Scientists have uncovered a group of T cells that may drive severe asthma, which gather in the lungs and seem most harmful in men who develop asthma in later life. The new research, published in MED, suggests asthma patients with these cells in their lungs may be more likely to have hard-to-treat, and potentially fatal, asthma attacks. These cells do not respond to the usual general therapy for asthma patients.
The scientists, from the University of Southampton and La Jolla Institute for Immunology (LJI), in California, uncovered these T cells, called ‘cytotoxic CD4+ tissue-resident memory T cells’, thanks to volunteers enrolled in the NHS clinic-based WATCH study. It follows hundreds of asthma patients of different ages, sexes, and disease severities. By following patients over many years, and analysing their immune cell populations, researchers are making new connections between asthma symptoms and immune cell activity.
“If you are male and you develop asthma after age 40, there’s a high chance this T cell population is in your lungs,” says LJI Research Assistant Professor Gregory Seumois, who co-led the study with LJI Professor Pandurangan Vijayanand.
“Once you understand the role of cells like these T cells better, you can start to develop treatments that target those cells,” says WATCH study director Dr Ramesh Kurukulaaratchy, Associate Professor at the University of Southampton and researcher at the NIHR Southampton Biomedical Research Centre.
Scientists now hope to learn more about these cells and their role in asthma development in order to develop personalised therapies for asthma patients.
How harmful T cells drive asthma
The ‘memory’ T cells help protect the body from viruses and bacteria it has encountered before, but the same T cell memory is a big problem for asthma patients. Their misguided T cells see harmless molecules, such as pollen, and produce a dangerous inflammatory response.
Men who developed asthma later in life had an overwhelming number of these potentially harmful T cells. Their lungs should have been home to a diverse bunch of CD4+ T cell types but, in this group, more than 65% of their cells were cytotoxic CD4+ tissue-resident memory T cells.
Personalised asthma treatments
Single-cell RNA sequencing by LJI scientists provides a ‘biomarker’ to help detect cytotoxic CD4+ tissue-resident memory T cells in more patients going forward.
Finding this biomarker represents a “paradigm shift” in asthma research, says Dr Kurukulaaratchy. Before now, scientists and clinicians separated asthma patients into just two groups: ‘T2 high’ and T2 low’. In a study published earlier this year, the research team showed the importance of drilling down to identify many more asthma patient subgroups; their analysis reveals that 93% of WATCH subjects with severe asthma were in the T2 high category.
Study co-author Professor Hasan Arshad, Chair in Allergy and Clinical Immunology at the University of Southampton, researcher at the NIHR Southampton Biomedical Research Centre, and Director of The David Hide Asthma and Allergy Research Centre, Isle of Wight says: “We have to think of severe asthma as having different subtypes, and the treatment has to be tailored according to these subtypes because one size does not fit all.”
The researchers now want to use sequencing tools and other techniques to discover additional biomarkers and asthma patient subtypes.
In a pivotal case for access to affordable medicines in South Africa, the Treatment Action Campaign (TAC) and Doctors Without Borders (MSF) Southern Africa – represented by SECTION27 – earlier this year came together to help champion access to lifesaving new cystic fibrosis treatments.
Cheri Nel, a South African woman living with cystic fibrosis, and the Cystic Fibrosis Association started legal action against Vertex Pharmaceuticals earlier this year, challenging Vertex’s monopoly on the treatments. The TAC and MSF approached the court to be joined as amici curiae. Vertex, an American pharmaceutical company, holds the patents for both Trikafta and Kalydeco – medicines that have the potential to significantly improve the lives of cystic fibrosis patients. However, at a price of US $311 000 per year per patient in the United States (over R5 million), it is out of reach for most people living with cystic fibrosis.
The court application is for a compulsory licence, which, if granted, will mean another manufacturer of generics for Trikafta and Kalydeco would be permitted to enter the South African market. In this case, it is likely that competition between manufacturers would affect the price of this medicine, thus making it more accessible. A compulsory licence allows the holder of the license to produce a patented product without the patent holder’s consent.
Johannesburg-based investment banker Cheri Nel is the driving force behind a court case that may result in dramatically expanded access to life-changing new cystic fibrosis (CF) medicines. PHOTO: Supplied
Spotlight previously reported that Nel’s lawyers argued that by failing to register or supply their CF medicines in South Africa, make them available in South Africa at reasonable prices, or license other companies to supply the medicines, Vertex is abusing its patents. They further argued that Vertex’s actions are violating the Constitutional rights of people with cystic fibrosis in South Africa, including the right to health care. (Spotlight previously reported on the issue here, here, and here.)
Cystic fibrosis is a devastating multi-system illness known for causing frequent and severe lung infections, liver and pancreatic damage, lung failure, and can result in the potential need for lung transplants even in children from as young as two years old.
This case will set an important precedent that can influence access to medicines not only in South Africa but around the world. The involvement of SECTION27, where I work, underscores the broader issue of affordable access to medicines and the impact of intellectual property on healthcare access.
At present, MSF and TAC are awaiting the court’s decision to be admitted as friends of the court, while in the main application, the respondent (Vertex) has filed answering affidavits.
And while the clock is ticking in the courts, many families in South Africa are waiting and holding on to the glimmer of hope access to this medicine represents. For many who live with cystic fibrosis, a successful outcome of Nel and the Cystic Fibrosis Association’s application will mean a life where they can breathe easier.
Among those waiting is 6-year-old Janco Koorts.
A journey of hope
His mother, Tanya Koorts, says living with cystic fibrosis is like fighting every day for every breath. She says Janco had been diagnosed with cystic fibrosis at the age of two. She has since been on a mission to raise awareness about this life-threatening disease. It is hope, her family, and the support from the cystic fibrosis community that has kept her going, she says.
