Top 5 Failed Clinical Trials in February 2021: Key Setbacks in Oncology, Fibrosis, Gene Therapy, and Otology

By Shuye

Based on the Industry News section of the PharmCube website, the NextPharma database, and publicly available information, the February 2021 issue of the Monthly Report on Clinical Studies has identified five notable studies that failed to meet their primary clinical endpoints for your reference. For more industry insights, click the “Read Original Article” link at the end of this article to visit the official PharmCube website.

1. Phase III Study of Imfinzi (durvalumab) in the Treatment of Head and Neck Squamous Cell Carcinoma

On February 5, AstraZeneca announced the latest progress from the Phase III KESTREL study evaluating durvalumab monotherapy or in combination with tremelimumab as first-line treatment for patients with PD-L1 high-expressing recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The results showed that durvalumab monotherapy did not meet the primary endpoint of prolonging overall survival (OS) compared to standard therapy (chemotherapy combined with cetuximab), and the combination therapy group also did not demonstrate an OS benefit (secondary endpoint). The safety and tolerability profiles of durvalumab monotherapy and its combination with tremelimumab were consistent with those observed in previous trials.

The KESTREL study is a randomized, open-label, multicenter, global Phase III clinical trial designed to evaluate the efficacy and safety of durvalumab or durvalumab in combination with tremelimumab versus the standard EXTREME regimen (cetuximab plus cisplatin or carboplatin plus 5-fluorouracil) as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The trial enrolled 823 patients across more than 200 centers in 23 countries/regions worldwide, including the United States, Europe, South America, and Asia. The primary endpoint was overall survival (OS) in patients with high PD-L1 expression treated with durvalumab monotherapy, and the key secondary endpoint was OS in patients receiving the combination therapy.

Based on the PACIFIC and CASPIAN studies, Imfinzi was successively approved for unresectable stage III non-small cell lung cancer (NSCLC) and extensive-stage small cell lung cancer (SCLC). Additionally, Imfinzi received approval in the United States and several other countries/regions for advanced bladder cancer. However, on February 22, AstraZeneca announced the voluntary withdrawal of this indication in the United States, as Imfinzi failed to meet the U.S. FDA’s post-marketing requirements for accelerated approval in the second-line treatment of bladder cancer.

As part of an extensive development program, Imfinzi is being evaluated as a monotherapy or in combination with other anticancer therapies, such as tremelimumab, for the treatment of solid tumors including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma (HCC), biliary tract cancer, esophageal cancer, gastric cancer, and gastroesophageal cancer.

2. Phase III Study of BAT8001 for the Treatment of Breast Cancer

On the evening of February 8, Bio-Thera Solutions announced that the HER2 ADC drug BAT8001 failed to meet the preset superiority target for its primary efficacy endpoint, progression-free survival (PFS), in its Phase III clinical trial compared to the control group (lapatinib combined with capecitabine). Based on the preliminary analysis results, Bio-Thera Solutions plans to engage in further communication with the National Medical Products Administration (NMPA) in the future.

However, not long after, in the early hours of the 9th, Bio-Thera Solutions once again issued an announcement, terminating the clinical trial of BAT8001 for HER2-positive breast cancer. Affected by this news, Bio-Thera’s stock price plummeted 18.73% against the market trend, marking its largest single-day drop since listing. The stock closed at RMB 25.03 per share that day, representing a 23.6% decline from its issue price of RMB 32.76 per share.

This study is a domestic, multicenter, randomized, open-label, active-controlled, superiority Phase III clinical trial. The enrolled population consists of patients with HER2-positive advanced breast cancer who have experienced treatment failure after prior therapy with trastuzumab (including marketed biosimilars) and taxanes, administered either as monotherapy or in combination.

Regarding the reasons for termination, Bio-Thera Solutions’ announcement provided the following explanation: “Given that it would be difficult for this drug to gain a competitive advantage amidst numerous targeted anti-tumor drugs, and in order to rationally allocate the company’s R&D resources and focus on advantageous projects within its development pipeline, the company has decided to terminate the clinical trials of BAT8001 after carefully considering the subsequent development risks associated with this project.”

Bio-Thera has invested RMB 226 million in the BAT8001 project, and terminating this project may result in Bio-Thera losing its competitive position in this field. However, Bio-Thera stated that this will not have a significant impact on its current and future production, operations, and performance, nor will it substantially affect its investment and strategic layout in innovative drugs. The company will continue to advance the research and development of its existing pipeline of innovative drug candidates.

HER2 is one of the most fiercely contested therapeutic targets in China. In the realm of antibody-drug conjugates (ADCs), Kadcyla has already received approval in China for the treatment of patients with early-stage HER2-positive breast cancer who have residual invasive disease following neoadjuvant therapy. Clinical studies of AstraZeneca/Daiichi Sankyo’s Enhertu (DS-8201) are also underway in China. Although no specific trials for HER2-positive breast cancer have been initiated domestically, international data demonstrate that Enhertu exhibits excellent efficacy in treating this indication. Among Chinese companies, RemeGen’s RC48 has advanced to Phase II clinical trials. For BAT8001, which is positioned as a competitor to Kadcyla, failure to achieve superiority over the control group (lapatinib plus capecitabine) would undoubtedly place it at a significant disadvantage in the competitive landscape. In such a scenario, timely termination of the study to cut losses would be a prudent decision.

