This week on Pipeline Moves, we start with the terminations of a Phase III trial in osteogenesis imperfecta, and two investigator-led Phase II studies in several oncology indications. On a good note, we review completions of a Phase III trial in psoriasis, a Phase II/III study in Smith–Magenis Syndrome, and a Phase II trial in leukaemia and lymphoma. We finish off with the resumption of a Phase II oncology trial.

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Phase III termination in bone disorder

Amgen’s Xgeva (denosumab) saw its Likelihood of Approval (LoA) plunge in osteogenesis imperfecta (OI) after a Phase III trial was terminated in this indication. The asset’s LoA decreased by 16 points to 15% in OI.

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

The trial status was marked as terminated on its ClinicalTrials.gov listing on 28 December, with GlobalData evaluating the asset on the next day. The trial was terminated due to safety concerns about high levels of calcium in the blood of the participants in the study.

The open-label, single-arm Phase III study (NCT02352753) evaluated the efficacy and safety of Xgeva in 153 subjects with OI. The enrolled participants were between the ages of two and 17 years old with a clinical diagnosis of OI, consistent with Type I-IV clinical severity. The study’s primary endpoint measured the change from baseline in lumbar spine bone mineral density within a time frame of up to 12 months.

The drug is a monoclonal antibody that targets and binds to the receptor activator of NF-KappaB (RANKL) preventing the RANKL/RANK interaction and signalling which regulates osteoclast formation and activation in normal bone modelling and remodelling. The asset acts by inhibiting osteoclast formation, function, and survival, thereby decreasing bone resorption. The drug is already marketed for bone metastasis, post-menopausal osteoporosis, and other indications.

Investigator-led oncology trial terminates

Bristol Myers Squibb’s Opdivo (nivolumab) saw its Phase Transition Success Rate (PTSR) in germ cell tumours drop ten points to 30% following an investigator-led Phase II trial termination. The trial was conducted by SCITO Association in Italy.

The Phase II trial (EudraCT-2017-000589-31) termination reason was not disclosed, as per the EU clinical trials registry listing. The trial’s status was changed on 2 January, as recorded by GlobalData Pharma Intelligence Center (PIC), and the PTSR change took effect 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 purpose of the multi-stage trial was to assess anti-tumour activity with Opdivo in germ cell tumour microsatellite instability (MSI) and/or DNA repair defects including mismatch-repair gene deficiency. Opdivo is an anti-PD-1 monoclonal antibody (mAb) marketed and under development for several cancers.

Termination of Phase II oncology study

Exelixis’s Cabometyx (cabozantinib) saw its PTSR in non-small cell lung cancer (NSCLC) fall by 10 points, settling at 35%, following an investigator-led Phase II trial termination. The trial’s status changed on the EU clinical trial registry to prematurely ended on 2 January, as recorded by GlobalData’s PIC. The PTSR change took place on 4 January.

The Phase II study (EudraCT-2018-002948-88), led by the University of Bologna, investigated Cabometyx’s antitumour activity, safety, and efficacy profile in pre-treated, advanced RET- rearranged NSCLC patients. The trial planned to recruit 25 participants and investigate response rate as its primary endpoint.

Cabometyx is an oral medication that works as an anti-neoplastic agent in cancer treatment. The FDA has previously approved Cabometyx for the treatment of five oncology indications over the last seven years. The drug candidate is also under development for further label expansions.

Phase III completion in psoriasis

Samsung Bioepis’s ustekinumab biosimilar saw an increase in its LoA by five points to 65% following a Phase III trial completion in moderate to severe plaque psoriasis. The study’s ClinicalTrials.gov listing was updated on 19 December. The corresponding LoA change took place on the following day.

The randomised, double-blind, multi-centre Phase III trial (NCT04967508) evaluated the efficacy, safety, tolerability, pharmacokinetics, and immunogenicity of the biosimilar compared to the originator biologic Johnson and Johnson’s Stelara. The trial enrolled 503 subjects. This was an increase compared to the 464 initially anticipated to participate in the trial.

