Monopar Therapeutics Inc., another company looking to attack the bane of many cancer patients – severe oral mucositis (SOM) – has filed for a $40.2 million IPO that will help advance into phase III its mucobuccal tablet of the adrenergic alpha2 agonist clonidine, branded Validive.

The Wilmette, Ill.-based firm has Validive in the works for SOM in patients undergoing radiotherapy for oropharyngeal cancer (OPC). In September 2017, Monopar exercised an option to license Validive from Onxeo SA, of Paris, which developed the compound through its phase II trial. In that experiment, Validive turned up clinically meaningful efficacy signals in the 64-patient OPC population that was randomized to placebo, Validive 50-mcg dose and Validive 100-mcg dose.

Specifically, the absolute incidence of SOM in OPC patients who received a dose of Validive 100 mcg once per day was reduced by 26.3% (incidence rate of 65.2% in placebo, 45% in Validive 50-mcg group, and 38.9% in Validive 100-mcg group). The median time to onset of SOM was 37 days in the placebo cohort, 45 days in the Validive 50-mcg cohort and no median time of onset was reached in the Validive 100-mcg group, since fewer than half of that cohort of patients developed SOM.

There was also a 37.8% reduction in the median duration of the SOM for the Validive 100-mcg group vs. placebo (41 days for placebo group, 34 days Validive 50-mcg group and 25.5 days Validive 100-mcg group) in patients who developed SOM. Median duration of SOM across all patients, including those who did and did not develop SOM, was 17 days in the placebo group and 0 days in each of the Validive 50- and 100-mcg groups. A positive dose response was seen in each of those three clinical endpoints. Patients in the Validive cohorts showed a safety profile similar to that of placebo. "While not designed by us, Onxeo's promising preclinical studies and phase II clinical trial have informed the design and conduct of what we believe will be an effective phase III clinical program," Monopar said in the S-1 filing related to the IPO.

Mucositis occurs when cancer therapy breaks down the rapidly divided epithelial cells lining the gastrointestinal tract, leaving the mucosal tissue open to ulceration and infection. Oral mucositis is "probably the most common, debilitating complication of cancer treatments, particularly chemotherapy and radiation," according to the nonprofit Oral Cancer Foundation, and "can lead to several problems, including pain, nutritional problems as a result of inability to eat, and increased risk of infection due to open sores in the mucosa. It has a significant effect on the patient's quality of life and can be dose-limiting," requiring patients to cut back on chemo.

Among the players in SOM is Malvern, Pa.-based Galera Therapeutics Inc., which last October began phase III testing of its small-molecule mimicker of superoxide dismutase, avasopasem manganese (GC-4419), in patients with head and neck cancer. Called ROMAN, a rough acronym for "Reduction in Oral Mucositis with Avasopasem maNganese," the randomized, double-blind, placebo-controlled phase III experiment is measuring how well avasopasem manganese can reduce the incidence and severity of radiation-induced SOM in adults with locally advanced, non-metastatic squamous cell head and neck cancer given seven weeks of radiation therapy plus cisplatin. (See BioWorld, Oct. 17, 2018.)

In the U.S., more than half of the patient population with cancer get radiotherapy at some point in their treatment. About 70% of such patients end up with SOM, defined by the World Health Organization as grade 3 or 4 – the most debilitating side effect of the radiotherapy. At grade 3, patients can only take liquids by mouth; at grade 4, they can take nothing.

Doxo analogue in phase II

Last year, in Expert Opinion on Investigational Drugs, an article noted that the initiation phase of oral mucositis "leads to a cascade of biological events which includes the activation of at least 14 canonical pathways, many of which provide actionable targets for drug therapy. Among the most studied is the nuclear factor kappa B (NF-kB), which is directly activated by chemo and radiotherapy or indirectly by ROS or receptor-bound cathelin-related antimicrobial peptides." Turning on NF-kB is associated with the expression of as many as 200 genes leading to the production and release of pro-inflammatory cytokines, cytokine modulators, stress responders and cell adhesion molecules, the authors add. Prospects that range from sandalwood oil rinse (San Antonio, Texas-based Santalis Pharmaceuticals Inc.) to intravenously infused therapies such as Galera's are being tried. In the latter category, Princeton, N.J.-based Soligenix Inc. has dusquetide (SGX-942) in a 190-patient phase III trial recruiting patients who are undergoing chemoradiation for squamous cell carcinoma of the head and neck. Also like Galera's candidate, dusquetide has fast track status from the FDA. The drug is an IDR, one in a new class of short, synthetic peptides with a mechanism of action whereby it modulates the body's reaction to both injury and infection toward an anti-inflammatory, anti-infective and tissue healing response. Although IDRs have no direct antibiotic activity, by modulating the host's innate immune system responses they increase survival after infections caused by a broad range of bacterial gram-negative and gram-positive pathogens. It also – this is where SOM comes in – accelerates resolution of tissue damage following exposure to a variety of agents, including bacterial pathogens, trauma and chemo and/or radiation therapy.

Monopar's OPC target population for Validive is the most rapidly growing segment of head and neck cancer patients, with an estimated 40,000 new cases of OPC in the U.S this year. The growth in OPC is driven by the increasing prevalence of oral human papillomavirus (HPV) infections in the U.S. and around the world, despite the availability of a pediatric/adolescent HPV vaccine. "The rate of OPC incidence in adults is not anticipated to be materially reduced for many decades due to low adoption of the vaccine," the company said in its filing.

Also in the pipeline is camsirubicin, an analogue of doxorubicin designed to reduce the cardiotoxic side effects generated by doxorubicin while retaining anticancer activity. Camsirubicin is not metabolized to the derivatives believed responsible for doxorubicin's cardiotoxic effects, Monopar said. A phase II trial has been completed in patients with advanced (e.g. unresectable or metastatic) soft tissue sarcoma. Another phase II experiment is underway. Further back is MNPR-101, described as a first-in-class humanized monoclonal antibody to the urokinase plasminogen activator receptor for the treatment of advanced cancers, for which IND-enabling work is nearly completed. As of June 30, Monopar had about $5.1 million in cash and cash equivalents.

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