Cheri Nel launched a court case against Vertex to force them to allow their generic cystic fibrosis drug to be imported into South Africa. Credit: Spotlight
By Catherine Tomlinson
Last year a South African woman took a multibillion-dollar United States pharmaceutical company to court with the aim of securing access to life-changing cystic fibrosis medicines. That case has now been dropped following a reduction in the price charged for the medicines in South Africa.
Cheri Nel, a Johannesburg-based investment banker, has dropped a potentially landmark court case against Vertex Pharmaceuticals. Nel was asking the Gauteng Division of the High Court in Pretoria to grant a compulsory licence to allow generic versions of a cystic fibrosis medicine called Trikafta to be imported into South Africa. No such compulsory licences on medicines have ever been granted in South Africa.
Trikafta, which was registered in the United States in 2019, has been hailed as a “miracle” treatment for cystic fibrosis, which causes severe damage to the lungs, digestive system and other organs in the body. The medicine is effective in treating around 90 percent of people living with the condition. It significantly improves the quality of life of people living with cystic fibrosis, eliminating many of its debilitating symptoms, while also slowing the disease’s progression and extending survival.
In February 2023, when Nel launched her lawsuit against the Boston-headquartered pharmaceutical company, the only way people in South Africa could access Trikafta was by travelling to Argentina to buy it from an Argentinian company selling a generic version of the medicine.
This is because Vertex, the company that holds the patents on Trikafta in South Africa, refused to register the medicine with the South African Health Products Regulatory Authority (SAHPRA) or identify a local distributor that could import unregistered Trikafta via Section 21 authorisations – a mechanism allowing importation of unregistered medicines.
The United States list price for Trikafta is currently over $300 000 (around R5.5 million at the current rand/dollar exchange rate) per person per year, which South Africans feared they would also have to pay if or when Vertex finally started supplying its medicine in the country. Researchers in the United Kingdom have estimated that Trikafta can be produced for under $6000 (around R110 000 at the current rand/dollar exchange rate) per person per year.
When Nel filed the case, generic Trikafta from Argentina – called Trixacar – was much cheaper than Vertex’s product (but still prohibitively expensive for many) at around $60 000, or almost R1 million per person per year. But the Argentinian company selling generic Trixacar faced potential patent infringement challenges if it shipped Trixacar to South Africa. Thus, the only way to get the medicine into South Africa at the time was to travel to Argentina to collect it. People living with cystic fibrosis in South Africa learnt how to do this through an informal network or Buyers Club of people around the world that were reliant on the Argentinian product.
Launching a legal case
Nel argued that Vertex was abusing its patents in South Africa by refusing to make Trikafta available in the country on reasonable terms, while also blocking other manufacturers from supplying the medicine in the country. If successful, Nel’s case would have allowed generic Trikafta to be shipped directly to South Africa, removing the need for travel to Argentina to access the medicine.
According to Nel, Vertex argued in the company’s answering documents to her legal filing that, as she was the only named applicant in the case, a compulsory licence for importation could only be considered for her.
Nel then worked with the South African Cystic Fibrosis Association (SACFA) to get other people living with cystic fibrosis admitted as co-applicants in the case. This process of seeking more people to join her case, she said, was time-consuming, difficult, and expensive, but more than 100 people were working towards being admitted as co-applicants before the case was dropped.
Under pressure, Vertex starts providing Trikafta in South Africa
As the case gained momentum and made headlines around the world, Vertex finally opened the door to allow some people living in South Africa to access their product.
In May 2024, Vertex identified Equity Pharmaceuticals as the local company through which Trikafta could be imported into South Africa via Section 21 authorisations. These authorisations are granted by SAHPRA to enable importation of an unregistered medicine and are meant to be used in exceptional circumstances to remedy the need for an unregistered medicine, such as when there is a shortage of the registered product.
While Vertex has not confirmed to Spotlight or stated publicly the price of Trikafta for people living in South Africa, Nel and Doctors Without Borders’ Candice Sehoma told us that the company is charging around R400 000 ($22 000) for a year’s supply of the medicine.
