Sagimet: Positive Topline Results from Phase 2b Trial of Denifanstat in Biopsy-Confirmed F2/F3 NASH

 Denifanstat achieved statistically significant results on primary and multiple secondary endpoints in a 52-week clinical trial of 168 NASH patients with stage 2 or 3 fibrosis

• Primary efficacy endpoints:
  • NASH resolution without worsening of fibrosis with ≥2-point reduction in NAS (NAFLD Activity Score) in 36% of denifanstat-treated patients vs 13% with placebo (p=0.002)
  • ≥2-point reduction in NAS without worsening of fibrosis in 52% of denifanstat-treated patients vs 20% with placebo (p=0.0001)
    
    
• Multiple secondary endpoints:
  
  
  • Fibrosis improvement by ≥ 1 stage with no worsening of NASH in 41% of denifanstat-treated patients vs 18% with placebo (p=0.005)
  • NASH resolution with no worsening of fibrosis in 38% of denifanstat-treated patients vs 16% with placebo (p=0.002)
  • MRI-PDFF decline from baseline ≥30% (responders) in 65% of denifanstat-treated patients vs 21% with placebo (p<0.0001)

Statistically significant improvements in additional markers of liver health, including artificial intelligence (AI) digital pathology-based fibrosis assessment, FAST Score, and ALT, and numerical improvements in LDL

Denifanstat was generally well-tolerated

Management to host live webcast at 8:00 a.m. ET on Monday, January 22, 2024

Sagimet Biosciences Inc. (Sagimet, Nasdaq: SGMT), a clinical-stage biopharmaceutical company developing novel fatty acid synthase (FASN) inhibitors designed to target dysfunctional metabolic and fibrotic pathways, today announced positive topline results from its FASCINATE-2 Phase 2b clinical trial of denifanstat versus placebo in biopsy-confirmed non-alcoholic steatohepatitis (NASH) patients with stage 2 or stage 3 fibrosis (F2/F3) at week 52. In this trial, denifanstat, an oral, selective FASN inhibitor, showed statistically significant improvements relative to placebo on both of the primary endpoints of NASH resolution without worsening of fibrosis with ≥2-point reduction in NAS, and ≥2-point reduction in NAS without worsening of fibrosis. Denifanstat-treated patients also showed statistically significant fibrosis improvement by ≥ 1 stage with no worsening of NASH, and a greater proportion of MRI-derived proton density fat fraction (MRI-PDFF) ≥30% responders relative to placebo.

Management will host a live webcast at 8:00 a.m. ET on Monday, January 22, 2024 to discuss the data; participants will have the opportunity to participate in a chat-based Q&A session. The webcast will be available here and in the Events & Presentation section of Sagimet’s website at www.sagimet.com, with an archived replay available for approximately 90 days following the event.

https://www.globenewswire.com/news-release/2024/01/22/2812908/0/en/Sagimet-Biosciences-Announces-Positive-Topline-Results-from-Phase-2b-FASCINATE-2-Clinical-Trial-of-Denifanstat-in-Biopsy-Confirmed-F2-F3-NASH.html

AstraZeneca makes available 1st, only FDA-approved anti-inflammatory rescue option for asthma

  AstraZeneca announces AIRSUPRA^® (albuterol/budesonide), is now commercially available in the US by prescription. AIRSUPRA received FDA approval in January 2023 for the as-needed treatment or prevention of symptoms of asthma and to help prevent sudden severe breathing problems (asthma attacks) in people aged 18 years and older.

AIRSUPRA contains a short-acting beta₂-agonist (SABA), to help relax the smooth muscles of the airways, and an inhaled corticosteroid (ICS), to help decrease inflammation in the lungs. AIRSUPRA was approved based on the results from two Phase III trials, MANDALA and DENALI. In MANDALA, AIRSUPRA was superior to albuterol in reducing the risk of severe asthma exacerbations in patients with moderate to severe asthma. In DENALI, AIRSUPRA had a similar onset of bronchodilation compared to albuterol in patients with mild to moderate asthma.

