Clinical Catch-Up: September 2-8

Clinical data

Last week was a busy week for clinical trial results. Here’s a look at some of the top stories and reporting.

Novartis reported results from two clinical trials evaluating improvements in heart structure and function, as well as long-term safety for Entresto (sacubitril/valsartan). The drug was being evaluated in patients with heart failure with reduced ejection fraction (HFrEF). The trials were the PROVE-HF and EVALUATE-HF trials. PROVE-HF was a Phase IV, 52-week, single-arm, open-label trial. This trial showed that patients receiving Entresto had significantly improved levels of an important biomarker, N-terminal pro-B-type natriuretic peptide (NT-proBNP). EVALUATE-HF is a Phase IV, multicenter, randomized, double-blind, active-controlled trial to evaluate Entresto’s effect on remodeling of the blood vessels of the heart and ventricular-vascular coupling. This study compared Entresto to enalapril. The EVALUATE-HF trial, however, showed that neither Entresto nor enalapril improved the primary endpoint, change in aortic impedance, which is a way of measuring vascular stiffness.

Novartis also presented data from its Phase III PARAGON-HF trial, which evaluated Entresto compared to active comparator valsartan in heart failure with HFpEF. The drug decreased the composite primary endpoint of total heart failure hospitalizations and cardiovascular death by 13%, which the company is calling a “near miss” for statistical significance.

AstraZeneca reported positive results from its Phase III THEMIS clinical trial of Brilinta (ticagrelor) plus aspirin for cardiovascular (CV) death, heart attack, or stroke. Compared to aspirin alone, the combination decreases these risks by 10%. The THEMIS trial population was patients with coronary artery disease (CAD) and type 2 diabetes (T2D) with no previous heart attack or stroke. The trial also had a sub-analysis of patients who had already had a percutaneous coronary intervention (PCI), which is a procedure used to open a blocked or narrowed coronary artery. In this analysis of this group, there was a 15% relative risk reduction compared to aspirin alone.

AstraZeneca also reported data from a study of its diabetes drug Farxiga (dapagliflozin) that showed it reduced mortality rates or worsening of heart failure by 26% in patients who had previously had reduced ejection fraction heart failure. The results from the Phase III DAPA-HF was the first outcomes trial with an SGLT2 inhibitor looking at heart failure in patients with reduced ejection fraction (HFrEF) with or without type 2 diabetes.

The Medicines Company presented results from ORION-11, a Phase III trial of inclisiran, a twice-yearly PCSK9 inhibitor for low-density lipoprotein cholesterol (LDL-C). The drug met its primary and secondary endpoints, was well-tolerated and had an excellent safety profile. The drug decreased placebo-adjusted LDL-C levels by 54% at day 510 and showed time-averaged placebo-adjusted LDL-C decreases of 50% from days 90 through 540.

Roche/Genentech announced results from the Phase III BLOCKSTONE trial of Xofluza (baloxavir marboxil). The therapy prevented influenza after exposure to an infected household member by 86% compared to placebo. The trial was focused on very specific exposures, but also showed that the therapy was effective when fewer criteria were observed, including fewer participants with the flu, with fever or one or more respiratory symptoms. Even inf those cases, there was a 76% reduction in the risk of household members developing the flu compared to 22.4% reduction for placebo.

Fate Therapeutics was given the go-ahead by the FDA for its Investigational New Drug (IND) application for FT596, the company’s first off-the-shelf chimeric antigen receptor (CAR) natural killer (NK) cell therapy that targets multiple tumor antigens. The company plans to launch a clinical trial of FT596 as a monotherapy and in combination with CD20-directed monoclonal antibodies for B-cell lymphoma and chronic lymphocytic leukemia.

Atossa Genetics completed enrollment of its Phase I clinical trial of a proprietary modified-release oral tablet form of its Endoxifen. The trial has enrolled and endorsed 24 participates in the last six weeks. The company will use the Phase I dosing data to conduct a Phase II trial on whether the drug reduces breast density. Mammographic Breast Density (MBD) can mask the detection of cancers, and 35 states have legislation requiring women be notified if they have MBD, indicating that they have a higher risk of breast cancer and that mammography may not be as effective in detecting breast cancer as a result.

