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Alpha-1 antitrypsin deficiency (AATD), or Alpha-1, is the most common genetic lung disorder in Ireland. In fact, Ireland has an unusually high prevalence of the condition — among the highest in Europe. Alpha-1 antitrypsin is a protein whose main function is to protect the lungs from infection and irritants, such as tobacco smoke. A deficiency of this protein can lead to symptoms such as breathlessness, wheezing and cough with phlegm, and can cause severe lung, liver and skin problems. The majority of people with Alpha-1 present with emphysema or chronic obstructive pulmonary disease (COPD). Smoking is the single biggest risk factor for the development of emphysema in Alpha-1 patients, and individuals with AATD who smoke develop severe early-onset emphysema.
Alpha-1 is under-diagnosed, with prolonged delays in diagnosis common. In addition, the majority of AATD individuals with emphysema are misdiagnosed as COPD patients.
The Alpha One Foundation in Ireland recently held its annual conference in the Marino Institute of Education in Drumcondra, Dublin. The conference featured presentations from a range of national and international experts on the diagnosis and treatment of Alpha-1.
Currently, almost 350 people have been diagnosed with the severe form of Alpha-1 in Ireland, however, it is estimated that around 3,000 people across the island have the condition. Diagnosis is through a simple blood test, which can enable early medical intervention and lifestyle changes, such as smoking cessation. As Alpha-1 is a genetic condition, the Alpha One Foundation strongly recommends that first-degree family members of people diagnosed with Alpha-1 should be tested as part of the National Alpha-1 Targeted Detection Programme, as well as the following: All people with emphysema and COPD; all people with asthma that is non-responsive to usual treatment; people with liver disease where the cause is unknown; people with reduced serum levels of alpha-1 antitrypsin and people with the panniculitis skin disease.
Currently, almost 350 people have been diagnosed with the severe form of Alpha-1 in Ireland, however, it is estimated that around 3,000 people across the island have the condition
One of the main talking points at the conference was the call for the reimbursement of the therapy, Respreeza, a highly purified Alpha-1 protein derived from human plasma (Alpha-1 proteinase inhibitor). The therapy is currently being assessed by the National Centre for Pharmacoeconomics (NCPE). This medicine is already available to patients in other European Union countries such as France, Greece, Spain, the Czech Republic, Slovakia and Italy.
Since a clinical trial of Respreeza – known as the RAPID study – began in Ireland in 2006, a total of 21 people have been offered access to the therapy by its maker on a compassionate-use basis. Some patients have been receiving this treatment for almost a decade. In addition to those patients currently in receipt of the therapy, it is estimated that a further 40 patients would benefit. The medication works by replacing the protein that is lacking in patients with AATD and slows down damage to the lungs in patients with severe disease. It is delivered once weekly by intravenous infusion. The administration of the human Alpha-1 proteinase inhibitor targets the lungs to restore the level of Alpha-1 antitrypsin in deficient patients. Alpha-1 antitrypsin has the role of inactivating some substances, such as elastase, normally produced by the body. In this way the human Alpha-1 proteinase inhibitor could oppose the effects of elastase.
The benefit with Respreeza is its ability to slow down the annual rate of lung density decline, as measured by CT scan compared to placebo over two years, reflecting a 34 per cent reduction.
One of the headline speakers at the conference was Prof Gerry McElvaney, Consultant Respiratory Physician and Head of the National Alpha-1 Centre at Beaumont Hospital, Dublin, who is known for his pioneering translational research and has published widely in the areas of cystic fibrosis (CF), Alpa-1, infection, immunity, and lung inflammation.
“We think it [Respreeza] will slow down the progression of emphysema in carefully selected patients with Alpha-1 antitrypsin deficiency,” Prof McElvaney told the Medical Independent (MI).
“And by doing so, it will decrease the need for lung transplantation, but also improve the quality of life for people with this condition. The data from this therapy are significant, but I think we can improve them. The only way we can improve them is by further study in the area. But this is a really important first step. A lot of medications or interventions will not achieve the desired result in its first iteration. But we will improve on it, we will tweak, and we will get a better result over time I think.”
The RAPID trial was the first well-powered randomised, placebo-controlled trial to use CT scan lung density as the primary outcome measure. CT scans are currently considered the most sensitive measure of emphysema detection. Prof McElvaney, however, said that health policy-makers and managers are not used to having their decisions on health services for people with lung problems being based on CT scans.
