A Superagonist, A Novel Anti-Obesity Agent from a Zebrafish Screen, and More News Highlights From January 2024


Among the small molecule highlights in January’s news were a $100M+ Series A for a PARP1 + PI3Kα focused company, clinical data with an SLC inhibitor for PKU, a 5-HT2C superagonist for seizures, and a NK1,3 dual antagonist for women’s health. A novel anti-obesity agent from phenotypic screening also made headlines, and the close of a major acquisition may bring relief to the industry. You can read more about these notable scientific highlights and more below.

Jnana Therapeutics Reports Proof-of-Concept Data for its First-in-Class SLC6A19 Inhibitor, JNT-517 

JNT-517, Jnana’s potential first-in-class, oral, allosteric SLC6A19 inhibitor and August 2023 Molecule of the Month, recently demonstrated a positive clinical proof-of-concept in a Ph. Ib trial (NCT05781399) in patients with phenylketonuria (PKU). Treatment with JNT-517 resulted in a significant mean blood Phe (phenylalanine) reduction of 51% at day 28, with a sustained response starting as early as seven days after treatment initiation. Additionally, 88% of the participants experienced more than a 30% reduction in blood Phe. Overall, JNT-517 was well tolerated, with no serious adverse events reported. 

The clinical success of JNT-517 lies in its unique mechanism of action, targeting a cryptic allosteric site on SLC6A19, a transporter responsible for kidney reabsorption of Phe back into the bloodstream. By blocking this pathway, JNT-517 effectively lowers harmful blood Phe levels, offering a new therapeutic avenue for individuals with PKU, a condition marked by PAH (phenylalanine hydroxylase) enzyme deficiency and severe neurological damage if left untreated. JNT-517 was granted FDA Rare Pediatric Disease designation in late 2022, highlighting its potential as a transformative treatment for patients suffering from PKU. You can read more about JNT-517 in our recent article here.

Bexicaserin (LP352) An Oral, Centrally Acting 5-HT2C Superagonist Reduced Seizures in a Ph. Ib/IIa Trial

Longboard Pharmaceuticals (formerly Arena Neuroscience) released topline data from its Ph. Ib/IIa trial (NCT05364021; n = 52) for bexicaserin (US10392390B2), a novel 5-HT2C receptor agonist aimed at treating seizures linked with developmental and epileptic encephalopathies (DEE). The clinical data showed that bexicaserin reduced seizures by 32.5% across all patient subtypes compared to placebo. The most common adverse events were drowsiness, decreased appetite, constipation, diarrhea, and lethargy. Of note, there were three serious adverse events (ankle fracture, constipation, increased seizures) leading to a discontinuation rate of 21% (9 out of 43 participants) in the bexicaserin arm.

Bexicaserin is a potential best-in-class 5-HT2C receptor superagonist that elicits a greater response than serotonin and, importantly, lacks activity for 5-HT2A and 5-HT2B receptors, which are associated with psychiatric disorders and valvular heart diseases, respectively. Bexicaserin significantly decreased seizure activities arising from various underlying pathologies such as genetic mutations affecting neuronal sodium channels, reduced GABAergic signaling, and excessive glutamatergic excitation. Given these promising results, Longboard is proceeding with preparations for global Ph. III trials.

Bayer's Elinzanetant Shows Promising Ph. III Results in Menopausal Symptoms with Dual NK1,3 Receptor Antagonism

Bayer has announced pivotal Ph. III trial (OASIS 1, NCT05042362 and OASIS 2, NCT05099159) results, showing the efficacy of elinzanetant (US7683056B2), the first dual neurokinin-1,3 (NK1,3) receptor antagonist, as a non-hormonal treatment for moderate to severe vasomotor symptoms (VMS) associated with menopause. Elinzanetant showed superiority in alleviating menopausal symptoms, particularly in reducing the frequency and severity of VMS from baseline to week 1 compared to placebo in postmenopausal women. Furthermore, it demonstrated improvements in sleep disturbances and overall menopause-related quality of life. Elinzanetant exhibited a favorable safety profile consistent with earlier studies, with the most commonly reported adverse events being headache, diarrhea, and somnolence.

From a mechanistic standpoint, elinzanetant exerts dual antagonism on NK1,3 receptors located on KNDy neurons, which are implicated in modulating vasomotor symptoms associated with menopause. Elinzanetant also targets NK1 receptors involved in sleep modulation related to menopause. This dual action differentiates it from fezolinetant (Veozah, Astellas), the first FDA-approved non-hormonal treatment for vasomotor symptoms, which exclusively inhibits NK3 receptors. Elinzanetant's simultaneous NK1,3 antagonism may offer an advantage in improving sleep quality, a potential benefit over fezolinetant, though direct comparative data is not available. The preliminary findings from the OASIS 1 and 2 trials are part of a larger clinical development program, with results from the OASIS-3 (NCT05030584) trial expected soon. Data from all three clinical trials will be submitted for regulatory approval for the treatment of moderate to severe VMS associated with menopause.

