Brain Hemorrhage in Boy with Hemophilia Treated with Transfusions

BY Margarida Azevedo 

Researchers in India recently reported the case of child with hemophilia and traumatic intracerebellar hemorrhage, who was successfully treated with transfusions of plasma. They recommend a conservative approach as a first line of treatment, before more invasive alternatives such as surgery.

The case report, “Intracerebellar haemorrage in a haemophilia child,” was published in the Asian Journal of Neurosurgery
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Hemophilia A is caused by deficiency of clotting factor VIII, and its treatment is usually managed with factor replacement products and medications. Access to these products, however, can be difficult for patients in developing nations.

A 12-year-old boy, with a history of transient loss of consciousness and vomiting, sustained a head injury in a fall, and was taken to SCB Medical College and Hospital, in Cuttack, Odisha. Through a computed tomography (CT) scan, physicians identified a well-defined lesion in the intracranial cavity of the boy’s brain. As acute intracerebellar bleeding was suspected, the child was advised to see a neurosurgeon. But his condition was stable, and his parents decided to differ.  Some six weeks after the incident, however, the boy returned to the hospital with symptoms of headache, intermittent vomiting, and an unsteady gait. Magnetic resonance imaging of brain revealed mid-posterior cerebellar, sub-acute, intracerebellar bleeding.

The boy’s coagulation profile was suggestive of moderately severe hemophilia. He was treated with six units of fresh frozen plasma and intravenous tranexamic acid, a medication used to control unwanted bleeding. This treatment led to clinical improvement  and, eventually, the hematoma spontaneously resolved. Such results indicate that early detection and correction of factor levels when intracranial bleeding occurs could prevent possible life-threatening complications.

“Choosing safe sports is vital for children with hemophilia. In case of traumatic intracranial bleed, prompt diagnosis and conservative approach through procoagulant transfusion and intravenous fibrinolysis inhibitors should be tried as first line of management. Before daring for surgery, sufficient amount of factor replacement should be kept available,” the researchers concluded.

 source: http://hemophilianewstoday.com/2016/08/30/brain-hemorrhage-in-hemophilia-boy-successfully-treated-with-transfusions/

New exciting aspect of the coagulation system

All the players in the coagulation system are known—or are they? Thrombin is a key enzyme in the system that controls clot formation; too much or too little can lead to either hemorrhage or thrombosis. At the medical plenary “Rethinking Events in the Hemostatic Process: Role of factor V and TFPI,” Rodney Camire, Philadelphia, Pennsylvania, USA, explained that extrinsic Xase, intrinsic Xase and prothrombinase are regulators of thrombin. “By dampening inhibitors you can control thrombin,” he said.

Camire shared his expertise with hundreds of attendees Monday morning. “FV is very similar to FVIII in some ways and needs to be processed at specific sites,” he said, pointing out however, that FV is a procofactor requiring proteolytic activation in the B domain. The role of the B domain is to keep the molecule active. By looking at sequences for the alignment of FV B domain, Camire and his research team experimented with how both the basic region (BR) and the acidic regions (AR) contribute to keeping the molecule active.

Camire stated that the FV BR fragment and FXa compete for FV-810 binding. There is a discrete segment of the B domain that serves an essential autoinhibitory function to maintain FV as a procofactor. “Disseminating this region is the driving force to unveil a high affinity binding site for FVa,” he explained.

He pointed out that an important step in thrombin generation is the activation of FV to FVa. Mr. Camire said that certain Australian snakes have a unique form of FV in their venom with these inhibitory sequences removed, thereby creating an active procoagulant cofactor.

Tissue factor pathway inhibitor (TFPI) naturally forms in the blood. TFPI binds FV in plasma, but shows no affinity to FVa. “There are two to three different forms of FVa that are generated during the initiation of coagulation that are sensitive to TFPI alpha (TFPIα),” said Camire.

Camire also said that there are new physiologic forms of FV. Citing research from east Texas (USA), individuals have been found that have a mutations in exon 13 of FV, which causes a spliced transcript. Thus, there are forms of FV that are B domainless, that lack the BR, but harbor in the acidic region. Known as FV short, this binds to TFPIα. These patients were shown to have 10 times the level of TFPIα. TFPIα via the BR can block FVa function. This is currently a therapeutic target for hemophilia treatment.