Reflecting on the start of their journey in the Northern Cape, she says, “The knowledge about cystic fibrosis is very little. We were lucky that Dr Jooste at the Kimberly public hospital diagnosed him so early on. After that, he sent us to the Red Cross Hospital in Cape Town and so our long journey of hope started.”
Later in a new job in a new city, the Koorts began again in Pretoria. They started Janco’s treatment at the Steve Biko Academic Hospital and then moved to the Charlotte Maxeke Johannesburg Academic Hospital.
“They don’t have much, but they do everything they can there to help. They also don’t have a lot of support but the people at Charlotte Maxeke helped Janco on his journey to stay breathing,” Koorts says, applauding the public health system.
Janco now has comprehensive medical aid which covers his monthly R48 000 medication bill and Koorts says she can now “breathe easier”. That, however, is just a fraction of the cost of living with cystic fibrosis.
When the Koorts family heard about Trixacar, a generic version of Trikafta, it only strengthened their resolve to save Janco’s life. The patent rights registered by Vertex Pharmaceuticals in South Africa, however, do not allow for the import of Trixacar. Trixacar is produced by the pharmaceutical company Gador in Argentina. Koorts will thus have to travel to Argentina to buy the medicine. This will cost about R400 000 to cover the travel costs and six boxes of Trixacar that will last six months, she says. (You can help the family fund this by donating here.)
‘a thief of joy’
Apart from the financial burden, having a young child with cystic fibrosis has affected the Koorts family mentally and emotionally.
“Cystic fibrosis is a thief of joy. Nobody speaks about fighting to save someone’s life,” says Koorts.
She says her family had to adjust to some of the social changes in their surroundings as well.
“At school, he has to fight for himself to stay alive. If we go to a restaurant and there are people smoking, it affects him and we have to move. So, as much as we have tried to give Janco a normal childhood, these social aspects will always hinder progress, and he is always reminded that he is sick. But I live in hope and so does he.”
In terms of her family relationships, Tanya says that her other children are healthy and for them to see their baby brother suffering every day hurts them.
“It’s painful as parents. Janco needs all the attention. I can’t go to a parent’s evening for my other kids. It’s difficult,” Koorts says.
She says she is proud of Janco.
“My child doesn’t know that he is dying. We fight every day so that Janco can have just one more breath.”
And that is ultimately what it is all about. From one perspective the exchange of documents in the High Court may seem abstract and full of legal technicalities. But let there be no doubt, for kids like Janco it is literally their futures that are being decided.
*Adams is a communications officer at SECTION27.
NOTE: This opinion piece was written by a staff member of SECTION27. Spotlight is published by SECTION27 and the TAC, but is editorially independent – an independence that the editors guard jealously. The views expressed in this piece are not necessarily those of Spotlight.
A new study from Aarhus University has shown that young people with mild asthma can experience inflammation and irritation from candles as well as cooking fumes. The results, published in Particle and Fibre Toxicology, suggest that asthma sufferers should try and reduce exposure, for example by opening kitchen windows while cooking.
For this randomised controlled double-blind exposure study, exposed 36 young asthmatics to three different exposures in the climate chambers at Aarhus University. They were exposed to emissions from cooking, emissions from burning candles and finally clean air. Each time, the participants were exposed for five hours under highly controlled conditions. Particles and gases were measured during exposures, and participants reported symptoms related to irritation and general well-being. Biomarkers in relation to airway and systemic inflammatory changes were assessed before exposure, immediately after exposure and again the next morning.
Karin Rosenkilde Laursen, a postdoc at the university’s Department of Public Health and co-author of the study, says:
“Our study shows that indoor air pollution caused by fumes from cooking and burning candles can lead to adverse health effects such as irritation and inflammation in young individuals with mild asthma. Among other things, we’ve found indications of DNA damage and signs of inflammation in the blood.”
When ovens are turned, pans put on the hob, or candles are lit, particulate matter and gases are produced, which can be inhaled. Previous studies have shown that these particles and gases can be detrimental to health. What sets this study apart is that the researchers have focused on the effects on young individuals with mild asthma, aged between 18 and 25, says Karin Rosenkilde Laursen:
“In the study, we observed that even very young individuals with mild asthma can experience discomfort and adverse effects if the room is not adequately ventilated during cooking or when burning candles. Young people are generally fitter and more resilient than older and middle-aged individuals. Therefore, it is concerning that we observed a significant impact from the particles on this particularly young age group.”
But not only people diagnosed with asthma need to keep an eye on the indoor climate, she says.
“Even though the study focused on young asthmatics, its findings are interesting and relevant for all of us. Winter is approaching, a time when we tend to light many candles and perhaps are less likely to open doors and windows while cooking. By prioritising a healthier indoor climate, even when we’re cosying up indoors, we may be able to help reduce the incidence of serious lung and cardiovascular diseases, as well as cancer.”
Karin Rosenkilde Laursen plans to follow up this study with another examining how emissions from cooking and candles affect healthy adults.
A new study suggests boys who smoke in their early teens risk damaging the genes of their future children, increasing their chances of developing asthma, obesity and low lung function.
This research, published in Clinical Epigenetics, is the first human study to reveal the biological mechanism behind the impact of fathers’ early teenage smoking on their children.
Researchers from the University of Southampton and the University of Bergen in Norway investigated the epigenetic profiles of 875 people, aged 7 to 50, and the smoking behaviours of their fathers.
They found epigenetic changes at 19 sites mapped to 14 genes in the children of fathers who smoked before the age of 15. These changes in the way DNA is packaged in cells (methylation) regulate gene expression (switching them on and off) and are associated with asthma, obesity and wheezing.
“Our studies in the large international RHINESSA, RHINE and ECRHS studies have shown that the health of future generations depends on the actions and decisions made by young people today – long before they are parents – in particular for boys in early puberty and mothers/grandmothers both pre-pregnancy and during pregnancy,” says Professor Cecilie Svanes from the University of Bergen and Research Director of the RHINESSA study. “It is really exciting that we have now been able to identify a mechanism that explains our observations in the cohorts.”