Synnovation Therapeutics Secures $102M Series A for PARP1 and PI3Kα Programs

Synnovation Therapeutics, a biotech founded by former Incyte executives, has recently secured a substantial $102 million in Series A funding, with chief financing from Third Rock Ventures. This investment will enable the development of Synnovation's lead clinical candidate, SNV1521, a potential best-in-class, CNS-penetrant, selective PARP1 inhibitor. SNV1521 is scheduled to enter a Ph. I trial for solid tumors (NCT06220864), with an expected enrollment of 76 subjects. The aim of developing next-generation PARP1 selective inhibitors is to mitigate the hematological toxicities associated with first-generation PARP1/2 inhibitors. While specific details about SNV1521 are not publicly disclosed, a  selected example from Synnovation’s patent application WO2023122140A1 illustrates a PARP1 inhibitor with single-digit nanomolar PARP1 potency. 

Another advanced preclinical asset in Synnovation’s portfolio includes SNV4818, a selective PI3Kα-H1047X mutant inhibitor. This compound is currently progressing through IND-enabling studies. Additionally, the biotech is focusing on the development of PI3Kα pan-mutant selective inhibitors. These molecules are being designed with the focus aimed at mitigating the toxicities associated with non-selective WT inhibition of PI3Kα, a concept recently covered in Drug Hunter case studies (STX-478 and RLY-2608). 

Novo Nordisk Expands its Obesity Portfolio by Licensing Eracal’s Anti-Obesity Program

Novo Nordisk has licensed an oral small molecule from EraCal Therapeutics as a potential anti-obesity treatment through a transaction valued at $255M. Specific details of the agreement remain undisclosed. EraCal, a spinout from the University of Zurich and Harvard University, operates under the leadership of biochemist Josua Jordi. The Board of Directors includes notable figures like Ann Kessler, a key contributor to the development and commercialization of Roche’s multimillion-dollar-a-year weight loss drug orlistat (Xenical).

EraCal Therapeutics has made significant contributions to obesity research, particularly highlighted by a publication in Science detailing their discovery strategy for identifying appetite modulators. The compounds, initially identified through a Zebrafish phenotypic screen, led to a decreased food intake by over 50%. Subsequent validation in mouse models reinforced the potential of these findings. While the full scope of EraCal's research program remains under wraps, a patent application has shed light on the biological activity of these molecules that serve as appetite suppressants. Compound 180 was selected from EraCal’s patent application (WO2022053541A1) as a representative example showing a 62% food intake reduction in diet-induced obese mice.

Bristol Myers Squibb Finalizes Mirati Acquisition

With all the concern about the FTC blocking mergers, it’s good to see Bristol Myers Squibb (BMS) has successfully completed the acquisition of Mirati Therapeutics, integrating it as a wholly owned subsidiary. This strategic acquisition significantly enhances BMS’s oncology portfolio, particularly with the inclusion of the KRAS(G12C) inhibitor adagrasib (Krazati). In addition, BMS has gained access to several other promising clinical-stage compounds from Mirati. Among them is MRTX1719, a novel MTA-cooperative PRMT5 inhibitor with potential first-in-class status (NCT05245500); MRTX1133, a KRAS(G12D) inhibitor (NCT05737706); and MRTX0902, an SOS1 inhibitor (NCT05578092). All of these assets are currently in Ph. I clinical trials.

FDA Approves Berdazimer as a Novel Topical Gel Transforming the Molluscum Contagiosum Treatment Landscape

In January, the FDA approved berdazimer (Zelsuvm), a novel, nitric oxide-releasing polymer for topical application to treat molluscum contagiosum infection. Berdazimer was discovered by Novan and developed by Ligand Pharmaceuticals. This marks a significant milestone in the treatment landscape for molluscum contagiosum infections in adults and pediatric patients one year and older, as it is the first and only topical prescription medication approved. Importantly, berdazimer facilitates at-home administration, a considerable advance over treatments like cantharidin, which requires supervision in a clinical setting. Molluscum contagiosum, characterized by red-colored skin lesions with a central, umbilicated viral core, is a highly contagious disease, affecting approximately six million Americans annually, primarily children. Notably, up to 73% of affected children remain untreated, highlighting the need for accessible treatments to mitigate the risk of further transmission.

Berdazimer's mechanism in treating molluscum contagiosum is not yet fully understood. However, the antiviral properties are potentially linked to its nitric oxide-releasing activity. Two Ph. III trials (B-SIMPLE 4 and B-SIMPLE 2) demonstrated berdazimer's efficacy in reducing lesion count when applied once daily. The most frequently reported adverse reactions (≥1%) were application site reactions. The discovery and chemical structure of berdazimer can be found here.


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