By Grant Zeng, CFA
Recently, Soligenix (NASDAQ:SNGX) held a webcast with investors and analysts. During the webcast conference, senior management from the company along with KOLs from the therapeutic area discussed in detail the potential of SGX942 as the standard of care for the treatment of oral mucositis in head and neck cancer patients.
SGX942 and the Innate Immune System
SGX942 is the company’s lead Innate Defense Regulator (IDR) candidate. Soligenix is developing SGX942 to treat infections and tissue damages. SGX942 represents a novel and innovative approach to therapeutically modulating the immune system by targeting the innate immune system and has the potential to target multiple indications.
IDRs provide a novel approach to the control of infection and tissue damage via highly selective binding to an intracellular adaptor protein, sequestosome-1, also known as p62, which has a pivotal function in signal transduction during activation and control of the innate defense system. Sequestosome is a recently identified target for modulation of innate defenses and is expressed in most cell types.
IDRs have no direct antibiotic activity but modulate host responses, increasing survival after infections with a broad range of bacterial Gram-negative and Gram-positive pathogens including both antibiotic sensitive and resistant strains, as well as accelerating resolution of tissue damage following exposure to a variety of agents including bacterial pathogens, trauma and chemo- or radiation-therapy.
Since IDRs target the host (and not the pathogen), IDRs do not engender resistance and are active against resistant pathogens. In vitro data indicate that the endothelium plays a significant role in IDR activity and animal studies show that IDRs selectively promote monocyte and macrophage recruitment to disease sites and accelerate resolution of disease. Though IDR action depends on monocytes and macrophages, there is no dependence on either the adaptive immune system (e.g., T cells and B cells) or neutrophils. This suggests that IDRs may be effective in immunosuppressed patients. Moreover, p62 functions downstream of signaling receptors (TLRs, NODs) responsible for sensing both infection and tissue damage, which gives it a role in innate immune modulation relevant to a wide range of diseases from infection (pathogen sensing) to colitis and mucositis (damage sensing).
SGX942 Has the Potential of Targeting Multiple Indications
SGX942 is a fully synthetic, 5-amino acid peptide with high aqueous solubility and stability. Extensive in vivo preclinical studies have shown that SGX942 reduces tissue damage associated with chemotherapy, radiation, trauma and inflammation. Although SGX942 is not directly antimicrobial, it accelerates pathogen clearance and increases host survival in a broad spectrum of bacterial infections including Gram positive and negative bacteria, and both drug sensitive and resistant strains, by directly targeting the host innate immune system.
Extensive animal data set points to high potential for development of a broad spectrum of SGX942 products based on the following attributes:
- ameliorate injury;
- reduce inflammation;
- fight both antibiotic sensitive and resistant infections;
- complement antibiotics; and
- protect immune-compromised animals.
More specifically, SGX942 ameliorates tissue damage in models of chemotherapy- or radiation-induced mucositis as well as DSS-induced colitis and has shown accelerated healing in a murine model of skin infection and injury. SGX94 is not a growth factor and does not promote tumor growth or protect tumors against treatment in a breast cancer xenograft model using the MCF-7 cell line.
Studies in murine models of bacterial infection have shown activity against a broad range of pathogens including methicillin-resistant S. aureus (MRSA), K. pneumoniae, E.coli, P. aeruginosa, and B. pseudomallei. SGX94 enhances the activity of antibiotics administered at sub-optimal doses. Studies in a model of MRSA bacteremia indicate that SGX94 is effective both therapeutically and prophylactically. SGX94 is most effective when administered by IV injection and has a very short plasma half-life (~10 minutes). When administered prophylactically in the MRSA model, a single dose of SGX94 is protective when injected up to 5 days before bacterial challenge, indicating a prolonged pharmacodynamic effect despite rapid plasma clearance.
In a double-blind, placebo-controlled Phase I clinical trial of SGX942 in 84 healthy volunteers with both single ascending dose and multiple ascending dose components, SGX942 showed a strong safety profile when administered IV over 7 days and was consistent with safety results seen in pre-clinical studies. Drug clearance in humans is rapid and similar to results seen in pre-clinical studies.
Development Status of SGX942 for the Treatment of Oral Mucositis
The company has completed a Phase II proof of concept (POC) study of SGX942 (NCT02013050) for the treatment of oral mucositis in head and neck cancer patients.
The Phase II Trial (IDR-OM-01)
The trial was initiated in December, 2013. This Phase II trial is a randomized, double-blind, dose-ranging, placebo-controlled trial, initially set to enroll approximately 75 subjects across three SGX942 dose groups (1.5 mg/kg, 3.0 mg/kg and 6.0 mg/kg) and placebo, focused on demonstrating the safety and biologic activity of SGX942 in patients with tumors of the mouth and oropharynx who often experience debilitating oral mucositis as a consequence of tumor treatment with chemoradiation therapy (CRT).
