Virus World

Long-term follow-up study data for Novartis’ one-time gene therapy for spinal muscular atrophy has shown promising milestone achievements. Data from LT-001, Novartis’ ongoing 15-year long-term follow-up (LTFU) study of one-time gene therapy Zolgensma® (onasemnogene abeparvovec), revealed significant milestone achievements for spinal muscular atrophy (SMA) patients. The latest data from two LTFU studies LT-001 and LT-002 was presented at the 2023 MDA Clinical & Scientific Conference.

Highlights included: 

• Sustained durability up to 7.5 years post-dosing; 100 percent achievement of all assessed milestones in children treated prior to SMA symptom onset
• Children in LT-001 treated after SMA symptom onset maintained or achieved additional milestones up to 7.5 years post one-time intravenous (IV) infusion
• All children (100 percent) in the presymptomatic intravenous cohort of LT-002 maintained or achieved all assessed motor milestones, including independent walking
• Additionally, children with SMA Type 2 treated with investigational intrathecal OAV101 maintained or achieved new development gains.

“…the fact that we’re seeing [some patients from the long-term follow up studies] maintain and, in some cases, gain motor milestones when they are nearly eight years old is truly transformational,” shared Dr Jerry R Mendell of Nationwide Children’s Hospital.

Additional data

Interim results from the 15-year LT-002 study was also presented. All patients (100 percent) were shown to maintain motor milestones achieved during their respective parent studies in the follow-up period. Results from the IV-administered cohort, which included 63 patients, demonstrated a single administration of Zolgensma provided consistent, substantial and durable efficacy over time. Notably, in the presymptomatic IV cohort, all children (100 percent) either maintained the highest milestone achieved during the parent study (walking alone) or achieved the milestone by the data-cut off. In total, six patients treated prior to SMA symptom onset and 16 treated after SMA symptom onset achieved new motor milestones in the follow-up period. There were no deaths, no serious treatment-emergent adverse events (TEAEs) related the gene therapy and no serious TEAEs that resulted in study discontinuation. The most frequently reported events were acute respiratory failure, dehydration, and pneumonia (each in five patients, 38.5 percent). No new safety signals were identified. Additionally, findings from the ongoing RESTORE registry were presented at the MDA conference. Patients with four or more copies of the survival motor neuron 2 (SMN2) gene treated with Zolgensma alone attained improvements in survival, motor function and achieved new milestones. The registry provides real-world evidence data to enhance the understanding of SMA patients cared for in routine practice. These results continue to highlight the importance of early identification and intervention to optimise outcomes for all SMA patients. “Data from the LT-001 and LT-002 studies showed that, regardless of the patient’s symptomatic status at the time of treatment, Zolgensma IV is an effective and durable treatment option,” commented Dr Sitra Tauscher-Wisniewski, Vice President Clinical Development & Analytics, Novartis Gene Therapies.

NICE’s recommendation of gene therapy Zolgensma

On 16 March 2023, the National Institute for Health and Care Excellence (NICE) recommended Zolgensma as an option in babies with presymptomatic 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and up to three copies of the SMN2 gene. This recommendation will allow routine access to onasemnogene abeparvovec, designed to help halt disease progression before symptom onset. Imran Kausar, General Manager at Novartis Gene Therapies UK commented on NICE’s decision: “Zolgensma will be the first treatment to be routinely commissioned for presymptomatic babies in England, and as it is imperative to diagnose SMA and begin treatment as early as possible, we welcome the decision by NICE for this recommendation.” There is no national newborn screening programme for SMA in the UK. Infants without a family history are only diagnosed if symptoms are identified. As this can take up to six months, an established programme is important. Following decision by the NICE committee that onasemnogene abeparvovec is effective in treating presymptomatic SMA, final guidance is expected to be published on 19 April 2023.

