Buzzy Lancet long COVID paper under investigation for ‘data errors’

 An early and influential paper on long COVID that appeared in The Lancet has been flagged with an expression of concern while the journal investigates “data errors” brought to light by a reader. 

An editorial that accompanied the paper when it was published in January of last year described it as “the first large cohort study with 6-months’ follow-up” of people hospitalized with COVID-19. The article has received plenty of attention since then. 

Titled “6-month consequences of COVID-19 in patients discharged from hospital: a cohort study,” the paper has been cited nearly 1,600 times, according to Clarivate’s Web of Science. Altmetric finds references to it in multiple documents from the World Health Organization.  

According to the expression of concern, dated November 24, a reader found inconsistencies between the data in the article and a later paper describing the same cohort of patients after a year of follow-up. That discovery sparked an investigation that is still ongoing: 

On Jan 8, 2021, The Lancet published an Article, 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study, by Chaolin Huang and colleagues.1 On Aug 28, 2021, The Lancet published an Article, 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study, by Lixue Huang and colleagues.2 We received an inquiry from a researcher on data inconsistencies between these two Articles, and we sought an explanation from the corresponding author of the two papers. On Nov 7, 2022, Lancet editors were informed that inconsistencies between the 6-month and the 1-year data were due to “some variables in the dataset used for the 6-month paper were mistakenly disrupted in order”. In view of the extent of these data errors, we now issue an Expression of Concern about the 6-month paper1 while we investigate further, including further statistical and clinical review of the corrected data. We will update this notice as soon as we have further information.

The corresponding author of both papers, Bin Cao of China’s National Center for Respiratory Medicine and the China-Japan Friendship Hospital in Beijing, has not responded to our request for comment. 

A profile of Cao published in Lancet Infectious Diseases last March described him as “a leading researcher in pneumonia and influenza” who “has been instrumental in increasing knowledge about COVID-19.” In addition to the follow-up study of hospitalized COVID patients: 

Cao’s seminal papers during the COVID-19 pandemic include the first report of the clinical characteristics of COVID-19 patients in Wuhan, the description of the risk factors for mortality for adult inpatients, and the results of trials testing the use of antiviral drugs, including lopinavir-ritonavir, to treat COVID-19 in China. 

We reached out to The Lancet’s press office and Richard Horton, the journal’s editor-in-chief, and received this statement: 

The Lancet Group treats all communications between editors and authors or readers as confidential. Investigations are continuing, and the Expression of Concern will be updated as soon as we have further information to share. More information about our policies is available here: https://www.thelancet.com/publishing-excellence

This year, The Lancet overtook the New England Journal of Medicine as the medical journal with the highest impact factor, in large part due to the papers it published about COVID-19. 

We’ve counted retractions for three of those papers, most notably a paper about the use of the drug hydroxychloroquine that claimed to use medical data from a company called Surgisphere. As Retraction Watch readers may remember, the article was retracted after sleuths questioned if the data were real, and the company would not produce it for review.

https://retractionwatch.com/2022/12/01/buzzy-lancet-long-covid-paper-under-investigation-for-data-errors/

Cardiovascular Risk Marker Improved With Common Rheumatoid Arthritis Drugs

 Rheumatoid arthritis patients treated with medications targeting the tumor necrosis factor (TNF) pathway or with standard disease-modifying anti-rheumatic drugs (DMARDs) showed substantial reductions in arterial inflammation, a key predictor of future cardiovascular disease, a randomized trial indicated.

After 24 weeks of treatment with a TNF inhibitor or with a three-DMARD combination regimen, patients had significantly lower values for the target-to-background ratio (TBR) in the carotid arteries and aorta relative to baseline, with little difference between the two study arms, reported Daniel Solomon, MD, of Brigham and Women's Hospital in Boston, and colleagues.

The reductions in this inflammation marker were "clinically important" but also somewhat puzzling, the researchers noted in Annals of the Rheumatic Diseases, because they expected the TNF inhibitors to outperform the DMARD combination.