In early March 2015, Soligenix received a positive recommendation from the Data Review Committee (DRC) to continue the enrollment. Following DRC review of available data on the subjects enrolled in the trial, the committee recommended that enrollment include an additional 20 subjects randomized into either a single SGX942 dose group or the placebo group to allow for a more targeted assessment of the drug's potential effect and to inform final dose selection in this patient population.
The primary efficacy assessment is the comparison of the incidence and/or duration of both ulcerative and severe oral mucositis throughout the subjects' 7 week course of CRT and for an additional 4 weeks thereafter. Other key efficacy measures will assess patient reported outcomes, pharmacoeconomic parameters such as hospitalization and radiation-associated side effects including mouth stiffness and dryness.
In August 2015, the trial completed the expanded enrollment.
The Initial Positive Data
In December 2015, Soligenix announced initial positive results from the Phase II clinical trial.
In June 2016, the Company presented the data at the Multinational Association for Supportive Care in Cancer (MASCC) conference in Adelaide, Australia.
The Phase II study enrolled 111 patients across three SGX942 dose groups (1.5, 3.0, and 6.0 mg/kg) and a placebo group and evaluated patients undergoing CRT for head and neck cancer.
This POC Phase II study achieved all objectives. In the 1.5 mg/kg treatment group, the median duration of severe oral mucositis was decreased by 50% in all patients, from 18 days to 9 days (p=0.099), meeting the prospectively defined statistical threshold of p<0.1.
In a subgroup of patients receiving the most aggressive chemoradiation therapy, the median duration of severe oral mucositis was reduced even more from 30 days to 10 days (67%, p=0.04). The sample size was reasonable as well.
The 1.5 mg/kg dose was identified as the best dose for future trials.
Further, a trend towards increased incidence of "complete response" of tumor at the one month follow up visit was observed (47% in placebo vs. 63% in SGX942 at 1.5 mg/kg). Decreases in mortality and significant decreases in infection rate were also observed with SGX942 treatment and are being further evaluated.
SGX942 was generally safe and well tolerated, consistent with the safety profile observed in the prior Phase I study conducted in 84 healthy volunteers.
The Long-Term Follow Up Data
In December, 2016, Soligenix announced the long-term follow-up data from the Phase II clinical trial.
The additional 12-month safety data remained consistent with the preliminary positive safety and efficacy findings from the Phase II study and provided further support for advancing SGX942 into a pivotal Phase IIb/III clinical trial.
Long-term follow-up visits conducted throughout 2016 further demonstrated that SGX942 was safe, well-tolerated, and did not interfere with CRT as demonstrated by improved survival and tumor resolution at one and 12 months. Overall, there were no drug-related toxicities identified in this study.
While the placebo population experienced the expected 12-month survival rate of approximately 80%, as defined in the Surveillance, Epidemiology, and End Results (SEER) statistics 1975-2012 from the National Cancer Institute, the SGX942 1.5 mg/kg treatment group reported a 12-month survival rate of 93% (7% mortality in the SGX942 1.5 mg/kg group compared to 19% in the placebo group). Similarly, tumor resolution (complete response) at 12 months was better in the SGX942 1.5 mg/kg treatment group relative to the placebo population (80% in the 1.5 mg/kg group compared to 74% in the placebo group).
In addition to safety, evaluations of other secondary efficacy endpoints, such as the utilization of opioid pain medication, indicated that the SGX942 1.5 mg/kg treatment group had a 40% decrease in the use of opioids at the later stage of the treatment phase of the trial, when OM is usually most severe and expected to increase pain medication use. This was in contrast to the placebo group, which demonstrated a 10% increase in use of opioids over this same period. These results were consistent with the observed significant decrease in the duration of severe OM. There were no differences observed in the rates of xerostomia (dry mouth) and trismus (limited jaw range of motion) across the SGX942 and placebo dose groups in the study.
The Implication and Future Development Plan
The positive results from the POC Phase II trial represents a significant milestone in the development of SGX942 for the treatment of oral mucositis. The Company already generated results in large number of animal models and from a phase I safety trial in healthy volunteers, but this is the first time SGX942, which is considered a new chemical entity, has been used to treat sick patients of oral mucositis in head and neck cancer patients. This is a very sick and difficult patient population to study where there are currently no FDA approved drugs to combat this condition.
The study met all of its objectives including defining a clinically effective dose of SGX942 – specifically the 1.5 mg/kg as seen in both the acute and long-term follow-up phases of the trial. The Phase II study also identified the most appropriate clinical endpoint and patient population to use in a future pivotal study.
The company is engaging the FDA and the European Medicines Agency (EMA) on the design of a pivotal Phase IIb/III clinical program. As of this writing, Soligenix announced that it has received positive Scientific Advice from the EMA for the development of SGX942 as a treatment for oral mucositis in patients with head and neck cancer receiving chemoradiation therapy. The Scientific Advice from the EMA indicates that a single, double-blind, placebo-controlled, multinational, Phase III pivotal study (IDR-OM-02), if successful, in conjunction with the Phase II dose-ranging study IDR-OM-01, is generally considered sufficient to support a marketing authorization application (MAA) to the EMA for potential licensure in Europe. The advice also provides several constructive suggestions to strengthen the study design and data collection that will be integrated into the final protocol.
This positive Scientific Advice outcome represents a significant step forward in the development of SGX942 as oral mucositis therapy and has the potential to accelerate the registration timetable in Europe. The company anticipates initiating this pivotal Phase III clinical trial in the first half of 2017.
Simultaneous with the FDA meeting, the company will be aggressively pursuing opportunities for partnership to support subsequent clinical trials with SGX942. With the compelling data from the Phase II trial, it’s our belief that it should be relatively easy to find a partner with favorable terms.
SGX942 has received fast-track designation from the FDA.
SGX942 Could be a Game Changer in the Treatment of Oral Mucositis
Mucositis is a debilitating condition involving extensive ulceration of the oral cavity that frequently affects cancer patients undergoing radiation and chemotherapy treatment. Roughly 90% of patients on radiation (43% severe) and 40% of patients receiving chemotherapy get mucositis. There are an estimated 500,000 cancer patients getting mucositis annually in the United States alone. World-wide, the potential market for mucositis will exceed $1 billion in the next few years.
Mucositis can be severely debilitating and can lead to infection, sepsis, the need for parenteral nutrition and narcotic analgesia. The gastrointestinal damage causes severe diarrhea. These symptoms can limit the doses and duration of cancer treatment, leading to sub-optimal treatment outcomes. We believe any treatment that accelerates healing and/or diminishes the rate of appearance of mucositis would have a significant beneficial impact on the quality of life of these patients and may allow for more aggressive chemotherapy.
Overall, clinically significant mucositis impacts almost all patients with head and neck cancer (HNC) treated with chemoradiation; 70% patients get severe mucositis. Patients develop extensive, deep, extremely painful ulcerations of the lining of the mouth and throat that requires narcotic analgesics. Despite narcotics, many patients have break-through pain which effects their ability to function (including eating). When asked, mucositis is most frequently reported as the worst treatment complication among HNC patients being treated with CRT.
The health and economic costs of mucositis in this population are profound: the incremental cost of mucositis is over $17,000 per patient with the condition and is largely driven with the need for hospitalization to manage dehydration or pain. Patients who are radiated are treated with small daily doses of radiation for about 7 weeks. Since the biological drivers of mucositis start immediately with the first dose of radiation, preventive strategies for mucositis start on day 1 and continue throughout the radiation course. Consequently, while the total number of new cases of HNC in the US is relatively small (about 50K new cases per year), the dosing opportunity is significant. HNC represents about 20% of the total potential mucositis market.
However, there are no approved, mechanistically-based prophylactic or treatment driven, interventions for mucositis in patients with HNC. A number of palliative devices are used for symptom management with modest results. Included in these are ‘magic mouthwash’ (a rinse usually formulated in hospitals and largely based on institutional folklore), GelClair, MuGard, Episil and Caphosol. Benzydamine HCl is approved in the EU and Canada for mucositis in radiated patients, but it fails to confer efficacy when concomitant chemoradiation is delivered (the standard of care). Low level laser therapy has been advocated by some. Its impact on tumor behavior and response to treatment is questionable.
Palifermin (Kepivance) is the only drug approved for the prevention of mucositis in patients with hematological malignancies who receive conditioning regimens prior to transplant. Its use is limited, probably because of cost ($10k for a 6 dose course) and because it has to be given prophylactically (the incidence of severe OM in this group is about 40% so one treats 10 when only 4 actually benefits). It is no longer available in Europe.
The mechanisms of mucositis have been extensively studied and have been recently linked to the interaction of chemotherapy and/or radiation therapy with the innate defense system. Bacterial infection of the ulcerative lesions is now regarded as a secondary consequence of dysregulated local inflammation triggered by therapy-induced cell death, rather than as the primary cause of the lesions. As a modulator of the innate immune system, SGX942 has the potential to target both primary and secondary causes of mucositis.
Given the proposed MOA, SGX942 has the potential to favorably impact other epithelial toxicities associated with radiotherapy including dermatitis, esophagitis and proctitis. In theory, it could also favorably impact other tissue-based injury such as fibrosis and, perhaps, systemic complications such as fatigue.
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