Top 10 Failed Global Clinical Trials of 2023: Lessons from Setbacks in Drug Development

According to Deloitte statistics, the development cost of a single new drug is approximately $2.3 billion, which means pharmaceutical companies need to take enormous risks to potentially bring these new drugs to market. When these new drug development projects fail, it is more important to reflect on the problems that arose and attempt to propose better scientific justifications and solutions.

Fierce Biotech’s Annual Review: Top 10 Most-Watched Failed Clinical Trials of 2023. These unsuccessful therapies came from both multinational corporations (MNCs) and biotech companies. Once the news of their clinical failures was announced, some drugs triggered stock market declines and raised concerns within the industry about entire drug categories.

However, the lessons learned from past failures are as important as the experience gained from successes. It is hoped that these failed clinical cases will serve as a warning to the industry, and that the biopharmaceutical field in 2024 will produce better data and treatment methods to meet more unmet clinical needs.

Indications:HIV
Pharmaceutical companies:Johnson & Johnson/Janssen
Modality：Vaccine

The failure of Janssen's HIV vaccine means that Johnson & Johnson has encountered obstacles in its new drug development for infectious diseases.

On January 18, 2023, Janssen announced the failure of the Mosacio Phase III clinical trial conducted globally. The trial involved the study of its HIV vaccine regimen on 3,900 enrolled patients, which consisted of administering an adenovirus vector-based vaccine four times within a year and using a soluble protein drug during the third and fourth follow-up visits. Janssen found that the therapy did not prevent HIV and anticipated that the study would not meet its primary endpoint, leading to the termination of the clinical trial.

This is already Johnson & Johnson's second failure in developing an HIV prevention vaccine. In 2021, a Phase IIb trial of a similar vaccine by Johnson & Johnson, named Imbokodo (or HVTN705), was conducted among women in five southern African countries. Through trial analysis, Johnson & Johnson calculated the vaccine’s efficacy at 25.2%. Although the vaccine was generally well-tolerated, its protection efficiency was too low to support further research, leading Johnson & Johnson to decide to halt the development of this vaccine.

Weeks after the failure of Mosacio's Phase III clinical trial, Fierce Pharma reported that Johnson & Johnson had begun a complete overhaul of its infectious disease R&D division, cutting jobs and entirely halting the development of an HIV vaccine. By August 2023, Johnson & Johnson’s infectious disease division had ceased all R&D operations, while the development of already marketed HIV-related products would continue in other departments within Johnson & Johnson.

Indications:Autoimmune Disease
Pharmaceutical enterprises: Nektar Therapeutics
Modality：IL-2

In February 2023, Eli Lilly announced the failure of the Phase II clinical trial for rezpegaldesleukin, a new IL-2 drug developed in collaboration with Nektar Therapeutics for the treatment of lupus erythematosus. Nektar had been conducting clinical research focusing on the indication of lupus erythematosus, hoping to expand the developmental potential of its drug. However, Lilly ultimately decided to discontinue the clinical trial for lupus erythematosus treatment and stated that it would reassess the prospects of rezpeg for treating atopic dermatitis. Finally, in April 2023, Lilly returned rezpeg to Nektar and handed over the original clinical study data.

A few months later, in August 2023, Nektar pointed out that its former partner, Eli Lilly, had made errors in the clinical data statistics for rezpeg. The incorrect data came from two Phase Ib clinical studies on rezpeg conducted by Eli Lilly for atopic dermatitis and psoriasis. Eli Lilly also confirmed these errors. Subsequently, Nektar filed a lawsuit against Eli Lilly.

Nektar Therapeutics announced the final results of its Phase Ib trial in October 2023, showing that rezpeg achieved relief and improvement in the treatment of atopic dermatitis through varying doses over 12 weeks, with sustained efficacy maintained for up to 36 weeks. Nektar initiated the Phase IIb study in the same month.

Indications:Atopic Dermatitis
Pharmaceutical company:BenevolentAI

Modality：Pan-Trk Inhibitor

AI Drug Development Faces Setbacks Amid Hype: BenevolentAI Announces Failure of Phase IIa Study for BEN-2293 in Atopic Dermatitis Treatment

Trk is best known as a target for cancer drugs, but BenevolentAI's artificial intelligence platform identified these targets as mediators of itch and inflammation in atopic dermatitis. BenevolentAI believes that BEN-2293 has the potential to treat mild to moderate symptoms of atopic dermatitis with fewer side effects compared to existing drugs.

But the drug did not outperform the placebo in improving the area and severity of dermatitis or pruritus, which were the secondary endpoints of this clinical study.

Thereafter, BenevolentAI discontinued the development of BEN-2293.

Indications:Non-Small Cell Lung Cancer
Pharmaceutical enterprises: Mirati Therapeutics 
Modality：Kinase Inhibitors

Mirati Therapeutics Is Ready to Open the Next Era of Cancer Treatment with Sitravatinib, but the Long-Awaited Good News Has Yet to Arrive.