"This theory was based on the fact that vascular endothelium is a select target for TNF where it induces pro-inflammatory, pro-coagulant and pro-apoptotic genes known to damage the endothelium," they wrote. "In addition, TNF induces endothelial adhesion molecules which mediate inflammatory cell trafficking to the arterial walls where oxidised low density lipoprotein (LDL) accumulates in an early stage of atherosclerosis."

Patients in the trial had active rheumatoid arthritis despite methotrexate treatment, suggesting they were experiencing "a high degree of systemic inflammation" that would diminish with any clinically effective step-up treatment, Solomon and colleagues speculated.

They conceived the study to evaluate the impact of different treatment strategies for rheumatoid arthritis on cardiovascular risk. Previous studies had indicated that biologic therapies do affect this risk, but they were largely observational or post-hoc analyses rather than randomized trials.

A total of 115 patients were assigned 1:1 to a TNF inhibitor (either adalimumab [Humira] or etanercept [Enbrel]) or to the addition of the DMARDs sulfasalazine and hydroxychloroquine to low-dose methotrexate for so-called triple therapy.

Mean patient age was just under 60, with disease duration averaging about 16 months. Some 70% were women and 80% were white. Arthritis severity ratings on the 28-joint Disease Activity Score (DAS28) system averaged 4.8 at enrollment.

TBR was assessed with ¹⁸F-fluorodeoxyglucose-PET and CT scans.

Mean baseline TBR values stood at 2.72 in the TNF inhibitor arm and 2.62 for those assigned to the triple DMARD regimen. After 24 weeks, these fell by 0.24 and 0.19 points, respectively. The difference between them did not approach statistical significance. The largest changes from baseline were seen in the aorta's most diseased segments.

Solomon and colleagues also looked for associations between the changes in TBR and DAS28 scores, finding only a very weak positive correlation.

Limitations to the study included the relatively small number of patients, short follow-up, and reliance on a biomarker of vascular inflammation instead of hard clinical outcomes. Solomon and colleagues explained that evaluating cardiovascular events would require "thousands of patients," far larger than any previous trial in rheumatoid arthritis patients.

Future studies could try other types of therapies such as inhibitors of the interleukin-6 and Janus kinase pathways and B-cell depletion, the researchers noted.

Disclosures

The study was funded by the National Institutes of Health; Amgen and AbbVie supplied the study drugs.

Solomon and other authors reported extensive relationships with pharmaceutical companies and other commercial entities.

Primary Source

Annals of the Rheumatic Diseases

Source Reference: Solomon DH, et al "Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arthritis" Ann Rheum Dis 2022; DOI: 10.1136/ard-2022-223302.

https://www.medpagetoday.com/rheumatology/generalrheumatology/102023

Brain Iron Chelation Linked With Worse Outcomes in Early Parkinson's

 Brain iron chelation with deferiprone was associated with worse parkinsonism symptoms and adverse events in early Parkinson's disease, the FAIRPARK-II trial showed.

From baseline to week 36, mean total scores on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) worsened more with deferiprone than placebo, reported David Devos, MD, PhD, of Université Lille in France, and co-authors in the New England Journal of Medicine.

Mean MDS-UPDRS scores were 34.3 in the deferiprone group and 33.2 in the placebo group at baseline. At 36 months, scores worsened by 15.6 points with deferiprone and 6.3 points with placebo (difference 9.3 points, 95% CI 6.3-12.2, P<0.001).

Symptom progression led to dopaminergic therapy in 22.0% of the deferiprone group and 2.7% of the placebo group. Nigrostriatal iron content decreased more in the deferiprone group, indicating target engagement. A total of 9.7% of people in the deferiprone group and 4.8% in the placebo group had serious adverse events.

The findings preclude testing higher doses of deferiprone and argue against further exploring the drug in Parkinson's disease, noted Douglas Galasko, MBBCh, of the University of California, San Diego, and Tanya Simuni, MD, of Northwestern University in Chicago, in an accompanying editorial.

