Advances in drug development
1.HUTCHMED's SYK inhibitor solplenib acetate is proposed for priority review
On December 7, the Center for Drug Evaluation (CDE) of the State Medical Products Administration of China announced on its official website that the sollepineb acetate tablets declared by Chi-Med are intended to be included in the priority review for the proposed indications: primary chronic thrombocytopenia (ITP) that has previously received first-line criteria** (glucocorticoids, immunoglobulins) that are ineffective or **. According to public information, this is a SYK inhibitor. The product explores the pivotal Phase 3 study of ESG-01 in China for ITP, which previously met the primary endpoint of sustained response rate and all secondary endpoints. Immune thrombocytopenia is a heterogeneous disease that can persist for years and has a low rate, even if the best is available. Although there are several approaches with different mechanisms of action, chronic diseases remain a challenge. Many patients develop resistance and are susceptible**. Therefore, there is still a large number of patients who do not respond well to the existing **, and new ** methods are urgently needed. Solepineb is a novel, highly selective oral spleen tyrosine kinase (SYK) inhibitor, administered orally once daily, intended for the treatment of ** hematological malignancies and autoimmune diseases. As a key protein in the B-cell receptor and FC receptor signaling pathways, SYK is a well-established target of various subtypes of B-cell lymphoma and autoimmune diseases. Because platelet destruction in immune thrombocytopenia is associated with SYK-regulated cellular phagocytosis of FC receptor-bound platelets, SYK inhibitors may be a promising prospect for immune thrombocytopenia**. According to an earlier press release from HUTCHMED, the company currently owns all rights to solopineb worldwide. Solepinib has earlier been included in the CDE as a breakthrough ** variety, with immune thrombocytopenia. Studies of solopineb in warm antibody, autoimmune hemolytic anemia and indolent non-Hodgkin lymphoma are also ongoing.
2.The complete response rate was 76%!Innovative Cancer** Receives FDA Breakthrough Designation and Fast Track Designation
Recently, CG Oncology announced that the U.S. FDA has granted Fast Track Designation and Breakthrough Designation to its oncolytic virus**Cretostimogene Grenadenorepvec (CG0070) for high-risk BCG non-reactive non-muscle-invasive bladder cancer (NMIBC) carcinoma in situ with or without TA or T1 (papillary) tumors. The FDA granted Fast Track Designation and Breakthrough Designation based on positive clinical trial results. At the 24th Annual Meeting of the Society of Urological Oncology (SUO) last week, CG Oncology presented interim analysis results from the Phase 3 clinical trial of BOND-003. The data showed that the complete response rate for patients with BCG-unresponsive NMIBC who received Cretostimogene Grenadenorepvec monotherapy** was 757%（n=50/66）。This was generally well tolerated, and the most common** related adverse events in the trial included transient grade 1 to 2 local genitourinary symptoms. No grade 3 or higher adverse events related to cretostimogene grenadenorepvec were observed. Cretostimogene Grenadenorepvec is an intravesical oncolytic virus** based on an engineered adenovirus type 5 (AD5) backbone that includes a tumor-specific promoter, and a granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene. After lysis of tumor cells, GM-CSF is released along with tumor-specific antigens and other danger signals. GM-CSF can activate dendritic cells (DCs), which recognize tumor antigens and present them to cytotoxic and helper T cells, thereby promoting their maturation. These T cells are then able to circulate throughout the body, recognizing and attacking residual tumor cells.
3.The overall survival rate was 81%, and BridgeBio Innovation** Acoramidis submitted a new drug application to the FDA
Recently, BridgeBio Pharma announced that it has submitted a New Drug Application (NDA) for Acoramidis to the US FDA for the treatment of ** patients with transthyretin-mediated amyloidosis (ATTR-CM) with cardiomyopathy. The application is based on positive results from the pivotal trial Attribute-CM, a Phase 3 study by BridgeBio to evaluate the efficacy and safety of acoramidis. BridgeBio announced positive topline results from the Attribute-CM trial in July this year. Unlike those observed in previous transthyretin (TTR) stabilizer trials, consistency in reducing the risk of cardiovascular-related hospitalization was observed across all predetermined patient subgroups at 30 months. **The time curves for the first occurrence of all-cause mortality and cardiovascular-related hospitalizations in the ** and placebo groups began to separate at month 3 and continued through month 30 with a hazard ratio of 0645（p=0.0008）。Notably, the overall survival rate at 30 months was 81% in the active** group of attribute-cm, which is similar to the survival rate of the age-matched general population in the US database (85%). At the same time, the annualized cardiovascular-related hospitalization rate in the ACORAMIDIS group was 029, with the U.S. database reporting 0 of the population with general health insurance26 similar. The results of the attribute-cm study also showed rapid clinical benefit in patients receiving acoramidis** in terms of the composite endpoint of all-cause mortality and cardiovascular-related hospitalizations. In addition, acoramidis was well tolerated and no potential safety signals were found. ACORAMIDIS is a next-generation, orally administered, high-potency small molecule stabilizer for TTR. It is designed to mimic the function of the protective TTR T119M mutation, maintain the normal tetrameric conformation of the TTR protein, and prevent the production of toxic amyloid.
