PDL1 x Protease

The first week of November was marked by numerous clinical trial announcements. Here’s a look. COVID-19-Related Todos Medical announced it was adding the Hillel Yaffe Medical Center as the second clinical trial site in Hadera, Israel for its ongoing Tollovir Phase II trial for hospitalized COVID-19 patients. Tollovir is an oral 3CL Protease antiviral/anti-cytokine therapeutic that blocks the 3CL Protease. The first site was the Shaare Zedek Medical Center in Jerusalem. Histogen and Amerimmune presented data from the Phase I trial of emricasan in mild symptomatic COVID-19. It had excellent safety and shortened clinical symptoms and speeded recovery compared to the placebo group. Emricasan is a potential first-in-class, oral pan-caspase inhibitor. NRx Pharmaceuticals provided new safety update on Zyesami (aviptadil) in the ACTIV-3b Critical Care Phase III trial by the NIH for life-threatening COVID-19. They found it was safe to administer to patients with critical COVID-19 who have no other therapeutic alternative. The trial is testing Zyesami and Gilead Sciences’ Veklury (remdesivir) alone and in combination in hospitalized COVID-19 patients with acute respiratory failure who require high-flow supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation. Pfizer announced it was halting its Phase II/III trial of Paxlovid, an antiviral against COVID-19. The drug reduced the risk of hospitalization or death by 89% compared to placebo in high-risk adults who were not hospitalized for treatment. They plan to an EUA as soon as possible. The drug is a SARS-CoV-2 protease inhibitor that blocks the 3CL protease. Non-COVID-19-Related Aurinia announced updated interim data from the AURORA 2 continuation study of Lupkynis (voclosporin) for lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE). In the interim analysis, patients receiving Lupkynis maintained meaningful decreases in proteinuria. And estimated glomerular filtration rate (eGFR), an important measurement of kidney function, stayed stable through month 30. Atai Life Sciences announced encouraging interim data from the first 8-patient cohort of its Phase IIa trial of RL-007 for Cognitive Impairment Associated with Schizophrenia (CIAS). RL-007 is a cholinergic, glutamatergic, and GABA type B receptor modulator. Calithera Biosciences shared interim safety and efficacy results from its Phase Ib study of CB-280 for adults with cystic fibrosis. CB-280 is an arginase inhibitor. It demonstrated linear pharmacokinetics with plasma exposure increasing proportionally with dose, and complete and continuous target inhibition in plasma was hit at the 100 mg dose and above. Hutchmed and AstraZeneca initiated a Phase III SAMETA study of savolitinib (Orphathys, in China) and Imfinzi (durvalumab) in patients with MET-driven advanced papillary renal cell carcinoma. Orpathys is an oral, potent, highly selective MET inhibitor, a receptor tyrosine kinase. Imfinzi is a PD-L1 checkpoint inhibitor. Merck presented new data from studies evaluating its anti-PD-1 checkpoint inhibitor Keytruda (pembrolizumab). Key data include exploratory 7-year follow-up from KEYNOTE-006 in advanced melanoma, updated findings from KEYNOTE-716 of Keytruda as an adjuvant for patients with resected stage IIB or IIC melanoma. Ribus Pharmaceuticals announced positive results from both single and multiple ascending dose portions of its Phase I trial of HU6 for multiple cardio-metabolic diseases. HU6 is a first-in-class, oral Controlled Metabolic Accelerator (CMA) therapy. It demonstrated robust and sustained target engagement with no obvious safety signals. Bayer presented analysis of the FIDELIO-DKD and FIGARO-DKD trials of finerenone in chronic kidney disease (CKD) and type 2 diabetes (T2D). Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist. Compared with placebo, finerenone decreased the risk of cardiovascular composite endpoint irrespective of SGLT-2i used at baseline. Ikena Oncology received the go-ahead from the FDA for a clinical trial of IK-930 for cancers harboring genetic mutations in the Hippo signaling pathway. IK-930 selectively binds TEAD and disrupts TEAD-dependent transcription of key genes involved in cancer progression, metastases, and therapeutic resistance. Acumen Pharmaceuticals presented the clinical trial framework of ACU193. ACU193 is a monoclonal antibody that selectively targets toxic soluble amyloid-beta oligomers for treatment of early Alzheimer’s. The presentation was the rationale for targeting that site and the clinical trial design of the Phase I INTERCEPT-AD trial. Metacrine reported topline results from its Phase IIa study of MET409 with Jardiance (empagliflozin) in type 2 diabetes and non-alcoholic steatohepatitis (NASH). MET409 is a farnesoid X receptor agonist. Jardiance is a sodium-glucose cotransport-2 inhibitor. The trial had favorable safety pro It has halted future development of its FX program in NASH and is prioritizing clinical development of MET642 into a Phase II trial in inflammatory bowel disease. Galecto entered into a clinical trial supply deal with Roche to explore GB1211 and Tecentriq (atezolizumab) in a Phase IIa trial in NSCLC. GB1211 is Galecto’s oral galectin-3 inhibitor. Tecentriq is Roche’s PD-L1 checkpoint inhibitor. uniQure announced a positive recommendation by the independent Data Safety Monitoring Board (DSMB) in the higher-dose cohort of the Phase I/II trial of AMT-130 for Huntington’s disease. The final 12 patients in the second cohort are now cleared for enrollment. The Ivy Brain Tumor Center at Barrow Neurological Institute, UC San Francisco and GlaxoSmithKline will run a Phase 0 clinical trial of Zejula (niraparib) in patients with newly diagnosed glioblastoma and recurrent glioma. Zejula is GSK’s oral, once-daily poly (ADP-ribose) polymerase (PARP) inhibitor. The trial will enroll up to 42 patients divided into two groups, Arm A for newly diagnosed glioblastoma patients, and Arm B for recurrent glioma patients with IDH mutation and ATRX loss. A Phase 0 trial is run in humans, but its purpose is to speed up and streamline the drug approval process. It uses only a few small doses of a drug in a smaller set of patients. Nanospectra Biosciences completed enrollment in the pivotal trial of AuroLase Therapy for focal ablation of prostate tissue via nanoparticle directed near infrared irradiation. AuroLase is the first and only ultra-focal ablation therapy designed to maximize treatment efficacy while minimizing side effects associated with surgery, radiation and alternative focal therapies. Rhythm Pharmaceuticals presented the first-ever data on the health-related quality of life (HRQOL) and experience of patients with Bardet-Biedl syndrome in its Phase III trial of setmelanotide. They also presented data from the Phase III trial of the drug in BBS and Alstrom syndrome and new hunger reduction data from the SRC1 and SH2B1 genetic deficiency cohorts in the Phase II Basket Trial. Semelanotide (Imcivree) is indicated for chronic weight management in adults and children six years of age and older with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. 7 Hills Pharma successfully completed its Phase I trial of 7HP349, which evaluated the drug in 60 healthy subjects. The drug is an immunostimulant being evaluated for its ability to improve immuno-oncology drugs, COVID-19 and influenza vaccines. AstraZeneca presented new subgroup analyses from the TULIP Phase III trial of Saphnelo (anifrolumab) in systemic lupus erythematosus. The drug is a first-in-class type 1 interferon antagonist. Its addition to standard therapy resulted in a greater decrease in SLE disease duration, standard therapy type and previous treatment, compared to standard therapy alone. CytoDyn announced two separate stories about its drug leronlimab today, one for nonalcoholic steatohepatitis (NASH) and the other for metastatic triple-negative breast cancer (mTNBC). Leronlimab is a viral-entry inhibitor, binding to CCR5, protecting T-cells from viral infection. In the Phase II NASH study, CytoDyn reported preliminary findings from five patients receiving leronlimab. The data suggests the fatty deposits were decreased by as much as 45% in all five patients compared to baseline measurement. Fibrosis, or scarring, was decreased by as much as 10% in four of the five patients. For the breast cancer study, CytoDyn updated results on patients receiving leronlimab who had CCR5+ mTNBC who had failed at least two lines of previous therapy. The ongoing data analysis is from 28 pooled patients, 16 