"The FAIRPARK-II trial provides evidence that deferiprone does not slow progression in Parkinson's disease, but the data from this trial could nevertheless stimulate studies to clarify the role of iron in the pathogenesis of Parkinson's disease," Galasko and Simuni wrote. "However, the findings raise cautions about iron chelation as a therapeutic intervention in neurodegenerative disorders."

Iron deposition in the brain occurs with aging and has been implicated in Parkinson's and other neurodegenerative disorders. Brain iron may be a plausible therapeutic target, but it also has a biological role in Parkinson's as a cofactor for tyrosine hydroxylase activity.

FAIRPARK-II was a phase II study of 372 people with newly diagnosed Parkinson's disease who had never received levodopa. Participants were screened from February 2016 through December 2019; they had a mean age of about 62 at baseline, and nearly two-thirds were men.

For 36 weeks, 186 people received oral deferiprone at 15 mg per kilogram of body weight twice a day and 186 people received placebo. The primary outcome was the change from baseline in MDS-UPDRS total scores, which range from 0 to 260 with higher scores representing worse impairment. The MDS-UPDRS assesses mental function, activities of daily living, and motor function.

A total of 118 participants (63.4%) in the deferiprone group and 165 (88.7%) in the placebo group completed the trial at week 36.

The primary outcome was imputed for 54 people in the deferiprone group and 11 people in the placebo group. Forty-one participants (22.0%) on deferiprone and five (2.7%) on placebo withdrew from the trial because their disease progression warranted dopaminergic therapy. Another 13 deferiprone participants and six placebo participants withdrew due to adverse events.

Brain MRI in a subgroup of participants showed that deferiprone was associated with a greater reduction of iron content in nigrostriatal pathways, particularly in the substantia nigra. Dopamine transporter imaging showed no differences between deferiprone and placebo.

Parkinson's disease progression was reported as an adverse event in 24.2% of the deferiprone group and 7.0% of the placebo group. Serious adverse events included agranulocytosis in two participants in the deferiprone group and neutropenia in three.

Deferiprone's detrimental effects became evident as more people left the trial to start dopaminergic therapy and by visual inspection of MDS-UPDRS graphs at month 3, Devos and co-authors noted.

"We speculate that the early separation of curves in favor of the placebo group may be consistent with a negative symptomatic effect of deferiprone rather than an accelerating effect on underlying disease progression," the researchers wrote.

"This conjecture is based on chelation of brain iron by deferiprone that presumably reduced activity of tyrosine hydroxylase, the rate-limiting enzyme for dopamine production, which is consistent with the increased levels of plasma prolactin, an inhibitor of which is dopamine," the team added.

Results should be viewed in the context of a hypothesis that deferiprone would have superior clinical outcomes, Devos and colleagues noted. "There was also a need for imputation of a large amount of clinical outcome data owing to participant dropout, particularly in the deferiprone group, and a lack of racial diversity."

Disclosures

The trial was supported by the European Union Horizon 2020 funding program. ApoPharma and Chiesi provided deferiprone and placebo for the study.

Devos reported no disclosures.

Galasko reported personal fees from Biogen, GE Healthcare, Springer, Eisai, Generian, and Cognition Therapeutics.

Simuni reported grants or personal fees from 4D Pharma, Acadia, AcureX, AskBio, Amneal, Blue Rock Therapeutics, Caraway, Critical Path for Parkinson's Consortium, Denali, Michael J. Fox Foundation, NeuroDerm, Roche, Sanofi, Sinopia, Sunovion, Takeda, UCB, Vanqua Bio, Voyager, Biogen, NINDS, Parkinson's Foundation, and Prevail.

Primary Source

New England Journal of Medicine

Source Reference: Devos D, et al "Trial of deferiprone in Parkinson's disease" N Engl J Med 2022; DOI: 10.1056/NEJMoa2209254.