“They are unfamiliar with that,” according to Prof McElvaney.
“But over the last 10 to 15 years there has been a sea change in the attitudes of outcomes in emphysema studies. And the FDA in the US accepts CT scans are a primary endpoint, partly through the work we have done here.”
Prof Robert Sandhaus, Professor of Medicine, National Jewish Health and University of Colorado, and Medical Director of the Alpha-1 Foundation, US, also spoke at the conference. He said that intravenous augmentation therapy was approved in the US in 1987 for AATD.
“At present there are four different products manufactured by four different companies available in the United States,” according to Prof Sandhaus.
“All are given intravenously on a weekly basis. When the first product was approved, the regulatory authorities in the United States demanded that a study be started to learn the natural history of Alpha-1. This became the NIH [US National Institute of Health] Registry of Patients with Alpha-1 Antitrypsin Deficiency, which, in the early 1990s, enrolled 1,129 patients and followed them over a five-year period. This registry provided some of the earliest evidence that augmentation therapy slowed lung function decline and improved survival. More recently, the RAPID study which looked at Respreeza added to this weight of evidence showing that augmentation therapy slows the progression of the emphysema caused by Alpha-1.”
Prof Sandhaus spoke about the importance of the various patient representative bodies established in the US for people with the condition. These include the Alpha-1 Association, the Alpha-1 Foundation, AlphaNet, and the Osteogenesis Imperfecta Foundation. Prof Sandhaus said the Alpha-1 Foundation established a dedicated laboratory for Alpha-1 to improve processes for testing.
“They also said they want to study the various kinds of Alpha-1,” he told the conference.
“We were finding first hand that there were 20, then 100, then 200 mutations in the Alpha-1 gene, so we set up a DNA bank that Alpha-1 patients could contribute their DNA to for further studies into the genetics of Alpha-1. It took the remnants of the registry in 1990 by the NIH and turned it into the Alpha-1 research registry that now has over 5,000 patients with Alpha-1 that can be used for clinical studies.”
Prof Sandhaus outlined how the US Foundation has given out €60 million in research funding since its founding and provides support not only for investigators in the US, but throughout the world. He also spoke about a recent initiative called TAP, which is a for-profit, venture/philanthropy, sub-corporation of the Foundation. TAP makes strategic investments in companies that are developing drugs that might be of benefit to Alpha-1 patients. The investment is contingent on the company applying their technology to treating or even curing Alpha-1.
Prof Sandhaus concluded his talk by saying Alpha-1 patients in the US have created, supported, staffed and benefited from these organisations.
“The ultimate goal is to cure Alpha-1,” he said. “Doctors are really hesitant to promise cures, or say, ‘that has to be the goal’, but the patients said ‘if you are not trying to cure this, what are you in this for’? So everyone in these organisations subscribes that their ultimate [goal] is to cure Alpha-1 antitrypsin deficiency. So basically these organisations are looking to put themselves out of business and are happy to do that.”
Prof McElvaney also discussed other areas of research he is engaged with regarding Alpha-1. The condition can cause liver problems in infants, children or adults – as well as lung disease. In people with Alpha-1, large amounts of AAT are made in the liver. In fact, nearly 85 per cent of this protein gets stuck in the liver. If the liver cannot break down the abnormal protein, the liver gradually becomes damaged and scarred.
Currently, there is no way to prevent the abnormal AAT from getting stuck in the liver.
“The liver disease in Alpha-1 is due to the accumulation of Alpha-1 in the liver,” Prof McElvaney told MI.
“So the treatment for that has to be different than the treatment for the lung disease. So it is not enough to replace the Alpha-1, we have to get rid of the Alpha-1 that is in the liver. The best way to do that is to prevent it being formed. We have, working with others, developed a silencing RNA technique, where we can pinpoint these sequences, which latch onto the messenger RNA and prevent it from being translated into protein and block it. So we, along with others, have developed an infusion, to take this conjugate directly to the liver. It would internalise in the liver. Then this conjugate would prevent the liver cells from producing Alpha-1, which in this case would be abnormal Alpha-1, and prevent it from accumulating in the liver, and causing inflammation and eventually cirrhosis or maybe cancer.”
*The Alpha One Foundation also provides a range of ancillary services to patients including counselling, expert advice, information packs and leaflets, and opportunities to enrol in clinical trials and to join the Alpha-1 patient support group. See www.alpha1.ie for more information.