This week on Pipeline Moves, we kickoff by looking at the terminations of a Phase II trial in myelodysplastic syndrome and a Phase I trial in unresectable metastatic and/or advanced malignancies. We also investigate the suspensions of a Phase II trial in triple negative breast cancer and a Phase I trial in colorectal cancer, head and neck cancer, and gastric cancer. To conclude we examine the Likelihood of Approval of two Phase III trials in familial chylomicronaemia and chronic urticaria/pruritus, and the completions of Phase II studies in major depressive disorder and Hepatitis B.

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Phase II trial termination

Johnson and Johnson’s Darzalex (daratumumab) saw its Phase Transition Success Rate (PTSR) drop in myelodysplastic syndrome after an investigator-led study in that indication was terminated.

The drug’s PTSR fell by 27 points to 31% in myelodysplastic syndrome. PTSR is the probability, given as a percentage, of a drug progressing successfully from one development stage to the next.

The trial’s status on ClinicalTrials.gov changed from completed to terminated on 21 September. According to the registry, the trial was terminated early because of lack of efficacy. GlobalData evaluated the asset on 25 September. The Phase II trial was sponsored by the University of Texas MD Anderson Cancer Center in collaboration with the National Cancer Institute.

The open-label Phase II trial (NCT03067571) evaluated the efficacy and safety of Darzalex in relapsed/refractory acute myelogenous leukaemia or high-risk myelodysplastic syndrome. The trial enrolled seven patients, far lower than the anticipated 36 patients.

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By GlobalData

Darzalex is marketed by Johnson and Johnson for the treatment of multiple myeloma, refractory multiple myeloma, and relapsed multiple myeloma. The intravenous and subcutaneously administered drug is an IgG1k human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38.

Novartis Phase I trial termination

Novartis’ KAZ-954 saw its PTSR decrease in solid tumours after a Phase I trial in the same indication was terminated. The drug’s PTSR dropped by 21 points, settling at 15% in solid tumours.

The open-label Phase I trial’s (NCT04237649) status was updated from active, not recruiting to terminated on ClinicalTrials.gov on 21 September, and GlobalData evaluated the asset on 26 September. According to the study’s ClinicalTrials.gov listing, the trial was terminated due to business reasons.

The Phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD) and recommended dose (RD) for expansion of single agent KAZ-954 in combination with Novartis’ PBF-509 (NIR178),  NZV-930 (SRF 373) and PDR-001 (spartalizumab). The trial enrolled 77 adult patients with unresectable metastatic and/or advanced malignancies.

The trial’s multiple co-primary endpoints measured the safety and dose intensity of the study treatment as well as the number of participants with dose interruptions and dose reductions over 36 months.

The asset is an antineoplastic agent with an undisclosed mechanism of action. The drug was under development for the treatment of advanced solid tumours and is now listed as inactive.

Merck’s Phase II trial suspension

Merck’s gene therapy to activate IL-12 for triple negative breast cancer (Interleukin-12 Gene Therapy, ADV/IL-12) saw its PTSR decrease in triple negative breast cancer (TNBC) after a Phase II trial in TNBC and anthracycline-refractory TNBC was suspended. The drug’s PTSR dropped by 18 points, settling at 20% in TNBC. The trial was sponsored by the Methodist Hospital Research Institute, which is based in Texas, US.

The open-label Phase II trial’s (NCT04095689) status was updated from recruiting to suspended on ClinicalTrials.gov on 18 September, and GlobalData evaluated the asset on the next day. According to the study’s ClinicalTrials.gov listing, the trial was suspended because stopping rules were met per protocol” and a “comprehensive review is needed prior to enrolling again.

The Phase II study evaluated the safety and efficacy of Sanofi’s Docetaxel (docetaxel) chemotherapy and Merck’s Keytruda (pembrolizumab) in combination with adenoviral-mediated interleukin-12 (ADV/IL-12) gene therapy in female patients with histologically TNBC who were refractory to standard neoadjuvant anthracycline-containing chemotherapy regimen.

The trial’s primary endpoint measured the asset’s pathological complete response (pCR) rate of Docetaxel chemotherapy and Keytruda plus IL-12 gene therapy in a timeframe of up to 18 weeks. The secondary endpoint measured treatment-related adverse events over the same period, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events.

The asset acts as an interleukin 12 (IL12) activator and is an adenoviral-mediated IL-12 gene therapy. The therapeutic candidate elicits anti-neoplastic activity by activating interleukin 12 and inducing potent anti-cancer immunity through T-lymphocyte and natural killer (NK) cell proliferation.

Suspension of Phase I trial

Mitsubishi Tanabe’s MT-8633 saw its PTSR drop in four cancer indications after a Phase I trial was suspended. The drug’s PTSR fell by 35 points to 30% in colorectal cancer, head and neck cancer, and gastric cancer. Additionally, the drug’s PTSR fell by 22 points to 18% in solid tumors.