‘Unique markers’
“Changes in epigenetic markers were much more pronounced in children whose fathers started smoking during puberty than those whose fathers had started smoking at any time before conception,” says co-lead author of the paper Dr Negusse Kitaba, Research Fellow at the University of Southampton. “Early puberty may represent a critical window of physiological changes in boys. This is when the stem cells are being established which will make sperm for the rest of their lives.”
The team also compared the paternal preconception smoking profiles with people who smoked themselves and those whose mothers smoked before conception.
“Interestingly, we found that 16 of the 19 markers associated with fathers’ teenage smoking had not previously been linked to maternal or personal smoking,” says Dr Gerd Toril Mørkve Knudsen from the University of Bergen and co-lead author of the study. “This suggests these new methylation biomarkers may be unique to children whose fathers have been exposed to smoking in early puberty.”
Teenage vaping ‘deeply worrying’
The number of young people smoking has fallen in the UK in recent years. But co-author Professor John Holloway, from the University of Southampton and the NIHR Southampton Biomedical Research Centre, is concerned about children taking up vaping.
“Some animal studies suggest that nicotine may be the substance in cigarette smoke that is driving epigenetic changes in offspring,” says Professor Holloway. “So it’s deeply worrying that teenagers today, especially teenage boys, are now being exposed to very high levels of nicotine through vaping.
“The evidence from this study comes from people whose fathers smoked as teenagers in the 60s and 70s, when smoking tobacco was much more common. We can’t definitely be sure vaping will have similar effects across generations, but we shouldn’t wait a couple of generations to prove what impact teenage vaping might have. We need to act now.”
The new findings have significant implications for public health. They suggest a failure to address harmful exposures in young teenagers today could damage the respiratory health of future generations, further entrenching health inequalities for decades to come.
Triple combination therapy can achieve positive, lasting effects in patients with cystic fibrosis (CF), according to the results of a study published in the European Respiratory Journal. Researchers from Charité – Universitätsmedizin Berlin and the Max Delbrück Center found that, in many patients, the therapy reduced mucus stickiness and lung inflammation, improving lung function and quality of life.
Two years ago, a research group headed by Charité and lead researcher Prof Marcus Mall showed that combination therapy involving three drugs – elexacaftor, tezacaftor, and ivacaftor – is effective in a large portion of patients with cystic fibrosis, a hereditary disease, meaning that the treatment noticeably improves both lung function and quality of life. Now, the team has investigated whether this form of treatment is also helpful in the long term, meaning over a period of 12 months or more. To examine this, the researchers focused on the sputum.
“In patients with cystic fibrosis, the mucus in the airways is very sticky because it doesn’t contain enough water and the mucins, the molecules that form mucus, adhere too much due to their chemical properties. This results in thick, sticky mucus, which clogs the airways, making it harder for patients to breathe and leading to chronic bacterial infection and inflammation of the lungs,” explains Mall, Director of the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and the Christiane Herzog Cystic Fibrosis Center at Charité.
In the current study, the researchers showed that a combination of elexacaftor, tezacaftor, and ivacaftor results in less viscous respiratory secretions and decreasing inflammation and bacterial infection in the lungs of cystic fibrosis patients. “What’s more, the effects lasted over the entire one-year study period. This is really important because previous medications caused a rebound in the bacterial load in the airways,” explains Dr Simon Gräber, who also works in the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine at Charité and was one of the co-leaders of the study. 79 adolescents and adults with cystic fibrosis and chronic lung disease participated in the trial.
A major step in treating cystic fibrosis, further research important
“This is a major step forward in treating cystic fibrosis,” Mall says. “At the same time, it would be premature to say that patients have been normalised, let alone cured. Chronic lung changes arising over many years of living with the disease cannot be reversed, unfortunately.” This means patients with advanced lung disease will still need to rely on established treatments involving inhaling mucus-thinning medications, taking antibiotics, and physical therapy.
“We plan to forge ahead with our research on how to make treatments that address cystic fibrosis via the molecular defects that cause the disease — like the triple medication combination studied here — even more effective. This includes starting treatment in early childhood with the goal of preventing chronic lung changes wherever possible,” Mall notes. “Aside from that, this therapy is not available to about ten percent of our patients right now due to their genetic conditions,” Gräber adds. “That’s why we are also hard at work on research involving new molecular treatments so we can treat all people with cystic fibrosis effectively.”
The researchers are also working to advance their understanding of mucus defects in cystic fibrosis and develop new mucolytics, drugs that thin and loosen the mucus. This research could also benefit patients with common chronic inflammatory lung diseases such as asthma and COPD.
Cystic fibrosis
Cystic fibrosis is one of the most common fatal hereditary diseases worldwide. As many as 8000 children, teens, and adults are living with the disease in Germany today. An imbalance in salt and water transport across mucosal surfaces of the body causes people with cystic fibrosis to produce thick, sticky secretions that harm organs such as the lungs, intestine and pancreas. This leads to progressive loss of lung function and shortness of breath, which still significantly lowers life expectancy despite advances in treatment. Some 150 to 200 children are born with this rare disease in Germany each year.
About the triple combination therapy
A combination of three drugs – elexacaftor, tezacaftor, and ivacaftor – became available in Europe in August 2020. The therapy noticeably improves lung function and quality of life in patients with the most common genetic defect involved in CF, F508del. This means the treatment is an option for nearly 90% of those living with cystic fibrosis. The combination therapy was approved for children starting at the age of six years in early 2022.
People in South Africa who fall ill with tuberculosis (TB) often also have other health issues. HIV, which drives much of the TB epidemic in South Africa, is the most obvious co-infection, but people who fall ill with TB are also more likely to have diabetes and mental health problems than the general public.
