take six to 12 months to show improvement. As the body of compelling data continues to grow in support of this novel therapy, we look forward to continuing to work with Dr. Kim on this important study as well as advancing enrollment in the 80-patient confirmatory Phase 3 FLASH2 replication study. We will plan to provide additional updates on the IIS as data becomes available."

The clinical study RW-HPN-MF-01, "Assessment of Treatment with Visible Light Activated Synthetic Hypericin Ointment in Mycosis Fungoides Patients" is designed as an open-label, multicenter clinical trial enrolling approximately 20 patients in the U.S. Patients have the potential to be treated for up to 54 weeks with twice a week dosing (visible light activation following ointment application by 24 ± 6 hours). The study also allows for potential transition to a "real-world" setting with home-use. The primary endpoint for the study is evaluating the number of treatment successes defined as ≥50% reduction in the cumulative mCAILS score from Baseline to end of the treatment. Study RW-HPN-MF-01 is supported by an FDA Orphan Products Development Grant of up to $2.6 million.

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 safe, 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 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 (Cycle 1), 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 this 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 responses also revealed a statistically significant improvement (p<0.0001) between the two timepoints, 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.

Following the first Phase 3 study of HyBryte for the treatment of CTCL, the FDA and the EMA indicated that they would require a second successful Phase 3 trial to support marketing approval. With agreement from the EMA on the key design components, the second, confirmatory study, called FLASH2, is expected to be initiated before the end of 2024. This study is a randomized, double-blind, placebo-controlled, multicenter study that will enroll approximately 80 subjects with early-stage CTCL. The FLASH2 study replicates the double-blind, placebo-controlled design used in the first successful Phase 3 FLASH study that consisted of three 6-week treatment cycles (18 weeks total), with the primary efficacy assessment occurring at the end of the initial 6-week double-blind, placebo-controlled treatment cycle (Cycle 1). However, this second study extends the double-blind, placebo-controlled assessment to 18 weeks of continuous treatment (no "between-Cycle" treatment breaks) with the primary endpoint assessment occurring at the end of the 18-week timepoint. In the first Phase 3 study, a treatment response of 49% (p<0.0001 vs patients receiving placebo in Cycle 1) was observed in patients completing 18 weeks (3 cycles) of therapy. In this second study, all important clinical study design components remain the same as in the first FLASH study, including the primary endpoint and key inclusion-exclusion criteria. The extended treatment for a continuous 18 weeks in a single cycle is expected to statistically demonstrate HyBryte’s increased effect over a more prolonged, "real world" treatment course. Given the extensive engagement with the CTCL community, the esteemed Medical Advisory Board and the previous trial experience with this disease, accelerated enrollment in support of this study is anticipated, including the potential to enroll previously identified and treated HyBryte patients from the FLASH study. Discussions with the FDA on an appropriate study design remain ongoing. While collaborative, the agency has expressed a preference for a longer duration comparative study over a placebo-controlled trial. Given the shorter time to potential commercial revenue and the similar trial design to the first FLASH study afforded by the EMA accepted protocol, this study is being initiated. At the same time, discussions with the FDA will continue on potential modifications to the development path to adequately address their feedback.

Additional supportive studies have demonstrated the utility of longer treatment times (Study RW-HPN-MF-01, see above), the lack of significant systemic exposure to hypericin after topical application (Study HPN-CTCL-02) and its relative efficacy and tolerability compared to Valchlor (Study HPN-CTCL-04).

In addition, the FDA awarded an Orphan Products Development grant to support the investigator-initiated study 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 the University of Pennsylvania 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 more than 1.7 million individuals living with the disease in the U.S. and Europe (European Union and United Kingdom). 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 approximately 31,000 individuals in the U.S. (based on SEER data, with approximately 3,200 new cases seen annually) and approximately 38,000 individuals in Europe (based on ECIS prevalence estimates, with approximately 3,800 new cases annually).