Augmentation Therapy: The Fight for Canada-wide coverage for Alpha-1 Antitrypsin Deficiency Patients
Over 200 alpha-1 antitrypsin deficient patients in Canada are not receiving the therapy they need to maintain the lung function and quality of life because they do not have private insurance or provincial coverage to afford treatment.1 Alpha-1 antitrypsin deficiency (A1AD) is a rare genetic disorder that affects 1 in 2,500 patients of European descent.2 Early signs of this disorder in childhood, such as coughing and shortness of breath, are often misdiagnosed as asthma and eludes diagnosis and treatment. By the ages of 20-50, the characteristic signs of A1AD such as lung function decline and scarring of the liver tissue in two processes known as emphysema and cirrhosis.3 As the disease progresses, patients may have to undergo a double lung transplant or face mortality due to their declining health. There are no curative treatments available for A1AD.1 While there are a few recommended lifestyle changes to manage liver and lung function, there is only one disease-specific therapy that can delay lung disease progression: augmentation therapy. Augmentation therapy involves intravenous (IV) infusions of antitrypsin proteins (AAT) from blood plasma to directly provide patients with the AAT proteins they lack. For patients who choose to undergo augmentation therapy, the tremendous cost of $60,000-$100,000 a year for the rest of their lives is often too high of a bill without provincial coverage.2 Currently, only British Columbia, Alberta, Manitoba, and Quebec offers coverage, leaving patients in the rest of Canada dependent on private insurance coverage. Private coverages often have lifetime caps and discontinue at 65, leaving patients without alternative therapies upon termination. Alpha-1 Canada is currently petitioning Canadian Blood Services (CBS) to offer augmentation therapy for all Canadians and has made their voice heard at the recent CBS Board Meeting. They are fighting for equitable coverage of augmentation therapy nationwide for A1AD patients.
A1AD is caused by an inherited mutation in the SERPINA1 gene, which prevents the production of the AAT protein.1 AAT protects the body from neutrophil elastase, an enzyme which is released from white blood cells to fight infection, but can also attack healthy tissues. As a result of AAT deficiency, neutrophil elastase can damage tissues in the lungs, liver, and skin. In the lungs, neutrophil elastase-induced damage causes emphysema, where the structure of air sacs in the lungs are damaged, making it difficult to empty the lungs.3 People affected by A1AD often suffer from shortness of breath, recurring respiratory infection and a hacking cough. Patients often receive the diagnosis of Chronic Obstructive Pulmonary Disease (COPD) or asthma rather than AAT deficiency and thus never receive the appropriate treatment. In the late stages of the disease, a double lung transplant is sometimes required. In the liver, patients often show poor results on liver function tests due to underlying cirrhosis. Liver disease can progress from scarring of the tissue to hepatic encephalopathy (altered mental state from brain damage), portal hypertension, splenomegaly, or thrombocytopenia.2 These pathologies increase the risk of developing hepatocellular carcinoma, a type of liver cancer. Additionally, 10% of A1AD patients also have panniculitis, which is characterized by hardened skin with painful lumps or patches.2
A1AD testing is recommended for adults with a family history of COPD and asymptomatic individuals with unidentified persistent obstruction.2 A1AD is diagnosed through genetic testing. If positive, people are immediately referred to be followed up by a liver and lung specialist who can monitor the extent of disease progression and promote lifestyle changes that can mitigate the disease. Routine liver enzyme tests are done to evaluate ALT levels, an indicator of liver function. Vaccinations against hepatitis A and B are recommended to preserve liver health along with avoidance of alcohol and other hepatotoxic agents.2 For the lungs, routine spirometry tests are used to measure FEV1, the forced expiratory volume of the lungs in one minute, a measure of lung function. Preventative measures like influenza and pneumococcal vaccines are highly recommended along with supplemental oxygen. For a subgroup of patients with FEV1 of 20-80% of predicted, augmentation therapy is recommended to increase levels of AAT in the plasma and lung interstitium to protect the lungs from neutrophil elastase-mediated damage.