Mirati had hoped to see a 3.5-month overall survival benefit from Sitravatinib in the Phase III SAPPHIRE trial, the results of which were announced in May 2023. Unfortunately, the final analysis showed that the drug did not meet this primary endpoint.

Sitravatinib is a spectrum-selective kinase inhibitor, and Mirati Therapeutics hopes to use it to help overcome resistance to immune checkpoint inhibitors.

In the randomized Phase III SAPPHIRE study, Mirati evaluated the combination of Sitravatinib and Nivolumab for treating non-squamous NSCLC patients whose disease progressed during or after platinum-based chemotherapy. The study aimed to compare the efficacy of the investigational drug combined with Nivolumab versus Docetaxel in this patient population. Patients in the experimental group received Sitravatinib orally once daily in addition to Nivolumab administered via intravenous infusion over 30 minutes. The primary endpoint assessed in the trial was OS, with secondary endpoints including adverse events, objective response rate, and progression-free survival.

Due to the failure to meet the primary endpoint, Mirati Therapeutics decided to terminate the development of the drug. However, BeiGene holds the rights for the development and commercialization of the drug in Asia, New Zealand, and Australia.

Indications:Diabetic Macular Edema
Pharmaceutical companies:Kodiak Sciences
Modality：Antibody-Conjugated Biopolymer

In July 2023, Kodiak Sciences announced that its investigational antibody-biopolymer conjugate (ABC) targeting VEGF, Tarcocimab Tedromer (KSI-301), did not meet the primary endpoints in two Phase III clinical trials for the treatment of retinal vascular diseases. The results also indicated an increased incidence of cataracts in patients treated with Tarcocimab Tedromer.

Previously, Tarcocimab Tedromer demonstrated efficacy in a separate trial involving 557 patients with neovascular age-related macular degeneration. However, it failed in two clinical trials codenamed GLEAM and GLITTER. As a result, Kodiak Sciences Inc. decided to terminate the clinical development program for this drug.

Last November, a new set of late-stage data for Tarcocimab Tedromer was released, indicating that the drug still has a chance of gaining approval, potentially pulling Kodiak Sciences back from the brink. In the cohort receiving the 5 mg dose of tarcocimab tedromer, the GLOW trial for the treatment of non-proliferative diabetic retinopathy showed that the drug met its primary endpoint. Kodiak subsequently announced the restart of Tarcocimab Tedromer's development.

Indications:Hidradenitis Suppurativa
Pharmaceutical companies: Acelyrin
Modality：Protein Inhibitor

The Unexpected Failure of ACELYRIN's IL-17A Inhibitor Shocks the Market. This Biotech Had Raised $540 Million for Its IPO Based on the Drug’s Potential.

However, when the clinical data of the drug were released, this enthusiasm began to collapse. In December 2023, Acelyrin announced the latest Phase IIb/III clinical data for Izokibep in treating Hidradenitis Suppurativa (HS). The results showed that the study did not meet its primary endpoint of HiSCR75 (at least a 75% reduction in abscesses and inflammatory nodules).

The trial was conducted in 175 patients with moderate to severe HS, aiming to evaluate the efficacy and safety of weekly (QW) and every two weeks (Q2W) izokibep (160mg) compared to placebo. The results showed that 39% of patients receiving izokibep weekly achieved HiSCR75 at week 16, compared to 34% for those treated every two weeks, and 29% in the placebo group, without achieving a statistically significant improvement.

Izokibep Failed to Outperform Placebo on the Primary Endpoint, Causing ACELYRIN's Stock Price to Plummet 58% to $11.60 on the Day of the Announcement.

More than two months later, Acelyrin announced that the failure of the clinical trial might be caused by errors from the CRO. Its team recently discovered that the CRO responsible for several clinical trials of izokibep made significant mistakes during the execution of the trials, resulting in incorrect group assignments, wrong dosage sequences, and both groups not being administered the drugs as planned. Although the issue was promptly identified and resolved, the potential impact is still under investigation. This has led Acelyrin to reasonably suspect whether there were also clinical execution errors in the previously failed Phase III trial for hidradenitis suppurativa.

Currently, the share price of Acelyrin has not recovered, hovering around the $6-7 mark since November 2023.

Indications:MASH

Pharmaceutical Company:Akero Therapeutics
Modality：FGF21 Analogues

In 2023, the development of MASH drugs was proceeding smoothly until Akero Therapeutics announced the failure of the Phase IIb clinical trial for efruxifermin.

In October last year, Akero Therapeutics announced the interim analysis results of the Phase IIb SYMMETRY study of efruxifermin (EFX) in patients with compensated cirrhosis (F4) and non-alcoholic steatohepatitis (NASH). The study showed a trend toward improvement in liver fibrosis, the primary endpoint, at week 36, but it was not statistically significant.

