This week on Pipeline Moves, we investigate the terminations of a Phase II trial in metastatic colorectal cancer and two Phase III trials in cardiovascular infections and acute kidney injury due to sepsis. We also look at positive developments from a Phase Ib trial that achieved its primary endpoint in non-alcoholic fatty liver disease (NAFLD), and completions of a Phase IIb study in metabolic syndrome and a Phase II trial in pouchitis.

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Phase II colorectal cancer trial terminated

Karyopharm’s Xpovio (selinexor) had a drop in its Phase Transition Success Rate (PTSR) in metastatic colorectal cancer after a Phase II trial was terminated in this indication. The PTSR decreased by 14 points, settling at 14%.

The reason for termination was marked as a sponsor’s decision according to the trial’s ClinicalTrials.gov listing. The trial’s status was updated on ClinicalTrials.gov on 14 September, with GlobalData evaluating the asset on the next day. PTSR is the probability, given as a percentage, of a drug progressing successfully from one development stage to the next.

The open-label, randomised Phase II study (NCT04854434) investigated the efficacy and safety of Xpovio alone or in combination with Merck’s Keytruda (pembrolizumab) in 78 adult patients with advanced or metastatic colorectal cancer.

Enrolled participants had a histologically proven diagnosis of unresectable metastatic colorectal cancer with a known rat sarcoma (RAS) mutation and a life expectancy higher than three months. The study also compared Xpovio monotherapy and Xpovio in combination with Keytruda against the standard of care which is Taiho Pharmaceuticals’ Lonsurf (trifluridine + tipiracil hydrochloride).

The trial’s primary endpoint measured progression-free survival (PFS) for up to three years following treatment. The study’s multiple secondary endpoints also evaluated overall survival, overall response rate and duration of response for a time period up to three years.

Xpovio is an Exportin 1 inhibitor which acts by blocking CRM1 (chromosome region maintenance 1 protein), a major nuclear export factor that is frequently overexpressed in cancer cells. This inhibition leads to an accumulation of tumour-suppressor proteins in the cell nucleus to amplify a tumour suppression function. The drug is marketed for multiple myeloma, diffuse large B-cell lymphoma and is under development for many indications including lung cancer and ovarian cancer.

Cardiovascular infection study terminated

ContraFect Corp’s CF-301 (exebacase) saw a significant drop in its Likelihood of Approval (LoA) in endocarditis and methicillin-resistant staphylococcus aureus (MRSA) infections following a Phase III trial termination in staphylococcus aureus bacteraemia and staphylococcus aureus (S. aureus) endocarditis.

The drug’s LoA decreased by 17 points to -3% in endocarditis and by 28 points in MRSA infections, settling at 2%. LoA is identified via GlobalData’s analysis using a combination of machine learning and its proprietary algorithm.

According to a ClinicalTrials.gov listing, the Phase III trial was terminated after the independent Data and Safety Monitoring Board (DSMB) recommended that the study be stopped for futility following interim efficacy analysis. The trial’s status was updated on ClinicalTrials.gov on 15 September, with GlobalData evaluating the asset on the next day.

The quadruple-masked, randomised Phase III study (NCT04160468) evaluated the efficacy and safety of CF-301 in combination with standard of care antibiotics (SoCA) compared to SoCA monotherapy in 249 patients with S. aureus bloodstream infections (BSI), including right-sided infective endocarditis (IE).

Enrolled participants were over 12 years old with a positive blood culture for S. aureus and at least two symptoms attributable to S. aureus BSI or IE. The trial’s co-primary endpoints measured treatment-emergent adverse events (TEAEs) through 60 days and the clinical responder rate in the MRSA population within 14 days.

CF-301 is a direct lytic agent that acts as a bacterial wall disruptor and leads to rapid bacteriolysis. The drug is a first-in-class treatment that can also suppress antibiotic resistance when used in combination with antibiotics. The recombinant enzyme is also under development for the treatment of prosthetic joint infections.

Termination of kidney injury trial

The LoA for AM-Pharma’s recAP (ilofotase alfa) dropped in sepsis and acute renal failure (ARF) after a Phase III trial in acute kidney injury due to sepsis was terminated. The drug’s LoA reduced by 14 points in sepsis, settling at 6%. It also decreased by 11 points to 4% in ARF.