While still unaffordable for many and much higher than the estimated cost of manufacturing, the R400 000 price is drastically lower than the R5.5 million price charged in the United States and originally feared for South Africa.
It seems improbable that Vertex would have offered the much reduced price to people living in South Africa had Nel not launched the court case
Some medical schemes now paying for Trikafta
As emerged in April this year, Vertex reached an agreement with some medical schemes in South Africa to provide the medicine for people on top-end plans.
“Four private healthcare providers are currently funding Trikafta for eligible patients and we are open for conversations with more insurance companies,” Vertex’s spokesperson Daria Munsel confirmed to Spotlight.
The exact nature of the conversations and/or agreements between Vertex and medical schemes in South Africa however remains somewhat unclear.
Discovery Health‘s CEO, Dr Ron Whelan, told Spotlight it has engaged Vertex about the “benefits available” and “affordable access” of the class of medications that Trikafta falls in but there is “no specific commercial agreement in place” in South Africa.
He noted that Discovery Health Medical Scheme members on the comprehensive and executive plans have a suite of benefits available for the treatment of cystic fibrosis with medicines like Trikafta “of up to R400 000 per annum” for eligible people.
According to Vertex, uptake of its product has been swift and is already starting to make a difference in the lives of people living with cystic fibrosis in South Africa. “Over 100 South Africans with CF [cystic fibrosis] have been prescribed our triple combination treatment in just the first two months of the medicine being available,” said Munsel.
The cystic fibrosis registry, an initiative which seeks to identify and collect data on the outcomes of people living with cystic fibrosis in South Africa, identified 525 people living with cystic fibrosis in the country as of December 2020. Experts believe there are many more undiagnosed cases.
Why did Nel drop the case?
Not only is Vertex’s price for people in South Africa now lower than the 2023 price of Argentinian generics, but the cost of a year’s supply of generic Trikafta from Argentina have increased from around $60 000 to around $100 000 due to hyperinflation in that country.
With Vertex now offering a price lower than the cost of Argentinian generics, Nel decided that her legal case was no longer the best avenue to enhance access to the medicine. The aim of the case “was to get access to the medication… to put pills in patients’ mouths”, she told Spotlight.
Nel said it is now probably better to redirect efforts to getting government at national or provincial levels to buy the medicine for patients in the public sector.
“There is a lot of work still to be done… my efforts are still there, it’s just being redirected,” she said.
“The fact that Trikafta will now be available in South Africa at a much lower price compared to generic versions globally, certainly undercuts the legal case for a compulsory license,” said Tendai Mafuma of SECTION27, a public interest law centre. The Treatment Action Campaign and Doctors Without Borders, represented by SECTION27, were admitted as friends of the court in the case.
Why won’t Vertex register its product in SA?
While much has changed because of Nel’s legal action, Vertex has held fast on its refusal to register Trikafta with SAHPRA.
When asked about Vertex’s plans to register Trikafta in South Africa, Munsel said: “We strongly believe that this [Section 21 Authorisation] is the fastest and most efficient route to sustainable access in South Africa, which does not require a regulatory filing.”
While registering medicines can be onerous and time consuming, it is a routine practice required for pharmaceutical companies to operate around the world. Full registration also typically requires that safety, effectiveness and quality is more closely scrutinised than is the case with Section 21 authorisations.
Nel believes that Vertex has chosen not to register Trikafta in South Africa because of the price transparency requirements embedded in South African law. If other countries know what price South Africa is paying then they may also demand a lower price, she said.
The law requires that there is a transparent pricing system for medicines sold in the private sector, but these requirements do not extend to unregistered medicines imported through Section 21 authorisations, explained Mafuma.
Note: SECTION27 was involved in the court case that is the subject of this article. Spotlight is published by SECTION27, but is editorially independent – and independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
In a new clinical trial, a drug commonly used to treat cystic fibrosis, dornase alfa, improved outcomes for patients with severe COVID pneumonia. The results, published in the journal eLife, also suggest that the drug could be used to treat other respiratory infections.
The study, found that the drug reduced hyper-inflammation in COVID pneumonia patients, which occurs when the body’s immune system reacts too strongly and can lead to tissue damage and death.
