HHS Secretary Alex Azar Touts White House Efforts to Cure Rare Diseases - Pulmonary Hypertension News
HHS Secretary Alex Azar Touts White House Efforts to Cure Rare Diseases - Pulmonary Hypertension News |
- HHS Secretary Alex Azar Touts White House Efforts to Cure Rare Diseases - Pulmonary Hypertension News
- Lethal Lung Disease and Biologics: Is There a Link? - MedPage Today
- PAH May Be Treated With Antiarrhythmic Tikosyn, Study Suggests - Pulmonary Hypertension News
| Posted: 06 Dec 2019 12:00 AM PST Despite skyrocketing healthcare costs, President Trump is committed to protecting the 30 million or so Americans with rare diseases and ensuring timely, affordable access to lifesaving treatments, the nation's highest-ranking health official said. "We have to think about how our financing system can protect those with serious and rare illnesses. When successful therapies are developed, they can be extremely expensive, so we need to ensure that Americans who suffer from rare diseases have ways to finance their care," said Alex Azar, secretary of the U.S. Department of Health and Human Services (HHS).  "In part, that means keeping the promise President Trump has made to Americans with pre-existing conditions: a guarantee we will maintain at the federal level," he added. "That's not changing. We want a system that works — and protects what works." Azar spoke to more than 900 delegates attending the 2019 NORD Rare Diseases & Orphan Products Breakthrough Summit in Washington, D.C. The Oct. 21–22 event, organized by the National Organization for Rare Disorders (NORD), also featured presentations by Norman E. "Ned" Sharpless, MD, acting commissioner of the U.S. Food and Drug Administration (FDA), and his predecessor, former FDA Commissioner Scott Gottlieb, MD. "Medicare and private insurance have made it possible for Americans to receive the most cutting-edge treatments," said Azar, the first U.S. cabinet secretary to address a NORD summit. "Securing longer, happier, healthier lives is the fundamental goal the president has for our healthcare system — especially for patients suffering from rare diseases." He added: "President Trump has a particular vision for healthcare that puts you, the patient, at the center and treats you like a human being, and not like a number. Such a system will provide you with the affordability you need, the control you want, and the quality you deserve." A new approach to rare diseasesNORD, a coalition of 280 patient advocacy organizations, is a longtime supporter of the Orphan Drug Act of 1983. This controversial law gives pharmaceutical companies tax and other incentives to develop therapies for rare diseases — which, according to the FDA, are those affecting fewer than 200,000 Americans. Of the 7,000 or so known rare diseases, roughly 90% still lack FDA-approved treatments, and more than half of those affected are children. As secretary of HHS, Azar oversees a fiscal 2019 budget of $1.2 trillion. The agency administers 115 programs across its 11 operating divisions, including the Centers for Medicare and Medicaid Services, the FDA, the National Institutes of Health (NIH), the Centers for Disease Control and Prevention, and the Health Resources and Services Administration.  In his 17-minute speech, Azar cited sickle cell disease (SCD) as a prime example of Trump's approach to the millions of people whose conditions are considered rare. "We believe we can make a meaningful impact quite soon on this terrible disease," he said, noting that the illness plagues about 100,000 Americans — particularly blacks and Hispanics — and causes excruciating pain as well as infections, lung damage, blindness, depression, and heart and kidney failure. "While sickle cell disease has been neglected for far too long, today there are many, many reasons for hope," Azar said. "In fact, it is one of the single most promising areas for biomedical research, and the Trump administration has made the disease a top priority. At HHS, we've set a goal of extending the lives of Americans with sickle cell disease by 10 years within 10 years." To that end, Trump late last year signed into law a bipartisan bill that reauthorizes a current SCD prevention and treatment program for nearly $5 million each year over the next five years. The Sickle Cell Disease and Other Heritable Blood Disorders Research, Surveillance, Prevention and Treatment Act of 2018 had been co-sponsored by Sens. Cory Booker (D-New Jersey) and Tim Scott (R-South Carolina). Azar: 'The cures are coming'Azar, 52, assumed leadership of HHS in January 2018 following his Senate confirmation. Before that, he headed the U.S. division of Eli Lilly & Company from 2012 to 2017. A longtime lobbyist for the pharmaceutical industry, he noted that 40 therapies to help manage SCD-related pain are currently being tested in clinical trials. "Market failures have led some diseases to be neglected for far too long," he said. "Government has a major role to play in helping to finance drugs for rare and neglected diseases. Companies have little incentive to develop a drug that may benefit only a small percentage of the population."  