from the company’s Compassionate Use Study, 10 from a Phase Ib/II trial and two from the Basket Study. Three-quarters, or 75%, of the patients who showed a lower level of circulating cells after receiving leronlimab demonstrated a 3600% increase in 12-month overall survival (OS) compared to a 980% increase in OS reported by CytoDyn on August 25, 2021. The updated data also hints at a 580% increase in 12-month Progression Free Survival (PFS) compared to up to a 660% increase in PFS they reported on August 25. Biogen presented data including more than 3,000 patients in Phase III clinical trials and about 1,7000 patients in the redosing trial, EMBARK, of Aduhelm. A late-breaking presentation covered new data from more than 7,000 plasma samples from the ADUHELM Phase III clinical trials that described the effect of the drug on plasma phosphorylated tau181 (p-Tau181) and how it correlates to amyloid beta plaques and disease progression. Amyloid beta and tau are abnormal proteins that aggregate in the brains of Alzheimer’s patients. They also presented results from more than 1,800 patients screened for the EMBARK re-dosing study with Aduhelm. This, they say will “shed light on the impact of stopping treatment in clinical trials.” Avidity Biosciences dosed the first patients in the Phase I/II MARINA trial of AOC 1001 for myotonic dystrophy type 1 (DM1). AOC 1001 decreased levels of a disease-related mRNA called DMPK. The drug is a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DMPK mRNA. NerveGen presented additional Phase I data for NVG-291. The drug, a protein tyrosine phosphatase modulator is being developed for nervous system injury that can be the result of trauma or diseases, such as multiple sclerosis or Alzheimer’s. Following the Phase I trial, it hopes to run bridging studies in healthy males and healthy premenopausal females, then initiate a Phase Ib/IIa trial in Alzheimer’s disease. It hopes to initiate Phase Ib/II trials in spinal cord injury and MS in 2022. Processa Pharmaceuticals announced that in its Phase Ib trial of its next generation capecitabinase dosage regimen (a combination of PCS6422 administered with capecitabine), the combination successfully inhibited dihydropyrimidine dehydrogenase (DPD), altering the metabolism of 5-FU at least during the first 24-48 hours after PCS6422 but not throughout the seven days of capecitabine dosing. Capecitabine is a widely used chemotherapeutic, a prodrug of 5-FU that is converted to 5-FU through three metabolic steps. However, about 80% of 5-FU is broken down to non-cancer killing metabolites. Combining the drug with PCS6422 results in needing less capecitabine to cause cellular apoptosis and death. Enlivex Therapeutics reported that its Phase II trial of Allocetra in pneumonia-associated sepsis had been authorized in Spain. Allocetra is being developed as a universal, off-the-shelf cell therapy to reprogram macrophages into their homeostatic state. Eyenovia enrolled the first set of patients in its Phase III VISION-1 study of MicroLine for improving near vision in patients with presbyopia. MicroLine is a proprietary pilocarpine formulation delivered via the company’s Optejet dispenser. Neurona Therapeutics got the go-ahead from the FDA to launch a Phase I/II trial of NRTX-1001 in drug-resistant mesial temporal lobe epilepsy (MTLE). NRTX-1001 is a regenerative neural cell therapy that might be able to repair hyperexcitable neural networks. Chimerix reported topline data from the 50-patient cohort of ONC201 for recurrent H3 K27M-mutant glioma. ONC201 is an oral dopamine receptor D2 antagonist and caseinolytic protease agonist. Talaris Therapeutics provided the first clinical update on its Phase III FREEDOM-1 study in living donor kidney transplant (LDTK) recipients, as well as a clinical update and additional data from ongoing follow-up of its fully-enrolled Phase II trial in LDKT recipients. The first two Phase III patients receiving FCR001 more than 12 months before the data cutoff were successfully weaned off all chronic immunosuppression without signs of rejection and with stable kidney function. In the Phase II patients, all 26 patients originally weaned off immunosuppression continued to stay off it without rejecting their donated kidney. Vaccitech published