4.Two phase III studies of Evobrutinib, an oral highly selective BTK inhibitor, failed Merck
On December 6, Merck announced updated results from two Phase III Evolution studies (EvolutionRMS 1 and EvolutionRMS 2) in Evobrutinib*** multiple sclerosis: Evobrutinib did not meet the primary endpoint of reducing annualized rate of ** (ARR) compared to teriflunomide. Evobrutinib is an oral, highly selective covalent Bruton's tyrosine kinase (BTK) inhibitor with central nervous system permeability and is expected to break through the blood-brain barrier and thereby inhibit smoldering foci to control disease progression in RMS. In October 2022, Merck had announced positive results from Evobrutinib in a phase II study with low ARR and stable Expanded Disability Status Scale (EDSS) scores in patients with RMS during the three-and-a-half-year period of receiving the drug**. In April this year, the FDA imposed a partial clinical pause on newly recruited patients and patients who had been on EVOVRUTINIB for less than 70 days due to liver damage in two patients in the phase III study. However, Merck noted that the patient did not develop symptoms, did not require any medical intervention or hospitalization**, and liver enzyme measures returned to normal after discontinuation of the study drug. For this phase III study, Merck said that the specific results will be published after a comprehensive evaluation of the study data. For a long time, the exploration of BTK inhibitors in non-oncology fields has attracted much attention, but the progress has been frustrated. Sanofi's Phase III study of tolebrutinib in multiple sclerosis and myasthenia gravis (mg) was partially suspended by the FDA due to the risk of liver damage. Subsequently, Sanofi also announced in its 2022 full-year financial report that it would discontinue the Phase III study of tolebrutinib for MG.
5.SYROS Small Molecule Combination** Delivers Brilliant Clinical Results, with 100% of Cancer Patients Meeting the Primary Endpoint!
On December 7, Syros Pharmaceuticals announced positive preliminary data from its ongoing Phase 2 trial of Select-AML-1, which evaluated its investigational small molecule Tamibarotene in combination with venetoclax and azacitidine** in patients with newly diagnosed, RARA-overexpressing acute myeloid leukemia (AML). Tamibarotene is an investigational oral, selective, retinoid receptor (RAR) agonist. The primary endpoint of the trial is complete response (CR) complete response with incomplete hematologic recovery (CRI). The analysis showed that evaluable CR CRI rates were 100% in patients who received Tamibarotene in combination with venetoclax and azacitidine ** (9, 9). In comparison, the CR CRI rate of patients receiving controls (venetoclax and azacitidine)** was 70% (7 10). Of these, 7 of the 9 evaluable patients (78%) who received Tamibarotene in combination with ** achieved CR and 2 patients (22%) achieved CR. Of the 10 evaluable patients who received control**, 3 (30%) achieved CR and 4 (40%) achieved CR. The median time to CR response was 21 days (range: 14-28 days) for patients receiving Tamibarotene in combination with ** compared with 25 days (range: 17-56 days) for patients receiving control**. 100% of patients in the Tamibarotene plus ** group achieved CR at the end of a cycle, compared with 60% in the control group. Consistent with prior clinical experience with the safety lead-in portion of the study, tamibarotene in combination with the approved doses of venetoclax and azacitidine** generally showed good tolerability, with no additive toxicities or new safety signals in the overall safety profile.