Another issue that is often mentioned at conferences and in journal articles, but that doesn’t often make the headlines, is the complex set of links between TB and liver problems. With the World Health Organization estimating that in the region of 300 000 people fall ill with TB in South Africa every year, the scale of the issue is likely to be substantial, although we do not have particularly good data on liver problems in South Africa, and even less so on people experiencing TB and liver problems together.
Complex interactions
Broadly speaking, the link between TB and the liver can be divided into two categories. First, there are the liver-related side effects of some TB treatments, and second, there is the interaction between TB and liver conditions such as viral hepatitis. In some cases, TB itself can also cause liver problems directly.
Start with hepatitis. Dr Louisa Dunn, Think TB Provincial TB Technical Lead in KwaZulu-Natal, explains that hepatitis is a general term meaning inflammation of the liver. She says that there are many causes of hepatitis, such as infections, alcohol, or an overdose of certain medications. There is also autoimmune hepatitis, where a person’s own immune system is attacking the liver. “Even lifestyle can cause inflammation in the liver from a build-up of fatty tissue, which is more common in people who are overweight and obese,” she says.
Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are thought to cause significant illness and death in South Africa. According to a study published in 2022, over 1.9 million people in South Africa are living with chronic HBV infection – earlier research put the number at 3.5 million. HBV can be treated and there is an effective childhood vaccine for it that has been used in South Africa since 1995.
Estimates for HCV are less certain than for HBV – an estimate of 400 000 chronic infections was quoted in an HBV and HCV investment case for South Africa. Highly effective cures for HCV infection have been developed over the last decade, although access to these cures remains limited. The Department of Health published viral hepatitis treatment guidelines in December 2019.
Given these numbers, some people in South Africa would simply, by chance, get both TB and hepatitis. But since there are common risk factors, co-infection will be higher than what one would expect purely through chance. HIV infection, for example, increases both a person’s risk of TB and HCV.
“There is no data from South Africa about viral hepatitis and TB co-infection that I am aware of,” says Dr Andrew Scheibe, a Technical Advisor for TB HIV Care and an infectious disease specialist at the University of Pretoria. He points out that people who use drugs and other groups of people who are marginalised, including people experiencing homelessness or people in prison, are at increased risk for these co-infections. The risk of HCV transmission is particularly high when people who inject drugs share needles.
In addition, as Dunn points out, TB itself can also cause hepatitis.
Hepatotoxicity
The picture is further complicated by the fact that several of the medicines used to cure TB have liver-related side effects. Drug-sensitive TB is treated with a combination of four different medicines, while drug-resistant TB is treated with anything from three to eight different medicines.
“Medications used to treat both drug-sensitive and drug-resistant TB can cause hepatitis through drug-induced liver toxicity (hepatotoxicity),” says Dunn. “The presence of other risk factors may further increase the risk of hepatitis in TB patients. These risk factors could be alcohol use, older age, malnutrition, co-infection with HIV or viral Hepatitis B, and taking other potentially hepatotoxic drugs with TB treatment.”
Wieda Human, project coordinator and communications officer at TB advocacy group TB Proof says 3 to 28% of people with TB may experience hepatotoxicity and other side effects. “Those who are already infected with the hepatitis B infection are at an increased risk for hepatotoxicity,” she says.
She refers to a study done in Ethiopia that found having hepatitis B and hepatitis C infection made having TB disease more severe. “This study also found that people with TB who have hazardous alcohol use have a 1.5 times increased risk of developing hepatitis C,” says Human.
What it means for treatment
Dunn says although it is less straightforward to treat a person with TB and hepatitis than a person with just TB, it is important to understand treatment is still available. “It involves establishing the cause for hepatitis and treating this where possible, for instance, treating a viral hepatitis [and TB] co-infection at the same time or [providing] support to reduce alcohol intake. It may involve closer monitoring and follow-up, changes to medications, including stopping treatments either permanently or temporarily, and using alternative more ‘liver-friendly’ treatment regimens,” she says.
“If the hepatitis is stable, then TB can be treated,” Scheibe says. He explains hepatitis B requires long-term treatment (there is no cure), while hepatitis C can be cured with direct-acting antivirals (recently registered in SA, but not yet on the Government Essential Medicines List, so not easily available in the public sector). He says HCV treatment may be delayed until the TB is cured.
No routine screening
South Africa’s National Strategic Plan for HIV, TB, and STIs 2023-2028 under Goal 2 sets out to reduce viral hepatitis morbidity through scale-up of prevention, diagnostic testing, and treatment. However, according to Dunn, screening for viral hepatitis infections, such as HBV, is not part of the current drug-sensitive or drug-resistant TB guidelines.
But she says everyone should be assessed for symptoms and risk factors for liver disease at the start of TB treatment – a sentiment Scheibe shares. According to them, these screenings are however performed at diagnosis of HIV infection before a person is commenced on antiretroviral treatment for HIV, as chronic hepatitis B infection has specific implications for HIV treatment.
“During [TB] treatment, it is critical that clinicians assess people for signs and symptoms that may suggest hepatitis at each visit and educate them on recognising these side effects as well,” says Dunn. “This includes loss of appetite, feeling tired and unwell, nausea, vomiting, abdominal pains, yellowing of the eyes and skin, and darkening of urine.”
Treatment guidelines for drug-induced liver injury are available here. The guidelines focus on the management of suspected drug-induced rash, kidney injury, and liver injury for patients on TB treatment and or antiretroviral treatment.
Scheibe adds that people at high risk for HCV should receive TB screening regularly due to potential exposure to TB (eg if living in closed settings with many people in contexts of high TB prevalence and /or with HIV co-infection).