Kaleido Biosciences announced data from a clinical trial of KB195 in patients with urea cycle disorders (UCD). In the study, no clinically significant safety signals were observed and there were no serious treatment-emergent adverse events. The therapy is a Microbiome Metabolic Therapy (MMT). The gut microbiome plays a major role in the production and consumption of ammonia, which is central to UCD, a group of serious, life-threatening, rare genetic diseases that can lead to hyperammonemia. KB195 was developed to decrease net ammonia production by modulating the metabolic output and profile of the microbiome.

Apellis Pharmaceuticals dosed the first patient in its Phase III trial of APL2 for treatment-naïve patients with paroxysmal nocturnal hemoglobinuria (PNH). It is the second Phase III trial the company has launched for this drug to treat PNH. PNH is a rare, chronic blood disorder that can lead to life-threatening complications. The PRINCE Phase III trial plans to enroll 54 treatment-naïve adults with PNH to evaluate the efficacy of APL-2 in PNH.

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Kura Oncology announced positive topline results from an investigator-sponsored Phase II trial of tipifarnib in relapsed or refractory urothelial carcinomas that carry HRAS mutations. The trial is designed to enroll at least 18 patients with the primary endpoint progression-free survival (PFS) at six months. Secondary endpoints included objective response rate, duration of response, and safety. The trial is being run at the Samsung Medical Center in South Korea. The trial met its primary endpoint even before enrollment was completed.

Kuros Biosciences indicated that the FDA had approved its IND to launch a Phase IIa clinical trial of Fibrin-PTH (KUR-113) in single-level transforaminal lumbar interbody fusion (TLIF) procedures in people with degenerative disc disease. It will use an autograft, the patient’s own bone, as a comparator. The IND is believed to be the first ever approved by the FDA to evaluate a drug/biologic combination for lumbar interbody fusion of the spine. KUR-113 is a natural fibrin-based healing matrix with an immobilized targeted bone growth factor designed to be applied directly into and around an intervertebral body fusion device as a gel.

Daiichi Sankyo announced results from ENTRUST-AF PCI, a trial of its Lixiana (edoxaban) plus a P2Y12 inhibitor compared to vitamin K agonist (VKA) plus P2Y12 inhibitor and acetylsalicylic acid (ASA), or aspirin. The trial was conducted in atrial fibrillation (AF) patients after successful percutaneous coronary intervention (PCI). The composite endpoint was major or clinically relevant non-major bleeding over 12 months.

Citius Pharmaceuticals reported the FDA accepted “time to catheter failure” as an acceptable primary efficacy endpoint for its Phase III pivotal trial for Mino-Lok. Mino-Lok therapy (MLT) is being compared to antibiotic lock therapy (ALT) to disinfect colonized catheters causing bacteremias and to keep the treated catheters functioning and infection-free for eight weeks after therapy.

Synlogic presented a full clinical data set from healthy volunteers and patient cohorts of a Phase I/IIa clinical trial of SYNB1618 for phenylketonuria (PKU). SYNB1618 showed a statistically significant increase in biomarkers in healthy volunteers and PKU patients, as well as GI tract activity of the second Phe-consuming function. All patients cleared the bacteria in the expected time frame with no evidence of colonization. There were no treatment-related serious adverse events.

Aduro Biotech dosed the first patient in its Phase II trial of ADU-S100 in combination with Merck’s Keytruda (pembrolizumab) as a first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). ADU-S100 is a novel STING pathway activator. STING is typically expressed at high levels in immune cells. The molecule has been tested in collaboration with Novartis in a Phase I trial as a monotherapy and is also being tested in combination with Bristol-Myers Squibb’s Yervoy (ipilimumab) in a Phase Ib combination trial with Novartis’ spartalizumab, an investigational checkpoint inhibitor.

