This week on Pipeline Moves, we start with positive topline results from two Phase III trials in Alagille syndrome and pulmonary arterial hypertension, and a Phase II trial in phenylketonuria. We also look into the completion of a Phase IIb study in kidney disease, resumed recruitment of a Phase Ib/II sarcoma trial, and suspension of a Phase II oncology trial. 

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Pulmonary hypertension drug sees positive Phase III topline data

Acceleron Pharma’s activin receptor type IIA-Fc fusion protein, ActRIIA-Fc (sotatercept), saw its LoA improve, following the announcement of topline results of a Phase III trial in pulmonary arterial hypertension (PAH ). Acceleron Pharma is a subsidiary of Merck

The asset’s LoA increased by nine points to 55% in PAH. The positive topline results were announced in a press release on 10 October and GlobalData evaluated the asset on 12 October.

The randomised, double-blind Phase III (STELLAR) study (NCT04576988) evaluated the safety and efficacy of ActRIIA-Fc treatment as an add-on to stable background PAH therapy. The trial evaluated ActRIIA-Fc treatment in combination with PAH standard therapy compared to a placebo combined with PAH therapy in 324 patients with PAH. The enrolled participants were adults with a confirmed diagnosis of PAH.

The study’s primary efficacy outcome was met, demonstrating a statistically significant and clinically meaningful improvement in a 6-minute walk, at 24 weeks following treatment. The primary endpoint was exercise capacity measured by how far patients can walk in 6 minutes. 

The trial’s secondary endpoints measured the proportion of participants achieving multicomponent improvement in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, in the 6-minute walk distance and in the WHO’s classification of PAH symptoms. The study achieved statistical significance in eight out of the nine secondary endpoints.

ActRIIA-Fc is an investigational, potential first-in-class activin receptor type IIA-Fc fusion protein that acts by increasing haemoglobin/haematocrit levels. The drug candidate was also under development for the treatment of chemotherapy induced anaemia (CIA), end-stage renal disease (ESRD), solid tumours, osteoporosis, and other diseases.

Positive Phase III topline results in genetic disorder

Albireo Pharma’s Bylvay (odevixibat) saw its Likelihood of Approval (LoA) in Alagille syndrome jump eight points to 50% after the company announced positive topline Phase III results. Albireo published results in an 11 October company press release, and the LoA change took effect on 13 October. 

LoA is the probability of a drug ultimately receiving market authorisation. LoA is identified via GlobalData’s analysis using a combination of machine learning and its proprietary algorithm, considering characteristics like therapy area, indication and molecule type.

The Phase III ASSERT trial (NCT04674761) met the primary endpoint of improvement in pruritus (p=0.002), measured by the Albireo Observer-Reported Outcome scratching score. The study also met its secondary endpoint of reduction in serum bile acids (p=0.001), as per the company press release. There were no reported study discontinuations, and the most common treatment-emergent adverse event was diarrhoea.

Alagille syndrome is a multisystem genetic disorder affecting the liver, heart, skeleton, eyes, central nervous system, kidneys and/or facial features. Bylvay is an ileal sodium and bile acid cotransporter, which is approved to treat progressive familial intrahepatic cholestasis, a rare liver disease. 

Based on the Phase III results, Albireo announced it plans to immediately submit regulatory filings for Bylvay in Alagille syndrome in the US and EU.

Positive topline data in Phase II metabolic trial

Synlogic ’s SYNB-1934 saw its Phase Transition Success Rate (PTSR) rise after the company announced positive topline results from a Phase II metabolic disorder trial. The PTSR increased by 10 points to 64% in phenylketonuria (PKU).

GlobalData evaluated the asset on 18 October after the company issued a press release the same day. PTSR is the probability, given as a percentage, of a drug progressing successfully from one development stage to the next.