Storing donor lungs for transplant at 10°C markedly increases the length of time the organ can live outside the body, according to results of a trial were published in the New England Journal of Medicine Evidence. These findings will help reduce the strain on hospitals, reduce waitlists and possibly eliminate the need to bump other surgeries for a lung transplant.
The multicentre, non-randomised clinical trial study of 70 patients demonstrated that donor lungs remained healthy and viable for transplant up to four times longer compared to storage at the current standard of ice cooler preservation of around 4°C. The study was led by a team of scientists at the Toronto Lung Transplant Program in UHN’s Ajmera Transplant Centre.
“The clinical impact of this study is huge,” says lead author Dr Marcelo Cypel, Surgical Director of the Ajmera Transplant Centre and a surgeon within UHN’s Sprott Department of Surgery.
“It’s a paradigm shift for the practice of lung transplant. I have no doubt that this will become the gold standard practice of lung preservation for the foreseeable future.”
Lungs available for transplant are currently limited by the length of time a donor organ can be kept viable. Increasing storage time allows for viable donor lungs to come from greater distances, increasing the potential for greater numbers of lungs becoming available for transplant and overcoming many of the hurdles around transplant logistics.
“In transplant, we still see a critical shortage of organs and people dying on the waitlist because there are not enough lungs to be transplanted,” says Dr Cypel, who is also a professor in the Division of Thoracic Surgery, Department of Surgery at the University of Toronto.
“It’s a great accomplishment to see that our research is now having an impact, and that we can actually have more cases done at our centre, with continued outstanding clinical results.
“Better organ preservation also means better outcomes for patients.”
Transplant surgeries could become planned procedures
The trial took place over 18 months at UHN’s Toronto General Hospital, the Medical University of Vienna, and Hospital Universitario Puerta de Hierro-Majadahonda in Madrid.
“The ability to extend the lifespan of the donor organ poses several advantages,” says study first author Dr Aadil Ali, adjunct scientist at the Toronto General Hospital Research Institute.
“Ultimately, these advantages will allow for more lungs to be utilised across farther geographies and the ability to improve recipient outcomes by converting lung transplantation into a planned rather than urgent procedure.”
Some advantages of this new 10°C standard for lung storage include the potential to reduce or eliminate the 24/7 schedule and urgency of lung transplant procedures. By increasing the length of time donor lungs are viable, transplant surgeries could become planned procedures, which avoids bumping scheduled surgeries and overnight transplantation.
The study also suggests the new preservation temperature will allow more time to optimise immunologic matching between donor and recipients, and the possibility of performing lung transplantation in a semi-elective rather than urgent fashion.
A surprising fact is that bitter taste receptors are found not just in the mouth, but elsewhere including the airways. Activating those receptors dilates up lung passageways, making them a potential target for treating asthma or chronic obstructive pulmonary disease (COPD). Now, researchers report in the Journal of Medicinal Chemistry that they have designed a potent and selective compound that could lead the way to such therapies.
Among the 25 different types of bitter taste receptors, the TAS2R14 subtype is one of the most widely distributed in tissues outside the mouth. Scientists are uncertain about the structure of the receptor, and they haven’t identified the particular compound or “ligand” in the body that activates it. However, a few synthetic compounds, such as the nonsteroidal anti-inflammatory drug (NSAID) flufenamic acid, are known to bind to and activate TAS2R14s. But these compounds aren’t very potent, and they don’t have similar structural features. These difficulties make it challenging to create a better ligand. Nevertheless, Masha Niv, Peter Gmeiner and colleagues used flufenamic acid as a starting point to design and synthesise analogues with improved properties. Next, the team wanted to extend that work to develop a set of even better TAS2R14 ligands.
Building on these earlier findings, the researchers made several new variations. They tested these compounds in a cell-based assay that measures receptor activation. This approach revealed that replacing a phenyl ring with a 2-aminopyrimidine and substituting a tetrazole for a carboxylic acid group was a promising strategy. One of the new ligands was six times more potent than flufenamic acid, meaning less of the compound was needed to produce a similar response as the NSAID. This ligand was also highly selective for TAS2R14 compared to non-bitter taste receptors, which could potentially minimise side effects. The researchers speculate that new compounds will help shed light on the structure, mechanism and physiological function of bitter taste receptors and guide development of drug candidates to target them.
Chronic obstructive pulmonary disease (COPD) affects one in 10 adults, reducing quality of life and making physical activity challenging as they struggle to get enough air. Research around a new breathing device developed by pulmonologists at the University of Cincinnati offers promise for improving their lives. The research was published in the journal Respiratory Care.
The device, called PEP Buddy, was created by Muhammad Ahsan Zafar, MD, and Ralph Panos, MD. “Dr Panos and I both see patients with COPD, and it’s a huge population,” says Zafar. “Their life really changes when they have COPD. They were active individuals but now they’re debilitated and limited, so we wanted to come up with something easy that helps improve their life.”
For people with COPD, it takes longer to get inhaled air out of their lungs with each breath due to tighter air tubes. Therefore, when they breathe fast, like during physical activities, air is retained in the lungs. This air stacking or “dynamic hyperinflation” is the main reason for breathlessness and also leads to lower oxygen levels. As the breathing gets difficult during physical activity, people become less and less active and more isolated.
Panos and Zafar developed a hands-free device that is the size of a whistle. Zafar said he looked at positive-expiratory pressure (PEP) breathing devices on the market and they were handheld, big and bulky, so they tried to come up with something that is very simple, lightweight and easy to use. The device is designed to be worn around the neck with a lanyard for day-to-day use and inserted into the mouth when needed, during or after exertion.
In the study, they examined people with COPD who were short of breath and gave them two tasks. “We conducted a six-minute walk test with and without the device,” says Zafar. “They were given the device to take home and use in their daily routines. In two weeks, there was a follow-up to see how PEP Buddy use impacted their shortness of breath and quality-of-life scores.”
