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May 10, 2022

Pipeline Moves: Boehringer, Stealth BioTherapeutics likely to see clinical trial progress of ophthalmic assets scuppered

Clinical Trials Arena also reviews AstraZeneca's Phase I AZD-0466 cancer trial termination.

By Urtė Fultinavičiūtė, Irena Maragkou, Adam Zamecnik and William Newton

In this edition of Pipeline Moves, we look into the Phase Transition Success Rate (PTSR) drop of two ophthalmic assets, as well as the termination of a Phase I cancer clinical trial sponsored by AstraZeneca. PTSR is the probability, given as a percentage, of a drug progressing successfully from one development stage to the next.

On to good news, we report on the PTSR increase of two additional assets, with Galera Therapeutics reporting positive Phase IIa esophagitis data and Ardelyx completing a Phase II hyperkalemia study.

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Boehringer suspends Phase I ophthalmic clinical trial

Boehringer Ingelheim’s BI-754132 saw its PTSR slide after a Phase I geographic atrophy trial was suspended due to ongoing safety evaluations. The PTSR decreased by 29 points to 28%.

GlobalData evaluated the asset on April 29 after a ClinicalTrials.gov update on April 28. The Phase I trial (NCT04002310) anticipated to enrol 30 patients with an advanced form of age-related macular degeneration. The trial has coprimary endpoints looking into dose-limiting events and adverse events.

Stealth ophthalmic asset fails Phase II clinical trial

Stealth BioTherapeutics’ elamipretide hydrochloride (Bendavia) had its PTSR in two ophthalmic indications drop following the asset failing in a Phase II trial. The PTSR for elamipretide decreased by 16 points in geographic atrophy and dry (atrophic) macular degeneration, settling at 9% and 7%, respectively. Top-line data from the Phase II ReCLAIM-2 trial (NCT03891875) was announced on May 2 via a media release, with GlobalData reviewing the asset May 4.

In the 176-patient ReCLAIM-2 trial, elamipretide did not meet the coprimary endpoints of low luminance visual acuity (LLVA) and geographic atrophy (GA) progression. While elamipretide showed improvement in LLVA compared to placebo, the mean change was not statistically significant. The observed improvement in visual function was not associated with reduced GA progression.

Elamipretide targets the inner mitochondrial membrane and enhances ATP synthesis in multiple organs. It is investigated in a range of common age-related diseases.

AstraZeneca terminates Phase I cancer trial

AstraZeneca’s oncological asset AZD-0466 saw a downturn in its PTSR in six indications after the termination of a Phase I study. The trial was ended due to a strategic change to its clinical development plan, as written on its ClinicalTrials.gov page. GlobalData appraised the candidate on 29 April after a ClinicalTrials.gov update the previous day.

The PTSR plunged by 33 points to 35% in chronic myelomonocytic leukemia and in small-cell lung cancer. AZD-0466 fell by 32 points to 33% in myelodysplastic syndrome, and by 31 points in lymphoma and acute lymphocytic leukemia, dropping to 30% and 33% respectively. The PTSR also dove by 23 points to 20% in solid tumours.

The Phase I trial (NCT04214093) was anticipated to enrol 102 subjects but recruited nine by the time it was terminated. The study sought to determine the safety, tolerability, pharmacokinetics, and preliminary antitumour activity in patients with advanced hematologic or solid tumours.

The study was split into two arms, with arm A including patients with solid tumours, lymphoma and multiple myeloma with low risk of tumour lysis syndrome (TLS). Meanwhile, arm B featured subjects with hematologic malignancies with an intermediate-to-high risk of TLS.

Apart from the terminated trials, AZD-0466 is being studied in a Phase I/II study (NCT04865419) as a potential monotherapy and combination treatment in subjects with advanced haematological malignancies. It is also set for another Phase I/II study (NCT05205161) as a monotherapy and combination treatment in advanced non-Hodgkin lymphoma patients.

AZD-0466 acts as a dual Bcl2/xL protein inhibitor targeting the hydrophobic surface binding groove BH3 of the anti-apoptotic proteins Bcl-2 and Bcl-xL. This lowers the threshold for cancer cell apoptosis.

Galera reports Phase IIa esophagitis data

Galera Therapeutics’ avasopasem saw its PTSR in esophagitis leap 16 points to 47% after positive topline Phase IIa results. The company published Phase IIa data in a May 2 press release, and the PTSR change took effect May 4.

The Phase IIa AESOP trial (NCT04225026) recruited 29 patients, with a primary endpoint of cumulative incidence of acute radiation esophagitis. Patients were concurrently undergoing intensity-modulated radiation therapy plus chemotherapy during the study and had chemoradiotherapy-induced esophagitis.

Two of the 29 patients experienced Grade 3 esophagitis, with none experiencing Grade 4 or 5 esophagitis. Esophagitis is measured across five grades, with Grade 1 being asymptomatic manifestation, Grade 3 normally involving hospitalisation, and patient death marked as Grade 5. Avasopasem was generally well-tolerated, with a safety profile on par with the standard adverse event profile of patients on chemoradiotherapy, according to the press release.

Avasopasem is a small molecule dismutase mimetic under development for radiation-induced esophagitis in patients with lung cancer, as well as radiation-induced severe oral mucositis in patients with head and neck cancer.

Phase II hyperkalemia trial completes

Ardelyx’s RDX-013 saw its PTSR in hyperkalemia jump 10 points to 23% after a Phase II study was completed. ClinicalTrials.gov updated the trial’s status to completed on May 4 and the PTSR change took place the next day.

The Phase II (NCT04780841) aimed to study the safety and efficacy of RDX-013 in treating patients with chronic kidney disease and elevated serum potassium levels. Hyperkalemia is a medical term used to describe having higher than normal levels of potassium in blood.

The trial was a two-part study. In Part A, the asset was tested at different doses, ranging from a low dose to a high dose administered twice daily. In Part B, the optimal dose of RDX-013 selected from Part A was evaluated against placebo.

For its primary endpoint, the 109-participant trial measured the change in serum potassium from baseline to the end of treatment with different doses of RDX-013 over a one-week period in Part A. Subsequently, the study examines the change in serum potassium over a four-week period in Part B.

RDX-013 functions as a potassium channel (KCN) activator, which opens ATP-sensitive potassium channels in vascular smooth muscle. The asset modulates the secretion of potassium in the gastrointestinal tract, thus decreasing systemic potassium and alleviating hyperkalemia.

Need to Know:

GlobalData’s proprietary model uses a combination of machine learning and an algorithm to calculate an individual drug’s PTSR. PTSR indicates the probability of a drug’s advancement to the next stage of clinical development. The model uses data points from the individual drugs, clinical trials, regulatory milestones, company, and financial databases.

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