According to the study’s ClinicalTrials.gov listing, the termination was due to a Data Monitoring Committee’s (DMC ) decision that while the study had no safety concerns, the prespecified futility threshold was met. A futility threshold refers to a trial’s inability to meet its endpoints. The trial’s status was updated on ClinicalTrials.gov on 12 September, with GlobalData evaluating the asset on the same day. 

The quadruple-masked Phase III study (NCT04411472) investigated the effect of recAP on the mortality of patients admitted to the intensive care unit (ICU) with acute kidney injury caused by sepsis. The participants were adult patients with a suspected or proven bacterial or viral infection that required vasopressor therapy.

The study was anticipated to recruit 1,600 patients but ended up enrolling only 661 subjects. The trial’s primary endpoint measured the all-cause mortality of participants within 28 days following recAP treatment.

RecAP is a proprietary alkaline phosphatase replacement under development for the treatment of hypophosphatasia, acute kidney injury (AKI) caused by sepsis (sepsis-associated AKI), and ulcerative colitis (UC).  The recombinant enzyme displays dephosphorylating and detoxifying activity, which protects against kidney injury.

Achieved primary endpoint in NAFLD

Altimmune’s ALT-801 (pemvidutide) saw its PTSR in NAFLD jump after achieving primary endpoint in a Phase Ib trial. The PTSR increased by 11 points to 81%. GlobalData evaluated the asset on 16 September after a company press release was issued on 14 September.

The double-blind, placebo-controlled Phase Ib trial (NCT05006885) recruited 94 diabetic and non-diabetic patients with NAFLD who are either overweight or obese. Three dose levels of ALT-801 were compared to placebo for 12 weeks evaluating safety and effects on hepatic fat fraction, anthropometric parameters, lipid metabolism, inflammatory markers and fibrosis markers.

The primary endpoint was met in all treatment cohorts. The 1.8mg dose cohort, of participants with and without diabetes, achieved a mean reduction of liver fat content of 68.5%, with 94.4% of subjects achieving 30% reduction in liver fat and 72.2% achieving 50% reduction in liver fat. ALT-801 was generally well tolerated. ALT-801 is a peptide-based GLP-1 and glucagon receptor agonist.

Completion of Phase IIb in metabolic syndrome

Afimmune’s epeleuton saw its PTSR in metabolic syndrome spring by seven points to 29% after the completion of a Phase IIb study. The trial’s status on its ClinicalTrials.gov listing changed from recruiting to completed on 9 September. GlobalData evaluated the PTSR change on 12 September.

Metabolic syndrome can be understood as a group of conditions, which includes hypertension or high cholesterol levels. Epeleuton is inhibits certain cytokines and fibrotic markers, which results in its anti-fibrotic and anti-inflammatory effects.

The double-masked trial (NCT04365400) evaluated the efficacy and safety of epeleuton capsules in adult patients with hypertriglyceridemia and type 2 diabetes. It measured the percentage change in triglycerides from baseline until week 16 as one of its co-primary endpoints. The second primary endpoint was the change in HbA1c from baseline until week 26. The trial was expected to enrol 240 subjects but concluded with 233.

Phase II pouchitis study completed

Applied Molecular Transport’s AMT-101 saw its PTSR in pouchitis jump 12 points to 75% following a Phase II trial completion. ClinicalTrials.gov updated the study’s listing from active, not recruiting to completed on 14 September, and the evaluation took effect on 16 September.

The Phase II FILLMORE trial (NCT04741087) enrolled 22 patients with chronic, antibiotic-resistant pouchitis. Pouchitis is inflammation along the lining of a pouch created during surgery, usually as a result of a procedure for treating ulcerative colitis.

The FILLMORE trial’s co-primary endpoints were stool frequency response and histological healing, both after 12 weeks. AMT-101 is an oral biologic that acts as an agonist of the interleukin 10 receptor, thereby restoring immune homoeostasis.

Need to know:

GlobalData’s proprietary model uses a combination of machine learning and an algorithm to calculate an individual drug’s PTSR and LoA. While LoA provides the probability of a drug ultimately receiving market authorization, PTSR indicates the probability of a drug’s advancement to the next stage of clinical development. The model uses datapoints from individual drugs, clinical trials, regulatory milestones, company, and financial databases.