Novartis Press Release (March 20, 2023) available here:

https://www.novartis.com/news/media-releases/novartis-shares-zolgensma-long-term-data-demonstrating-sustained-durability-75-years-post-dosing-100-achievement-all-assessed-milestones-children-treated-prior-sma-symptom-onset 

Moderna Inc (MRNA.O) said on Thursday its COVID-19 shot was about 93% effective through six months after the second dose, showing hardly any change from the 94% efficacy reported in its original clinical trial. However, it said it still expects booster shots to be necessary ahead of the winter season as antibody levels are expected to wane. It and rival Pfizer Inc (PFE.N) and BioNTech SE (22UAy.DE) have been advocating a third shot to maintain a high level of protection against COVID-19.  During a second-quarter earnings call, Moderna CEO Stephane Bancel said that the company would not produce more than the 800 million to 1 billion doses of the vaccine that it has targeted this year. "We are now capacity constrained for 2021, and we are not taking any more orders for 2021 delivery," he said.  Moderna shares fell 3.6% to around $403.87 in pre-market trading after closing at $419.05 on Wednesday. The Moderna data compares favorably to that released by Pfizer and BioNTech last week in which they said their vaccine's efficacy waned around 6% every two months, declining to around 84% six months after the second shot. Both the Moderna and Pfizer-BioNTech vaccines are based on messenger RNA (mRNA) technology. The comment comes as public health officials across the world debate whether additional doses are safe, effective and necessary even as they grapple with the fast-spreading Delta variant of the coronavirus. Meanwhile, Pfizer is planning to seek authorization for a third shot later this month, and some countries like Israel have begun or plan to start administering a booster shot to older or vulnerable people.

BOOSTER CANDIDATES 

Separately, Moderna said its studies of three different booster candidates induced robust antibody responses against variants, including the Gamma, Beta and Delta variants. "Our COVID-19 vaccine is showing durable efficacy of 93% through six months, but recognize that the Delta variant is a significant new threat so we must remain vigilant," Bancel said.  It said neutralizing antibody levels following the boost approached those observed after the second shot. For this year, Moderna has signed vaccine contracts worth $20 billion in sales. It has agreements for $12 billion in 2022, with options for another roughly $8 billion in sales and expects to produce between 2 billion and 3 billion doses next year. The company, however, has not been able to keep pace with the much larger Pfizer, which expects to manufacture as many as 3 billion doses this year and 2021 sales to top $33.5 billion. Moderna's vaccine was authorized for emergency use in adults in the United States in December and has since been cleared for emergency or conditional use in adults in more than 50 countries.  The company expects to finish its submission for full approval with the U.S. Food and Drug Administration this month. It posted second-quarter sales of $4.4 billion, slightly above expectations of $4.2 billion drawn from 10 analysts polled by Refinitiv. Its COVID-19 shot is the firm's first authorized product and sales were just $67 million a year earlier. Moderna earned $2.78 billion, or $6.46 a share, beating quarterly expectations of $5.96 a share. 

Reporting by Michael Erman in New Jersey and Manas Mishra in Bengaluru; editing by Kirsten Donovan, Edwina Gibbs and Arun Koyyur

The new coronavirus resurged again and again in the body of an infected man, eventually killing him while showing evidence of fast-paced evolution. Manuela Cernadas and Jonathan Li at Brigham and Women’s Hospital in Boston, Massachusetts, and their colleagues followed the course of COVID-19 in a 45-year-old man with a long-standing autoimmune disorder, who was on a medication regimen that included powerful immunosuppressants (B. Choi et al. N. Engl. J. Med. https://doi.org/fhv8; 2020). Roughly 40 days after the man first tested positive for SARS-CoV-2, follow-up tests indicated that the virus was dwindling — but it surged back, despite antiviral treatment.   The man’s infection subsided and then returned twice more before he died, five months after his first COVID-19 diagnosis. Genomic analysis showed that the man had not been infected multiple times. Instead, the virus had lingered and quickly mutated in his body.

Original study published in NEJM (Nov. 11, 2020):

https://doi.org/10.1056/NEJMc2031364

A new study in the American Journal of Preventive Medicine presents new data that address important questions pertaining to the containment of the coronavirus pandemic: When should COVID-19 quarantine really end and which continuing symptoms may be more indicative of a positive test in recovered patients? The study was conducted by the Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy, where a multidisciplinary healthcare service was established for all patients who have recovered from COVID-19 to study what happens to them after recovery and to assess the impact of the virus on their bodies. Investigators report that close to 17 percent of patients considered fully recovered from COVID-19 tested positive for the virus in follow-up screening. Patients who continued to have respiratory symptoms, especially sore throat and rhinitis, were more likely to have a new positive test result. This suggests the persistence of these two symptoms should not be underestimated and should be adequately assessed in all patients considered recovered from COVID-19. 