The Phase I trial’s (NCT03859752) status was updated from completed to suspended on ClinicalTrials.gov on 22 September, and GlobalData evaluated the asset 25 September. According to the study’s ClinicalTrials.gov listing, the study was suspended due to financial funds being withdrawn. The study was sponsored by Tokyo, Japan-based Open Innovation Partners, a Mistubishi collaboration partner.

The purpose of this open-label, first-in-human study was to assess the safety, tolerability, and pharmacokinetics of MT-8633 in patients with solid tumours expressing c-MET. The trial enrolled 15 patients.

MT-8633 exhibits a cytotoxic effect by delivering the toxin to MET-expressing cells. The monoclonal antibody (mAb) is under development for the treatment of c-Met expressing solid tumors.

Approval prospects rise in Phase III trial

Ionis Pharmaceuticals’ olezarsen saw its Likelihood of Approval (LoA) in familial chylomicronaemia (Type I hyperlipoproteinemia) rise by 7 points to 35%, after the biotech announced positive topline results from its Phase III trial.

LoA is identified via GlobalData’s analysis using a combination of machine learning and a proprietary algorithm. LoA can be calculated for a drug by considering characteristics like therapy area, indication and molecule type.

The California, US-based company unveiled the results on 26 September . GlobalData appraised the asset the day after.

The randomised, double-blind, placebo-controlled trial (NCT04568434) met its primary efficacy endpoint – the candidate demonstrated a statistically significant reduction in triglyceride (TG) levels at the 80 mg monthly dose of olezarsen at six months compared to placebo. TG levels continued to lower at 12 months. Events of acute pancreatitis, a key secondary endpoint, were 100% lower – zero events in the treatment group compared to 11 events in the placebo group. A lower 50 mg dose did not yield the same results for primary endpoint efficacy.

A total of 66 adults were randomised to receive placebo or olezarsen subcutaneous injections at 80 mg or 50 mg doses. 

Ionis reported favorable safety and tolerability profile of the candidate. There was one reported death in the study, with Ionis stating it was not related to the study drug. 

Olezarsen is an antisense RNA oligonucleotide that inhibits the production of apolipoprotein C-III protein – a protein important in TG metabolism in the blood.

Ionis stated it plans to file a new drug application (NDA) to the US Food and Drug Administration (FDA) in early 2024.

Approval prospects increase in Phase III trial

BCN Peptides’ DD-04107 saw its LoA increase in chronic urticaria and pruritus rise after the completion of a Phase III trial. The LoA grew by six points to 46% and 44%.

On 26 September, GlobalData updated the Phase III trial (2022-001374-60) status to completed via the European clinical trials registry listing.  The purpose of the randomised, double-blind, placebo-controlled study was to evaluate the antipruritic efficacy of the topical application of DD-04107 in histamine-induced itch.

DD04107 acts by blocking the activity of TRPV1.  The synthetic peptide is under development for the treatment of pruritus or urticaria.

Phase II trial completion

Neurocrine Biosciences’ NBI-1065846 (TAK-041) saw its PTSR increase in major depressive disorder (MDD) after a Phase II trial in MDD and anhedonia was completed. The drug’s PTSR rose by nine points, reaching 38% in MDD.

The randomised Phase II trial’s (NCT05165394) status was updated from ongoing, not recruiting to completed on ClinicalTrials.gov on 18 September, and GlobalData evaluated the asset on the next day.

The Phase II study evaluated the efficacy of NBI-1065846 compared with placebo on the improvement of symptoms of anhedonia in participants with MDD. The study recruited 93 adult participants with a primary diagnosis of MDD. The trial’s primary endpoint measured the change in anhedonia severity, as measured by a change in Dimensional Anhedonia Rating Scale (DARS) score, within a timeframe of 57 days post-treatment with the asset.

NBI-1065846 is a probable G-protein coupled receptor 139 (GPR139) agonist. GPR139 is expressed in brain areas and the asset exhibits neuroprotection by agonizing GPR139 and regulating the dopamine D2 receptors to reduce cognitive impairment. The drug is also under development for the treatment of negative symptoms and cognitive impairment associated with schizophrenia.

Completion of Phase II trial

Golden Biotechnology’s  Hocena (antroquinonol) saw its PTSR increase in hepatitis B after the completion of a Phase II trial. The drug’s PTSR grew by five points to 37%. PTSR is the probability, given as a percentage, of a drug progressing successfully from one development stage to the next.

The status of the Phase II trial (NCT03625102) was updated from active, not recruiting to completed on ClinicalTrials.gov on 13 September, and GlobalData evaluated the asset on the following day. The purpose of this single-centre, double-blind, randomised, placebo-controlled, study was to evaluate Hocena in patients with hepatitis B. The trial enrolled 60 patients.

Hocena acts by inhibiting the activity of the enzyme farnesyl protein transferase and restores the Ras-mediated control of cell proliferation and differentiation. The New Taipei City, Taiwan-based company is developing the drug candidate for the treatment of relapsed acute myeloid leukaemia, acute myeloid leukaemia, non-squamous non-small cell lung cancer, and other indications.

Read the last edition:

Pipeline Moves: Advancement prospects plunge for Parkinson’s drug after trial termination

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.