Soligenix, a late-stage bio-pharmaceutical company developing products that address unmet medical needs in the areas of inflammation, oncology and biodefense, announced that agreement has been reached with the US Food and Drug Administration (US FDA) on the design of a pivotal, phase 3 clinical trial evaluating its product SGX301 (synthetic hypericin) for the treatment of cutaneous T-cell lymphoma (CTCL).

SGX301 is a novel, first-in-class, photodynamic therapy utilising safe visible light for activation.  The active ingredient, synthetic hypericin, is a potent photosensitizer which is topically applied to skin lesions and activated by visible fluorescent light.  This treatment approach avoids the risk of secondary malignancies (including melanoma) inherent with the frequently employed DNA-damaging chemotherapeutic drugs and other photodynamic therapies that are dependent on ultraviolet A (UVA) exposure.  Topical hypericin has demonstrated safety in a phase 1 clinical study in healthy volunteers.  In a phase 2, double-blind, placebo-controlled clinical study in CTCL patients, the drug was safe and well tolerated, with 58.3 per cent of the CTCL patients responding to SGX301 treatment compared to only 8.3 per cent receiving placebo (p ? 0.04).

“I enthusiastically support Soligenix in their efforts to improve outcomes for patients with CTCL, affecting up to 50,000 patients in the US,” stated Alain Rook, MD, director, Cutaneous Lymphoma Programme, Hospital of the University of Pennsylvania.  “I have had a lengthy scientific and clinical interest in hypericin and am pleased that the Soligenix team is advancing this product to a phase 3 clinical study.  I believe that SGX301 has the potential to be a major step forward in the treatment of CTCL by providing a safer alternative therapy over the course of the patients’ disease than is currently available.”

Based on the positive results demonstrated in the phase 2 study of SGX301, the upcoming phase 3 protocol will be a highly powered, double-blind, randomised, placebo-controlled, multicentre trial and will seek to enroll approximately 120 patients. The trial will consist of three treatment cycles, each of 8 weeks duration.  Treatments will be administered twice weekly for the first 6 weeks and treatment response will be determined at the end of Week 8.  In the first treatment cycle, approximately 80 patients will receive SGX301 and 40 will receive placebo treatment of their index lesions.  In the second cycle, all patients will receive SGX301 treatment of their index lesions and in the third (open-label) cycle all patients will receive SGX301 treatment of all their lesions.  Subjects will be followed for an additional 6 months after the completion of treatment. The primary clinical efficacy endpoint is treatment response assessed using the CAILS (Composite Assessment of Index Lesion Severity) score evaluating the three worst index lesions at the end of Cycle 1 (Week 8).  The trial is anticipated to begin in the first half of 2015 with primary data available in the second half of 2016.

“We are pleased to have FDA agreement on our phase 3 protocol design in CTCL,” stated Christopher J. Schaber, PhD, president and chief executive officer of Soligenix. “We are excited to move forward with this pivotal trial in an effort to address the significant unmet medical need in this orphan disease.”

Cutaneous T-cell lymphoma (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 Programmemed to migrate to the skin.  These skin-trafficking malignant T-cells migrate to the skin, causing various lesions to appear that may change shape as the disease progresses, typically beginning as a rash and eventually forming plaques and tumors.  Mycosis fungoides (MF) is the most common form of CTCL.  It generally presents with skin involvement only, manifested as scaly, erythematous patches.  Advanced disease with diffuse lymph node and visceral organ involvement is usually associated with a poorer response rate to standard therapies.  A relatively uncommon sub-group of CTCL patients present with extensive skin involvement and circulating malignant cerebriform T-cells, referred to as Sézary syndrome.  These patients have substantially graver prognoses than those with MF.

With CTCL mortality is related to stage of disease, 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.  Treatment of early-stage disease generally involves skin-directed therapies.  Most MF treatments are not approved by the FDA.  One of the most common unapproved therapies used for early-stage disease is oral 5 or 8-methoxypsoralen (Psoralen) given with ultraviolet A (UVA) light, referred to as PUVA.  Although having demonstrated a level of efficacy, psoralen is a mutagenic chemical that interferes with DNA causing mutations and other malignancies.  Moreover, UVA is a carcinogenic light source that when combined with the psoralen, results in serious adverse effects including secondary skin cancers; therefore, the FDA requires a Black Box warning for PUVA.

CTCL constitutes a rare group of NHLs, occurring in about 4 per cent of the approximate 500,000 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 20,000 individuals in the US, with approximately 2,800 new cases seen annually.

SGX301 is a novel, first-in-class, photodynamic therapy utilising safe visible light for activation.  The active ingredient in SGX301 is synthetic hypericin, a potent photosensitizer which is topically applied to skin lesions and then activated by fluorescent light 16 to 24 hours later.  Hypericin is also found in several species of Hypericum plants, although the drug used in SGX301 is chemically synthesized by a proprietary manufacturing process and not extracted from plants.  Importantly, hypericin is optimally activated with visible light thereby avoiding the negative consequences of ultraviolet light.

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 both settings, it appears that the mode of action is an induction of cell death in a concentration as well as a light dose-dependent fashion.  These effects appear to result, in part, from the generation of singlet oxygen during photoactivation of hypericin.

Hypericin is one of the most efficient known generators of singlet oxygen, the key intermediate for phototherapy.  The generation of singlet oxygen induces necrosis and apoptosis in adjacent cells.  The use of topical hypericin coupled with directed visible light results in generation of singlet oxygen only at the required site.  The use of visible light (as opposed to cancer-causing ultraviolet light) is a major advance in photodynamic therapy.  In a published phase 2 clinical study in CTCL, patients experienced a significant response with topical hypericin treatment as compared to placebo:  58.3 per cent compared to 8.3 per cent (p ? 0.04), respectively.  

SGX301 has received orphan drug designation from the US FDA. The US Orphan Drug Act is intended to assist and encourage companies to develop safe and effective therapies for the treatment of rare diseases and disorders.  In addition to providing a seven year term of market exclusivity for SGX301 upon final FDA approval, orphan drug designation also positions Soligenix to be able to leverage a wide range of financial and regulatory benefits, including government grants for conducting clinical trials, waiver of expensive FDA user fees for the potential submission of a New Drug Application for SGX301, and certain tax credits.