The next step will be to conduct larger clinical trials, with the ultimate goal of approving dornase alfa for wider use. As well as COVID, dornase alfa has the potential to treat other respiratory infections such as those caused by influenza or bacterial pneumonia, and even other lung diseases such as pulmonary fibrosis.
Since the beginning of the COVID pandemic, the proportion of SARS-CoV-2 infections that result in death has fallen, partly due to increased immunity from prior infection or vaccination, as well as improved treatments such as the steroid dexamethasone, which helps to tackle the hyper-inflammation that was a key factor in many COVID deaths. But this treatment isn’t suitable for some patients and is not always successful in severe cases.
In this study, researchers from UCL, UCLH and the Francis Crick Institute set out to assess whether dornase alfa could be used to improve outcomes for patients admitted to hospital with severe COVID pneumonia who required oxygen.
Out of a total of 39 participants, 30 were randomised to receive twice-daily treatment with nebulised dornase alfa in addition to best available care (BAC) which included dexamethasone, with nine patients randomised to BAC only.
Patients treated with dornase alfa had a 33% reduction in systemic inflammation on top of the reduction provided by dexamethasone, as measured by C-reactive protein (CRP) levels in the blood over seven days or until they were discharged from hospital.
Dr Venizelos Papayannopoulos, senior author of the study from the Francis Crick Institute, said: “Dexamethasone has been highly successful in treating patients with severe COVID-19 pneumonia and is now standard care in the UK. But it isn’t suitable for some patients, such as those with diabetes, those that do not require oxygen, and in very severe cases it may not be enough. Dornase alfa can be used to treat a wider variety of patients and gets right to the heart of the inflammatory response. Based on these results, we think it will be a valuable tool for tackling severe COVID-19 illness.”
Patients treated with dornase alfa were also more likely to need less oxygen and be discharged sooner compared to patients who received BAC. These additional benefits could help to free up beds and resources in the UK’s busy hospitals.
The next step will be to conduct larger clinical trials to ensure dornase alfa is safe and effective for treating severe COVID pneumonia. There is also potential for the drug to be trialled for other respiratory infections and conditions, such as acute exacerbations of pulmonary fibrosis, where inflammation of already scarred lung tissue affects how well oxygen can be absorbed.
A cystic fibrosis drug targeting the basic defect that causes the condition has been shown to be safe and effective in newborns aged four weeks and above, new research involving RCSI University of Medicine and Health Sciences and Children’s Health Ireland has found.
The finding is described as a “huge moment” for cystic fibrosis by one of the lead researchers. The study included the first baby in the world with cystic fibrosis to be diagnosed from birth and enrolled directly onto a trial of this sort.
The drug, ivacaftor (Kalydeko), is the first drug designed to treat the basic defect in cystic fibrosis. It was originally approved for adults, then sequentially over several years for older and younger children. Currently, it is approved for babies aged four months and older, however, this new research suggests that it is safe and effective for babies as young as four weeks of age.
Cystic fibrosis experts predict that the earlier treatments can begin, the more likely that progression of the condition can be slowed down or halted in children, and this is the focus of several international research studies led by RCSI and Children’s Health Ireland. The findings of this study could pave the way for eligible newborns to start treatment on the medicine at the time of diagnosis (typically at newborn screening) rather than having to wait until they are four months old.
“This is a huge moment in cystic fibrosis,” said Paul McNally, Associate Professor of Paediatrics at RCSI and Consultant in Respiratory Medicine at CHI. McNally is one of the authors of the new study which was published in the Journal of Cystic Fibrosis.
“Over the years ivacaftor, or Kalydeko, has been put through clinical trials in younger and younger children. Now, through this study, it has been shown to be safe and effective all the way down to four weeks of age,” he said.
“This is an important development because almost all children are diagnosed through newborn screening at around this time. The availability of a treatment that targets the underlying cause of the disease in newborns and can be started immediately at diagnosis will provide a huge sense of reassurance and hope for families.”
Cystic fibrosis is an inherited disease that mainly affects the lungs and digestive system. Ireland has the highest incidence of the condition in the world: approximately 1400 children and adults in Ireland live with the condition and more than 30 new cases of cystic fibrosis are diagnosed here each year, typically around four weeks of age through the newborn screening programme.