The study found 72% of the participants had a significant impact in reducing their shortness of breath and improving their quality of life. Among those who would drop their oxygen levels during walking, 36% of them did not drop oxygen levels when using PEP Buddy. This is the first mechanical device to show such an impact on oxygen levels in people with COPD.
Maja Flannery, a PEP Buddy user with chronic lung disease and airflow obstruction, says the device has changed her day-to-day living.
“I am so happy that I was lucky enough to be part of the study and able to use this great little device to breathe better,” Flannery says. “I use it when I get up in the morning. It helps with the air requirement when changing position from laying down to standing and exercises my lungs to get them more prepared for the day. I find it helpful in getting the trapped air out as I am active, so I can play longer points during tennis, and also recover between points more quickly. My friends at tennis laugh that it is my ‘magic whistle.'”
UC’s Zafar says the next step in this research is to conduct a long-term study to see the impact on the use of rescue inhalers, emergency department visits and long-term symptoms and functional capacity in people with COPD. PEP Buddy may also be a promising addition to pulmonary rehabilitation programs for faster improvement and sustaining better outcomes. They are also exploring other uses of PEP Buddy in health care.
“As a physician I feel gratified that we are providing something new that can actually improve people’s lives,” says Zafar. “That’s where my passion is. These people are really debilitated with not many tools in their hand to improve their symptoms right now. PEP Buddy will be one such tool.”
Cystic fibrosis (CF), which is caused by a faulty gene inherited from one’s parents, is a debilitating disease requiring difficult and time-consuming treatment and resulting in premature death. CF causes mucus in the body to thicken, with often disastrous consequences in organs such as the lungs and pancreas, and triggers a range of symptoms in people living with the condition, including chronic coughing, wheezing, and malnutrition. Ongoing treatment of symptoms often requires children with CF to miss school and can make it difficult for adults with CF to hold steady employment.
Yet, a new class of medicines introduced over the past decade called CFTR modulator therapies offers new hope to people living with CF – dramatically reducing CF’s symptoms and allowing people with CF to live longer healthier, and more productive lives.
These new treatments, whose research and development benefited from significant public and philanthropic financing, have been hailed as a “miracle” for people with CF. As antiretrovirals did for HIV, the introduction of CFTR modulator therapies is transforming cystic fibrosis from a progressive, life-threatening illness into a chronic, manageable condition. CFTR modulator therapies are so effective because they address the underlying cause of cystic fibrosis symptoms – a malfunctioning protein made by the CFTR gene.
But, more than a decade after the introduction of the first CFTR modulator therapy to treat CF in the United States, no CFTR modulator therapies are yet registered in South Africa and only a fraction of patients who need this therapy have access to it, and that is only after jumping through some extraordinary hoops. As a result, the only way for the vast majority of people to manage CF in South Africa is to aggressively prevent and treat its symptoms using older therapies. This is no small task for patients and their families, as it can require time-consuming, daily physical therapy to loosen mucus in the lungs and weeks-long hospital stays to treat infections. In severe cases, treating cystic fibrosis can even require a lung transplant.
Without access to CFTR modulator therapies, people with CF in South Africa continue to die prematurely. The average age of death of people with CF in South Africa was 27.5 in 2020. People in the global North live almost twice as long. The life expectancy of people living with cystic fibrosis in the United States is now 50 and is expected to lengthen as a result of newly introduced treatments.
Why can’t people in South Africa access CFTR modulator therapies?
As a person living with cystic fibrosis, or the parent of a child with cystic fibrosis, it can be unbearable to know there is a medicine that could allow you to breathe easier, keep you or your child out of hospital, and even prevent the need for a lung-transplant or premature death, but that you can’t have it, largely due to decisions taken by one company.
As recently detailed in the New York Times, one company holds a monopoly on the manufacture and sale of CFTR modulator therapies and is choosing not to make new CF treatments available to people in the developing world through the normal channels. Vertex, the company that holds monopoly patents on all available CFTR modulator therapies, is – for the most part – not registering or marketing its CFTR modulator therapies in developing countries. Registration is typically required before a drug can be marketed in a country.
While Vertex does offer some compassionate use and donation access programmes in select developing countries, Vertex Save Us, a global coalitional of advocates seeking affordable and universal access to CFTR modulator therapies, says these efforts reach only a small minority of patients that could benefit from the treatments and are restricted to countries with which Vertex believes it can secure a reimbursement deal.
Some activists suggest that the neglect of patients in developing countries is part of a strategy to squeeze the highest possible prices for CFTR modulator therapies from health systems in wealthy countries, with which Vertex has been locked in extended negotiations. Offering lower prices to developing countries for its CF medicines could provide ammunition to wealthy countries in demanding lower prices.
“This is a really fundamental and really simple example of how unfettered profit-driven business practices basically sacrifice the lives of people, particularly those of people who happen to live in low- and middle-income countries,” says Diarmaid McDonald, medicine access advocate and Director of the UK-based advocacy group, Just Treatment.
Vertex charges over R5 million ($322 000) annually for its most effective CFTR therapy, Trikafta (which must be taken as a life-long treatment) in the United States. But researchers in the United Kingdom have shown that the medicine can be manufactured and profitably marketed at a fraction of that cost.
Does Vertex plan to register its products in South Africa?
In response to queries from Spotlight regarding whether Vertex plans to register its drugs in South Africa and what the timeline for doing this is, the company indicated that they did not plan to register their medicines but would supply them via Section 21 authorisations – a mechanism allowing for importation of unregistered medicines into the country.
“As seen in other rare disease areas, bringing medicines to patients in South Africa is challenging as the reimbursement system and willingness to invest do not support a viable path to sustainable access. Analyses show that most novel, high-value medicines targeting disease areas comparable to and including CF are not on the Prescribed Minimum Benefits (PBM) list. There is therefore no obligation for funders to reimburse the costs of these medicines even after a lengthy regulatory registration process,” said Vertex’s Director of International Communications Daria Munsel.