The open-label and two-arm trial (NCT04534842) enrolled 20 participants to assess the safety, efficacy, and tolerability of SYNB1618 and SYNB1934. Participants had to complete a customised diet run-in period before receiving the treatment and adhere to a diet menu throughout the trial.

The primary endpoint measured the change in plasma levels of labelled D5-phenylalanine (D5-Phe) after a meal challenge before and after the treatment period of 15 days. Results were consistent and positive for both drug candidates. 

Both assets showed a meaningful reduction in the secondary endpoint of fasting plasma Phe levels, with SYNB1618 decreasing by 20% and SYNB1934 by 34%, according to the press release. Synlogic announced that SYNB1934 will be moving to a Phase III trial which is expected to begin in H1 2023.

SYNB-1934 is a synthetic biotic which activates a programmed metabolic pathway to transform phenylalanine into t-cinnamic acid. PKU is a rare inherited disorder that causes phenylalanine to build up in the body.

AstraZeneca completes Phase IIb kidney disease trial

AstraZeneca’s AZD-5718 saw its PTSR in chronic kidney disease (CKD) grow by eight points to 42% after the completion of a Phase IIb trial. The trial’s status on ClinicalTrials.gov changed from active, not recruiting to completed on 6 October. GlobalData evaluated the treatment’s status the following day.

The 613-subject study (NCT04492722) examined the dose-response efficacy, safety and, pharmacokinetics (PK) of AZD-5718 in subjects with proteinuric CKD. The trial measured the change in urine albumin to creatine ratio (UACR) from baseline over a 20-week timeframe as the primary outcome. AstraZeneca expects results from this study to be ready in H1 2023, based on the company’s H1 2022 result update.

AZD-5718 is a reversible 5-lipoxygenase-activating protein (FLAP) inhibitor, which helps in controlling leukotriene, and the treatment of cardiovascular disease.

Investigator-led oncology trial restarts recruitment

Amgen’s Imlygic (talimogene laherparepvec) saw its PTSR rise by 10 points settling at 37% after recruitment was restarted on investigator-led Phase Ib/II soft tissue sarcoma study. On 4 October, the study’s status on Clinicaltrials.gov was updated from suspended to recruiting. The PTSR change took place on 7 October.

The single-arm, open-label study (NCT04599062) was previously suspended as researchers were evaluating trial design, as per the ClinicalTrials.gov listing. The trial will investigate the safety and tolerability of Imlygic when combined with radiation therapy for soft tissue sarcoma. The University of Iowa aims to recruit 46 patients for this study. 

The primary endpoint of the Phase Ib trial concerns the number of participants with dose-limiting toxicities and the Phase II endpoint is evaluating the number of subjects with pathologic tumour necrosis of less than or equal to 90% following concurrent Imlygic treatment and radiation therapy.

Imlygic is a cancer vaccine comprising of a recombinant herpes simplex type-1 virus (HSV), which acts as an immunostimulating and antineoplastic agent. Imlygic was approved for the treatment of melanomas in October 2015. This was the FDA’s first-ever approval of a genetically engineered oncolytic virus that acts as immunotherapy.  

Phase II oncology trial suspended

Shanghai Bioray Laboratory ’s BYC-001 saw its PTSR drop after a Phase II trial in certain haematological malignancies was suspended. The PTSR plummeted by 8 points to 16% in non-Hodgkin lymphoma (NHL) and by 23 points to 21% in B-Cell acute lymphocytic leukaemia (ALL). GlobalData evaluated the asset on 13 October, following a ClinicalTrials.gov update on the previous day. 

The Phase II trial (NCT03229876) was suspended by the sponsor, according to the trial listing. The purpose of this study was to evaluate the safety and efficacy of ascending doses of BYC-001 in patients with relapsed or refractory B-cell haematological malignancies.

BYC-001 is comprised of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting CD19. The Shanghai-based company is developing the therapeutic candidate for the treatment of relapsed and refractory NHL, ALL, and B-cell NHL.

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.