In summary he said blocking TFPI function will enhance coagulation. “Antibodies targeting TFPI are in clinical trials. Specific B domain sequences are key autoinhibitory elements responsible for keeping FV as a procofactor. Dismantling these sequences drives FV activation. These mutations change a weak splice site into a strong splice site.”




source: http://www.wfhcongressdaily.org/2016/07/new-exciting-aspect-of-the-coagulation-system/

Jeanne White-Ginder: mother of Ryan White

Hear the Ryan White Story as told by his mother, Jeanne White-Ginder. Ryan was a boy living with hemophilia and diagnosed with AIDS following a transfusion of tainted clotting factor in December 1984.

The WFH is very proud to be able to welcome Jeanne White-Ginder to the WFH 2016 World Congress. Jeanne will be telling the story of her son Ryan White, who was born with hemophilia and was diagnosed with AIDS following a transfusion of tainted clotting factor in December 1984. At the time, Ryan was 13 years old and was attending school and living in Komono, Indiana. He was given six months to live.

When Ryan tried to return to school after receiving his AIDS diagnosis, he fought AIDS-related discrimination in his Indiana community and was barred from attending public school. Ryan and his mother rallied for his right to attend school through a legal battle that gained national attention. The White family became the face of public education about AIDS.  His story captured the hearts of people worldwide including—most famously—Elton John and Michael Jackson, who both befriended the White family.

Ryan ultimately earned the right to return to school and continued to be a spokesperson for AIDS.  He spoke before the President’s Commission on AIDS, held regular media and talk show appearances, and spoke to over 10,000 teachers and educators at the Louisiana Superdome. Surprising his doctors, Ryan lived five years longer than expected. He died in April 1990, one month before his high school graduation and only months before the United States Congress passed the legislation bearing his name in August 1990: the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act, which provides care and treatment to over 500,000 people each year.

Since Ryan died in 1990, Jeanne has continued to tell their story, educating people about the disease in the hope of making the world a more educated, compassionate and caring place for people living with HIV/AIDS.

source: http://www.wfhcongressdaily.org/2016/07/jeanne-white-ginder-mother-of-ryan-white/

Options in delivery of gene therapy explored

Scientists involved in cell-based therapy for bleeding disorders provided updates on this exciting discipline of gene therapy Tuesday morning. David Lillicrap, Canada, the chair of the session, “Gene Therapy”, said the momentum of clinical gene therapy is remarkable.

Chritopher B. Doering, Atlanta, Georgia, USA, took the audience through the process of using stem cells in gene therapy of hemophilia A. Stem cells were first applied to T cells in the 1990s, but safety concerns led the research back into academic laboratories, said Doering.

“Stem cells are rare populations of unspecialized cells that are self-renewing and can become other cells,” began Doering. “Donor cells from a non-affected individual (from the blood) are transplanted into the patient. In order to apply to hemophilia, this may require gene transfer.”

In order to implant stem cells, some of the patient’s cells must be negated to make room for the new cells. Doering said that it is possible to use the patient’s own cells harvested peripherally or from bone marrow.

Challenges to using stem cells include the optimization of transgene expression and producing biosynthesis, and also safe and effective pre-transplantation conditioning and clinical vector manufacturing, said Doering. “Stem cells can last for the life time of an individual so we have a potential cure.  We need only to target a few cells as each stem cell will produce hundreds of daughter cells.”

A pilot clinical trial design has been approved the US Food and Drug Administration with a single site trial at Emory University, USA, to start.

Matthew Porteus, Stanford, California, USA, said that genome editing is a method to correct disease causing variants. “This is a precise, controlled mutagenesis of the genome. Creating a break in the DNA will cause the cells look for this and make a repair. So we can stimulate mutations at the site of the break.”

The repair could change the DNA sequence to one that already exists in the genome or to something novel using synthetic biology. This second option “Creates a new therapeutic phenotype in the cell. In hemophilia it might be used to overly express a clotting factor,” said Porteus.