"Clinicians and researchers have focused on the acute phase of COVID-19, but continued monitoring after discharge for long-lasting effects is needed," explained lead investigator Francesco Landi, MD, Ph.D., Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, and Catholic University of the Sacred Heart, Rome, Italy.

The study included 131 patients who met the World Health Organization (WHO) criteria for discontinuation of quarantine at least two weeks prior to the follow-up visit. The WHO criteria specify that the patient should be fever-free without fever-reducing medications for three days, show improvement in any symptoms related to COVID-19, be more than seven days past symptom onset, and test negative for the SARS-CoV-2 virus twice, at least 24 hours apart, with reverse transcription PCR (RT-PCR) testing. A new RT-PCR test was administered at the time of post-acute care admission. Demographic, medical, and clinical information was collected, with an emphasis on the persistence of symptoms and signs related to COVID-19 such as cough, fatigue, diarrhea, headache, smelling disorders, loss of appetite, sore throat, and rhinitis.  Twenty-two (16.7 percent) of the patients tested positive again. There was no significant difference between patients with positive and negative test results in terms of age or sex. None of the patients had fever and all reported improvement in their overall clinical condition. Time since onset of disease, number of days hospitalized, and treatments received while hospitalized were not significant. However, some symptoms such as fatigue (51 percent), labored breathing (44 percent) and coughing (17 percent) were still present in a significant percentage of the patients studied, although there were no significant differences between individuals with a positive or negative test. The only two symptoms that were higher and significantly prevalent in patients with a positive test were sore throat (18 percent vs. 4 percent) and signs of rhinitis (27 percent vs. 2 percent). 

Our findings indicate that a noteworthy rate of recovered patients with COVID-19 could still be asymptomatic carriers of the virus," Dr. Landi observed. "The main question for the containment of SARS-CoV-2 pandemic infection that still needs to be answered is whether persistent presence of virus fragments means the patients is still contagious. The RT-PCR test looks for small fragments of viral RNA. A positive swab test can reveal if patients are still shedding viral fragments, but it is not able to discern whether they are or aren't infectious." Importantly, the investigators recommend that for patients who continue to have symptoms potentially related to COVID-19, it is reasonable to be cautious and avoid close contact with others, wear a face mask, and possibly undergo an additional nasopharyngeal swab.

Original study in JAMA (Sept. 18, 2020):

https://doi.org/10.1016/j.amepre.2020.08.014

The research at Bristol's Southmead Hospital is part of a project looking into the longer-term effects of coronavirus. A total of 81 patients out of 110 discharged from Southmead Hospital in Bristol were still experiencing symptoms from the virus, including breathlessness, excessive fatigue and muscle aches, after 12 weeks. Many were struggling to carry out daily tasks such as washing, dressing or going back to work, the study found. The majority of patients reported improvements in the initial symptoms of fever, cough and loss of sense of smell, and most had no evidence of lung scarring or reductions in lung function. The findings are part of North Bristol NHS Trust's Discover project, which is studying the longer-term effects of coronavirus - so-called Long COVID. A total of 163 patients with coronavirus were recruited to the study, and of those 19 died. The remainder were invited for a three-month check-up and 110 attended. Most (74%) had persistent symptoms - notably breathlessness and excessive fatigue - with reduced quality of life.

Only patients who required oxygen therapy in hospital had abnormal radiology, clinical examination or spirometry - a test used to assess how well your lungs work - at the follow-up appointment. An intensive care doctor told Sky News in June that he was still suffering COVID-19 symptoms three months after contracting the disease. Dr Jake Suett, 31, had no underlying health conditions but was still suffering chest pain, breathlessness, blurred vision, memory loss, a high temperature, concentration problems. The doctor, who works for the NHS in Norfolk, said at the time: "I still get out of breath doing the washing up or walking around the house. "I spent three days just gasping for breath in bed, I really thought I was going to die, it was very distressing. "Things have improved since then, but not much and only very, very slowly. I've had gastrointestinal symptoms and shooting pains in my hands and feet too." MPs from the All Party Parliamentary Group on coronavirus heard earlier this month from previously fit people whose lives have been turned upside down by a host of symptoms.