“Given this, we believe that sustainable access could be achieved through ‘Section 21’ (on a named patient basis), which provides the fastest and most efficient route to access for rare disease medicines in South Africa,” Munsel added. “As part of this effort, we are currently in discussions with relevant stakeholders in the private insurance system to ensure sustainable access is available to eligible CF patients in South Africa.”
However, Munsel declined to identify the local company with which Vertex has signed an agreement for distributing its medicines, saying, “We can confirm that we have recently signed a distribution contract with a local distribution partner for our CF medicine in South Africa. Given that reimbursement conversations are still ongoing, it is inappropriate for us to name other parties for the moment.”
For now, the lack of transparency about the local distributor effectively blocks the use of Section 21 authorisations for importing Vertex’s medicines into South Africa, as patients and clinicians must supply details of local distributors in their applications to the South African Health Products Regulatory Authority (SAHPRA) for authorisation to import unregistered drugs.
Vertex did not respond to a question from Spotlight regarding what price it would charge patients in South Africa able to secure Section 21 authorisations to import their medicines.
Landmark court case seeks to challenge Vertex’s monopoly in South Africa
Vertex has secured a global monopoly over CFTR modulator therapies by aggressively pursuing patents related to the class of drugs around the world. These patents prevent other companies from manufacturing and marketing CFTR modulator therapies and give Vertex wide latitude in setting prices.
Between 2007 and 2016, Vertex filed six patents in South Africa related to the CFTR modulator therapies, Kalydeco and Trikafta. While Vertex received marketing approval to sell Kalydeco and Trikafta to treat CF in the United States in 2012 and 2019, respectively – it has still not applied for registration of either product in South Africa.
What this means is that despite Vertex’s failure to take steps to register or market its medicines in South Africa years after doing so in the US, patents granted to Vertex in South Africa block any other companies from supplying the medicines to CF patients in the country.
“The bottom line is that people are dying, they need to be able to access affordable treatments,” says Kelly du Plessis, founder of Rare Diseases South Africa. “If Vertex isn’t going to be able to come to the party in South Africa, then fine. We respect their choice, but then move out the way and allow someone else to do it. You can’t maintain the market and hold it ransom, but also not do anything from your perspective to help.”
According to Fatima Hassan, director of the Health Justice Initiative, “You can’t have a system where you file your patents, [but then] you refuse to bring a product to market or you have it at such an excessive price in the country with the highest inequality in the world, but then you don’t allow any generic manufacturers to come in at a lower price.”
Cheri Nel, a woman living with cystic fibrosis in South Africa, and the Cystic Fibrosis Association have now gone to court to challenge Vertex’s monopoly. On 7 February 2023, Nel’s lawyers submitted a Notice of Motion to the Court of the Commissioner of Patents (within the High Court) requesting that the court grants a compulsory license to override Vertex’s patents on Kalydeco and Trikafta.
Nel and the Cystic Fibrosis Association are seeking a compulsory license on the grounds that the patents held by Vertex are being abused. Nel’s lawyers argue that by failing to register or supply their CF medicines in South Africa, make them available in South Africa at reasonable prices, or license other companies to supply the medicines, Vertex is abusing its patents. They further argue that Vertex’s actions are violating the Constitutional rights of people with cystic fibrosis in South Africa, including the right to health care.
If granted, a compulsory license in South Africa would effectively override Vertex’s monopoly and allow the importation of generic cystic fibrosis medicines into South Africa, as well as their manufacturing in the country.
The legal action taken in South Africa is being pursued simultaneously with broader global efforts, led by Vertex Save Us, to overcome Vertex’s monopoly on CFTR modulator therapies and ensure universal access for all people who can benefit from these treatments.
“South Africa is the only country where papers have been launched with courts to start a legal process to try and secure a compulsory license, although the process is playing out in other countries following the most logical, legal routes set out in their national law,” explains McDonald.
“Requests of the government to issue compulsory licenses [have been made] in both Ukraine and in Brazil. And in India, it’s a petition of the government requesting that they revoke the patent under the terms of the Indian patent law,” says McDonald.
Any precedent for granting compulsory license on a medicine in South Africa?
If Nel and the Cystic Fibrosis Association’s pursuit of a compulsory license on the cystic fibrosis medicines is ultimately successful, then the issuing of a compulsory license order will be the first time this type of license is granted in the country on a pharmaceutical product. While South Africa has not issued a compulsory license on a medicine, the Treatment Action Campaign (TAC) has previously used competition law to overcome patents impeding access to affordable antiretroviral medicines in South Africa.
TAC cases at the Competition Commission and the threat of ‘compulsory licensing’ resulting from these cases led several multinational companies to grant voluntary licenses that enabled manufacturing and marketing of generic ARVs in the country. Generic competition resulted in massive price decreases for ARVs and has been critical to South Africa’s success in building the world’s largest public sector HIV treatment programme.
While South Africa’s courts have not issued a compulsory license on a medicine, its own challenges in securing access to affordable HIV medicines contributed to the affirmation and strengthening of the rights of countries to issue compulsory licenses to address health challenges within international trade law in the early 2000s. Both developing and developed countries have subsequently used compulsory licensing to improve access to critical health tools under patent including for HIV, cancer, and more recently, COVID-19.
The Fix the Patent Laws coalition, a coalition of over forty patient groups in South Africa, has long called on government to amend South Africa’s patent laws to improve the usability of compulsory licensing provisions to address health challenges in the country. The landmark court case of Nel vs Vertex will provide important insight into the ongoing need for these reforms in the country.
