Pharmaceutical Company Wins Key Patent For Novel Mucositis/Stomatitis Radiation Proctitis Products

Pharmaceutical Company Wins Key Patent For Novel Mucositis/Stomatitis Radiation Proctitis Products

Dallas-based biopharmaceutical company Access Pharmaceuticals, Inc. has been notified by the Japan Patent Office that a patent for AccessPharma’s MuGard and ProctiGard products has been granted. The patent covers a wide range of liquid formulations for prevention and treatment of mucosal diseases and disorders.

For example, Oral mucositis (OM) is a common, painful, debilitating side effect of some radiation and chemotherapy cancer treatments. Severe OM is also associated with adverse quality of life, weight loss, increased opioid use, gastrostomy-dependent feeding, greater numbers of emergency room and unplanned office visits, and hospitalizations. Oral Mucositis is characterized by sores and ulcers in the mouth and throat that make swallowing difficult or impossible. It is estimated that 97% of patients receiving radiation for head and neck cancer, 70% of patients receiving stem cell transplantation and up to 40% of patients receiving conventional chemotherapy develop oral mucositis. OM’s incremental cost in the head and neck cancer (HNC) population is estimated to be around $18,000.

Rectal mucositis, and specifically Radiation Proctitis (RP) is inflammation and damage to the lower portion of the colon, primarily the sigmoid colon and rectum, after exposure to x-rays or ionizing radiation as part of radiation therapy. RP is most common after treatments for cancer, such as cervical, colon, and prostate cancer. RP can be acute, occurring within weeks of initiation of therapy, or can occur months or years after treatment. Experts believe that RP occurs due to damage to the blood vessels that occurs as part of the radiation therapy.

Unhappily, OM and RP treatment options for patients with HNC are thin on the ground. Several agents have US Food and Drug Administration marketing allowances as medical devices including GelClair, Episil, Mucotrol, Caphosol, and MuGard, but evaluation of medical devices is typically markedly less rigorous than for biologics or drugs. In addition, use of so-called magic mouthwashes is relatively common. Typically, composition of such agents leans on institutional folklore and objective assessments of their efficacy have been marginal. In a comparative trial, the efficacy of a “magic mouthwash” formulation was no better than a control solution.

However, AccessPharma believes both MuGard and ProctiGard can offer patients benefits when undergoing anticancer treatments, and is backing that contention with scientific evidence.

Access points to one of the oldest peer-reviewed oncology journals, the American Cancer Society’s journal publication, Cancer, featuring MuGard as the topic of its May 2014 edition cover article. The publication, entitled “Multi-Institutional, Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Efficacy of a Mucoadhesive Hydrogel (MuGard) in Mitigating Oral Mucositis Symptoms in Patients Being Treated With Chemoradiation Therapy for Cancers of the Head and Neck,” (First published: 11 February 2014Full publication history DOI: 10.1002/cncr.28553) discusses data on Access’s post-marketing clinical trial that evaluated the efficacy of MuGard in controlling symptoms caused by oral mucositis in 120 patients receiving chemoradiation therapy for the treatment of cancers of the head and neck. In the trial, MuGard was shown to be superior to the sham control saline-bicarbonate rinse in mitigating oral mucositis symptoms and delaying oral mucositis progression.

MuGard Mucoadhesive Oral Wound Rinse is marketed as a medical device, indicated for management of oral mucositis/stomatitis (that may be caused by radiotherapy and/or chemotherapy) and all types of oral wounds (mouth sores and injuries), including aphthous ulcers (canker sores) and traumatic ulcers, such as those caused by oral surgery or ill-fitting dentures or braces. MuGard provides the oral mucosa with a thin protective hydrogel layer which the company says has been demonstrated in several clinical studies of mucositis to benefit patients in terms of reduced pain and discomfort as well as a reduction in objective mucositis scores.

ProctiGard is a treatment option for rectal mucositis, and specifically radiation proctitis, is inflammation and damage to the lower portion of the colon, particularly the sigmoid colon and rectum, after exposure to x-rays or ionizing radiation as part of radiation therapy. RP is most common after treatments for cancer, such as cervical, colon, and prostate cancer. RP can be acute, occurring within weeks of initiation of therapy, or can occur months or years after treatment. AccessPharma says experts believe RP occurs due to damage to the blood vessels that occurs as part of the radiation therapy. rectal mucositis and radiation proctitis,. ProctiGard received 510(K) FDA clearance in July 2014. Access currently holds global commercialization rights for ProctiGard.