The NIH announced on Oct. 23 plans to invest at least $100 million over the next four years toward developing "affordable, gene-based cures" for both SCD and HIV. The Bill & Melinda Gates Foundation will also put $100 million toward this goal. Yet that's only part of the challenge, said Azar. Paying for all these new treatments could be a bigger battle — especially considering the $2.1 million price tag for the recently approved Novartis gene therapy Zolgensma for spinal muscular atrophy. "Gene therapies have typically carried unprecedented high prices, and the same will likely be true for a cure for sickle cell. Progress must prompt us to think about how we're going to finance the delivery of these cures," he said. "The cures are coming — thank God they are — but when they arrive, we've got to be ready to get them to patients who desperately need them," Azar added. "All of the actors involved — HHS, private payers, innovators, legislators, and patient advocates — need to be thinking now about how to build a system together that can support access to these cures. "The whole point of a health insurance system like we have is to ensure that if you are struck by a serious illness — let alone one that is rare and highly unlikely — our system is there to care for you."  ×  |
| Lethal Lung Disease and Biologics: Is There a Link? - MedPage Today Posted: 24 Dec 2019 09:00 AM PST  This story was originally published Sept. 4, 2019. As part of MedPage Today's year-end review of 2019's top stories, we are republishing it along with an update on what has happened since. A new, potentially life-threatening parenchymal lung disease is increasingly being detected in patients with systemic juvenile idiopathic arthritis (sJIA), according to recent reports. Systemic JIA is distinct from other forms of JIA in that the arthritis is accompanied by quotidian spiking fevers, rash, and serositis. In many patients, the diagnosis has been a dismal one. In approximately 10% to 15% of patients, a severe, often lethal complication known as macrophage activation syndrome (MAS) develops, which can result in hemophagocytosis and release of cytokines such as interferon (IFN)-γ, hepatic dysfunction, and coagulopathy. However, pulmonary involvement in sJIA typically has been mild, most often manifesting as pleuritis or pleural effusion. Traditionally, sJIA had been treated with corticosteroids and NSAIDs, but the introduction of cytokine-targeting biologics some 15 years ago led to rapid, life-changing improvements in up to two-thirds of patients. These agents include the interleukin (IL)-1 inhibitors anakinra (Kineret) and canakinumab (Ilaris) as well as the IL-6 inhibitor tocilizumab (Actemra). Clinical trials of canakinumab and tocilizumab for sJIA were published in 2012 in the New England Journal of Medicine, accompanied by an editorial co-authored by Elizabeth D. Mellins, MD, of Stanford University. At the time, she noted that the new agents "signal a new era in the treatment of systemic JIA," but warned that "cytokine blockade may create an imbalance in the cytokine network, thereby driving or unmasking previously uncommon complications." An early warning of a possible new disease complication was a study published in 2013 of 25 patients with lung manifestations including pulmonary arterial hypertension in 64%, interstitial lung disease in 28%, and alveolar proteinosis in 20%. Mortality at 10 months following the onset of pulmonary disease approached 70%. Mellins then organized a meeting in 2016 where rheumatologists, pulmonologists, and pathologists discussed 33 cases of sJIA involving interstitial lung disease; the high mortality prompted her to begin reporting the concerning findings at conferences. Questions were being raised linking possible exposure to biologics with the unusual lung disease because of the temporal association. "Given that sJIA and its adult counterpart disease, adult-onset Still's disease, have been recognized for over 120 years, it is striking that this complication was not recognized and described until the past decade," said Michael A. Ombrello, MD, who heads the Translational Genetics and Genomics