Krystal Biotech launched a Phase I/II trial of KB105 in transglutaminase-1 (TGM1) deficient autosomal recessive congenital ichthyosis (ARCI), dubbed the GEM-3 study. KB105 is an HSV-1 based gene therapy designed to deliver a human TGM1 gene in patients with ARCI. ARCI is a debilitating rare skin disease marked by excessive, thick scaling of the skin, which causes multiple chronic health conditions.

CytoDyn filed an IND and a Phase II clinical trial protocol with the FDA for treatment of non-alcoholic steatohepatitis (NASH). The trial is to determine if leronlimab can control liver fibrosis associated with NASH. The Phase II trial would be a 60-patient, multi-center, randomized, double blind placebo-controlled study of leronlimab in adults with NASH.

Celyad dosed the first patient with CYAD-01 in the DEPLETHINK trial using the recently approved optimAb manufacturing process. CYAD-01 is an investigational CAR-T therapy where the patient’s T-cells are engineered to express CAR based on NKG2D, a receptor expressed on natural killer (NK) cells. It binds to eight stress-induced ligands expressed on tumor cells. The OptimAb manufacturing process utilizes a shortened cell culture and incorporates a selective PI3K inhibitor. This results in a product that is enriched for T cells with a memory-like phenotype. Preclinical data demonstrate that CYAD-01 produced using the OptimAb manufacturing process drives improved anti-tumor activity in an aggressive acute myeloid leukemia (AML) model compared to CYAD-01 produced with the previous mAb manufacturing process. The trial is the DEPLETHINK Phase I trial, a dose-escalation study to evaluate a single infusion of CYAD-01 for relapsed/refractory AML and myelodysplastic syndromes.

Ardelyx reported positive results from its Phase III AMPLIFY trial of tenapanor in combination with phosphate binders in chronic kidney disease (CKD) patients on dialysis whose hyperphosphatemia was not controlled with binders alone. The trial met the primary endpoint as well as all key secondary endpoints. It showed a statistically significant decrease in serum phosphorus levels in the tenapanor-phosphate binder cohort compared to phosphate binders alone.

Bristol-Myers Squibb announced that its Phase III CheckMate -548 study of Opdivo (nivolumab) added to current standard of care to treat brain cancer, newly diagnosed glioblastoma multiforme (GBM), did not meet one of its primary endpoints, progression-free survival (PFS). The trial will continue to evaluate the other primary endpoint, overall survival (OS). CheckMate -548 is evaluating Opdivo and temozolomide and radiation compared to temozolomide and radiation alone. The patients have newly diagnosed GBM that is 06-methylguanine-DNA methyltransferase (MGMT)-methylated. The data monitoring committee recommended the trial continue as planned, with an estimated primary completion date in February 2022. Secondary endpoints are PFS as assessed by the investigator, and OS rate up to two years.

Esperion completed patient enrollment in the CLEAR Cardiovascular Outcomes Trial designed to evaluate bempedoic acid and if it decreases risk of cardiovascular events in patients intolerant to statins. The endpoints are a predetermined number of major adverse cardiac events (MACE). The company expects the trial to be completed in the second half of 2022. It is a Phase III trial. Eligible patients are at high risk for cardiovascular disease or with cardiovascular disease who are only able to tolerate less than the lowest approved daily dose of a statin. The trial has enrolled 14,032 patients at 1,200 locations in 32 countries.

ASIT Biotech announced that its Phase III trial of gp-ASIT+ in grass pollen rhinitis was on track to deliver results by mid-December. The immunotherapy is administered in only three weeks prior to the grass pollen season. There are 651 patients in the trial from 69 centers. The trial sites were chosen in collaboration with the European Aeroallergen Network (EAN) of the Medical University of Vienna, based on their pollen count history. All sites have reached their end-of-2019 pollen season.

Opthea presented data from its Phase IIb trial of OPT-02 with Lucentis (ranibizumab) compared to ranibizumab alone for wet age-related macular degeneration (AMD).  The company indicated the combination therapy showed superior vision gains compared to the control group of Lucentis alone. OPT-302 is a soluble form of vascular endothelial growth factor receptor 3 (VEGFR-3). It blocks the activity of VEGF-C and VEGF-D that cause blood vessels to grow and leak, which contributes to several retinal diseases.

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