Samsung’s ustekinumab biosimilar binds with high affinity and specificity to the IL-12 subunit beta used by both interleukin (IL)-12 and IL-23 cytokines and is administered intravenously and subcutaneously.

Phase II/III completion in developmental disorder

Rhythm Pharmaceuticals’s Imcivree (setmelanotide) saw an increase in its LoA by six points to 45% in Smith–Magenis Syndrome (Chromosome 17p11.2 Deletion Syndrome), following a Phase II/III trial completion. The study’s Clinicaltrials.gov listing was updated from active, not recruiting to completed on 13 December. The corresponding LoA change took place on 16 December.

The non-randomised, multi-centre Phase II/III trial (NCT03013543) studied the effect of setmelanotide on weight, hunger assessments and other factors in patients with rare genetic disorders of obesity.

The primary endpoints of the study measured the effect of setmelanotide on body weight reduction and the proportion of patients in several rare genetic disorder subgroups who achieve at least 5% body weight reduction.

The clinical trial investigated rare genetic disorders, such as pro-opiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, Smith-Magenis Syndrome, melanocortin 4 receptor (MC4R) deficiency obesity, steroid receptor coactivator-1 (SRC1) deficiency obesity and SH2B1 deficiency obesity. Smith-Magenis Syndrome is a developmental disorder that affects multiple organ systems of the body.

Setmelanotide is a MC4R agonist that causes a decrease in food intake. The drug is an injectable solution formulated for the subcutaneous route of administration. As of June 2022, setmelanotide became the first and only FDA-approved therapy that targets a root cause of early-onset, severe obesity and hyperphagia associated with Baret Biedl Syndrome. Currently, the only marketed drug for Smith-Magenis Syndrome is Vanda Pharmaceuticals’ tasimelteon.

Phase II oncology trial completes

Johnson and Johnson’s daratumumab saw its PTSR increase after a Phase II study completion. The PTSR grew by 16 points to 36% in relapsed or refractory precursor B-cell acute lymphoblastic leukaemia and by 20 points to 55% in lymphoblastic lymphoma. The PTSR also increased by 24 points to 44% in T-cell acute lymphoblastic leukaemia. The trial’s status on ClinicalTrials.gov was changed on 22 December, with the PTSR updated the following day.

The Phase II trial (NCT03384654) evaluated the safety and efficacy of daratumumab, in addition to chemotherapy in paediatric participants and young adults. The trial enrolled 47 patients. This was a significant decrease compared to the original number of 69 patients that were anticipated to participate.

Daratumumab is marketed as Darzalex by Johnson and Johnson for the treatment of multiple myeloma, primary systemic amyloidosis, 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.

Phase II oncology trial resumes

Xcovery’s ensartinib saw its PTSR rise in four oncology indications after an investigator-sponsored Phase II trial resumed recruiting following a suspension. ClinicalTrials.gov updated the trial listing from suspended to recruiting on 28 December, and the PTSR change took effect the next day.

The PTSR rose eight points to 33% in non-Hodgkin’s lymphoma; nine points to 32% in neuroblastoma; 12 points to 22% in central nervous system (CNS) tumours; and 13 points to 21% Letterer-Siwe disease.

The 98-patient, open-label Phase II trial (NCT03213652) was previously suspended due to drug supply issues, as per ClinicalTrials.gov. As a primary endpoint, the study measures objective response rate (ORR), with secondary endpoints evaluating adverse events (AEs) and progression-free survival (PFS).

Ensartinib inhibits anaplastic lymphoma kinase (ALK), an enzyme that, when altered, can lead to cancer proliferation. Ensartinib gained approval for treating non-small cell lung cancer (NSCLC) in China in 2020 and is sold under the brand name Bemena.

The Phase II trial is sponsored by the US National Institute of Health’s (NIH) National cancer Institute (NCI), with the Children’s Oncology Group listed as a collaborator. Xcovery is based in Palm Beach Gardens, Florida.

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.