Unit at the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Md. In a recent editorial accompanying a study of 18 patients with this complication, Peter A. Nigrovic, MD, of Brigham and Women's Hospital in Boston, cautioned that the task today is to "seek with urgency to understand this dark cloud over the otherwise dramatically successful advent of biologic treatment in sJIA." "The storm is here, and navigating sJIA treatment has become even more challenging than before," Nigrovic wrote. The multicenter cohort Mellins and her colleagues have now published a retrospective study of 61 patients, in which 46 of 61 exhibited a constellation of unusual clinical findings, including acute erythematous clubbing. This subgroup was notable for exposure to the IL-1 and 6 inhibitors, with the predominant pathology being pulmonary alveolar proteinosis/endogenous lipoid pneumonia (PAP/ELP). Among affected children, 5-year survival was only 42%, Mellins' group reported on the recently established pre-peer review platform medRxiv. They analyzed clinical, radiologic, pathologic, and genetic data from their cohort compared with 471 sJIA patients in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry. The clinical picture at presentation included few if any respiratory symptoms, although hypoxia was detected in 43% and pulmonary hypertension in 30%. Other clinical findings included pruritic rash in more than half of patients and eosinophilia in more than one-third. In 38%, anaphylaxis to tocilizumab was reported, compared with 0.6% of those in the comparator cohort. Unexplained abdominal pain also was observed. High levels of serum ferritin and lymphopenia were observed during the year prior to the onset of lung disease, suggesting a possible "extended incubation phase associated with smoldering inflammation," Mellins and colleagues observed. The most common pattern seen on chest CT involved peripheral septal thickening with or without ground glass opacities, although less frequent patterns included peripheral consolidation and peribronchovascular consolidation as well as hyper-enhancing lymph nodes. Radiologic evidence of fibrosis was uncommon, and pleural effusion was rare. Among patients who had biopsy or autopsy tissue analysis, the patchy PAP/ELP pattern was accompanied by vascular abnormalities. On electron microscopy, macrophage accumulation was seen, but genetic analysis found no association with genes that cause primary hereditary PAP. Patients in the lung disease group were significantly younger than CARRA registry controls at sJIA diagnosis (2.3 vs 5.2 years) and also more often had trisomy 21 (9.8% vs 0.2%), which can increase susceptibility to adverse drug events. Survival was "drastically lower" among patients with lung disease, with mortality rates of 159 per 1,000 patient-years compared with a U.K. cohort of patients with systemic JIA treated with biologics (3.9 per 1,000), and the most common causes of death were diffuse lung disease and MAS. Most patients (19 of 23 biopsied) with PAP/ELP had been exposed to IL-1/IL-6 inhibitors, with a median time from initiation of treatment to the onset of lung disease of 1.2 years. "Thus, IL-1/IL-6 inhibitor exposure may promote development of a PAP/ELP-like disease in a subset (apparently small and perhaps genetically susceptible) of sJIA patients, among the substantially larger group of patients who derive striking benefit from these inhibitors," Mellins and colleagues wrote. There are a number of possible explanations for an association between lung disease and IL-1/IL-6 inhibition, she said. One is that a subset of patients met the criteria for drug-related eosinophilic systemic syndrome, which is a potentially life-threatening hypersensitivity reaction characterized by skin eruptions and hematologic abnormalities including high eosinophil counts. Another hypothesis is related to an earlier study of children with sJIA, in which some children developed evidence of a type I interferon response induced by anakinra. A second study found that anakinra responders showed an exaggerated response to interferons (both type I and type II), suggesting that the pathology may be driven by interferons. Notably, an underlying type I interferonopathy has recently been described in trisomy 21. In addition, a mouse model has demonstrated that interferon-γ upregulation can cause a similar pattern of lung inflammation. It's also possible that cytokine inhibitors can influence the larger cytokine network, making the child more responsive to other cytokines, or can affect homeostasis in the lung. "There are multiple ways these inhibitors might increase vulnerability