3. Phase III Study of Ziritaxestat for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)

On February 10, Galapagos NV and Gilead Sciences issued a joint announcement to terminate the Phase III ISABELA study of the autotaxin inhibitor ziritaxestat in patients with idiopathic pulmonary fibrosis (IPF). This decision was made based on the recommendation of the independent data monitoring committee, which concluded that the benefit-risk profile of ziritaxestat no longer warranted further development.

Meanwhile, the two companies announced that they would also halt all clinical trials of ziritaxestat, including the long-term extension of the Phase IIa NOVESА study in diffuse cutaneous systemic sclerosis. The discontinuation of all clinical studies undoubtedly raises concerns about safety issues, not merely efficacy. Gilead stated that relevant exploratory data will be presented at future medical conferences.

Ziritaxestat (GLPG1690) is an autotaxin inhibitor. Autotaxin, an extracellular enzyme, catalyzes the synthesis of various lysophosphatidic acid (LPA) species with different fatty acid chains. LPA is a class of important signaling molecules that play diverse roles in immune responses and the maintenance of tissue homeostasis. Although LPA appears to promote pulmonary fibrosis, its functions in other tissues remain unclear. Idiopathic pulmonary fibrosis (IPF) is a disease with high mortality, exceeding that of many cancers, with a 5-year survival rate of approximately 20%. There are few therapeutic options for IPF; currently, apart from Boehringer Ingelheim’s Ofev and Roche’s Esbriet (acquired from InterMune), no other innovative drugs have been marketed.

In July 2019, Gilead Sciences entered into a 10-year global R&D partnership with Galapagos, paying a $3.95 billion upfront fee and making a $1 billion equity investment to secure licensing rights for ziritaxestat and begin sharing the costs of Phase III development. In addition to ziritaxestat, Gilead had high hopes for filgotinib; however, in August 2020, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) for filgotinib’s New Drug Application due to safety concerns. The two companies have since abandoned clinical registration studies for filgotinib in the United States. In retrospect, this $5 billion collaboration may prove to be one of the most unsuccessful biotechnology deals in recent years.

4. Phase I/II and Phase III Studies of LentiGlobin Gene Therapy for the Treatment of Sickle Cell Disease (SCD)

On February 16, Bluebird Bio announced that it had suspended the Phase I/II (HGB-206) and Phase III (HGB-210) clinical studies of its LentiGlobin gene therapy for sickle cell disease (SCD) due to a suspected unexpected serious adverse reaction of acute myeloid leukemia (AML).

Bluebird Bio stated that it is investigating the cause of the subject’s acute myeloid leukemia (AML) to determine whether there is any association with the use of the BB305 lentiviral vector in the manufacturing of its LentiGlobin gene therapy. Additionally, Zynteglo, a product already marketed in Europe for the treatment of thalassemia that also utilizes the BB305 lentiviral vector, has been affected and its sales have been suspended. In response to this news, Bluebird Bio’s stock plummeted nearly 40% on the day, closing at $28.44.

Gene therapy and oncolytic viruses have emerged as highly prominent fields in recent years, with many pharmaceutical giants establishing strategic positions in these areas. However, a greater number of companies currently opt to use adeno-associated viruses (AAV). Although the likelihood of AAV integrating into the human genome is lower compared to lentiviral vectors, similar concerns persist.

In this instance, although viral vector DNA was detected in the tumor cells of AML patients, a direct causal relationship between the BB305 lentiviral vector and the development of AML requires further investigation and confirmation; additionally, the occurrence of myelodysplastic syndrome (MDS) in patients in Cohort C of the HGB-206 trial also contributed to the suspension of the study.

5. Phase III Study of Otividex for the Treatment of Ménière's Disease

On February 22, Otonomy announced that the Phase III clinical trial of Otividex for the treatment of Ménière’s disease (formerly known as Meniere’s disease) failed to meet its primary endpoint. Following this announcement, Otonomy’s stock fell 44%, closing at $3.

Meniere’s disease is an idiopathic inner ear disorder characterized primarily by endolymphatic hydrops. Its clinical manifestations include recurrent episodes of rotational vertigo, fluctuating hearing loss, tinnitus, and aural fullness, which can lead to permanent hearing loss. Otividex is a sustained-release formulation of dexamethasone. This trial is a prospective, randomized, double-blind, placebo-controlled Phase III study conducted in the United States and Europe.

In 2017, Otonomy announced that Otividex had met the primary endpoint in its Phase III clinical trial for the treatment of Meniere's disease, and stated that it would engage in clinical development discussions with the FDA as required for the marketing application of Otividex. It now appears that the earlier analysis results were not accepted by the FDA.

In July 2020, Otonomy submitted a revised statistical analysis plan for the trial to the FDA, proposing the use of a negative binomial model for the primary analysis of patient-reported daily vertigo count data. Otonomy believed that this statistical model would provide the most appropriate method for analyzing the clinical data for Otividex, based on the combined datasets from the Phase IIb (AVERTS-2) and Phase III clinical trials. However, using the negative binomial model, Otividex did not demonstrate a statistically significant advantage over placebo in the intention-to-treat (ITT) population (n=148; p=0.312) for the primary endpoint of determined vertigo days (DVD) at month 3.