Secondary Source

New England Journal of Medicine

Source Reference: Galasko D, Simuni T "Lack of benefit of iron chelation in early Parkinson's disease" N Engl J Med 2022; DOI: 10.1056/NEJMe2213120.

https://www.medpagetoday.com/neurology/parkinsonsdisease/102035

Amid Buyout Buzz, Mirati Pushes Phase III NSCLC Study to Final Analysis

 Amid rampant buyout speculation, Mirati Therapeutics reported that it will continue its final analysis of the Phase III SAPPHIRE trial following an interim survival analysis.

Friday, San Diego-based Mirati announced its commitment to completing the late-stage study assessing investigational spectrum-selective kinase inhibitor, sitravatinib, combined with the checkpoint inhibitor Opdivo, in patients with non-small cell lung cancer (NSCLC). 

Mirati is developing the combination treatment as a third- or fourth-line option for patients with NSCLC. Mirati officials said that they anticipate the final data analysis ought to be out by mid-2023.

Mirati didn’t share additional details about the ongoing study in the announcement.

The company is assessing sitravatinib in clinical trials as a treatment for patients who are resistant to prior immune checkpoint inhibitor therapy and who have progressed on platinum doublet therapy.

Beyond the combination with Bristol Myers Squibb’s Opdivo, Mirati has also paired the drug with BeiGene’s checkpoint inhibitor, tislelizumab.

Buyout Rumors Swirl

The information comes fewer than two weeks after reports surfaced that the company was considered a takeover target.

Citing unnamed sources familiar with the matter, Bloomberg reported the company garnered interest from large pharmaceutical companies. Bloomberg didn’t identify any potential buyers, and the sources said no deal was imminent.

This wouldn’t be the first time Mirati has been considered a target for acquisition. Last year, rumors surfaced that Merck was considering a bid for Mirati.

Mirati has a market cap of $5.1 billion. Some larger companies are reportedly interested in late-2022 bolt-on deals to complement or diversify their portfolios and pipelines.

Wednesday, Horizon Therapeutics confirmed it was being courted by three large pharmaceutical companies—Johnson & Johnson, Amgen and Sanofi. Horizon Therapeutics is significantly larger than Mirati, with a market cap of more than $23 billion.

GSK, which went through a split earlier this year separating its pharmaceuticals business from its consumer health business, is also rumored to be targeted for acquisition.

Swiss Pharma giant Novartis, which has a long history with GSK, was reported to be interested in acquiring the U.K. company.

Any such deal would be massive, as GSK has a market cap of nearly $70 billion.

https://www.biospace.com/article/amid-buyout-buzz-mirati-pushes-phase-iii-nsclc-study-to-final-analysis/

Athira’s Alzheimer’s Therapy Climbs Ranks in a Competitive Space

 Athira Pharma’s experimental Alzheimer's therapy, fosgonimeton, continues to show reductions in known biomarkers associated with the disease and signs of cognitive and functional improvement in patients with mild-to-moderate Alzheimer's. 

On Thursday, Bothell, Wash.-based Athira presented biomarker data from the Phase II ACT-AD study showing that fosgonimeton produced reductions in biomarkers of neurodegeneration (NfL) and neuroinflammation (GFAP) compared to placebo among patients who were not taking acetylcholinesterase inhibitors.

The data, presented at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference, will further inform the necessary sample size required for Athira's ongoing Phase II/III LIFT-AD study.

Fosgonimeton is a small molecule designed to enhance the activity of hepatocyte growth factor and its receptor, MET, in order to impact neurodegeneration and regenerate brain tissue.

Hans J. Moebius, chief medical officer at Athira, told BioSpace the biomarker improvements also significantly correlated with improvements in clinical outcomes at week 26.