In recent years, new medicines have emerged that target the basic defect that causes cystic fibrosis. Ivacaftor (Kalydeko) is one such treatment. It targets a genetic change seen in around 4% of people with cystic fibrosis worldwide, and around 10% in Ireland.
Siblings Kara (aged 5) and Isaac Moss (aged 2) both participated in the study through Children’s Health Ireland. Kara was part of an earlier phase of the study that paved the approval of the drug in older infants and led to the latest trial that Isaac took part in.
Isaac was the first baby with cystic fibrosis in the world to be diagnosed from birth and enrolled directly onto a trial of these ground-breaking treatments.
“Both Kara and Isaac are doing really well and remarkably are not experiencing any of the typical symptoms of cystic fibrosis at the moment,” said their mother Debbie.
“Research studies like this one are so important to ensuring that children get access to the right treatments as early as possible. With the right medications, they can enjoy a healthy childhood and look forward to a brighter future”
Ivacaftor is manufactured by pharmaceutical company Vertex Pharmaceuticals, who are currently applying to the European Medicines Agency for an extension to the marketing authorization for Ivacaftor down to one month of age.
The study involved researchers from RCSI, Children’s Health Ireland, the U.S. and the UK.
Asthma and cystic fibrosis are diseases which affect the lungs of children and adults. Previous research has shown that genetic and environmental factors during pregnancy and early childhood can contribute to the way children and young adults are affected by these lung diseases.
In her thesis, Emma Caffrey Osvald, PhD student at Karolinska Institutet looked for new factors that may influence the development and outcomes of asthma and cystic fibrosis. In the four included studies, Emma used data from a clinical cohort and national health and demographic registers and a quality register on individuals born in Sweden to shed light on potential factors which impact the course of asthma and cystic fibrosis. Her findings should be useful when creating clinical guidelines and policies for the prevention and management of respiratory disease in children and young adults.
What are the most important results in your thesis?
“In my first study, we show that mothers with asthma have an increased likelihood of having a child with asthma and that higher lung function in pregnancy is associated with a decreased likelihood of having a child with asthma. However, asthma or lung function in the mother does not impact childhood growth. In the second study, we see that parental social standing (socioeconomic status, measured as parents’ education and income) is associated with the onset of asthma in childhood. By comparing the social standing and onset of asthma among first cousins we see that parental education may be directly linked to the onset of asthma. In the third study, we also show that there is a connection between having asthma in childhood or young adulthood and death between 1 to 25 years of age. The likelihood of death between 1 to 25 years of age is higher if the person also has a life-limiting disease but not altered by the parents social standing at the child’s birth. In the final study, we see some association between low parental social standing and severe disease and lung function decline among persons with cystic fibrosis, however low parental social standing does not impact growth. So we found that there are factors in the parents (including during the pregnancy and social standing) which impacts the onset of asthma. Asthma increases the risk of mortality between 1 to 25 years and low parental social standing is shown to be associated with severe disease and lung function decline in persons with cystic fibrosis.”
Why did you become interested in this topic?
“I have wanted to learn more about epidemiology ever since my ex-job project as a medical student and these PhD projects have allowed me, as a paediatric pulmonologist, to explore the factors which influence onset and outcomes for children and young adults with respiratory disease. Asthma and CF are two chronic diseases which we meet as part of our routine clinical practice and for me it has been really interesting to avail of both clinical data and national register data and a variety of statistical methods to further our understanding of these diseases.“
What do you think should be done in future research?
“Areas which will interest me in my future research continues to be the determinants and outcomes of respiratory disease in childhood. For me, the future of register-based research lies in the combining of clinical data with register data. There is more to explore in regards to risk factors for acute respiratory disease such as severe pneumonia and empyema, but also the outcomes for persons with asthma and CF, such as presence of comorbidity or educational attainment.”
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.
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.
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.
Researchers have discovered that, counterintuitively, certain cells move faster in thicker fluid – such as mucus as opposed to blood – because their ruffled edges sense the viscosity of their environment and adapt to increase their speed.
