TSRL, Inc. and physicians at the University of Michigan are working to develop oral radioprotectants to improve patient compliance and preserve bone during radiation therapy.
Oral amifostine as a selective chemo- and radioprotectant
Radiotherapy is a cornerstone in the treatment of head and neck cancer (HNC) . Depending upon the type and extent of HNC, radiotherapy can be employed as a primary treatment, as an adjuvant to surgical tumor resection, or in combination with chemotherapy. Despite its effectiveness in controlling tumor cell proliferation, radiotherapy is limited by health complications associated with damage to healthy, normal cells and tissue. Amifostine (AMF) is currently the only FDA-approved radioprotectant drug product for cancer patients receiving radiation. Its widespread adoption has been limited by a less-than-ideal route of administration (IV infusion) and associated side effects, including hypotension, nausea and vomiting .
We believe that rapid infusion at high doses are necessary to offset the rapid clearance of AMF, as well as WR-1065, its active metabolite, to ensure efficacious exposure levels during radiotherapy. The high dose levels combined with rapid metabolic conversion result in high initial plasma exposure levels of WR-1065, a major factor initiating the onset of hypotension. However, the overall PK/PD relationship of AMF and WR-1065 is poorly understood and data from preclinical and clinical studies suggests that reduced input rates of AMF result in lower levels of systemic WR-1065, while retaining target tissue levels . An oral AMF product that retains cyto- and radioprotective properties while alleviating adverse side effects maximizes the effectiveness of radiotherapy treatment. In turn, this reduces healthcare costs and improves quality of life for HNC patients.
Solution & Benefits
We are developing a novel oral formulation of AMF with a specific target product profile in mind. First, we aim to preserve the demonstrated efficacy of AMF in protecting healthy craniofacial tissue from radiation damage, as well as for maintaining the bone-regenerating cellularity that promotes healing after radiation. To do this we demonstrate that therapeutically active concentrations of WR-1065 can be maintained in target tissues. Second, we aim to mitigate the known side effects of AMF that have been observed after IV administration by minimizing peak WR-1065 exposure in plasma. Third, we are constructing a cost-effective product development plan capitalizing on a 505(b)2 regulatory strategy to offer hospitals a more affordable way to incorporate amifostine into their cancer treatment paradigms. Our strategy involves an oral drug delivery technology designed for modified release of AMF to maximizes delivery of WR-1065 to the target tissue with reduced systemic exposure levels to mitigate or eliminate hypotension.
Regulatory Benefits: Orphan Indication
Market: After MedImmune, Inc. acquired rights to Ethyol® from ALZA Corporation in 2001, worldwide sales reached their peak in 2005 at nearly $90 million per year before generic sales of amifostine began in 2008. Based on average wholesale prices (AWP), the cost of Ethyol per patient was $1,711, meaning roughly 52,600 patients were treated worldwide per year . This represents a fraction of the total patients that amifostine is indicated for, including patients receiving cisplatin for treatment of advanced ovarian cancer as well as the HNC patient population illustrated above. We intend to seek Orphan Drug Designation to develop our orally available amifostine analog as a radio- and chemoprotective for treatment of HNC, followed by additional indications for cancers requiring RT. We expect a novel oral amifostine analog to reach over $192 million in annual sales five years after first commercial launch.
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