Using homologous recombination to change single nucleotide variants can be delivered on an adeno-associated virus (AAV) nanoparticle. “In research with sickle cell disease there is about a 20 percent success rate. We can also insert a gene cassette into a safe harbor or single location in the genome,” said Porteus.

“Targeting transgene addition without knocking out the target gene or knocking it into a highly expressed gene has some exciting applications,” noted Porteus. “There are opportunities and challenges for in vivo gene editing for hemophilia. There would be no need to give patients conditioning agents and it is a potential method to edit cells that naturally make clotting factors.” One drawback however, is a lesser ability to monitor efficacy and off-target effects, he added.

Porteus noted that an ethical concern of genome editing is equity and distribution and how to take it to the parts of the world where most people with hemophilia live.

Brigit E Riley, Sangamo BioSciences, USA, delivered new data on FVIII using AAV delivery. “Using AAV in clinical and preclinical trials for FIX has been successful, however there is a lag in the clinic for FVIII.”

She said liver-directed AAV FVIII CDNA gene therapy is being explored as liver cell DNA is separate from transgene DNA. Recombinant AAV is efficient and stable long-term in tissues that do not divide such as the liver, brain and muscle.

FVIII is not an ideal gene for AAV as it is constrained by gene size and low efficiency of transcription/translation. Thus, it requires multi-factorial modifications. “With the modifications, virus yield was improved 8 to 10 fold,” said Riley.

She noted that data from in vitro design saw good correlation between FVIII activity and levels along a range of doses. In vivo wild type mouse data showed FVIII level 2 times normal. In vivo hemophilia A mouse model FVIII activity was 3 times normal and levels were stable over time. A reduced bleeding time was also observed.  In vivo non-human primate data FVIII levels were 4 to 6 times normal levels. “Follow-up dose finding studies are aimed at determining minimal dose,” said Riley.

The challenge of financial incentives is one area to still be addressed. Porteus pondered, “With no established reimbursement model for a one time gene therapy, it begs the question, ‘Are stakeholders willing to take a chance on experimental curative therapies that have a different conceptual basis when the current paradigm has transformed the lives of hemophilia patients?’”

source:http://www.wfhcongressdaily.org/2016/07/options-in-delivery-of-gene-therapy-explored/

Inhibitors – What Have We Learned?

A medical session this afternoon chaired by Brigitte Keller-Stanislawski, of the Paul-Ehrlich-Institute and Mike Soucie, of the Centers for Disease Control and Prevention will ask the question, “Inhibitors, what have we learned?” Inhibitors to FVIII are today the most serious complication of treatment for hemophilia but there is contradictory information about how best to avoid inhibitors, especially in previously untreated patients (PUPs), the most vulnerable group.

Most inhibitors develop within the first 50 exposure days but questions remain about whether the choice of treatment product during that period has an effect on the risk of developing inhibitors. The recently published SIPPET paper suggests that, in PUPs, the risk of developing an inhibitor when using certain recombinant FVIII products is higher than when using plasma-derived FVIII concentrates that contain von Willebrand factor. The study was the first prospective, randomized, multicenter open-label trial in this area. It compared PUPs treated with recombinant factor VIII (rFVIII) to those treated with plasma-derived factor VIII concentrate containing von Willebrand factor (pdFVIII/VWF). The results showed a higher rate of inhibitor (neutralizing antibody) development in the rFVIII-treated subjects compared to pdFVIII/VWF-treated subjects.

However, other datasets do not support the conclusion that the class of recombinant products carries a higher risk. This session will survey these contradictory studies and continue the debate. Dr. Keller-Stanislawski will describe an individual patient meta-analysis of the France coag, UKCHDO and PedNet/ RODIN studies on recombinant products. This analysis involves a very large cohort of PUPS all followed out to 50 exposure days or more. Other speakers will discuss the clinical and laboratory aspects of the immunologic basis of inhibitor development and further data related to the roles of product class and von Willebrand factor. Come to hear the latest thinking on this controversial and important topic.

Source: http://www.wfhcongressdaily.org/2016/07/inhibitors-what-have-we-learned/

The future of hemophilia treatment is very promising

source: http://www.wfhcongressdaily.org/2016/07/wfh-vice-president-medical-the-future-of-hemophilia-treatment-is-very-promising/

Hemophilia treatment has entered an exciting era, with new products making diagnosis and treatment available for a far larger population than ever before, said WHF Vice-President Medical Marijke van den Berg during her Tuesday morning VP Medical Plenary address.