The paper published in Cancer reports results of a multi-institutional, randomized, double-blind, placebo-controlled 2-arm parallel trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck. The report’s coauthors are Ron R. Allison MD, Aaron A. Ambrad MD, Youssef Arshoun MD, Richard J. Carmel MD, Doug F. Ciuba MD, Elizabeth Feldman MS, DMD, MS, Steven E. Finkelstein MD, Ranjini Gandhavadi MD, Dwight E. Heron MD, Steven C. Lane MD, John M. Longo MD, Charles Meakin MD, Dimitrios Papadopoulos MD, David E. Pruitt MD, Lynn M. Steinbrenner MD, Michael A. Taylor MD, William M. Wisbeck MD, Grace E. Yuh MD, David P. Nowotnik PhD, Stephen T. Sonis DMD, DMSc, and the study has been registered at under registration number NCT01283906.

MugardbottleMuGard is a proprietary viscous liquid mucoadhesive hydrogel (MAH) formulation. Access says results of open-labeled trials suggested that it created a palliative barrier over injured mucosa and reduced objective mucositis scores compared with historical data. However, as is the case of other OM devices, data from a multi-institutional controlled clinical trial were lacking. The objective of the present investigation was to assess MuGard’s efficacy as an intervention for OM induced by standard CRT used for the treatment of HNC. The study replicated OM trials used to evaluate drugs or biologics and included a multi-institutional, double-blind, randomized, placebo-controlled design. In this way, we sought to establish a more rigorous standard for the assessment and clinical adoption of devices intended for OM.

This trial’s objective of was to determine how a mucoadhesive hydrogel (MuGard), a marketed medical device, would fare when tested with the strictness of a conventional multi-institutional, double-blind, randomized, placebo-controlled study format.

The study’s primary endpoint was a reduction in mouth and throat soreness (MTS) associated with OM as defined by area under the curve (AUC) of the OMDQ MTS question 2 (Q2) score. Q2 is a 5-point categorical scale in which patients grade MTS from 0 (no soreness) to 4 (extreme soreness)[3] which is a component of the OMDQ in that it tracks very well with objective (WHO score and opioid use) and subjective measurement of OM severity.[3, 13]

Secondary endpoints included delay to onset of OMDQ score of>2 (previously described in literature to align with severe mucositis) and time to OM resolution. Health and resource use endpoints were opioid use, gastrostomy placement and feedings, subjects’ ability to eat, radiation treatment breaks, unplanned office and emergency room visits and changes in body weight during CRT.

A total of 120 subjects planned to receive chemoradiation therapy (CRT) for treatment of head and neck cancers were randomized to receive either MuGard or sham control rinse (SC) during CRT. Subjects completed the validated Oral Mucositis Daily Questionnaire. Weight, opiate use, and World Health Organization (WHO) oral mucositis (OM) scores were recorded. Subjects who dosed at least once daily during the first 2.5 weeks of CRT were included in the efficacy analysis.

Of the 120 subjects enrolled, 78 (SC, N=41; MuGard, N=37) were eligible for efficacy analysis. Both cohorts were similar in demographics, baseline characteristics, primary tumor type, and planned CRT regimen. MuGard effectively mitigated OM symptoms as reflected by area under the curve of daily patient-reported oral soreness (P=.034) and WHO scores on the last day of radiation therapy (P=.038). MuGard was also associated with nonsignificant trends related to therapeutic benefit including opioid use duration, and OM scores (WHO criteria) at CRT week 4. Rinse compliance was identical between cohorts. No significant adverse events were reported, and the adverse event incidence was similar between cohorts.

The study coauthors conclude that scientific rigor of OM clinical trials required for assessment of drugs or biologics has not typically been applied to testing of medical devices which can be marketed with minimal or no supportive clinical data, and in the current environment in which evidence-based decision making is a mandate, they believed it highly desirable to define medical device efficacy more rigorously using a multi-institutional, randomized, double-blind, placebo-controlled approach that characterizes typical drug trials.

The primary efficacy endpoints of this trial were based on a symptom-dependent, patient-reported measurement for OM: MTS scored by criteria delineated by OMDQ Q2. Endpoint selection was based on 3 considerations: the OMDQ was validated in a variety of patient populations; OMDQ Q2 scores correlate well with objective and functional measures of OM; combining OMDQ self-assessment with objective measures of mucositis provided an opportunity to assess MuGard’s overall clinical benefit.

Saline-bicarbonate rinse was selected as the SC rinse because it is safe and physically resembles MuGard. A preservative in SC imparted a slight medicinal flavor similar to that in MuGard. The coauthors add that because saline-bicarbonate rinse is a treatment for OM symptom amelioration recommended by the National Cancer Institute, it is probably not a true sham or placebo, and possibly, control subjects derived some benefit from its use thereby providing a bias against MuGard. The finding that the percent of ulcerative or severe mucositis among SC subjects was less than typically reported, substantiates its possible benefit.