In fact, efruxifermin has already shown efficacy in early-stage patients, but Akero Therapeutics hopes to demonstrate a reduction in liver fibrosis in more advanced patients. Analysts at Mizuho at the time suggested that the patients' conditions may have been too severe, leading to poor treatment outcomes—a situation akin to Alzheimer's disease or cancer.

Akero Therapeutics has since entered Phase III clinical trials to evaluate the efficacy of efruxifermin in pre-cirrhotic patients with MASH. The first patients were dosed in December 2023, with data expected to be released in March.

Indications:Duchenne Muscular Dystrophy (DMD)
Pharmaceutical enterprises:Sarepta Therapeutics
Modality：Gene Therapy

Sarepta Therapeutics' DMD Dilemma Warrants Special Attention.

In October 2023, Sarepta announced the latest data from the Phase III confirmatory clinical trial EMBARK of the DMD gene therapy Elevidys. The study did not meet the primary endpoint of NSAA but achieved the secondary endpoints TTR and 10MWR.

Elevidys functions by delivering micro-dystrophin expression via AAV. On May 13 last year, the FDA advisory committee voted 8:6 in favor of Elevidys being approved through the accelerated approval pathway. In June last year, the FDA approved Sarepta's Elevidys as the first gene therapy for treating Duchenne muscular dystrophy (DMD). However, since Sarepta used the level of micro-dystrophin expressed by Elevidys as a surrogate endpoint, the FDA required the completion of confirmatory clinical studies to verify clinical benefits. The price set by Sarepta for Elevidys is $3.2 million.

Although the EMBARK clinical trial failed, CEO Doug Ingram stated his determination to continue efforts, calling the study "up to standard" and showing "evidence of efficacy." He added that the clinical results indicated the drug "altered" the course of DMD in patients, and Sarepta has had "encouraging" early discussions with the FDA regarding these data.

Subsequently, Sarepta submitted supplementary data to the FDA, using data from EMBARK to support a labeling expansion request, seeking approval for all DMD patients. If Sarepta can successfully persuade the FDA, Elevidys will move beyond its accelerated approval status to gain full approval.

Indications:Atrial Fibrillation with Stroke Risk
Pharmaceutical enterprises:Bayer
Modality：Factor XIa Inhibitor

For Bayer, the failure of asundexian could be a multi-billion-dollar mistake.

In November last year, Bayer announced it would terminate the Phase III clinical trial of its blood thinner asundexian, citing that asundexian's "efficacy was lower" than Eliquis, which was co-developed by BMS and Pfizer. This prompted Bayer to halt the study early while continuing to advance the drug’s development in another Phase III clinical trial.

Asundexian is a novel oral anticoagulant FXIa inhibitor that prevents pathological thrombosis by inhibiting Factor XIa, thereby preventing the recurrence of ischemic events. Bayer regards asundexian as the company's next-generation blockbuster anticoagulant drug. Earlier this year, company executives predicted that asundexian’s ultimate annual sales would exceed $5 billion, and it was originally expected to be a competitor to Pfizer's blockbuster drug Eliquis.

This is not the first failure for asundexian. In 2022, asundexian failed to outperform a placebo in two mid-stage trials aimed at treating patients recovering from heart attacks and strokes, as the drug did not reduce the combined incidence of silent brain infarctions or ischemic strokes.

Currently, Bayer still holds hope for atrial fibrillation patients who are not suitable for oral anticoagulant therapy. A clinical study targeting this indication began in early November 2023.

Indications:Multiple Sclerosis
Pharmaceutical enterprises:Merck

Modality：BTK Inhibitor

MSD has been looking for an opportunity to create a blockbuster drug. The company pinned its hopes on the BTK inhibitor evobrutinib, but evobrutinib encountered failure in clinical trials. The therapy failed to outperform Sanofi's Aubagio in two Phase III multiple sclerosis (MS) clinical trials.

BTK Inhibitors Hold Promise for Novel Treatment Options in Multiple Sclerosis and Other Autoimmune Diseases. However, the Setback of Evobrutinib Has Raised Questions Within the Industry About BTK Inhibitors.

In December 2023, Merck announced the latest results of two Phase III EVOLUTION studies (evolutionRMS 1 and evolutionRMS 2) on evobrutinib for the treatment of relapsing multiple sclerosis: compared with teriflunomide, evobrutinib did not meet the primary endpoint of reducing the annualized relapse rate (ARR). The annual relapse rate of evobrutinib was almost the same as that of the control drug Aubagio.

Merck's competitors in this field include Sanofi, BeiGene, Novartis, and Roche, whose candidate drugs have entered Phase II or Phase III clinical trials.

Merck has outlined its marketed products, internal pipeline, and the strategic direction of "external innovation," but the future of evobrutinib remains uncertain.