6.Significant improvement in ORR in drug-resistant solid tumors!Innovative target monoclonal antibody combinations** demonstrate positive anti-tumor activity
On December 7, Catalym announced positive results from its ongoing Phase 2A trial of GDFATHER-2. The results of the trial showed that Catalym's investigational monoclonal antibody visugromab in combination with the PD-1 inhibitor nivolumab** showed anti-tumor activity in patients with non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC) who had experienced PD-1 PD-L1 inhibitor** and subsequently developed** or were resistant to the drug. In addition, the combination** has demonstrated a favorable safety profile and tolerability. The analysis showed that an objective response rate (ORR) of 14 was observed in both UC and NSCLC patients according to RECIST criteria8% and 21 for non-squamous NSCLC1%, all of whom are third- to fourth-line patients with anti-PD-1 PD-L1** refractory disease as defined by strict criteria. In addition, significant improvement in duration of response (DOR) was also observed, with a mean DOR of more than 11 months in patients with non-squamous NSCLC and more than 10 months in patients with UC, with 6 to 8 patients still having a consistent response. In terms of safety, the majority of post-emergence-emergent adverse events (TEAEs) reported in the trials were mild to moderate, with only 5Grade 3 TEAE occurred in 2% of patients (9 174), showing that the combination** was well tolerated overall and had a safety profile in patients with pro-multiline progression**. Visugromab is a monoclonal antibody targeting tumor-derived growth differentiation factor-15 (GDF-15), a locally-acting immunosuppressant that promotes immune** resistance. Neutralization of GDF-15 by visugromab has the potential to reverse key cancer resistance mechanisms and re-achieve an effective anti-tumor response by enabling immune cell activation and tumor infiltration.
7.Haichuang Pharmaceutical's URAT1 inhibitor was approved for Phase 2 clinical trial in the United States
On December 7, Haichuang Pharmaceutical announced that its self-developed Class 1 new chemical drug URAT1 inhibitor HP501 sustained-release tablets for the clinical trial application of gout-related hyperuricemia has been approved by the US FDA. Excessive intake of purine compounds, increased uric acid synthesis in the body, or decreased excretion are the main causes of hyperuricemia. Uric acid is mainly excreted in the body through the kidneys, and the decrease in the excretion of uric acid in the kidneys is one of the mechanisms that cause hyperuricemia. Long-term hyperuricemia causes urate crystals to be deposited under the skin and in the joints, causing gout. Urate anion transporter 1 (URAT1) inhibitors are one of the main types of drugs for hyperuricemia. These drugs reduce urate reabsorption by inhibiting the activity of urat1, thereby promoting uric acid excretion and lowering blood uric acid levels. HP501 is a highly active and highly selective URAT1 inhibitor independently developed by Haichuang Pharmaceutical, which is intended to be developed for ** hyperuricemia and gout. The results of preclinical pharmacology, pharmacokinetic and toxicological studies have proved that the product is safe and effective. Haichuang Pharmaceutical has completed a number of phase 1 and 2 clinical studies, and the results show that HP501 has good efficacy, safety and tolerability in ** hyperuricemia and gout. It is reported that HP501 monotherapy for ** hyperuricemia gout has completed a number of clinical phase 1 and phase 2 trials, and preparations for phase 3 clinical trials are being carried out. In addition, Haichuang Pharmaceutical is also carrying out clinical research on the combination of HP501 sustained-release tablets and xanthine oxidase inhibitors for long-term treatment of primary hyperuricemia.
8.Sino-American Ruikang small activation RNA drug was declared for clinical trial in Australia
On December 6, Ractigen Therapeutics announced that it has submitted a Phase 1 clinical trial application for its first small activation RNA (SARNA) drug RAG-01 in Australia. This clinical study is an open-label, multicenter Phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of RAG-01 in patients with non-muscle-invasive bladder cancer (NMIBC) who do not respond to BCG. The move symbolizes the company's official emergence as a clinical-stage biopharmaceutical company and marks an important breakthrough in the field of RNA activation, according to a press release. RNA activation (RNAA) technology is a clinically validated technology that enables endogenous gene activation and uses double-stranded RNA targeting gene promoter regions to activate gene expression to restore the level of sexual proteins. RNA activation technology is a scarce platform technology in the field of biomedicine, and has broad application prospects in the development of first-class drugs. As one of the new pioneers of small nucleic acid drugs that have mastered both intrahepatic and extrahepatic delivery, Zhongmei Ruikang has developed a number of unique international innovative small nucleic acid drug delivery platform technologies, and has established a highly differentiated small nucleic acid drug pipeline for indications covering neurodegenerative and neuromuscular diseases, tumors, metabolic and hematologic diseases, etc. RAG-01 is a double-stranded SARNA drug that specifically targets the activation of tumor suppressor gene p21, activating the expression of p21 gene through RNA mechanism to inhibit tumor cell proliferation, induce apoptosis and senescence. Preclinical efficacy studies have shown that RAG-01's ** can significantly inhibit the growth of bladder cancer tumors in animal models and demonstrate sufficient safety profile through the extrahepatic small nucleic acid delivery system LICOTM independently developed by Zhongmei Ruikang.