The session covered a variety of studies in people with severe hemophilia A that demonstrate how early prophylaxis can prevent bleeding and is key for joint outcome. This replaces episodic therapy, which has been a frequently used hemophilia treatment regimen since the 1970s.

“Modern hemophilia treatment has completely changed the phenotype—but not in countries where early treatment is not available,” she said.

Ms. van den Berg cited a very large U.S. study of patients with severe hemophilia A, divided into four birth-date cohorts. Even in the age group born in the 1980s, disability was too high, she said, with more than five joint bleeds over six months, despite very high clotting factor consumption.

The large, international Musculoskeletal Function in Hemophilia (MUSFIH) study of children with severe hemophilia A showed that even very high factor dosing resulted in substantial bleeding, van den Berg said. The study also showed that the number of bleeds—but not the dose of episodic treatment—is responsible for joint outcome. This is a key understanding because joint function deteriorates after age 12.

Ms. van den Berg cited a small, randomized study showing that low-dose prophylaxis, rather than episodic treatment, reduces bleeding by 80 percent. Research also shows that early diagnosis is crucial. “Remember, more than 50 percent of those with severe hemophilia A have a negative family history,” van den Berg said.

But when and how do you start prophylaxis? van den Berg said research suggests that the key is to start earlier than age 3 because physical examination scores increase with treatment delay. Other research shows that low-dose prophylaxis should be done a minimum of once a week.

There is a correlation between joint scores and dosage of factor replacement. “With a 1,000-1,500 dose, there’s a lot to gain,” van den Berg said. The good news for people in developing countries, where factor supply is limited, is that data show that lifetime prophylaxis with 1,000 IU per kilo is much more effective than episodic treatment. “You can significantly improve outcome with limited factor consumption,” she said.

However, to implement low-dose prophylaxis, comprehensive care centres are crucial, van den Berg said. She recently toured two international hemophilia training centers that are excellent examples of this: the centre in Campinas, Brazil, led by Margareth Castro Ozelo, and the centre in Johannesburg, South Africa, led by Johnny Mahlangu. The Johannesburg centre serves 1,200 patients, with an impressive 35 percent on prophylaxis and home therapy.

Unfortunately, these centres are the exception. Recent data from Africa show that not even 5 percent of hemophilia patients are diagnosed. “The main reason is because limited or no treatment is available,” van den Berg said.

The WFH Humanitarian Aid Program will substantially address that deficit. From 2016 to 2020, the program plans to provide a predictable supply of 500 million IUs of factor, van den Berg said. Availability of products will lead to more diagnosis, and that will lead to more training and, in some cases, corrective surgery.

In conclusion, van den Berg said that the evidence shows that only primary prophylaxis can prevent joint disease, and episodic treatment is not an appropriate regimen for severe hemophilia A. After joint bleeds, signs of arthropathy appear even with very high-dose prophylaxis. And signs of loss of joint function are often visible at puberty due to growth spurts.

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Think of self-care in a new way

Patrick Lynch formed a company, Believe Unlimited, and created an online comedy series styled after the TV show “The Office.” Dubbed “Stop the Bleeding,” the series—available at stbhemo.com—is a mockumentary about a dysfunctional bleeding-disorders nonprofit organization. It uses humor to tackle serious topics like self-care and self-infusion, women with bleeding disorders and the history of hemophilia.

In 2007, Patrick Lynch’s younger brother, Adam, died of an intracranial bleed at age 18. Both Patrick and Adam were born with severe hemophilia A.

Patrick was only 22 at the time. “As you can imagine, the months and, quite frankly, the years that followed were challenging. I remember saying, ‘[Hemophilia] got him. It’s not supposed to happen to us anymore, but it got him,’” Patrick said during the Wednesday morning “Empowerment Through Self-Care” plenary.
Desperate to discover why Adam died, Patrick searched for a clue. He found it in the bottom of a duffel bag buried in a corner in Adam’s college dorm room. The bag was full of factor. Patrick suspects his brother had stopped his prophylaxis.