Earlier this year, Athira reported the ACT-AD study missed meeting its primary endpoint. However, a planned analysis of subgroup data showed cognitive and functional improvements through fosgonimeton's modulation of the HGF/MET system. This allowed Athira to amend its LIFT-AD study to investigate the drug as a monotherapy.

The data suggested there was a drug interaction that reduced the benefits between fosgonimeton and the concomitant acetylcholinesterase inhibitors in the control group, Moebius said. 

He added that there was a sizeable difference in efficacy between patients who received the combination compared to fosgonimeton alone, and improvements in biomarker data were larger and statistically significant in fosgonimeton-only patients.

"The bottom line is we can conclude that clinical endpoints are highly correlated to biomarkers of neurodegeneration and neuroinflammation," Moebius said. "It’s neuroprotective and [it] is improving blood-based biomarkers and the clinical outcomes."

He noted the company will enroll up to 150 additional patients to ensure the LIFT-AD trial is well-powered to achieve its primary endpoint. Full enrollment of the Phase II/III trial is expected in the middle of 2023, with topline results coming in early 2024.  

An Increasingly Competitive Space

Athira’s results were announced two days after Eisai presented data from the Phase III CLARITY AD trial of lecanemab, which showed a slowing of cognitive decline in some patients. 

Howard Fillit, cofounder and chief scientific officer of the Alzheimer’s Disease Defense Foundation, said the data is “welcome news” for Alzheimer’s patients. However, he said it should only be a starting point to defeating the disease.

“We have a lot of ground to cover to get from the 27% slowing lecanemab offers to our goal of slowing cognitive decline by 100%."  

Moebius speculated that the Eisai data would ultimately result in regulatory approval of lecanemab. Still, like Fillit, he said more work needs to be conducted to bring greater benefit to Alzheimer’s patients.

Looking at the significant need in the Alzheimer’s community, Moebius said he believes the FDA has maintained unwavering support for new therapeutics for this indication, something he believes will still be in effect when Athira is ready to take fosgonimeton to the regulator. 

https://www.biospace.com/article/athira-pharma-s-alzheimer-s-therapy-climbs-ranks-in-a-competitive-space/

GSK Notches Phase III Win for Jemperli in Endometrial Cancer

 GSK plans to file for approval of Jemperli in endometrial cancer after the checkpoint inhibitor met its primary endpoint in the Phase III RUBY trial, the company announced Friday. 

Based on the strength of the interim analysis, GSK said it intends to seek regulatory approval in the first half of 2023. Full data from the RUBY study will be presented at a later date.

A GSK spokesperson told BioSpace that if approved, based on this data, Jemperli has the potential to become the first anti-PD-1 plus platinum-based chemotherapy treatment combination approved in primary advanced or recurrent endometrial cancer.

Additionally, the spokesperson stressed the RUBY data is the only trial that shows show improvement in progression-free survival for an immuno-oncology therapy in combination with standard-of-care chemotherapy in this indication.

Data showed Jemperli (dostarlimab) combined with chemotherapy generated a statistically significant and clinically meaningful improvement in investigator-assessed progression-free survival (PFS) in patients with primary advanced or recurrent endometrial cancer. The combination was assessed as a first-line treatment for these patients. 

When GSK conducted the interim analysis, the company stated the combination of Jemperli and chemotherapy generated a significant and clinically meaningful benefit in the “prespecified mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) patient subgroup,” as well as in the overall population. 

The overall survival data from the RUBY was immature at the time of the analysis. But, the company noted this morning that a favorable trend was observed in the overall population and in the subgroups of patients.

In 2021, the FDA approved Jemperli for patients with dMMR recurrent or advanced endometrial cancer. The regulatory agency also granted accelerated approval to Jemperli for the treatment of adult patients with dMMR recurrent or advanced solid tumors.

A Multi-Faceted Therapeutic

Other indications could be on the horizon for Jemperli. Last month, GSK presented data showing Jemperli generated positive results as a first-line treatment for non-small cell lung cancer in the Phase II PERLA trial.

