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SNGX: What Can We Expect from the Upcoming Interim Analysis of Phase III SGX301 for CTCL?

By Grant Zeng, CFA



Soligenix (NASDAQ:SNGX) is a late-stage biopharmaceutical company with two Phase III candidates. SGX301 is in Phase III clinical trial to treat cutaneous T-cell lymphoma (CTCL); and SGX942 is in Phase III study to treat oral mucositis in head and neck cancer.

While we are waiting for the interim analysis of SGX301 in the coming month, we recently interviewed Dr. Richard C. Straube, Sr. VP & Chief Medical Officer of Soligenix (SNGX) with respect to the prospect of this late stage candidate. Following are the summary of what we get from Dr. Richard Straube.

Grant: What is the mechanism of action of SGX301?

Dr. Straube: SGX301, synthetic hypericin ointment, is applied only to the skin lesions and is absorbed into the skin. The drug is selectively taken up by malignant cells at up to 10-fold higher levels than into healthy cells. The drug is transported to the Golgi body/endoplasmic reticulum of the cell. When exposed to visible light (maximal absorbency at 530-600 nm- yellow/ orange light), the high photosensitizer drug absorbs the energy and is converted to a high-energy state. This form of the drug interacts with the intracellular oxygen to produce singlet-oxygen which in turn activates the mitochondrial apoptotic pathway leading to the programmed cell death of that cell. Visible light is delivered to the lesions using the proprietary Light Panel that consists of cool-light fluorescent light bulbs. The light treatment is carefully calibrated to produce a specific amount of light energy.

Grant: How is it different than other photodynamic therapies (i.e., PUVA) and systemic treatments?

Dr. Straube: The most commonly used phototherapy for psoriasis and CTCL treatment (off-label use) is psoralen drug (P; given as either a pill or ointment) that is activated with ultraviolet A (UVA) light and the treatment is called PUVA. Psoralen operates primarily through the intercalation within double-stranded DNA and this causes many cells to die but leaves some cells with DNA damage that over time can lead to secondary cancer, like many anticancer drugs. For activation, psoralen requires exposure to ultraviolet light in the 320-400 nm range (UVA), that portion of the sunlight spectrum associated with the development of skin cancers, including melanoma, and skin aging. Thus, the treatment consists of a mutagenic drug with a carcinogenic activation source. Although PUVA is very effective, studies have shown that prolonged use is associated with an increased risk of skin cancers and melanoma; as a result, PUVA carries a Black Box warning in its package labeling. When psoralen is given as an oral drug, the drug is distributed throughout the body to both healthy and cancerous cells and can lead to inadvertent tissue damage including the retinas, so that dark sunglasses are necessary after taking the oral drug. It is important to note that PUVA, although often used in CTCL, is not approved for use in CTCL.

Systemic therapies are usually reserved for the treatment of CTCL patients with more advanced, late disease and many are associated with a variety of safety concerns.     

Grant: What else is approved in early stage and/or front-line treatment of CTCL?

Dr. Straube: Currently, there are no drugs approved for first line therapy of CTCL. Most of the drugs used in early stage CTCL are being used either off-label or earlier than the indication recommends, which is not ideal. For most patients, early stage disease is treated with skin-directed therapy. The commonly used drugs are:

• Bexarotene (Targretin®) which is a retinoid- derivative of vitamin A (similar to Accutane®) approved in mycosis fungoides when “other therapies are insufficient”. The mechanism of action is somewhat unclear. It is teratogenic, enhances insulin activity that can, in diabetes, lead to hypoglycemia, associated with hyperlipidemia and hypothyroidism, can be associated with skin irritation (itching, burning, redness, and/or rashes), and is expensive.

• Nitrogen mustard compounds, most commonly mechlorethamine (Mustargen™ and Valchor™) approved for patients who have failed “prior skin-directed therapy”. This acts as an alkalizing agent that damages DNA (with the potential of secondary cancers with prolonged use) and is associated with allergic skin reactions (redness, swelling, itching, skin ulcers or blisters, skin infection) in ~25% of patients and hyperpigmentation of skin.

• Other drugs are occasionally used but are not approved for CTCL including other retinoid drugs (such as tazarotene), other nitrogen mustard related drugs (carmustine [AKA: bis-chloroethylnitrosourea, BCNU, BiCNU],cyclophosphamide, ifosfamide, melphalan, and chlorambucil) but these carry with them similar side-effect profiles to their analogs.

Grant: What is the Phase III trial design and endpoints?