“I spent a considerable amount of time thinking about why he fell off his regimen,” Patrick said. “I finally determined that it was because my brother never identified as having a bleeding disorder. That took him off his regimen.”

Patrick has never felt the same way. He developed an inhibitor as a child, but immune tolerance induction eradicated it when he was 13. He was able to go on prophylaxis and live, as he refers to it, “A much more empowered life.” He got involved in high school theater and majored in acting at Boston University.
Patrick has always valued self-care for his hemophilia, but Adam’s death made him realize that others—particularly children—may not.

“It made me think about how we as a community are engaging young people,” he said. “And I saw an opportunity to use my acting background to create something that didn’t exist.” His brother didn’t connect to the bleeding disorders community in traditional ways, but like many young people, he loved comedy and the internet.

So Patrick formed a company, Believe Unlimited, and created an online comedy series styled after the TV show “The Office.” Dubbed “Stop the Bleeding,” the series—available at stbhemo.com—is a mockumentary about a dysfunctional bleeding-disorders nonprofit organization. It uses humor to tackle serious topics like self-care and self-infusion, women with bleeding disorders and the history of hemophilia.

“We want to teach young people with a bleeding disorder, but we really want to inspire them,” Patrick said. The goal is to replace the stigma and fear of hemophilia with the idea that the disease can be “Funny or cool or even uplifting,” he said.

Since launching “Stop the Bleeding”, Patrick’s company has also created a live speaker series called “Powering Through”; the Impact Awards to recognize teens with bleeding disorders; a monthly podcast called “Bloodstream” and a claymation series called “Helping Hany” that examines the psychosocial implications of being a girl with a bleeding disorder. He’s also produced videos for the WFH Treatment for All initiative.

All of this fits within Patrick’s definition of self-care. “My journey and understanding of self-care has evolved,” he said. “It’s not just self-infusing, stretching, and maintaining a good diet. For me, self-care is giving back to and empowering the community.”

He also acknowledges that he has a “Privileged definition of self-care—a privilege not shared by 75 percent of our community in developing nations.” That’s why he believes people from the developed world have an obligation to help others who aren’t able to self-infuse or do other aspects of self-care because they lack treatment options. This can include asking product manufacturers how they help people in developing countries and contributing to the WFH Humanitarian Aid Program.

“I miss my brother. For years, I thought about him every day,” Patrick said, his voice breaking. “Let’s continue to ramp up our efforts for our brothers and sisters in developing countries so one day they too may enjoy a privileged definition of self-care.”

source: http://www.wfhcongressdaily.org/2016/07/multidisciplinary-plenary-empowerment-through-self-care-patrick-james-lynch-wednesday-july-27th-930-1000/

Hepatitis C: a virus with serious implications for hemophilia patients

Unlike HIV and HBV, hepatitis C (HCV) is not a disease for life. Cure rates have risen from 10% to now over 95% since the virus was discovered in 1991.

Dilip Moonka, Detroit, Michigan, USA, took the stage first Wednesday morning during “Hepatitis C Update: Complications and Side Effects.” Looking forward, he said drugs for HCV will be taken orally, have a cure rate of over 95%, will require less than 12 weeks of therapy and will be well tolerated.

Moonka said that in individuals exposed to the virus:

• 20% will clear the virus
• 75% to 85% will develop chronic infection
• 5% to 20% will develop cirrhosis, and
• Typically it takes 20 years to develop cirrhosis
• 5% to 20% of patients with cirrhosis will develop liver cancer

“You have to continue to screen for liver cancer if HCV has been cured if you have cirrhosis,” said Moonka. “Persons infected with HCV should refrain from excessive alcohol use and should be vaccinated against HAV and HBV if not immune.”

Moonka said there are two tests that are used to confirm HCV. The first is an HCV antibody test to screen for the virus. The HCV RNA (PCR) in the confirmatory test.

In order to successfully treat the virus, the patient’s genotype needs to be known. “The drug Harvoni is effective with genotype 1,” he said, warning that this drug should be used with caution if the patient is taking amiodarone and should be avoided if creatinine clearance is less than 30 ml/minute. “The drug AbbVie [offers] is also very well tolerated, even though more pills are taken. Zepatier can be given to those with renal failure and we will still see cure rates close to 100%.” Drugs are also available for other genotypes that elicit a cure rate of more than 95%.