Advances in drug development
Next city!AbbVie's $8.7 billion acquisition of neuroscience company CerevelOn December 7, AbbVie announced that it had entered into a definitive agreement with Cerevel Therapeutics to acquire Cerevel Therapeutics for $45 per share in cash, with a total equity value of approximately $8.7 billion. Upon completion of the acquisition, AbbVie will have access to Cerevel Therapeutics' strong neuroscience pipeline, including potential drug candidates for a variety of conditions, including psychiatric, Parkinson's and mood disorders. Emraclidine, a late-stage clinical-stage product in Cerevel's pipeline, is a highly selective positive allosteric modulator (PAM) targeting muscarinic M4 and is considered a potential best-in-class next-generation antipsychotic. Previously reported Phase Ib clinical results for **psychosis** showed that emracridine had good efficacy and safety, supported oral once-a-day without dose titration, and had an AE rate of 52 versus 52 percent. In contrast, the AE rate of the competitor Karxt's Emergent-1 trial was 54% versus 43%, twice a day and dose titration was required, confirming that the product's improved target subtype selectivity could improve the safety of its targeted drugs. Currently, the product is undergoing two Phase II registrational studies. In addition, emraclidine also has great potential for dementia-related psychosis such as Alzheimer's disease and Parkinson's disease. In addition to Emraclidine, Cerevel has a number of pipeline assets that have advanced in clinical development and have best-in-class potential. T**Apadon is a first-in-class oral dopamine D1 and D5 receptor-selective partial agonist for Parkinson's disease that is currently in Phase III studies with the potential to be a single agent and adjuvant. CVL-354 is a potential best-in-class kappa-type opioid receptor (KOR) antagonist currently in Phase I clinical trials. CVL-354 has the potential to significantly improve efficacy and tolerability compared to existing major depressive disorder (MDD)*. Darigabat is a 2-3-5-selective GABAA receptor PAM for refractory epilepsy and anxiety disorders, in Phase II clinical trials. Alphamab Oncology Suzhou and Tebao Biosciences have reached a biologics licensing cooperationOn December 6, Alphamab and Alphamab announced that they have signed a cooperation agreement on the licensing of KN056 or KN069 (licensed products) independently developed by Alphamab Suzhou. According to the terms of the agreement, the geographical area of the licensed product is Chinese mainland, and the licensed indication area is the prevention and ** of non-alcoholic fatty liver disease (NASH, or fat-related metabolic disease).Tebao Biopharma will be solely responsible for the clinical development and commercial sales of the licensed products within the scope of the license, and will pay up to RMB4Equity payments (including upfront payments and milestones) of $900 million and sales royalties as a percentage of net sales. Alphamab Oncology Suzhou retains all rights and interests in KN056 and KN069 outside the scope of the license. KN056 and KN069 are bio-innovative drugs independently developed by Alphamab Suzhou to regulate human metabolism. Among them, KN056 has a significantly longer in vivo half-life than the existing weekly dosage form GLP-1 agonists, which is expected to further reduce the dosing frequency and improve the compliance and convenience of patients. KN056 has been in Phase 1 clinical studies in healthy subjects in China and New Zealand for the target indication of type 2 diabetes mellitus, and has shown good safety and tolerability to date. KN069 has demonstrated significant metabolic regulation in preclinical studies. Dr. Ting Xu, Founder and Chairman of Alphamab Suzhou, said, "We are delighted to have entered into a collaboration with Tebao Biotech on the KN056 or KN069 projects. These two projects are important achievements of Suzhou Alphamab Oncology's protein engineering technology, which have differentiated advantages compared with other similar products, and are expected to provide safer, more effective and more convenient solutions for metabolic diseases. We look forward to fully exploiting the clinical potential of KN056 or KN069 in the field of NASH through this collaboration." ”