The approach to treating asthma symptoms with rescue has changed. The 2023 Global Initiative for Asthma (GINA) report supports a rescue approach that treats both symptoms and inflammation together. Combination SABA/ICS is now recommended as a rescue option for adults with asthma regardless of ICS maintenance medication. According to GINA, recommendations for a change in rescue approach were largely based on the risk associated with SABA-only treatment of asthma. AIRSUPRA is the only FDA-approved, as-needed SABA/ICS asthma rescue now available in the US and is designed to treat both symptoms and inflammation.

https://www.biospace.com/article/releases/airsupra-albuterol-budesonide-now-available-as-the-first-and-only-fda-approved-anti-inflammatory-rescue-option-for-asthma/

Pharvaris: FDA Lifts Hold of Deucrictibant for Prophylactic Treatment of HAE

  Pharvaris (Nasdaq: PHVS), a clinical-stage company developing novel, oral bradykinin B2 receptor antagonists to treat and prevent hereditary angioedema (HAE) attacks, today announced the U.S. Food and Drug Administration (FDA) has lifted the clinical hold on the Investigational New Drug (IND) application for deucrictibant for the prophylactic treatment of HAE attacks following review of data from a 26-week rodent toxicology study.

https://www.biospace.com/article/releases/pharvaris-announces-fda-lifting-of-the-clinical-hold-of-deucrictibant-for-the-prophylactic-treatment-of-hae-attacks/

BioNTech Dua,lityBio Initiate Pivotal Phase 3 Trial Of Antibody-Drug Conjugate in Metastatic Breast Cancer

 

• The pivotal Phase 3 trial with BNT323/DB-1303 follows positive Phase 1/2 safety and efficacy data in patients with Human Epidermal Growth Factor Receptor 2 (“HER2”)-expressing advanced solid tumorswith early signs of anti-tumor activity in heavily pretreated patients with HER2-low and HER2-positive breast cancer
• The trial is expected to enroll 532 patients with Hormone Receptor-positive (“HR+”) and HER2-low metastatic breast cancer progressing on hormone therapy at clinical trial sites worldwide, initially in China, followed by sites in the United States, Europe, and additional regions
• The clinical milestone is in furtherance of BioNTech’s and DualityBio’s strategic objective to advance BNT323/DB-1303 into late-stage development in multiple high unmet medical need cancer indications

https://www.biospace.com/article/releases/biontech-and-dualitybio-initiate-pivotal-phase-3-trial-of-antibody-drug-conjugate-candidate-bnt323-db-1303-in-metastatic-breast-cancer/

Bristol Builds First-Line Case for Opdivo-Yervoy Combo in mCRC with Phase III Data

 Bristol Myers Squibb on Saturday released results from the Phase III CheckMate -8HW study showing that the combination of its PD-1 inhibitor Opdivo (nivolumab) and its CTLA-4 blocker Yervoy (ipilimumab) improved progression-free survival in certain metastatic colorectal cancer patients when used in the first-line setting.

Patients treated with the dual immunotherapy regimen saw a 79% drop in the risk of disease progression or death compared with chemotherapy. This effect was “statistically significant and clinically meaningful,” with a p-value less than 0.0001, according to BMS’s announcement.

At the time of the analysis, patients in the Opdivo plus Yervoy arm had not yet reached median progression-free survival (PFS), while chemotherapy counterparts saw a median PFS of 5.9 months. The PFS benefits associated with BMS’s combo regimen were apparent as early as three months and persisted throughout the duration of the study.

BMS presented these late-breaking data at an oral session during the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, held Jan. 18-20 in San Francisco.

Dana Walker, vice president and global program lead of gastrointestinal and genitourinary cancers at BMS, in a statement called these findings “unprecedented” while Thierry Andre, head of the Medical Oncology Department at Sorbonne University in Paris, said that these data could have “practice-changing potential.”

CheckMate-8HW is a randomized and open-label trial enrolling approximately 830 patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer. Patients in the control arm received the investigator’s choice of chemotherapy.

In addition to efficacy, CheckMate-8HW also assessed the safety of the combo regimen and found that its adverse events were consistent with what had been previously documented—and were manageable with established protocols. Treatment-related adverse events were more common in the chemotherapy arm.

CheckMate-8HW is ongoing and will continue to evaluate its second primary endpoint of PFS in patients receiving the immunotherapy combo versus Opdivo alone.

Saturday’s readout could position BMS to challenge Merck’s dominant PD-1 blocker Keytruda (pembrolizumab), which in June 2020 won the FDA’s approval as a first-line treatment option for MSI-H/dMMR metastatic colorectal cancer. This regulatory win was backed by data from the KEYNOTE-177 trial, which put Keytruda’s risk reduction at 40% for disease progression and death.

BMS’s PD-1/CTLA-4 combo could come out on top with a 79% risk reduction. Still, without direct head-to-head trials, it remains impossible to reliably compare Keytruda with the Opdivo/Yervoy regimen, particularly given differences in patient characteristics between the two trials.

https://www.biospace.com/article/bms-builds-first-line-case-for-opdivo-yervoy-combo-in-mcrc-with-phase-iii-data/

6 Neuro Data Readouts to Watch in the First Half of 2024

 With a plethora of promising candidates moving through clinical trials, there are several upcoming data readouts of interest in both the neurodegenerative and neuropsychiatric spaces. Targeting amyotrophic lateral sclerosis (ALS), major depressive disorder, Huntington’s disease and many other worthy indications, here are six mid- to late-stage data readouts for candidates you’ll want to have on your radar. 