Magdy El-Ekiaby, Egypt, told the audience that Egypt is one of the countries in the world with the highest rate of infections. The HCV burden is great, with the 15 to 59 year age group estimated to be 7% infected. “This is an endemic infection with social, economic and political implications,” he said. “On-going transmission is still occurring with up to 200,000 new patients each year.”

He said the economic burden is $670 million USD and intangible costs to society and families cannot be assessed. “Curing one patient saves $10,000 and preventing an infection saves $20,000.”

Until 2006 Egypt did not have a comprehensive national program for control of HCV. At that time the objectives became to track prevalence, implement infection control, expand access to treatment and ensure high quality scientific research. In the 2011 to 2014 action plan, new drugs were launched and 400,000 patients were treated. “Government scaled up treatment centers nationwide and they should reach 100 by the end of 2016,” said El-Ekiaby. “Treatment guidelines are updated regularly and there is fast track registration of all approved new drugs with special pricing.” The government pays for 83% of costs, health insurance pays 9% and 8% is out of pocket.

Real-life results shows that therapies have close to a 95% cure rate. “To achieve elimination, we need to increase annually the number of treated patients. Without significantly changing treatment strategies, HCV will remain a highly prevalent problem for the next 20 to 30 years,” he said.

Gerard O’Reilly, Ireland, told the audience that he was born in 1959 with severe hemophilia A. He received his first treatment at age 12, which gave him a better quality of life, but he had to travel long distances for on-demand treatment.

“In the 1970s, treatments became life changing and I could finish my education and work,” said O’Reilly. “The 1980s saw contaminated product and in 1986 I received a diagnosis of HIV. Still trying to cope with this, in the 1990s they told me about a second virus, called non-A/non-B.” Diagnosed with HCV he was offered his first treatment of interferon and spent ten months on injections which caused mood swings, nausea and were mentally draining.

“In 1997 new AVR drugs came on the market and within three months of taking them my HIV was undetectable, but my liver showed signs of fibrosis so my biggest challenge became hepatitis C.” With his liver moving toward cirrhosis, it was ten more years before a new drug came onto the stage.

Doctors discovered a tumor on his liver in 2013. Chemotherapy was injected into the vein that fed the tumor. “I went to get a liver transplant, but failed the assessment as they discovered I needed a triple bypass. In the meantime the tumor started to grow and spread.” He had a liver transplant in 2014 with no rejection issues. “I now have 58% clotting factor, so good-bye hemophilia!” But the HCV virus still had be tackled. HCV treatment is cost prohibitive in Ireland.

O’Reilly started his treatment in 2015 and was cleared of virus. However, the virus returned aggressively in May of 2016. He expects to start retreatment in September. “Life has changed a lot for me without hemophilia. I have a regime of walking every day. Hepatitis C is a very nasty virus, but with the support of friends I have learned a lot.

source: http://www.wfhcongressdaily.org/2016/07/hepatitis-c-a-virus-with-serious-implications-for-hemophilia-patients/

Lessons from NASA: What is an appropriate level of risk?

Since the 1980s, when about 10,000 people with hemophilia tested positive for HIV after receiving contaminated blood, assessing and managing risk has been a core principle in the bleeding disorders community. This applies not only to blood supplies that can be infected with both known and unknown viruses, but also to the development of new treatment products.

In the Wednesday morning plenary “Managing the Risk of Human Space Flight: Lessons From 50 Years of NASA Human Space Flight,” Michael Lutomski, a former international space station risk manager for NASA, noted that both the hemophilia community and NASA operate in environments that do not tolerate risk or failure. And yet, risk is unavoidable. So what is the best way to deal with these types of situations?

One key is continuous risk management, Lutomski said. We already do this almost every day of our lives, he said, using the example of choosing a flight to Orlando to attend this Congress. For instance, you may have managed the risk of missing a connecting plane by choosing a longer connection time.

NASA has a mind-boggling level of risk, Lutomski said, with a 3.4 percent failure rate in launches each year. “Can you imagine crossing the street or driving a car with those odds—you’d never do it,” he said.