The researchers’ combined results in cancer and fibroblast cells suggest that the viscosity of a cell’s surrounding environment is an important contributor to disease. The findings, published in Nature Physics, may help explain tumour progression, scarring in mucus-filled lungs affected by cystic fibrosis, and the wound-healing process.
“This link between cell viscosity and attachment has never been demonstrated before,” noted Sergey Plotnikov, assistant professor at the University of Toronto and a co-corresponding author of the study. “We found that the thicker the surrounding environment, the stronger the cells adhere to the substrate and the faster they move – much like walking on an icy surface with shoes that have spikes, versus shoes with no grip at all.”
Understanding why cells behave in this surprising way is important because cancer tumours create a viscous environment, which means spreading cells can move into tumours faster than non-cancerous tissues. Since the researchers observed that cancer cells speed up in a thickened environment, they concluded that the development of ruffled edges in cancer cells may contribute to cancer spreading to other areas of the body.
Targeting the spreading response in fibroblasts, on the other hand, may reduce tissue damage in the mucus-filled lungs affected by cystic fibrosis. Because ruffled fibroblasts move quickly, they are the first type of cells to move through the mucus to the wound, contributing to scarring rather than healing. These results also imply that cell movement might be controlled by changing the viscosity of the lung’s mucus.
“By showing how cells respond to what’s around them, and by describing the physical properties of this area, we can learn what affects their behaviour and eventually how to influence it,” says Ernest Iu, PhD student at the University of Toronto and study co-author.
Plotnikov added, “For example, perhaps if you put a liquid as thick as honey into a wound, the cells will move deeper and faster into it, thereby healing it more effectively.”
Asst Prof Plotnikov and Iu used advanced microscopy techniques to measure the traction that cells exert to move, and changes in structural molecules inside the cells. They compared cancer and fibroblast cells, which have ruffled edges, to cells with smooth edges. They determined that ruffled cell edges sense the thickened environment, triggering a response that allows the cell to pull through the resistance – the ruffles flatten down, spread out and latch on to the surrounding surface.
The experiment originated at Johns Hopkins, where assistant professor Yun Chen, lead author of the study, and Matthew Pittman, PhD student and first author, were first examining the movement of cancer cells. Pittman created a viscous, mucus-like polymer solution, deposited it on different cell types, and saw that cancer cells moved faster than non-cancerous cells when migrating through the thick liquid. To further probe this behaviour, Asst Prof Chen collaborated with U of T’s Plotnikov, who specialises in the push and pull of cell movement.
Plotnikov was amazed at the change in speed going into thick, mucus-like liquid. “Normally, we’re looking at slow, subtle changes under the microscope, but we could see the cells moving twice as fast in real time, and spreading to double their original size,” he explained.
Typically, cell movement depends on myosin proteins, which help muscles contract. Asst Prof Plotnikov and Iu reasoned that stopping myosin would prevent cells from spreading, however were surprised when evidence showed the cells still sped up despite this action. They instead found that columns of the actin protein inside the cell, which contributes to muscle contraction, became more stable in response to the thick liquid, further pushing out the edge of the cell.
The teams are now investigating how to slow the movement of ruffled cells through thickened environments, which may open the door to new treatments for people affected by cancer and cystic fibrosis.
Antisense oligonucleotides (ASOs), are molecules that can be used to control protein levels in cells. Researchers detail in Nature how they leveraged ASO technology to develop the first FDA-approved treatment for spinal muscular atrophy called Spinraza®. The drug has helped over 11 000 patients make more of a protein that certain neurons in the spine need.
Cold Spring Harbor Laboratory Professor Adrian Krainer, who developed the drug, has been searching for more ways ASOs can help treat other disorders. He has identified cystic fibrosis (CF), where patients produce insufficient amount of the protein CFTR. His team discovered how to use ASOs to make more of an imperfect but still functional version of CFTR. This could lead to a new treatment approach that may help alleviate CF symptoms.
The imperfect CFTR protein results from a gene mutation. The faulty instructions to produce the protein are eliminated and the protein isn’t made, since in general, imperfect proteins may be disruptive. Prof Krainer’s ASOs trick cells into following the faulty instructions and making the imperfect CFTR protein. His team found that, in this case of CF, having an imperfect version of the protein is better than having none at all. Their method improved the function of lung cells, suggesting the ASO strategy could improve symptoms in CF patients with this mutation.