1. Sanofi and Denali’s SAR443820/DNL788

Amyotrophic lateral sclerosis

In the ALS space, Sanofi is expected to announce topline results from the Phase II HIMALAYA trial of SAR443820/DNL788, which it is developing with partner Denali Therapeutics, according to a Denali press release. SAR443820/DNL788 is a small molecule inhibitor of RIPK1, a critical signaling protein in a canonical inflammatory and cell death pathway, according to Denali. Increased RIPK1 activity in the central nervous system is thought to drive neuroinflammation and cell death, contributing to neurodegeneration.

Part A of the double-blinded, randomized, placebo-controlled HIMALAYA trial, which has completed enrolling all 305 participants, involves evaluating patients’ change from baseline on the ALS Functional Rating Scale-Revised (ALSFRS-R), a tool used to determine disease progression. The primary outcome for Part B of the HIMALAYA program, the open-label extension, is the combined assessment of the function and survival (CAFS) score. 

SAR443820/DNL788 holds the FDA’s Fast Track designation for the treatment of ALS. Sanofi and Denali are also developing SAR443820/DNL788 for multiple sclerosis, for which it is being tested in the Phase II K2 study.

2. Intra-Cellular Therapies’ Lumateperone

Major depressive disorder

According to Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, major depressive disorder (MDD) is an area to watch this year. “There are several readouts in major depressive disorder,” he told BioSpace. Among those, he highlighted anticipated Phase III datasets for Intra-Cellular Therapies’ Caplyta (lumateperone).

Intra-Cellular’s lead asset, lumateperone won approval in 2019 for schizophrenia and received a label expansion in December 2021 for depressive episodes associated with bipolar disorder. Now the company is seeking a third indication, MDD, and expects data from two Phase III studies during the first half of 2024.

Lumateperone, an oral antipsychotic medication, is currently being assessed in a three-part Phase III program for MDD. Studies 501, 502 and 505 are testing the drug in adult patients who are having inadequate response to an approved antidepressant. The primary endpoint for these studies is change in Montgomery Asberg Depression Rating Scale (MADRS) total score after six weeks, while a key secondary endpoint is change in CGI-S score over the same period of time. The company anticipates topline data from Study 501 in the first quarter of 2024 and for Study 502 in Q2, according to a January corporate presentation.

In another Phase III trial, reported in March 2023, lumateperone eased the burden of depressive episodes in patients with MDD or bipolar depression with mixed features. Suvannavejh said these data, along with lumateperone’s approval for depressive episodes associated with bipolar disorder, “gives us a level of confidence” in the drug.  

3. Annexon Biosciences’ ANX005

Guillain-Barré syndrome

Brisbane, Calif.–based Annexon Biosciences is expecting pivotal data from a Phase III trial of its lead candidate ANX005, being developed for Guillain-Barré syndrome (GBS), during the first six months of 2024. There are no FDA-approved treatments for GBS, a potentially fatal, serious autoimmune condition of the nervous system that can cause paralysis, neurodegeneration and cognitive impairment, according to an Annexon press release outlining expected 2024 milestones.

GBS is caused by an autoantibody attack on the peripheral nerves, triggering the complement cascade (C1q). ANX005 is designed to inhibit C1s along with the entire complement pathway. It has received both Fast Track and Orphan Drug designations from the FDA in this indication. 

A Phase III study testing the efficacy, safety, pharmacokinetics and pharmacodynamics of ANX005, an investigational monoclonal antibody, completed enrollment in 2023 and is on track to read out data before July, Annexon noted in the press release.

In a Phase Ib trial, ANX005 “showed rapid and consistent improvement in muscle strength” and “improvement in neuronal damage and clinical function in patients with GBS,” according to Annexon. 

4. Wave Life Sciences’ WVE-003

Huntington’s disease

One of the most intractable neurodegenerative illnesses, Huntington’s disease continues to stump biopharma, but companies aren’t giving up. One of these is Cambridge, Mass.–based Wave Life Sciences, which is testing an antisense therapy, WVE-003, in the Phase Ib/IIa SELECT-HD trial. Wave anticipates sharing data from the 30 mg multi-dose cohort of this study with extended follow-up, along with all single-dose data, in the second quarter of 2024, according to a company press release outlining 2024 milestones.

Huntington’s disease is caused by a CAG repeat in the first exon of the huntingtin (HTT) gene. This mutation causes brain cells to die, leading to a host of progressive cognitive, psychiatric and movement symptoms, including an involuntary jerking or writhing movement, also known as chorea.