Claire Hastie, a member of a Long COVID support group on Facebook, described how she used to cycle 13 miles to work but can no longer walk 13 metres and is now largely confined to a wheelchair with her children providing much of her care. The research at Southmead Hospital is due to continue, with researchers collaborating with the University of Bristol to look at the participant blood tests, rehabilitation therapies and psychological support. Dr Rebecca Smith, from North Bristol NHS Trust, said: "There's still so much we don't know about the long-term effects of coronavirus, but this study has given us vital new insight into what challenges patients may face in their recovery and will help us prepare for those needs." 

My first Covid-19 symptoms appeared March 14. More than 100 days later, Covid-19 is still with me. Some days I wonder if it will ever leave. In the early days, as my symptoms fluctuated, I was determined not to go to the emergency department or urgent care because it seemed like there were too many people who needed the help more than I did. Maybe I was especially sensitive to overcrowding in emergency departments because I’m a physician. But it turns out that this strategy was a common one. In New York City, where I live and work, there were more than 5,000 excess deaths not directly linked to Covid-19 between March 11 and May 2, likely because people were delaying care or not going to emergency departments or urgent care due to fear of contracting Covid-19 or oversaturating the medical system.

I did eventually go to the emergency department one day when the abdominal pain and nausea were severe. Routine testing showed that the level of liver enzymes in my blood was higher than it should have been, but not much more, and I was sent home. Once day 14 had passed, my fear of an impending respiratory collapse turned into an uncertainty about the trajectory of my disease and a desperation for answers. I contacted my doctors regularly, hoping their responses would bring relief in the form of some intervention. Yet most of their efforts did little to significantly change the course of my symptoms.....

The cardiovascular complications of acute coronavirus disease 2019 (COVID-19) are well described, but the post-acute cardiovascular manifestations of COVID-19 have not yet been comprehensively characterized. Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes. We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease.

These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease. Individuals with COVID-19 are at increased long-term risk for a wide range of cardiovascular disorders, even for individuals who were not hospitalized during the acute phase of the infection.

Published Nature Medicine (Feb. 7, 2022):

https://doi.org/10.1038/s41591-022-01689-3 

Researchers at the University of North Carolina and the Fred Hutchinson Cancer Research Center in Washington have developed a way to evaluate vaccines' long-term efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19).  The team conducted a series of simulation studies mimicking the trial of the Pfizer/BioNTech vaccine BNT162b2 to investigate the duration of protection under various blinded and unblinded crossover designs. Dan-Yu Lin and colleagues recommend the "rolling crossover" design, where participants that were previously placebo recipients are vaccinated in a timely manner. Under this design, the team's approach can be used to determine when a booster vaccination would be required. This information is also useful for modeling the impact of COVID-19 vaccines at the population level. The approach only requires minimal assumptions and can be applied to both blinded and unblinded crossover designs, irrespective of the length of further follow-up. A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer review.

Interim trial results only provide data on short-term efficacy

The large-scale administration of vaccines that provide long-term protection against SARS-CoV-2 infection would help bring the COVID-19 pandemic to a halt. Interim results from a number of phase 3 clinical trials have demonstrated vaccine efficacy that far exceeds the thresholds required by the World Health Organization and US Food and Drug Administration. Given that vaccine efficacy can wane over time as immune memory declines and viral antigens change, it is crucial to establish how long protection lasts and when booster doses may be required, says the team.

How might long-term vaccine efficacy be estimated?

Once a vaccine receives Emergency Use Authorization (EUA), placebo-controlled data is still collected in ongoing trials for as long as possible, but at some point, all placebo recipients should be offered the vaccine. Under one approach called "rolling crossover," placebo participants are vaccinated at around the same time that general population members of the same priority tier are vaccinated.  The researchers have now shown how to estimate long-term vaccine efficacy in trials that apply this staggered vaccination under both blinded and unblinded crossover strategies. The method fully adjusts for staggered enrollment, change of background incidence over time, and the prioritization of higher-risk individuals during the crossover process.

How effective is the approach?