Historically, different components of plasma have been distilled for the treatment of autoimmune disorders, hemophilia, and acute infections. Notably, an ethanol precipitation technique, known as Cohn fractionation, has been used to extract high-quality albumin preparations to treat wounds. Conveniently, AAT is a byproduct of this process and can be repurposed for augmentation therapy.4
Augmentation therapy is a drug therapy approved in Europe, United States, and Canada based on its pharmacokinetic safety, in vitro (studies on cell cultures) efficacy studies, and nonrandomized observational data gathered from the Alpha-1 National Registry. There are three observational studies showing that augmentation therapies significantly slow the decline of FEV1, but only one trial showed a reduction in mortality.2 However, the study of 1,129 AAT deficiency cases from the national registry showed that there was no significant difference between FEV1 in patients receiving augmentation therapy versus those who did not. However, in a subgroup of patients with a baseline FEV1 of 35-49% of predicted, researchers were able to detect a significant difference in favour of augmentation therapy.2 This data has been used to inform the current guidelines for who should be receiving augmentation therapy. However, there are opponents arguing that there is insufficient evidence to continue the use of augmentation therapy because of the lack of a large-scale randomized controlled trial, one of the highest levels of evidence to support medical practices. In the medical literature, there are two very small randomized controlled trials showing that augmentation therapy, when compared to placebo, can preserve lung density but does not improve exacerbation or quality of life.4 There are no large-scale trials to support a more definitive conclusion due to the small number of patients.4 It is important to note that augmentation therapy cannot be used to treat liver function decline. The complete lack of therapies in this field will be a key area of pharmaceutical research in the coming years.
Alpha-1 Canada is an organization devoted to representing the interests and progressing the research and treatment for individuals affected by A1AD. Angela Diano, the Executive Director of Alpha-1 Canada, is calling for equity in patients access to augmentation therapy across Canada. Currently, augmentation therapy is only covered in the provincial formularies of British Columbia, Alberta, Manitoba, and Quebec. For the 40% of A1AD patients in Ontario and much more in other provinces, patients must either rely on private insurance or be deprived of therapy that can improve their quality of life and delay lung transplants and mortality. Diano believes that augmentation therapy is the only plasma-derived product not currently offered by CBS and petitions for its approval. Additionally, Alpha-1 Canada has placed a request for information on why augmentation therapy is currently not distributed by CBS and for the approval process for plasma products.
Angela Diano advocates that “Alpha-1 Canada recognizes and commends Canadian Blood Services for their efforts to develop a plasma plan, but our patient base needs Canadian Blood Services to recognize a patient group that has an expectation that all patients requiring plasma-derived treatments are treated equally, and we would like the steward of the Canadian blood system to provide augmentation therapy to Alpha-1 patients across Canada. We look forward to dialogue with CBS in 2018 on how we can begin the process to achieve this goal.”
At the December 7th, 2017 Board Meeting of Canadian Blood Services, Dr. Graham Sher, CEO of CBS, announced that an official response to both these questions would be issued. Dr. Graham Sher also added that for a plasma product to be distributed by CBS, it needs to meet two criteria: (1) it must be made from human plasma, and (2) it must be used in transfusion medicine. We eagerly await a response to help direct the future of the provision of augmentation therapy to Canadians.
1. Diano A, Sher G. Canadian Blood Services Board Meeting (Dec. 9, 2017). In: CBS Board Meeting. Ottawa; 2017. https://blood.ca/en/about-us/board-minutes-and-calendars.
2. Brode SK, Ling SC, Chapman KR. Alpha-1 antitrypsin deficiency: A commonly overlooked cause of lung disease. CMAJ. 2012;184(12):1365-1371. doi:10.1503/cmaj.111749.
3. Communications LHNC for B. Alpha-1 Antitrypsin Deficiency. National Institutes of Health. https://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency. Published 2017.
4. Wewers MD, Crystal RG. Alpha-1 antitrypsin augmentation therapy. COPD. 2013;10 Suppl 1(646):64-67. doi:10.3109/15412555.2013.764402.
Cite This Article:
Zhang B., Chan G., Palczewski K., Lewis K., Ho J. Augmentation Therapy: The Fight for Canada-wide coverage for Alpha-1 Antitrypsin Deficiency Patients. Illustrated by L. Nguyen. Rare Disease Review. February 2018. DOI:10.13140/RG.2.2.24228.17280.