WVE-003 is designed to preferentially lower mutant HTT (mHTT) protein levels by targeting a single nucleotide polymorphism called SNP3 that appears on the mHTT transcript, Wave CEO Paul Bolno told BioSpace in a previous interview. An estimated 40% of adults with Huntington’s carry SNP3 in association with the Huntington’s mutation, Bolno said.

Wave presented data in September 2022 from SELECT-HD showing early indications of decreases in mHTT in the cerebrospinal fluid. Wildtype HTT [wtHTT]—the good type of huntingtin protein—was preserved at both doses, the company reported.

A recently posted preclinical study reinforced the importance of wtHTT-sparing biology and that the protein’s preservation is also “important in delaying the progression of the disease,” Bolno told BioSpace last week. “These data will be the first repeat-dose assessment of wildtype [huntingtin] preservation with mutant huntingtin knockdown.”

For Wave, the anticipated results also have implications for an existing collaboration agreement with Takeda, which has the option to co-develop and co-commercialize WVE-003. Per the press release, these data are expected to inform Takeda’s decision on whether or not to opt in. However, under the terms of the agreement, Wave retains control of development and regulatory approval in either case, Bolno noted. So the company is more focused on whether the program “goes the distance in terms of delivering a medicine to patients,” he said.  

5 and 6. Praxis Precision Medicines’ PRAX-562 and PRAX-628

Epilepsy

Two key anticipated data readouts in the epilepsy space come from Praxis Precision Medicines.

First, topline results from the Phase IIa PPR study of PRAX-628 in patients with photo-paroxysmal response (PPR) epilepsy are expected in the first quarter of this year. Positive preliminary analysis of the study’s 15-mg cohort “exceeds expectations” in terms of drug activity, according to a Praxis clinical portfolio update. The new data are expected to be released following completion of the 45-mg cohort.

PRAX-628, which targets focal epilepsy, is a next-generation, functionally selective small molecule targeting the hyperexcitable state of sodium-channels in the brain. Initial data show the candidate “has a good tolerability profile, a potentially wide therapeutic index” and the ability to reach efficacious concentrations within 24 hours, according to Praxis.

Also expected during the first half of 2024 are results from the Phase II EMBOLD study testing PRAX-562, a unique sodium channel modulator, in pediatric patients with SCN2A and SCN8A developmental epilepsies.

PRAX-628 and PRAX-562 are both based on Praxis’ Cerebrum small molecule platform, which leverages a “deep understanding of neuronal excitability and neuronal networks,” according to Praxis’ website.  

https://www.biospace.com/article/6-first-half-2024-neuro-data-readouts-to-watch-/

ArriVent Biopharma Seeks to Net Over $156M Potentially in IPO

 Initial public offering activity continues to perk up early in the new year with ArriVent Biopharma unveiling its plans to net over $156 million in its IPO, according to the company’s SEC documents filed Monday.

The biotech will offer over eight million shares of its common stock, priced between $17 and $19 per share. If the IPO is priced at $18 per share, it expects to net $135.7 million  or potentially as much as $156.7 million if underwriters purchase additional shares. The company will trade on the Nasdaq under the ticker symbol AVBP.

ArriVent plans to leverage the cash from the IPO for several purposes. According to the SEC filing, the company intends to use between $50 million and $60 million for its NDA approval of furmonertinib, its cancer treatment which is being developed as a first-line treatment for patients with non-small cell lung cancer (NSCLC).

In addition, ArriVent wants to use $30 million to $40 million to support the development of the drug for NSCLC patients with PACC mutations and another $5 million to $10 million to develop the drug in combination with SHP2i in NSCLC with classical EGFRm. Another $5 million to $10 million will also go towards developing its antibody-drug conjugate (ADC) collaboration with Aarvik.

While ArriVent said that the IPO will provide the company with a cash runway into 2026, the offering “will not be sufficient” to complete the development and commercialization process for all its candidates and will need to raise “substantial additional capital” in the future.

“Although we currently anticipate using the net proceeds from this offering as described above, there may be circumstances where a reallocation of funds is necessary. It is difficult to estimate with certainty the exact amounts of the net proceeds from this offering that may be used for the above purposes,” the company’s SEC filing stated.

ArriVent detailed some of its IPO plans earlier this year, while Moderna-backed Metagenomi announced its plans to go public. However, ArriVent isn’t the only company looking to enter the public markets as a flurry of biotechs has started in 2024 with planned IPOs. 

Last week, CG Oncology revealed that it looks to secure over $200 million in its IPO. At the same time, neurology biotech Alto Neuroscience and CAR-T company Kyverna Therapeutics also announced their respective plans to launch public offerings.  

https://www.biospace.com/article/arrivent-biopharma-seeks-to-potentially-net-over-156m-in-ipo-/