Who can benefit from Kalydeco and Trikafta
While cystic fibrosis is caused by a defect of the CFTR gene, over a thousand different types of mutations can occur in the gene that causes CF. People with CF must inherit a mutated gene from each parent in order to develop CF illness. The type of gene mutations that each person with cystic fibrosis inherits from their parents determines their eligibility for different CFTR modulator therapies.
Vertex, which has a monopoly over the entire class of CFTR modulator therapies available for CF, currently markets six medicines made up of different combinations of active ingredients that seek to correct the faulty CFTR protein (produced by the CFTR gene).
Kalydeco, made with the active ingredient ivacaftor, was the first CFTR modulator therapy approved to treat CF, yet it is only effective in treating five percent of people living with CF. Trikafta, which was approved in the U.S. in 2019 and combines three active ingredients – elexacaftor, tezacaftor and ivacaftor – is effective in treating 90 percent of people living with cystic fibrosis.
How many people in South Africa could benefit from Trikafta?
The recently established South African Cystic Fibrosis Registry has compiled health and demographic data for 525 people diagnosed with cystic fibrosis in the country. According to 2020 registry data, 450 patients (85.7%) would benefit from currently available CFTR modulator treatments. Dr Marco Zampoli, paediatric pulmonologist at the University of Cape Town, estimates that around 35 patients are currently sourcing generic CFTR modulators in their personal capacity from overseas (see more below on how a small group of patients in the country are accessing treatment from Argentina).
While the registry counts 525 patients diagnosed with CF in South Africa, the true number of people born with CF in the country is likely far higher. Zampoli estimates (using population and genetic data) that between two and three thousand babies could have been born with cystic fibrosis in South Africa since 1999.
“We think a lot of them are probably dying from a very young age without being diagnosed with cystic fibrosis as it looks similar to other common things like malnutrition, TB, and HIV,” says Zampoli.
While improving CF detection and diagnosis can save lives and will also increase the number of known patients in the country that could benefit from currently available CFTR modulator therapies, many of the new patients identified from better detection efforts would be unable to benefit from existing treatments. This is because black Africans are less likely than people of Caucasian descent to have the mutations that are responsive to currently available treatment.
Zampoli, however, notes that research is underway that will likely deliver new treatments that benefit patients who are ineligible for currently available drugs and adds “we’re going to be facing the same issues [of unaffordability] down the line… when we do eventually license a drug that will target their specific genes.”
How do a few people in South Africa get access to CFTR modulators?
While the South African government is not currently in negotiations with Vertex, price negotiations with health systems in wealthy countries have often dragged on for years, as price remained a sticking point.
People living with severe cystic fibrosis, however, do not have years to wait as their disease advances, placing them at risk of severe complications and death. Some have joined together to start a CF Buyers Club. The Buyer’s Club supports CF patients from around the world in buying generic versions of CFTR modulators from Argentina.
Argentina has taken steps to set strict criteria for granting patents and limit the granting of patents on certain types of claims related to pharmaceutical products. As a result, Vertex has not been granted patents on its CFTR modulator treatments in Argentina, and two Argentinian pharmaceutical companies, Gador and Tuteur, are legally manufacturing generic versions of these medicines.
While the Argentinian companies producing these medicines are unwilling to export them to South Africa for fear of facing patent infringement challenges from Vertex, Argentinian pharmacies will supply medicines to CF patients from South Africa visiting Argentina.
“You need to have a doctor’s script and you need to have a Section 21 authorisation,” explains Belinda Nell, a South African advocate working to facilitate access to CF medicines in South Africa. “You’ve got to fly to Argentina in your personal capacity or have a family representative go there and collect [the medicines] and then fly back.”
South Africans holding Section 21 authorisations from SAHPRA can legally travel with up to six months’ medicine supply on them.
While the CF Buyers Club provides an important access pathway enabling some people in South Africa to access life-saving CFTR modulator therapies, this pathway is not a feasible mechanism to ensure access to the CF medicines for all patients that could benefit from them.
The cost of generic CF medicines from Argentina is a fraction of the prices charged by Vertex. They are, however, still prohibitively high for most people living in South Africa. The annual cost of generic Trikafta from Argentina is almost R1 million ($60 000) [other CFTR modulator therapies (tezacaftor/ivacaftor and lumacaftor/ivacaftor) can be bought from Argentina for around R245 000 ($15 000) annually]. The medicine costs, combined with the costs of biannual travel to Argentina, are simply unaffordable for most.
How can a CL further reduce prices?
As seen with other classes of drugs, such as antiretroviral medicines for HIV, and antiviral medicines for Hepatitis C, the introduction of generic competition is expected to substantially reduce the cost of CF medicines.
If compulsory licenses are granted in the countries that they are being sought by Vertex Save Us, or if Vertex buckles under the pressure for expanded and affordable access to CF medicines and grants voluntary licenses allowing other companies to produce generics, then prices are expected to fall.
An analysis of the costs of production of CF medicines produced by health economists shows that generic Trikafta can be manufactured and sold with a 10 percent profit margin for around R93 000 ($5700) per patient per year – 2% of what is charged for the medicine by Vertex in the United States. While supplying medicines at this price would remain a stretch for South Africa’s public health sector, the introduction of new CF medicines must be considered within the context of potential cost savings arising from reduced hospitalisation periods and fewer transplants.
“The ripple effects of an effective CL campaign and petition in South Africa would be felt globally,” says McDonald. “First of all, I think we would see increased interest from generic suppliers… that could help to… drive down prices… this would [also] show the rest of the world that… accepting the unquestioned, monopoly power of Vertex is not necessary – you can put the lives of your citizens over the profits of that drug company.”
Note:The Fix the Patent Laws coalition and the TAC are mentioned in this article. Tomlinson worked at the TAC until 2012 and was a member of the Fix the Patent Laws steering committee until 2019. SECTION27 has also applied to be admitted as amici curiae to the case. Spotlight is published by SECTION27 and the TAC, but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