And yet, Lutomski said the common perception—even at NASA—was that space flight had the same level of risk as flying on an airplane. However, in 1986, the Challenger explosion changed that—much like the AIDS crisis changed the common perception that blood transfusions were inherently safe.

NASA responded to the Challenger crisis by rethinking how it handled risk. It instituted a risk-based decision-making framework and a risk threshold. Astronauts sign statements noting that they understand risks like a death rate of one out of every 270 crew members on a six-month expedition to the International Space Station. “We now have a more healthy realization of what risks we’re really taking,” Lutomski said.

One of the best ways to mitigate risk is to self-report, Lutomski said. But people have many reasons for not participating in risk assessment and reporting. They think they have no risk, their programs are too small, making risk public will kill a program, they prefer to deal with problems as they arise, identifying risks is bad for their career, it’s not their job to fill out bureaucratic forms, or they can’t assess risk because they can’t predict the future.

Not only does a successful risk-management system need to overcome those arguments, but it also needs to be humble and open to new information, Lutomski said. At NASA, that translates into continually questioning performance, looking at risks, and responding appropriately to failures when they occur.

source : http://www.wfhcongressdaily.org/2016/07/lessons-from-nasa-what-is-an-appropriate-level-of-risk-for-the-hemophilia-community/

Gene therapy offers encouraging possibilities for hemophilia care

The 2016 WFH World Congress has seen incredible enthusiasm and excitement about the topic of gene therapy, said David Lillicrap, Canada, when he chaired “Medical Free Papers – Gene Therapy” yesterday afternoon.

The 2016 WFH World Congress has seen incredible enthusiasm and excitement about the topic of gene therapy, said David Lillicrap, Canada, when he chaired “Medical Free Papers – Gene Therapy” yesterday afternoon.

Lindsey George, Pennsylvania, USA, spoke first about rAAV mediated gene transfer for hemophilia B.

She said that in 2011, research showed success for AAV8 vector for FIX, as there was no evidence of late toxicity sustained expression with circulating FIX activity levels of 1% to 6%. “The goal of gene transfer is sustained long term expression,” said George. “We want consistent and predictable results to subsequently build upon.”

In her team’s research, they used SPK-9001 investigational vector. Those that did not have neutralizing antibodies to this vector were eligible for the trial. The transgene was a single strain. “The study enrolled adult males with FIX > 2% and no underlying HBV or HCV. The vector administrated intravenously over one hour, outpatient.”

“The 4 subjects treated all have negative rAAV neutralizing antibodies with SPK-9001 at a dose of 5 x 1011 vg/kg. We followed for 532 days and to date no subject required immunosuppression, there was no inhibitor development, we saw a marked reduction in factor use and bleeding events. 5 x 1011 vg/kg confers sustained FIX expression without need for immunosuppression,” she said. “To our knowledge these data represent the highest levels of sustained FIX expression at the lowest dose. Additional subjects and continued observation are needed to confirm initial results.”

John Pasi London, UK, said we have a completely new generation of therapies. “These require single infusion eliminating the dependency on repeated FVIII injections over a lifetime.”

Pasi told of research done with an AAV5 capsid vector, using a single stranded DNA. “This has been tested extensively in preclinical animal models. In this study we enrolled nine patients; eight were on prophylaxis and three had previous HCV infection. No participant had HIV or inhibitor to FVIII.”

Pasi said liver function elevation was relatively mild. FVIII expression on low dose had no change in baseline, while mid-dose showed stable FVIII activity for over 28 weeks. “In seven patients on high dose (BMN 270 at 6E13 vg/kg), all had FVIII activity levels and six showed > 50 IU/dl. Bleeding essentially ceased after two weeks.”

Wolfgang Miesbach, Germany, also addressed hemophilia B with the premise that factor level determines phenotype. “We used the molecule AMT-060, which was prepared in the pharmacy, infused over 30 minutes by IV with 24 hour observation in the hospital.”

He said the gene cassette was same as used in the St. Jude/UCL study and corresponded to a meaningful reduction in FIX usages.

Adult patients with severe or moderate hemophilia B were included. Excluded from study were those with preexisting neutralizing AAV5 antibodies, FIX inhibitors, active HB, active HCV and uncontrolled HIV.