to PAP lung disease," Mellins explained in an interview. "At the moment I'm in favor of the notion that multiple factors may be involved, all of which need to be explored." She and her colleagues noted that more than 50 additional cases of lung disease have been observed in patients with sJIA, and there also have been reports in the FDA adverse event website of unusual lung disease in adults with rheumatoid arthritis and adult-onset Still's disease treated with IL-1/IL-6 inhibitors. However, these anti-cytokine agents also are used in the treatment of autoinflammatory diseases, including the hereditary periodic fever syndromes, and there have been no reports to date of the development of an analogous form of lung disease in patients with these conditions, Ombrello noted. "Therefore, if anti-cytokine treatment contributes to the development of sJIA lung disease, it seems to do so in a way that is specific to sJIA pathophysiology (or the pathophysiology of a subset of sJIA)," Ombrello told MedPage Today. Mellins' group noted that their analysis was limited by the retrospective data and may be influenced by channel bias, and emphasized that a causal relationship between IL-1/IL-6 targeting and lung disease cannot be presumed. The Cincinnati 18 "We first started seeing this in 2010," said Alexei A. Grom, MD, of Cincinnati Children's Hospital Medical Center, and through 2018, the center has treated 74 patients with systemic JIA, which has long been a referral center for sJIA. He and his colleagues published the 18-patient study from their center, in which lung-disease cases were matched with 36 sJIA patients who had no apparent pulmonary complications. Those with the lung disease had predominantly systemic symptoms, were younger at the time sJIA was diagnosed, often in the first year or two of life (OR 6.5), had previous episodes of MAS (80% vs 20%, OR 14.5), and had very high serum levels of IL-18, at 27,612 versus 5,413 pg/mL, his group reported in Arthritis & Rheumatology. Respiratory symptoms such as tachypnea were subtle and sometimes even absent at presentation. Digital clubbing was common, and affected patients had similar pain and disability as controls. During approximately 1 year of observation, 14 of the patients remained stable or improved, and none died. A "striking" number of adverse events to cytokine-targeted biologic agents was observed, particularly with tocilizumab. All but one of the 18 patients had been exposed to at least one biologic agent. CT scan findings in this group of patients included pleural, septal, and peribronchovascular thickening, "ground glass" or "tree-in-bud" opacities, and lymphadenopathy. In eight of the patients, open lung biopsies were done and all showed distinctive histopathologic findings characteristic of PAP/ELP, with foamy alveolar macrophages, eosinophilic proteinaceous material, and lipid accumulation. There also was a CD4+ T cell infiltrate, fibrosis, and vasculopathy. However, despite some similarities with what is seen in primary PAP, which results from the inability of alveolar macrophage to clear the protein and lipids, the number and appearance of the macrophages and degree of inflammation were more prominent than in autoimmune or hereditary PAP. "Our data suggest that although PAP-like features are indicative of macrophage dysfunction, it is not likely to be caused by intrinsic macrophage defects as in primary PAP. Alternatively, alveolar macrophage function may be altered by the external inflammatory milieu of sJIA and MAS, promoting the deviation of macrophage differentiation away from the phenotype required for surfactant recycling," Grom and colleagues wrote. "The lung disease that is described in these patients is most similar to PAP, but the pathologic and radiographic features are heterogeneous," said Ombrello, who was not involved in the studies. "Nonetheless, the lung disease observed in these sJIA cohorts seems to be distinct from the other forms of lung disease that can develop in the context of inflammatory or autoimmune diseases, as well as distinct from the primary conditions that lead to PAP," Ombrello said. Because the histologic picture suggested that macrophage dysfunction could be implicated in the lung disease, Grom's group analyzed bronchoalveolar lavage fluid, and found significant increases in IL-18 levels, a cytokine that contributes to the pathophysiology of MAS, possibly through induction of interferon-γ. Moreover, gene expression analysis found substantial upregulation in genes such as CXCL10 and CXCL9 that are associated with interferon-γ and MAS, further supporting a possible link between interferon-γ and the lung disease. In his editorial commenting on this study, Nigrovic stated, "The fact that most sJIA lung disease patients have a history of MAS and high IL-18 suggests that they are particularly prone to IFN-γ excess, and thus potentially to IFN-γ-mediated activation of alveolar macrophages." Biologics to blame? Grom, however, does not believe that biologic exposure is to blame for the new lung disease. "I think we need to be very careful with that [concept]. Certainly it remains a major concern that we may be inducing this disease with biologics, but I've been to China recently, specifically to see very similar patients who have never been exposed to a biologic. They did not do biopsies but the patients I saw looked very similar and their chest CTs looked similar as well," he told MedPage Today. "Also, in December I was in Israel for a rheumatology society meeting with other pediatric rheumatologists. I showed them images from our patients and asked if they were seeing this in Israel, and there had not been a single case. They have a similar approach to management as we do although they use more steroids, and at least half of them had been trained in the States," he said. In addition, other areas of Europe where biologics are commonly used, the lung disease remains very rare. In a very recent series of 42 sJIA patients from Utrecht whose median age was 7.1 years and who were treated with first-line anakinra, only one developed pulmonary disease, and that occurred during a fatal episode of MAS. "These observations underscore the critical need for well designed multicenter epidemiologic studies including different geographic areas with different patterns of medication utilization to define risk factors and support strategies to prevent development of this disorder," Grom's team concluded. "It's really important to underscore how powerfully useful these drugs are in sJIA, and the number of children affected by these lung manifestations is very small," Mellins emphasized to MedPage Today. "It is premature to make treatment recommendations solely on the basis of our findings," she and her colleagues wrote, stressing that management should be individualized and that urgent efforts should focus on improved detection and prevention. Ombrello made a similar point. "These studies have not demonstrated any evidence that there is a causal relationship between sJIA lung disease and anti-cytokine therapies in sJIA," he said. "As a result, these studies should not change the therapeutic approach to sJIA." As for treatment of the lung complications, Mellins said that is still a work in progress: some children have resolved their lung disease, but the numbers are too few to assess any treatment strategies. "But clinicians should pay attention to red flags, such as young age at sJIA onset, lymphopenia, and the loss of response to therapy," she said. In her cohort, some children had been well controlled but flared and then lung disease was detected. "But we don't know which is the cart and which is the horse -- whether developing lung disease stimulates systemic inflammation or whether systemic inflammation is a serious risk factor for lung disease," she said. Prophylaxis for pneumocystis pneumonia is recommended, she noted. "Another difficulty is that our ability to diagnose this condition is not great," Grom told MedPage Today. "We pick it up late, when there are already irreversible fibrotic changes in the lung. There is a dissociation between the relatively mild clinical presentation and the severity of the histopathologic findings or massive lung disease on chest CT," he said. He also argued that patients with the clinical pattern his group described -- early onset, recurrent MAS, and very high IL-18 -- should be carefully monitored for signs of lung disease and have a low threshold for obtaining a chest CT. "Given the surprisingly high mortality of sJIA lung disease reported in these studies, it is critically important to incorporate screening tests for pulmonary disease into the routine management of children with sJIA," Ombrello concluded. The multicenter study on medRxiv was supported by the systemic JIA Foundation, the Lucile Packard Foundation for Children's Health, the CARRA-Arthritis Foundation, the Life Sciences Research Foundation, a Bio-X Stanford interdisciplinary graduate fellowship, a Stanford graduate fellowship, the Computational Evolutionary Human Genetics fellowship, the Bill & Melinda Gates Foundation, and the National Institutes of Health. The study authors reported financial relationships with Novartis, AB2Bio, Novimmune, SOBI, and Boehringer Ingelheim. The Cincinnati study was supported by the National Institutes of Health, the Systemic Juvenile Idiopathic Arthritis Foundation, and the Cincinnati Children's Research Foundation. Its authors reported financial relationships with Novartis, EMD Serono, R-Pharm, Boehringer Ingelheim, UCB, Bristol Myers Squibb, Pfizer, Janssen, Eli Lilly, Roche, Juno, Novimmune, and AB2Bio. Nigrovic has been supported by the National Institutes of Health, the Fundación Bechara, and the Arbuckle Family Fund for Arthritis Research. He also has received financial support from Novartis, Pfizer, Sobi, Bristol-Myers Squibb, Quench Bio, and Simcere. 2019-12-24T12:00:00-0500  |
