One of the severe, dose-limiting side effects of the chemotherapy drug cisplatin is ototoxicity, or drug-induced hearing loss, which can be permanent in some cancer patients.
A new therapy called DB-020 developed by Boston-based Decibel Therapeutics aims to eliminate or minimize ototoxicity for patients receiving cisplatin, which is a commonly used chemotherapy for multiple types of cancers as both a single agent and as a combination therapy.
Recently announced interim results from a phase 1b clinical trial of DB-020 found it protected against hearing loss in patients who had not previously been treated with cisplatin (https://ir.decibeltx.com/news-releases/news-release-details/decibel-therapeutics-reports-positive-data-interim-analysis).
The early study results included 17 evaluable patients who were treated with a placebo in one ear and with DB-020 in the other ear up to three hours prior to receiving chemotherapy.
Fifteen patients suffered some hearing loss in the placebo-treated ear, mostly after the first treatment. Of the 15, 13 patients experienced partial or complete protection against ototoxicity in the contralateral ear treated with DB-020 prior to receiving cisplatin infusion in the study.
The interim analysis also found DB-020 to be safe and well-tolerated by patients with generally mild adverse effects reported in study participants who were treated with high doses of cisplatin every 21 or 28 days. Those results were consistent with the results of a phase I clinical trial of the new gene therapy in healthy volunteers.
Importantly, DB-020 did not appear to alter system levels of cisplatin in study participants, reducing any concern about it detracting from the benefits of the widely used drug.
DB-020 is a novel, proprietary formulation of sodium thiosulfate known for its other medical uses including as an antidote for cyanide poisoning. There are no FDA-approved therapies to prevent or treat cisplatin-induced cytotoxicity.
The phase 1b clinical trial of DB-020 is an ongoing, randomized, double-blind, placebo-controlled, multicenter trial. Audiometric measurements are made at the baseline before the first cisplatin infusion, before each subsequent cycle of cisplatin, and at the end of treatment.
Recently, John Lee, Chief Development Officer at Decibel, shared additional insight into the interim analysis with The Hearing Journal.
THJ: What was the impetus for investigating this research question?
Lee: Cisplatin, a systemically delivered, anti-neoplastic agent, is one of the most commonly used chemotherapeutics despite severe, dose-limiting side effects. It is a backbone of combination cancer therapy backed by the National Comprehensive Cancer Network and European Society of Medical Oncology due to its broad anti-tumor effects across multiple cancers.
The same mechanism that enables cisplatin to kill cancer cells also makes it toxic to the highly specialized cells within the inner ear, including hair cells. And so, unfortunately, ototoxicity is a known serious adverse effect of cisplatin-based chemotherapy that can result in significant, permanent hearing loss in patients.
Despite the risk and prevalence of ototoxicity, the therapeutic and potential curative benefits of more intensive cisplatin chemotherapy regimens still outweigh less intensive or split dose regimens and continue to put patients at high risk for ototoxicity. The impact of hearing loss can be devastating and is often associated with tinnitus, imbalance, or a debilitating sensitivity to sound.
Cisplatin is commonly used with curative intent. As such, protecting the patient’s quality of life after cisplatin chemotherapy should be of high interest to both physicians and patients. DB-020 was conceived based on the belief that preventing hearing loss before it occurs would be of value in patients receiving cisplatin
THJ: What was the key discovery or what were most important findings in new study data?
Lee: The data we presented were top-line results from an interim analysis of our ongoing Phase 1b clinical trial. In the clinical trial, enrolled patients are randomized to receive one of two doses of DB-020 in one ear and a placebo in the other ear, enabling each patient to serve as their own control.
The interim analysis included data collected from 19 cisplatin--naïve cancer patients being treated with high doses of cisplatin.
In the results of the interim analysis, we observed that DB-020 was generally well tolerated. Ototoxicity was commonly observed in the ears that received a placebo (88%). However, we observed that in the same patients 87% were partially or completely protected from ototoxicity in their DB-020-treated ears.
THJ: What, if anything, has surprised you about the -results of the ongoing research thus far?
Lee: We knew from previously published research that ototoxicity is a frequent, debilitating side effect of cisplatin chemotherapy. Our observations were consistent with previous literature supporting a high incidence of ototoxicity in oncology patients undergoing treatment with cisplatin. Notably, however, in our interim analysis cohort, we observed that ototoxicity was perhaps even more frequent than previously realized.
After the first cycle of cisplatin, in the placebo ears, 76% of patients experienced hearing loss in the clinical frequency range that met the ototoxicity criteria established by the American Speech-Language-Hearing Association. By the last evaluable test, when patients had received an average of 2.2 cycles of cisplatin, 88% of patients experienced ototoxicity in their placebo ears.
THJ: Is there anything others might misunderstand about your latest findings?
Lee: DB-020 is locally delivered to the ear through an intra-tympanic injection. The therapeutic concept is that by delivering DB-020, a cisplatin inactivator, directly into the middle ear, we will enable diffusion into the inner ear space ahead of receiving cisplatin. In this way, the intention of local delivery of DB-020 to the ear is to inactivate cisplatin once it has entered the inner ear and before it damages the sensory cells, thus preventing hearing loss. The hearing results reported in the interim analysis were measured from patients in this study who received injections of DB-020 and placebo in each ear ahead of each round of cisplatin.
THJ: What are the clinical implications, if any, of the new data and/or ongoing research?
Lee: Given the incidence of ototoxicity, a prophylactic therapeutic that may prevent loss of hearing could impact the management of patients who are undergoing cisplatin treatment.
In addition to the incidence of ototoxicity, the degree of hearing loss experienced by each patient is an important predictor of outcomes.
In our interim analysis (IA), ears treated with placebo lost on average approximately 30 dB of high-frequency hearing (average thresholds from 4,000-8,000 Hz).
To put this in perspective, the patients began the study with average hearing, age-matched to a 58-year-old person, approximately the average age of the patients in the IA. A few months later, following dosing with cisplatin, hearing in the placebo ears had rapidly declined to that of a 76-year-old.
Importantly, in the same patients, just in their other ear, -DB-020 protected hearing, resulting in an average change of 8 dB from baseline.
In order to characterize the expected impact of this hearing loss on the audibility of speech, for each patient, the proportion of the speech signal that is audible was calculated using the speech intelligibility index. We did this for the placebo ear and the DB-020 ears at baseline and the last testing session following cisplatin administration.
In placebo ears, more than half of patients lost > 10% of speech audibility and nearly a quarter lost > 20% of speech audibility secondary to cisplatin administrations. The maximal speech audibility loss was 51% in a placebo ear.
In the same patients, most ears treated with DB-020 experienced less than 10% changes in speech audibility.
In total, speech audibility loss was reduced by 80% in DB-020 treated as compared to placebo ears.
THJ: What further research needs to be done on this topic?
Lee: We are working with KOLs to integrate this data and the findings from the interim analysis into an overall clinical development plan that can optimize the path from here through subsequent clinical investigation and hopefully ultimately seek approval for DB-020. We expect to consult with regulatory agencies, potentially in the US and internationally as part of that planning.
THJ: Is there anything that you would like to add?
Lee: We believe these positive data showcase the integrated capabilities that Decibel has implemented to develop innovative therapeutics for conditions of the inner ear. There are no validated targets with clinical readouts for drug development in the otology space, which makes preclinical to clinical translation of novel therapeutics especially critical. Decibel has invested significant efforts to understand the unique biology of the inner ear and has applied this knowledge in the development of our clinical candidates and translation to the clinic. We aspire to apply the same rigor and preclinical testing performed for DB-020 to all of our preclinical programs.
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