results from the Phase I trial in the Middle East of the ChAdOx1 MERS vaccine candidate. The vaccine was generally well tolerated and induced robust antibody and T cell immune responses in healthy volunteers. Codexis and Nestle Health Science dosed the first patient in a Phase I trial of CDX-7108. The drug is a lipase variant engineered to overcome the limitations of traditional pancreatic enzyme replacement therapy (PERT) deficiencies. PERT is the primary treatment for exocrine pancreatic insufficiency (EPI), a GI-tract condition caused by disease that impair pancreatic function, such as pancreatitis, pancreatic cancer, Crohn’s disease, celiac disease and cystic fibrosis. Chinook Therapeutics presented data on its BION-1301 and atrasentan clinical programs. BION-1301 is a novel anti-APRIL monoclonal antibody in Phase I/II studies for patients with IgAN. Data was presented from Cohort 1 in Part 3 of the study. It was well-tolerated and durably reduced serum IgA and IgM levels, and to a lesser extent IgG levels. In a Phase I trial, atrasentan demonstrated consistent and predictable safety, tolerability and linear dose-proportionality in healthy Chinese, Japanese and North American adults of non-Asian descent. Longeveron selected bioRASI as its CRO for its Phase II trial of Lomecel-B infusion in Alzheimer’s patients. Lomecel-B is derived from culture-expanded medicinal signaling cells sourced from the bone marrow of young, healthy adult donors. Orchestra BioMed presented long-term clinical results and ISH subgroup data from the MODERATO II trial of BackBeat Cardiac Neuromodulation Therapy in patients with hypertension and an indication for a pacemaker. The results demonstrated a mean reduction of 17.5 mmHg in office systolic blood pressure in all BackBeat CNT treated patients who completed 24-month follow-up. KemPharm presented data on serdexmethylphenidate/d-Methylphenidate capsules for children with ADHD. The trial hit the primary endpoint, showing greater improvements from baseline and the Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP) with Azstarys versus placebo. MagForce received the greenlight from the FDA to proceed with Stage 2B with the final protocol of the pivotal U.S. study for the focal ablation of prostate cancer with the NanoTherm therapy system for intermediate risk prostate cancer. Up to 100 patients are planned to be treated. Calithera Biosciences terminated its Phase II KEAPSAKE trial based on lack of clinical benefit in an interim analysis. The study was evaluating telaglenastat plus standard-of-care chemoimmunotherapy as front-line therapy in patients with stage IV non-squamous non-small cell lung cancer (NSCLC) whose tumors have a KEAP1 or NRF2 mutation.

--No pruritus observed during 14-day treatment of the once-daily human therapeutic dose of 15 mg. --FXR target engagement biomarker FGF19 increased 1632% on Day 14 of treatment with 15 mg, once-daily. --FXR target engagement biomarker C4 decreased 93% on Day 14 of treatment with 15 mg, once-daily. --Mean LDL-C values remained within the normal range during 14-day, once daily treatment with 15 mg. --There were no treatment-emergent ALT and AST elevations during 14-day, once daily treatment with 15 mg. --Doses selected for Phase II trial in patients with NASH, which will be initiated by the end of 2021. [16-June-2021] SHANGHAI, June 16, 2021 /PRNewswire/ -- Gannex, a wholly owned company of Ascletis Pharma Inc. (HKEX: 1672), fully dedicated to the R&D and commercialization of new drugs in the field of non-alcoholic steatohepatitis (NASH), today announces positive topline results of safety and pharmacodynamic biomarkers from the U.S. Phase I trial of NASH drug farnesoid X receptor (FXR) agonist ASC42. The ASC42 Phase I trial in the U.S. was a first-in-human, randomized, placebo-controlled, double-blind single-ascending dose (SAD), multiple-ascending dose (MAD), and food effect trial in 64 healthy subjects receiving ASC42 or matching placebo. Doses in the SAD portion ranged from 5 to 200 mg doses and in the MAD portion ranged from 5 to 50 mg administered once-daily for 14 days. The food effect on ASC42 pharmacokinetics was studied with a dose of 15 mg. The primary objective was to evaluate the safety, pharmacokinetics and pharmacodynamics of ASC42 