The team’s discovery spotlights a new way ASOs can be used to treat disease. The study was led by Young Jin Kim, a former MD-PhD student in the Krainer laboratory. Prof Krainer hopes to continue expanding the potential of ASO technology in therapeutics. He thinks in the future ASOs may increasingly become a way to tailor therapies specific to an individual’s unique genetic mutations. “If more of this type of drug, ASOs, are approved,” Prof Krainer said, “I wouldn’t be surprised if in the not-so-distant future ASOs become a routine way to make personalised medicines.”
Scientists have harnessed a computational approach usually used in oil exploration to search for cures for rare genetic diseases such cystic fibrosis. By using the method to analyse the spatial relationships between different variants of a protein, instead of the relationships between test wells across an oil field, the researchers can obtain valuable information on how disease affects a protein’s underlying shape and how drugs can restore that shape to normal.
The new method, detailed in the journal Structure, runs with just a few gene sequences collected from people with disease. Then, it determines how the structure of each corresponding variant protein is associated with its function, and how this functional structure can affect pathology and be repaired by therapeutics. To test the techniques, the researchers showed why existing drugs for cystic fibrosis fall short of curing the disease.
“This is an important step forward for treating rare diseases,” said senior author William Balch, PhD, professor of Molecular Medicine at Scripps Research. “The fact that we can get so much information from a few gene sequences is really unprecedented.”
Studies on inherited diseases often rely on the precise three-dimensional shape of a protein affected by disease. But genetic diseases can be caused by thousands of gene variants, some of which destabilise or change the protein shape in ways that make isolating the protein for further investigation much more difficult than usual.
Prof Balch, with Scripps Research senior staff scientist Chao Wang and staff scientist Frédéric Anglés, instead wanted to use natural variation to their advantage. So the group developed a method called variation-capture (VarC) mapping to analyse the natural array of gene sequences which exist in the human population and determine the mechanism by which they each changed a protein’s structure to cause disease.
Among other statistical tools, Prof Balch’s group integrated the methods that oil companies use to draw inferences about the location of an oil reservoir using only a small number of test wells. With only a few gene sequences, this let the researchers determine the most likely structural mechanisms driving function for each variant leading to disease, as well as model how drugs impacted those structural functions.
In the case of cystic fibrosis, disease is caused by genetic variants in the cystic fibrosis transmembrane conductance regulator (CFTR), leading to a buildup of mucus in the lungs. More than 2000 variants of the CFTR gene have been identified, and many of these variants were known to have very different effects on the CFTR protein, but it has been difficult to compare and contrast these variants to guide how patients with different variants should be treated differently in the clinic.
“When you want to treat patients, you really have to appreciate that different therapeutics might target different variants in completely different ways, and that’s why our approach that looks at many different variants all at once is so powerful,” explained Wang. “Our approach not only reveals how these variants contribute to each patient’s biology, but also connects them in a way that each variant can inform how to manage the others.”
The researchers input about 60 genetic variants found in the cystic fibrosis population into their VarC program. The analysis captured how each amino acid residue talks to every other residue to generate function, and revealed that most of the cystic fibrosis patients had the same net effect on the protein: an unstable inner core.
When the program modelled how existing cystic fibrosis drugs impacted the structures, the researchers discovered that, despite the drugs’ effect on CFTR structure, none of them effectively stabilised the protein’s hidden inner core. This was like how the location of an oil reservoir in a complex landscape can be revealed by test wells.
Now that the researchers better understand the structural deficiencies in CFTR in cystic fibrosis patients, they say that the job of developing an effective drug to fix it is much easier. Potential compounds can be modelled in advance of lab experiments for their effect on the inner core of the CFTR protein.
“In most drug discovery, you throw thousands of compounds at a protein and see which ones change it, often without fully understanding the mechanism,” said Prof Balch. “To fix a thing, you must first understand the problem.”
Already, his team is applying the method to other rare genetic diseases, as well as pursuing new drugs to treat cystic fibrosis.
