liafensine (DB104) / Denovo - LARVOL DELTA

ANK3 as a Novel Genetic Biomarker for Liafensine in Treatment-Resistant Depression: The ENLIGHTEN Randomized Clinical Trial. (PubMed, JAMA Psychiatry) - P2 | "This represents a first successful prospective genetic biomarker-guided trial in psychiatry. ClinicalTrials.gov Identifier: NCT05113771."

Biomarker • Clinical • Journal • CNS Disorders • Depression • Mood Disorders • Psychiatry • ANK3

Time-resolved analysis of Bacillus subtilis DB104 Spo0A-mutant transcriptome profile and enhancement of recombinant protein release. (PubMed, J Microbiol) - "Further, the mutant displayed elevated vegetative autolysin expression, resulting in reduced cell viability in the stationary phase. We also introduce the novel potential of R211E in a recombinant protein expression system that facilitated protein release into the supernatant, providing valuable insight for future research in metabolic engineering and efficient production systems in B. subtilis."

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AprMH1 subtilisin from Bacillus zhangzhouensis MH1: Molecular cloning, characterization, and homology modeling. (PubMed, Int J Biol Macromol) - "The isolated aprMH1 gene, consisting of 1146 bp and encoding a 381amino acid protein, was successfully cloned and overexpressed in Bacillus subtilis DB104...AprMH1 was found to belong to a distinct alkaline subgroup within the true subtilisin subfamily, exhibiting superior activity and stability at higher temperatures, making it a promising candidate for applications in harsh industrial environments. These novel properties highlight the potential of AprMH1 for future industrial processes, especially in the detergent sector."

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FDA Grants Fast Track Designation For Biomarker-Guided DB104 (liafensine) in Patients with Treatment-Resistant Depression (TRD) (PRNewswire) - "Denovo Biopharma LLC...announced that the US Food and Drug Administration (FDA) has granted Fast Track designation for DB104 (liafensine) being developed for treating patients with treatment-resistant depression (TRD). Fast Track designation may potentially expedite the review of a drug that is intended for the treatment of a serious or life-threatening disease or condition and demonstrates the potential to address an unmet medical need for such a disease or condition."

Fast track • CNS Disorders • Depression

Use of a Novel Pharmacogenomic Biomarker to Enrich Responders for Liafensine in Treatment-Resistant Depression Patients in a Phase 2b Clinical Study (ASCP 2024) - "Whether a genomic biomarker associated with the treatment response to a particular treatment can be utilized to for CNS drug development 2. Whether this biomarker can be applied in precision medicine in CNS, particularly the depression population in the real world."

Biomarker • Clinical • Late-breaking abstract • P2b data • CNS Disorders • Cognitive Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Pain • Psychiatry

ENLIGHTEN: A Biomarker-Guided, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Liafensine in Patients With Treatment-Resistant Depression (clinicaltrials.gov) - P2 | N=197 | Completed | Sponsor: Denovo Biopharma LLC | Recruiting ➔ Completed | Trial completion date: Jul 2024 ➔ Mar 2024 | Trial primary completion date: Jun 2024 ➔ Feb 2024

Biomarker • Trial completion • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Mood Disorders • Psychiatry

Exploring and Engineering Novel Strong Promoters for High-Level Protein Expression in Bacillus subtilis DB104 through Transcriptome Analysis. (PubMed, Microorganisms) - "Our work demonstrates the construction of a highly efficient expression system for B. subtilis DB104 based on transcriptome data and promoter engineering. This system enables rapid, inducer-free protein expression within 24 h. It can be used as a valuable tool for various industrial applications."

Journal • EGF • HER-2

Biochemical characterisation of a novel broad pH spectrum subtilisin from Fictibacillus arsenicus DSM 15822. (PubMed, FEBS Open Bio) - "To identify a possible candidate for the enzyme market, here we cloned the gene of the subtilisin SPFA from Fictibacillus arsenicus DSM 15822 (obtained through a data mining-based search) and expressed it in Bacillus subtilis DB104...Moreover, SPFA exhibited high tolerance to 5 % (w/v) SDS and 5 % H O (v/v). The biochemical properties of SPFA, especially its tolerance of remarkably high pH, SDS and H O , suggest it has potential for biotechnological applications."

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Time-Course Transcriptome Analysis of Bacillus subtilis DB104 during Growth. (PubMed, Microorganisms) - "However, the expression timing of the spore coat gene was only affected by the relevant sigma factor. This study can help to understand gene expression and regulatory mechanisms in B. subtilis species by providing an overall view of transcriptional changes during the growth of B. subtilis DB104."