versus placebo. Biomarkers for FXR target engagement were assessed through measurement of 7α-hydroxy-4-cholesten-3-one (C4), a blood biomarker of bile acid synthesis that decreases with FXR activation, and Fibroblast Growth Factor 19 (FGF19), a hormone produced after FXR activation in the intestine that regulates bile acid synthesis as well as glucose and lipid metabolism. Based on both mouse and rat NASH animal models, the predicted human therapeutic dose was 15 mg once-daily. ASC42 Phase I topline data showed that during 14-day treatment with15 mg once-daily, Day 1 and Day 14 FGF19 levels increased 1195% and 1632% from the pre-dose level, respectively; Day 1 and Day 14 C4 levels decreased 88% and 93% from the baseline, respectively. Based on these data, 15 mg once-daily dose has been selected as one of 3 doses to be studied in the Phase II trial in patients with NASH, that will be initiated by the end of 2021. The magnitude of FGF19 increase and/or C4 decrease may be used to project potential levels of liver fat reduction in patients with NASH, with a ≥30% relative liver fat reduction on MRI-PDFF potentially correlating with an increased likelihood of histologic benefit. Overall, ASC42 was safe and tolerated and there were no study drug related SAEs or premature discontinuations. Notably, there was no pruritus, mean LDL-C values remained within normal limits and there were no treatment-emergent ALT and AST elevations for 14-day, once daily dosing with 15 mg. In addition, there was no significant food effect on the pharmacokinetic pro ASC42 with a high fat meal. Melissa Palmer, M.D., Chief Medical Officer of Gannex, said, "We are excited about the safety and tolerability pro ASC42 and looking forward to initiating a Phase II trial by the end of 2021." Handan He, Ph.D., Chief Scientific Officer of Ascletis, said, "We are thrilled by our discovery team's successful prediction of the ASC42 human therapeutic dose using the preclinical PK/PD data. This expertise has enabled us to accelerate many of our internal discovery programs." ASC42 is an in-house developed, novel non-steroidal, selective, potent FXR agonist with best-in-class potential. ASC42 is an oral tablet formulation developed with in-house proprietary technology and is stable at room temperature. ASC42 is expected to be used alone and in combination with thyroid hormone receptor beta (THR-β) agonist ASC41 or fatty acid synthase (FASN) inhibitor ASC40. About Ascletis Ascletis is an innovative R&D driven biotech and listed on Hong Kong Stock Exchange (1672.HK). Ascletis is committed to developing and commercializing innovative drugs in the areas of NASH, cancer lipid metabolism and oral checkpoint inhibitors, viral hepatitis and HIV/AIDS for unmet medical needs in China and globally. Led by a management team with deep expertise and a proven track record, Ascletis has developed into a fully integrated platform covering the entire value chain from discovery and development to manufacturing and commercialization. Ascletis has three marketed products and seventeen R&D pipeline drug candidates or combination therapies (eleven of them developed in-house). 1. NASH: Gannex, a wholly-owned company of Ascletis, is fully dedicated to the R&D and commercialization of new drugs in the field of NASH. Gannex has three clinical stage drug candidates against three different targets – FASN, THR-beta and FXR, and three combination therapies. 2. Cancer lipid metabolism and oral checkpoint inhibitors: focus on a pipeline of oral inhibitors targeting FASN which plays a key role in cancer lipid metabolism and a pipeline of oral PD-L1 small molecule inhibitors as the next generation checkpoint inhibitors. 3. Viral hepatitis: (i) Hepatitis B: focus on breakthrough therapies for HBV clinical cure with subcutaneously injected PD-L1 antibody - ASC22 and Pegasys® as cornerstone drugs. (ii) Hepatitis C: successfully launched all oral regimen of ASCLEVIR® and GANOVO® combination (RDV/DNV regimen); and ASC18 fixed dose combination (FDC) is an upgraded version of RDV/DNV regimen with bridging study finished. 4. HIV/AIDS: ASC09F is a FDC treatment of HIV targeting protease. The clinical trial application of ASC09F has been approved. For more information, please visit . Company Codes: HongKong:1672