| PAH May Be Treated With Antiarrhythmic Tikosyn, Study Suggests - Pulmonary Hypertension News Posted: 16 Dec 2019 12:00 AM PST Tikosyn (dofetilide), a medicine approved by the U.S. Food and Drug Administration (FDA) to treat heart arrhythmias, may be used to treat pulmonary arterial hypertension (PAH), a recent study suggests. The findings warrant further investigation into the therapy's potential positive effects for patients with PAH, the researchers stated. The study, titled "Increased Smooth Muscle Kv11.1 Channel Expression in Pulmonary Hypertension and Protective Role of Kv11.1 Channel Blocker Dofetilide," was published in The American Journal of Pathology. Kv11.1 potassium selective channels are especially known for their important role in the heart, as they help maintain a normal beating rhythm. These channels also play important functions in other organs, such as the brain, where they are responsible for controlling neurons' excitability (their ability to send signals). Moreover, "Potassium channels are essential for proper lung function, and defects in ion channels have been linked to various respiratory diseases. However, surprisingly little is known about Kv11.1 channel expression and function in normal lung tissue," the researchers said. In two lung diseases in particular — PAH and chronic obstructive pulmonary disease (COPD) — different types of potassium channels have been implicated in the process of vascular remodeling that causes the narrowing of blood vessels in the lungs. "Despite the importance of Kv11.1 channels for many physiologic processes, their expression and function in the pulmonary vasculature [blood vessels] and their potential role in PAH- and COPD-associated vascular remodeling have not been investigated," the researchers said. In this study, researchers from Georgetown University Medical Center discovered that the lungs of patients with COPD associated with PAH and rats with experimentally-induced PAH had significantly more Kv11.1 channels, compared to lungs of healthy humans and rats. Importantly, when they examined lung tissues from healthy volunteers and animals, they found that Kv11.1 channels were present only in large pulmonary arteries (PAs) — the arteries that connect the heart to the lungs. However, when they analyzed samples from patients with COPD associated with PAH and rats with PAH, they discovered these channels were present not only in large PAs, but also in blood vessels of small caliber (those that are less than 100 μm in diameter). Moreover, they discovered the increase in the levels of Kv11.1 channels in lung tissues of sick rats accompanied the process of vascular remodeling as PAH progressed. When they treated animals with Tikosyn — a pharmacological inhibitor of Kv11.1 channels that's marketed by Pfizer — they managed to halt the process of vascular remodeling. In these animals, Tikosyn increased the diameter of the lumen (inside) and reduced the thickness of PA walls to values identical to those seen in healthy rats. "Our study suggests that Kv11.1 channel blockers may have therapeutic potential for treatment of PAH. Specifically, we have shown that dofetilide, which is already FDA-approved as an antiarrhythmic and therefore has passed all of the drug safety requirements, can be considered for repurposing for treatment of patients with PAH," Tinatin I. Brelidze, PhD, assistant professor of pharmacology in the department of pharmacology and physiology at Georgetown University Medical Center, and senior author of the study, said in a press release. Drug repurposing refers to the process of testing a medication with established safety in conditions other than those for which it was originally approved. This strategy offers many advantages over developing a new therapy, namely financial and time-saving gains.  Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns. × Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns. Latest Posts  |
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