The approach provides an unbiased estimation for the entire curve of placebo-controlled vaccine efficacy as a function of time passed since vaccination, up to the point where most placebo recipients have been vaccinated. In a series of simulation studies of the BNT162b2 vaccine trial, the researchers considered 40,000 participants who had been randomly assigned to vaccine or placebo over the course of 4 months. Following approval of the vaccine during the 5th month based on interim results, participants underwent staggered vaccination over the following 5 months. The outcome of interest was time to development of symptomatic COVID-19. The estimated curve of time-varying vaccine efficacy could be used to determine when a booster vaccination would be required to ensure sustained protection. This information is also important for mathematical modeling of the impact COVID-19 vaccines have at the population level.....

Cites research available in medRxiv (Jan.21, 2021):

https://doi.org/10.1101/2021.01.13.21249779

Long-term SARS-CoV-2 shedding was observed from the upper respiratory tract of a female immunocompromised patient with chronic lymphocytic leukemia and acquired hypogammaglobulinemia. Shedding of infectious SARS-CoV-2 was observed up to 70 days, and genomic and subgenomic RNA up to 105 days past initial diagnosis. The infection was not cleared after a first treatment with convalescent plasma, suggesting limited impact on SARS-CoV-2 in the upper respiratory tract within this patient. Several weeks after a second convalescent plasma transfusion, SARS-CoV-2 RNA was no longer detected. We observed marked within-host genomic evolution of SARS-CoV-2, with continuous turnover of dominant viral variants. However, replication kinetics in Vero E6 cells and primary human alveolar epithelial tissues were not affected. Our data indicate that certain immunocompromised patients may shed infectious virus for longer durations than previously recognized. Detection of subgenomic RNA is recommended in persistently SARS-CoV-2 positive individuals as a proxy for shedding of infectious virus.

Published in Cell (November 4, 2020):

https://doi.org/10.1016/j.cell.2020.10.049

(Reuters) - GlaxoSmithKline Plc said an injection of its cabotegravir drug given every two months, in combination with Johnson & Johnson’s rilpivirine, was recommended for approval to treat HIV infections by a panel of the European health regulator. The treatment is a long-acting regimen, which can reduce the number of doses required to 12 or six per year instead of a daily intake of pills. If approved, it would be the first complete long-acting HIV regimen requiring dosing just once in two months (in the EU region), GSK said. The combination as an injection is already approved in Canada and is currently under review in the United States. Shares of GSK were trading up 2.5% at 1410.4p, while J&J shares were marginally up during premarket trading. Gilead’s Truvada daily oral pill is currently the standard of care for preventing HIV, but GSK hopes to challenge its dominance by making shorter, long-lasting regimens and less toxic alternatives through its ViiV Healthcare unit.

The positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency comes months after GSK said cabotegravir was found to be 66% more effective in preventing HIV infections than Truvada. Some 75 million people worldwide have been infected with HIV and about 32 million people have died since it began in the 1980s. While final approvals are up to the European Commission, it generally follows the CHMP’s recommendation and endorses them within a couple of months.

GSK public announcement (Oct. 16, 2020):

https://www.gsk.com/en-gb/media/press-releases/viiv-healthcare-receives-positive-chmp-opinion-for-long-acting-regimen-for-the-treatment-of-hiv/

Morbidity can happen over a long-term period, so it is a harder variable to study and track in the early stages of a pandemic than death. Anecdotal reports and early data, though, show that Covid-19 morbidity may be a very real concern. According to a publication in JAMA, which followed several  Covid-19 patients over several weeks, many had long-lasting symptoms and impairments (including headaches and debilitating fatigue) that didn’t resolve when their active infection cleared.

All of these cases were considered “mild” and didn’t result in the use of a ventilator or a stay in the ICU. And they occurred in people from a variety of age groups, not only older adults and the infirm. Yet despite these “low risk” factors, patients were still experiencing major impacts from the disease months after contracting it. A handful of studies about Covid-19 (as well as scholarship on previous coronaviruses) bears this out. Covid-19 infection can have long-term impacts on the lungs, heart, immune system, and even the brain. These include an increased risk for heart attacks, future respiratory infections (including more severe cases of flu), and neurological impacts like cognitive impairment.

Original study published in JAMA (July 9, 2020):

https://doi.org/10.1001/jama.2020.12603