Failed Long COVID Drug Trial Reveals Critical Study Design Flaws as New Company Plans Restart
核心洞察
Berlin Cures (搜索)' Phase 2 trial of BC 007 (rovunaptabin) for long COVID (搜索) failed in November 2024 due to poor patient selection and inadequate outcome measures, despite some participants experiencing dramatic symptom improvements.
A separate smaller trial at University Hospital Erlangen found significant improvements in fatigue and post-exertional malaise using more targeted selection criteria and validated ME assessment tools.
Former Berlin Cures (搜索) CEO Oliver von Stein has launched APTA Therapeutics (搜索) to acquire the drug's assets and plans new studies within 18 months, focusing on better patient stratification and collaboration with long COVID (搜索) experts.
Berlin Cures (搜索)' highly anticipated Phase 2 trial of BC 007 (rovunaptabin) for long COVID (搜索) ended in failure in November 2024, but the setback has yielded valuable lessons for future drug development in this complex disease area. Despite the trial's negative results, some participants experienced dramatic symptom improvements, and the drug is now being revived under new leadership with plans for more targeted studies.
The autoantibody-targeting infusion BC 007 was originally developed for chronic heart failure (搜索) before being repurposed for long COVID (搜索). Berlin Cures (搜索) hypothesized that the drug could alleviate symptoms by neutralizing autoantibodies (搜索) that block G-protein coupled receptors (搜索) (GPCRs (搜索)), which are involved in many biological pathways affecting circulatory and nervous systems.
Trial Participant Experiences Highlight Drug's Potential
Shayna Bhalla, a trial participant who had been debilitated by long COVID (搜索) symptoms including fatigue, headaches, and neurological issues, experienced a dramatic recovery during the study. "In the last few months, I have literally regained life," Bhalla said in November 2024, noting she was able to resume university classes and daily activities.
However, when Berlin Cures (搜索) announced the trial's failure and the company's closure due to lack of funding, Bhalla was devastated. "I feel like I'm back at zero," she said. The abrupt end left participants who had benefited from the treatment without access to the drug.
Study Design Flaws Undermined Results
Expert analysis revealed multiple design flaws that likely contributed to the trial's failure. The study used an unreliable biomarker test to select participants, measuring how plasma affects cardiomyocytes to identify GPCR autoantibodies (搜索). "There are no good studies demonstrating that there's a difference between patients and healthy controls in how the plasma makes cardiomyocytes respond," said Dr. Artur Fedorowski, a cardiologist at the Karolinska Institute (搜索) who specializes in dysautonomia.
Study participants noticed inconsistencies in the testing process. "Multiple people got screened at multiple screening sites multiple times," said Claudia, a trial participant. People with long COVID (搜索) went to different sites "until they finally got a positive result" to qualify for participation.
The trial's broad inclusion criteria accepted any adult with "chronic fatigue" and "at least one additional symptom" following documented SARS-CoV-2 infection. This approach failed to account for long COVID (搜索)'s complexity as an umbrella term covering different disease patterns.
Inadequate Outcome Measures Miss Key Symptoms
The study used the Functional Assessment of Chronic Illness Therapy (FACIT) survey to track fatigue, but experts noted this tool fails to capture post-exertional malaise (PEM), a cardinal feature of myalgic encephalomyelitis (搜索) (ME) that many long COVID (搜索) patients experience. PEM involves worsened symptoms following activity and can include pain, sleep problems, cognitive issues, and muscle weakness beyond simple fatigue.
"Not only does the FACIT survey fail to capture PEM, it can't determine differences in severity," said Chloé de Canson, a patient-researcher with long COVID (搜索). Participants could regain significant function but still score poorly if they felt "tired."
This measurement problem affected participants like Bhalla, who experienced dramatic improvement but may not have shown corresponding changes on the survey. Another participant, Emma, reported symptom improvements but found it "challenging" to answer survey questions that didn't match her PEM experience.
Contrasting Success in Smaller Erlangen Study
A separate 30-patient trial at University Hospital Erlangen demonstrated BC 007's potential when proper selection criteria and outcome measures were used. Published as a preprint in December 2024, this study found "significant improvement" for fatigue and PEM following infusions.
The Erlangen researchers focused on an "autoimmune subgroup" of long COVID (搜索) patients, requiring positive GPCR autoantibody tests plus moderate to severe scores on ME scales and at least three common symptoms. They excluded patients with documented organ damage from COVID-19, representing a potentially different long COVID subset.
The study used multiple symptom surveys, including tools designed and validated for ME patients, which showed significant improvements with BC 007. "We don't have any long COVID (搜索)-specific validated instruments," explained Bornali Bhattacharjee, associate director of Yale University's Center for Infection and Immunity, "so it's best to use multiple tests together and capture a range of data."
The Erlangen trial also employed a crossover design where all 30 patients received BC 007, with groups receiving either drug-then-placebo or placebo-then-drug sequences.
New Company Plans Targeted Approach
Former Berlin Cures (搜索) CEO Oliver von Stein has launched APTA Therapeutics (搜索), acquiring the previous company's assets and planning continued BC 007 development. Von Stein acknowledged the Phase 2 trial was "not an optimum study in design" and attributed the failure to inadequate patient selection rather than drug ineffectiveness.
"We had a disappointing outcome, I would like to believe, most likely because we did not have an optimum patient selection program in place," von Stein said. He emphasized that future research must "pay great attention to the patient selection, really try to specify who we think is best to enter these trials."
APTA plans to work with Erlangen researchers and other European university clinics specializing in long COVID (搜索) and related diseases. The company aims to conduct small cohort studies and compile data for a larger, more robust Phase 3 trial within 18 months.
"The hope is maybe within 18 months... to have enough robust data that could form the basis of a registration study [Phase 3 trial], where we've teased out a lot of these unknowns and thereby really maximize the chance of getting this drug to market," von Stein said.
Broader Implications for Long COVID Research
The BC 007 experience reflects challenges familiar to researchers studying ME, POTS, and similar complex chronic diseases. Long COVID (搜索) affects 6-7% of adults globally and represents an umbrella term for diseases with different symptom patterns, making universal treatments unlikely.
Helen Brownlie, a patient-researcher with ME in the UK, noted that randomized controlled trials work best "when you have a well-delineated disorder, a well-established protocol for treating that disorder with a robust evidence base, and then a new drug that you want to compare" to existing treatments. For long COVID (搜索), "all of this is nonexistent."
The Patient-Led Research Collaborative (PLRC), comprising scientists living with long COVID (搜索), recommends "starting with smaller signal-finding trials" that can inform larger studies. They also emphasize protecting against post-exertional malaise during study procedures and involving patient feedback throughout the research process.
Despite the setbacks, trial participants remain committed to advancing research. "I would do it again," said participant Jakob, "because taking part in trials is the only way we can defeat this disease with new medication."