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Denovo Biopharma's Biomarker Strategy Could Give New Life To Failed Depression Drug

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NEW YORK – A biopharmaceutical company developing precision therapeutics is hoping that its genetically targeted approach can breathe new life into a failed depression drug.

San Diego-based Denovo Biopharma is in the midst of its ENLIGHTEN study, a Phase IIb clinical trial of the drug DB104, also known as liafensine. In the trial, Denovo is testing the activity of the triple reuptake inhibitor in select patients with treatment-resistant depression. Liafensine, which Denovo licensed from Curia (previously known as Albany Molecular Research), targets transporters for dopamine, serotonin, and norepinephrine.

"There are a lot of pharmacogenomics companies in [the central nervous system field], but none of them are [developing] true companion diagnostic biomarkers," like those used to identify best responders to precision cancer medicines, said Wen Luo, founder, CEO, and CSO of Denovo. He hopes that Denovo will become one of the first companies to do so with liafensine.

Denovo, which Luo founded in 2012, acquires drugs that have failed late-stage clinical trials in all-comer populations and assesses their activity in biomarker-targeted patient subsets, explained Michael Haller, the company's chief business officer and head of US finance. The firm developed a biomarker discovery platform that uses machine learning to analyze genomic data from patients in drug trials and pinpoint differences between responders and non-responders. For that analysis, the company performs whole-genome sequencing on archived clinical samples collected within previously conducted trials.

Using this platform, Denovo is able to identify novel biomarkers that are not obvious, Haller said, adding that the firm hopes to acquire one to three drugs each year that it determines it can revive with a biomarker strategy.

So far, Denovo has acquired eight drugs, four of which are under development in cancer indications and another four in neurology. That includes liafensine, which Curia developed and licensed to Bristol Myers Squibb, only to have BMS return the rights to Curia after it failed Phase IIb trials. Although the drug didn't best other antidepressants on the market in studies, more than 2,000 patients received liafensine as part of those development efforts, according to Denovo.

The firm has since licensed global R&D, production, and marketing rights for liafensine from Curia. Even though company executives declined to disclose the financial details of the transaction, they said that Denovo acquired patients' blood samples from previous clinical trials as part of the deal, which allowed researchers to assess drug response variation using its discovery platform. In 2020, Denovo ultimately identified a single-nucleotide polymorphism in the ANK3 gene that it believes predicts response to liafensine — a proprietary biomarker that it now calls Denovo Genomic Marker 4 (DGM4).

Retrospective analysis using data from prior liafensine trials has shown that "patients [who] have that biomarker and received liafensine did much better than either those who do not have the biomarker or those who received standard of care, regardless of the biomarker," Haller said. If clinical trials confirm this finding, liafensine could be the first newly approved genetic biomarker-driven mental health treatment, he said.

Investigators are currently recruiting participants both with and without the DGM4 biomarker for the multicenter ENLIGHTEN study and plan to enroll about 180 subjects with treatment-resistant depression. In order to partake in the trial, patients must have inadequate responses to at least two antidepressants in the last five years as defined by the Massachusetts General Hospital's Antidepressant Treatment Response Questionnaire.

Participants are randomized to one of two experimental dosing arms of liafensine, or to a placebo arm. Researchers are tracking how the interventions change patients' scores on the Montgomery-Asberg Depression Rating Scale after six weeks.

Within ENLIGHTEN patients will not only be screened for the biomarker of interest but also evaluated to ensure they meet psychiatric and other clinical requirements for enrollment. DGM4 is a germline biomarker that shows up in around 20 percent of the general population, and Denovo expects patients with depression will carry this biomarker at similar rates. 

At an initial visit, patients will provide a blood sample for genotyping to identify whether they have the biomarker. For every five patients enrolled with the DGM4 biomarker, one patient without it will also be enrolled. However, patients will remain blinded to their biomarker status during the trial. 

To raise awareness about the ENLIGHTEN study and streamline enrollment, Denovo launched a gene registry through which patients with treatment-resistant depression can learn about the opportunity to partake in the trial. Patients who register online are sent a free at-home kit to collect a saliva sample for biomarker analysis. If they're a candidate and decide to pursue enrollment in the trial, they must complete another genetic test at a trial site to confirm their results.

"If you're going to screen everyone [for the first time] at the clinical trial site, you're going to lose 80 percent of patients right away because of the biomarker," Luo said, adding that the gene registry allows researchers to pre-screen a larger number of possible participants and makes the process more efficient. 

Denovo hopes to have a data readout for the ENLIGHTEN trial by year-end or early 2024. If the trial is successful, Denovo is hoping it will attract the attention of a larger pharmaceutical company, to which it can license the drug for further development and commercialization. That's the approach Denovo is hoping to take initially for all the drugs it is working on reviving, but eventually, the firm hopes to commercialize its own products.

Denovo also plans to codevelop companion diagnostics for therapeutics with commercialization potential and expects to partner with a diagnostic company to create a test for the DGM4 biomarker. Already, Denovo has a partnership with Qiagen to develop a blood test for one of its investigational cancer treatments.

While there are pharmacogenetics companies that market testing services for personalizing depression drugs, Denovo's leaders don't view them as competition. With its biomarker strategy, the company is aiming to relaunch drugs as new treatment options that need a companion diagnostic to identify eligible patients. The "DGM4 biomarker will clearly differentiate liafensine from other depression drugs," Haller wrote in an email. "This is so different than the current standard of care, which is to simply try one drug after another to determine which ones might work and which ones won't."