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New robust subtilisins from halotolerant and halophilic Bacillaceae. (PubMed, Appl Microbiol Biotechnol) - "The protease genes were cloned and expressed in Bacillus subtilis DB104...• Four new subtilisins were biochemically characterised in detail. • The four proteases show potential for future biotechnological applications."

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ENLIGHTEN: A Biomarker-Guided, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Liafensine in Patients With Treatment Resistant Depression (clinicaltrials.gov) - P2 | N=180 | Recruiting | Sponsor: Denovo Biopharma LLC | Not yet recruiting ➔ Recruiting

Biomarker • Enrollment open • CNS Disorders • Depression • Mood Disorders • Psychiatry

Biochemical characterization of a novel oxidatively stable, halotolerant and high-alkaline subtilisin from Alkalihalobacillus okhensis Kh10-101. (PubMed, FEBS Open Bio) - "The protease gene was cloned and expressed in Bacillus subtilis DB104...The protease is highly oxidatively stable to hydrogen peroxide and retained 58 % of residual activity when incubated at 10 °C with 5 % (v/v) H O for 1 h while stimulated at 1 % (v/v) H O . Furthermore, SPAO was very stable and active at NaCl concentrations up to 5.0 M. This study demonstrates the potential of SPAO for biotechnological applications in the future."

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A Biomarker-Guided, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Liafensine in Patients With Treatment Resistant Depression (clinicaltrials.gov) - P2 | N=180 | Not yet recruiting | Sponsor: Denovo Biopharma LLC | Trial completion date: Apr 2024 ➔ Jul 2024 | Initiation date: Mar 2022 ➔ Jun 2022 | Trial primary completion date: Mar 2024 ➔ Jun 2024

Biomarker • Trial completion date • Trial initiation date • Trial primary completion date • CNS Disorders • Depression • Mood Disorders • Psychiatry

A Randomized, Double-Blind, Placebo-Controlled Study of Liafensine in Patients With Treatment-Resistant Depression (clinicaltrials.gov) - P2; N=180; Not yet recruiting; Sponsor: Denovo Biopharma LLC

Clinical • New P2 trial • CNS Disorders • Depression • Mood Disorders • Psychiatry

Umbelliferone Decorated Water-soluble Zinc(II) Phthalocyanines - In Vitro Phototoxic Antimicrobial Anti-cancer Agents. (PubMed, Chemistry) - "aureus 3150/12 and B. subtilis DB104) and Gram-negative bacteria (E...They are even capable to inactivate Gram-negative bacteria, whereas the dark toxicity remains low. These unique water-soluble compounds can be regarded as all-in-one type photosensitizers with broad applications ranges in the future."

Journal • Preclinical • Infectious Disease • Oncology

Denovo Biopharma gets exclusive rights to liafensine (The Pharma Letter) - "US biopharma firm Denovo Biopharma says that it has obtained an exclusive license to liafensine (DB104)...from contract research and manufacturing organization Albany Molecular Research (Nasdaq: AMRI)."

Licensing / partnership • Depression

Denovo Biopharma announces breakthrough discovery of a novel genetic biomarker for DB104 (liafensine) for depression (PRNewswire) - "Denovo Biopharma...today announced it has successfully discovered a novel genetic biomarker associated with DB104 response to treat depression using its proprietary biomarker discovery platform....DB104 was licensed from Albany Molecular Research, Inc. following its return from Bristol-Myers Squibb, who had conducted two phase 2b clinical trials in treatment-resistant depression with this first-in-class triple reuptake inhibitor targeting transporters for dopamine, serotonin, and norepinephrine."

Biomarker

Decolorization of Acid Green 25 by Surface Display of CotA laccase on Bacillus subtilis spores. (PubMed, J Microbiol Biotechnol) - "The optimum temperature for the decolorization of Acid Green 25 by the DB104 (pSDJH-EA) spore was found to be 50°C. Upon treatment with known laccase inhibitors, including EDTA, SDS, and NaN, the decolorization rate of Acid Green 25 by the DB104 (pSDJH-EA) spore decreased by 23%, 80%, and 36%, respectively."

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Bacillus subtilis Spore Surface Display of Haloalkane Dehalogenase DhaA. (PubMed, Curr Microbiol) - "To this end, we cloned recombinant Bacillus subtilis spores pHY300PLK-cotg-dhaa-6his/DB104(FH01) for the delivery of DhaA from Rhodococcus rhodochrous NCIMB 13064...The hydrolyzing activity of DhaA displayed on spores towards the HD analog 2-chloroethyl ethylsulfide was 1.74 ± 0.06 U/mL (P < 0.01), with a specific activity was 0.34 ± 0.04 U/mg (P < 0.01). This is the first demonstration that DhaA displayed on the surface of B. subtilis spores retains enzymatic activity, which suggests that it can be used effectively in real-world applications including bioremediation of contaminated environments."

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