However, despite greater opioid use by control subjects, MuGard was superior to SC in ameliorating the onset and course of symptomatically significant OM as reflected by the statistically significant difference between MuGard and sham cohorts, the study’s primary endpoint. In addition, MuGard use was associated with other favorable outcomes compared to control and although these failed to reach statistical significance, the researchers say consistency of signals trending in the same direction are noteworthy. The researchers report that whereas 50 percent of patients using SC noted MTS scores within 15 days of the start of radiation, that frequency of OM was not seen in the MuGard arm until day 37 (NS). Of the 24 subjects in each study cohort requiring oral opioid analgesics, those treated with MuGard used narcotics for a median 12.5 days compared to 27.5 days for control subjects (NS). Subjects treated with MuGard were better able to maintain baseline weights than controls. Consistent with prior studies, mean weight loss in the SC cohort was 9.14%. In contrast, mean weight loss in the MuGard cohort was 5.28%.

Moreover, clinician-WHO assessments of OM scored midway through radiation and the LDRT trended in favor of MuGard. At LDRT, this trend reached statistical significance, although the reason for this finding is unclear, since MuGard’s formulation does not include known biologically active components. The coauthors suggest that MuGard likely forms a thin, temporary protective hydrogel layer over the mucosa, although conceivably, MuGard might entrap mucins, which have been identified as having a protective role in chemotherapy-induced mucosal injury, and additional studies are needed to test this hypothesis.

The researchers say they did not attempt to stratify endpoints by dosing frequency, and note that despite MuGard’s efficacy in attenuating MTS, it was not superior to SC in impacting subjects’ ability to swallow, eat, or drink. Nor did MuGard significantly alter gastrostomy reliance, unplanned office visits, emergency room visits, or hospitalizations.

The coauthors also observe the significance of this study as representing the first multicenter, randomized, placebo-controlled assessment of a medical device indicated for OM treatment, and express hope that this study design provides a template for evaluation of other agents in the medical device class and in that way raises the threshold of their clinical use to a level that is similar to pharmaceuticals, MuGard tested in a standard clinical trial format demonstrated its superiority to SC in mitigating OM symptoms, delaying OM progression, and its safety and tolerability, and the coauthors conclude that study results support the addition of MuGard to the armamentarium for the management of oral mucositis in patients being treated with standard radiation therapy protocols for HNC.

“Oral mucositis is one of the most challenging adverse side-effects we face when treating our cancer patients,” commented Dr. Ron R. Allison of Carolina Radiation Medicine, Greenville, NC. Dr. Allison, a principal investigator in the MuGard trial, notes that “From a patient quality-of-life perspective, the reduction in mouth-and-throat soreness and reduced dependence upon opioids are extremely important. Patients using MuGard showed better weight maintenance, indicative of a superior nutritional status during the intensive cancer treatment regimen. As a physician, I was particularly impressed by the fact that the reduction of oral mucositis severity and mouth-and-throat soreness in the MuGard group was statistically significant.”

This study was funded by Access Pharmaceuticals, Inc., and Drs. Feldman, Finkelstein, Lane, Taylor, Wisbeck, and Yuh have received research funding from Access Pharmaceuticals, Inc. Dr. Allison has received an honorarium from Access Pharmaceuticals, Inc. Dr. Nowotnik was an employee of Access Pharmaceuticals, Inc. when the study was conducted Dr. Sonis is a paid consultant for Clinical Assistance Programs, LLC (the contract research organization that conducted this study), a consultant for Actogenix, Alder, Galera, Synedgen, Pfizer, Piramal, Polymedix, BioAlliance, and is Chief Scientific Officer for Biomodels, LLC. All other authors made no disclosure.

MuGard is available by prescription only and is contraindicated in patients with known hypersensitivity to any of the ingredients in the formulation. MuGard received 510(k) clearance from the U.S. Food and Drug Administration and is marketed by AMAG Pharmaceuticals, Inc. in the United States. MuGard is also licensed in China, RHEI/Jian An, and in Korea with Hamni Pharmaceuticals.

Access Pharmaceuticals, Inc. is an emerging biopharmaceutical company that develops and commercializes proprietary products for the treatment and supportive care of cancer patients. Access developed MuGard and ProctiGard and is developing multiple follow-on products. Access also has other advanced drug delivery technologies including CobaCyte-mediated targeted delivery and CobOral-oral drug delivery, its proprietary nanopolymer delivery technology based on the natural vitamin B12 uptake mechanism. For additional information on Access Pharmaceuticals, visit:

Access Pharmaceuticals, Inc.

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