Dr. Straube: The Fluorescent Light Activated Synthetic Hypericin (FLASH) clinical trial is a pivotal, placebo-controlled, double-blind, multicenter study that is scheduled to enroll approximately 120 evaluable subjects. In the trial, patients with a proven diagnosis of mycosis fungoides Stage IA, IB, or IIA will apply study ointment twice weekly for 6 weeks to each of the three prospectively selected index lesions. Light therapy with the proprietary Light Panel is administered about 24 hours later. The severity of the lesions is assessed using the Composite Assessment of Index Lesions Score (CAILS), an accepted, standard scale for lesion assessments in dermatology. The index lesions are graded at baseline and then again two weeks after the last light therapy (to allow the full effect of the therapy to be seen). An improvement of at least 50% in the cumulative CAILS score is classified as a successful treatment. Patients are randomized 2:1 to the SGX301: placebo for this portion of the study. Other secondary endpoints evaluated will include the number of complete responses, changes in the histology of lesions, the patients’ general health, and the duration of the improvements.

In addition to the primary treatment portion of the trial, two open-label “Cycles” are included in the trial. In Cycle 2 of the trial, the three index lesions in all patients will be treated with open-label SGX301 and this data will provide information on the value of a second course of SGX301 (in patients that were randomized to SGX301 in the randomized portion of the trial) and demonstrate the consistency of SGX301 treatment (in patients randomized to placebo in the randomized portion of the trial). An optional Cycle 3 was included in the design as a compassionate use Cycle 3 in which all patients were offered SGX301 to all of their lesions.

Grant: What is the purpose of the interim analysis? What will it potentially tell you and when is it?

Dr. Straube: As with every pivotal clinical trial, the number of patients scheduled for enrollment is based on the desired statistical parameters for the trial including the statistical threshold of success (the critical p-value, usually 0.05) and the power of the trial (the risk of not being able to reach the statistical threshold if the drug is actually effective). In addition, the following assumptions are needed for the calculation: the success rate in the placebo group and expected improvement in the rate with the drug. These later assumptions are most often based on prior trials with the drug; however, these rates are usually based on smaller trials so that the actual rates may be somewhat different. The interim analysis is a common technique to check these assumed rates and re-adjust the size of the trial if the assumptions were inaccurate. This dramatically decreases the risk that the trial is declared “negative” because the placebo patients did better than assumed or the drug was somewhat less effective than assumed- despite the drug actually being of benefit. Review of the unblinded data by our independent Data Monitoring Committee will lead to one of the following recommendations to Soligenix following the Interim Analysis:

• Stop the trial for overwhelming futility- unlikely that the trial will be statistically significant even if the number of patients enrolled is doubled
• Stop the trial for overwhelming success- the data is so compelling that further enrollment is not needed
• Continue the trial as planned- the original assumptions were reasonably accurate
• Increase the sample size- the placebo rate, the drug effect rate, or both are different enough from the original assumptions that more patients will need to be enrolled to maintain the desired statistical parameters (p-value threshold of 0.05 and desired power of >90% for this trial)

It is important to understand that the company will remain blinded to the actual data unless the recommendation of the committee is to stop the trial. A recommendation to continue the trial with either the original number of patients or an increased number of patients does not guarantee that the trial will be successful but does provide reassurance that the trial has the originally calculated chance of success when completed.

Grant: Do you think this study will support US approval, if positive?
Dr. Straube: Obviously, the probability of approval in the USA is dependent on the actual data from the trial. Nonetheless, Soligenix is confident that given the theoretical safety of the drug/light combination in this Orphan Disease, a positive study will support approval of the treatment.

Grant: What is your intellectual property position?

Dr. Straube: Here are the summary of our major IP

• Natural hypericin well known – no patent protection
• Method of synthesis granted for synthetic hypericin (Expiry: 2030)
• Formulation & Method of use in CTCL granted (Expiry: 2022)
• Method of use in psoriasis granted (Expiry: 2022-2031)
Methods of synthesis and formulation for synthetic hypericin granted (Expiry: 2034) 
• CTCL orphan drug designation: 7 years market exclusivity (US)
• CTCL orphan drug designation: 10 years market exclusivity (EU)

Grant: What is the US and EU market potential?

Dr. Straube: It is conservatively estimated that there are 20,000 CTCL patients in the USA and an equal number of patients in Europe with 2,000- 3,000 new cases per year in each area. It is important to note that the incurable disease has an indolent course with improvements seen after treatment but frequent recurrences requiring periodic retreatment for years or decades. Although a definitive commercial plan has not been developed/disclosed by the Company as yet, our guidance has been that the potential world-wide market for CTCL is in the $250 million range.

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