Also this year, treatment with Jemperli sent 12 rectal cancer patients into complete remission. In that small study, Jemperli was assessed as a first-line treatment for MMRd locally advanced rectal cancer. As BioSpace reported at the time, the data was so positive it was considered “unheard of.”

In the RUBY study, Jemperli continued to maintain a consistent safety and tolerability profile. The most common treatment-related adverse events were nausea, alopecia, fatigue, peripheral neuropathy, anemia, arthralgia, constipation and diarrhea.

For GSK, the good news from the RUBY study follows its decision to pull its multiple myeloma drug Blenrep from the U.S. market at the request of the FDA following its failure in a confirmatory study. BioSpace reported that Blenrep failed to “induce significantly superior progression-free survival” in patients with relapsed or refractory multiple myeloma, compared to pomalidomide and low-dose dexamethasone.

GSK also restricted the use of its PARP inhibitor Zejula to a specific population as a second-line maintenance treatment for ovarian cancer following updated Phase III data. GSK gained both Zejula and Jemperli in its acquisition of Tesaro. 

https://www.biospace.com/article/gsk-eyes-additional-endometrial-cancer-approval-for-jemperli/

CTAD: TauRx Touts Safety Profile as Anavex Stumbles over Data Discrepency

 As the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference continues, TauRx Pharmaceuticals and Anavex Life Sciences presented positive data from their alternatives to the anti-amyloid approach. 

TauRx's Oral Candidate Shows Strong Safety Profile

Based in Scotland and Singapore, TauRx is developing hydromethylthionine mesylate (HMTM), which targets Tau pathology in Alzheimer’s. While patients on Biogen's Aduhelm face bi-weekly injections, HMTM is an oral candidate with a strong safety profile.

Phase III data released in October showed HMTM significantly slowed cognitive and brain atrophy compared to historical controls, TauRx reported. The company faced challenges with the placebo group, so data from publicly available placebo arms from other AD trials were used to prove efficacy.

During its CTAD presentation, TauRx shared topline data from the trial that showed sustained improvement in cognition over 18 months over pre-treatment levels in participants with mild cognitive impairment.

According to the press release, “sustained cognitive improvement over baseline has not been seen with any other late-stage treatment for Alzheimer's currently being studied.”

A data scrape by the Alzheimer’s Association in January showed 143 agents currently in clinical trials for AD.

A unique aspect of HMTM is its safety profile. The drug showed no risk of amyloid-related imaging abnormalities (ARIA), a side effect seen in nearly 40% of AD patients taking Aduhelm in Biogen’s Phase III studies.

Armed with efficacy data, a robust safety profile and convenient oral dosing, TauRx is prepping for regulatory submissions in the U.K., U.S. and Canada.

Anavex's Positive Data Marred by Mathematical Slip

Anavex is attempting to treat the mild cognitive impairment associated with Alzheimer's disease via a small molecule activator of the sigma-1 receptor (SIGMAR1).

Research suggests SIGMAR1 is pivotal to promoting neuroplasticity and restoring homeostasis in neural cells.

Anavex announced that patients treated with its SIGMAR1 activator, ANAVEX2-73 (blarcamesine), were 84% more likely to have improved cognition scores of –0.50 points or better compared to patients on placebo. On average, the patients who saw gains showed improvement of    –4.03 points, a difference considered significant.

However, Anavex is facing some suspicion over trial results. In its press release, the biopharma reported the drug led to a 45% slower rate of decline compared to placebo patients. But Investor’s Business Daily reported that a math error in the CTAD presentation indicated the drug may have slowed cognition by 33% instead.

According to Edward Hammond, CMO of Anavex, the company plans to “discuss these findings with regulatory authorities in the context of the ongoing clinical development of ANAVEX 2-73 in this indication."

BioSpace has reached out to Anavex for further comment.  

https://www.biospace.com/article/ctad-taurx-touts-safety-and-efficacy-as-anavex-stumbles-over-potential-data-error/