No evidence of sustained AAVS capsid specific T cell activation was found. As expected all patients developed anti AAV5 antibodies. “A single treatment of 5 x 1012 gc/kg AMT in 5 patients was generally well tolerated after 30 weeks,” he said. “Results were stable with durable FIX activity and a mean of 5.4%. In 4 of 5 patients we saw discontinuation of FIX prophylaxis. This supports a wide application of AAV5 based gene transfer approach.”

source : http://www.wfhcongressdaily.org/2016/07/medical-late-breaking-gene-therapy-chair-marijke-van-den-berg-wednesday-july-27th-1415-1545/#.V5sLSN4mZjs.facebook

Researchers Question Health-Related Quality of Life for Youth, Young Men with Hemophilia

August 12, 2016

by Margarida Azevedo

 Researchers at several Canadian institutions investigated the tendencies of health-related quality of life (HRQoL) among teenagers and young adults with hemophilia A (HA) and found that young adults demonstrated more joint disease and worse HRQoL when physical function and pain were considered.

The research paper, “Generic and disease-specific quality of life among youth and young men with Hemophilia in Canada,” published in BMC Hematology, provides new information for the selection of HRQoL parameters for future hemophilia clinical trials.

The objective assessment of patient status and outcomes of different therapeutic strategies is usually achieved by measurement of bleeding rates, joint and musculoskeletal status, pain, and physical and social function. Health-related quality of life (HRQoL) assessment aims to measure the impact of a disease and chosen treatment on the patient. Such tools basically consist of self-administered questionnaires. At the present, there are very few published studies on long-term trends of HRQoL in hemophilia.

HRQoL in hemophilia may be not only be determined by change in physical status, but also “influenced by common social events such as educational, vocational or relational changes associated with transition from adolescence to adulthood” the authors wrote. The study enrolled 13 youth (ages 12.9-17.9 years) and 33 young adults (ages 18.4-28.7 years) with moderate (7 %) and severe (93 %) HA, from six treatment centers in Canada.

According to results, the youth had minimal joint damage, when compared to young adults. HRQoL scores for SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS), for both age groups, were comparable to published Canadian norms. But the differences for Physical Functioning and Bodily Pain were clinically meaningful and statistically significant —  young adults presented declining function when compared to the youth. Lifelong prophylaxis treatment correlated positively with better PCS scores, but was also associated with worse MCS scores.

The study concluded: “Comparatively little is known about factors that might influence longitudinal patterns of HRQoL in patients on a stable treatment regimen. The current results form the foundation for a longitudinal study to examine the impact of biological factors and life events on the HRQoL of youth and young adults with hemophilia followed prospectively for 3 years.”

source: http://hemophilianewstoday.com/2016/08/12/quality-of-life-among-youth-young-men-with-hemophilia-in-canada/

Preventive Hemophilia Treatment Still Faces Obstacles, but Future Looks Promising

by Magdalena Kegel

Prophylactic hemophilia treatment can save patients with severe forms of the disease from the long-term consequences of joint damage and other complications. A report by Dr. Suchitra S. Acharya, MD, of Hofstra Northwell School of Medicine in New York, gives a detailed overview of the current state and future perspectives in this area of treatment.

The report, “Advances in Hemophilia and the Role of Current and Emerging Prophylaxis,” financed by Baxalta and published in the American Journal of Managed Care, also emphasizes several barriers to optimal treatment that still exist, underscoring the need for continuous research.

Prophylactic, or preventive treatment, of hemophilia emerged after reports that patients with severe disease who were continuously treated were similarly impacted by their disease as those with moderate or mild hemophilia — rarely bleeding spontaneously, and very seldom developing joint damage caused by repeated bleeding.

Several clinical trials confirmed that both bleeding episodes and joint damage were largely prevented by prophylactic treatment. Also, more severe complications, such as intracranial bleeding, were prevented by this approach, and today, prophylactic treatment is increasingly being used worldwide.

Studies have also shown that the earlier treatment is started, the larger the chances of preventing joint damage, but starting treatment in older children, adolescents, or adults have also shown good results. But once joint damage is established it cannot be reversed by preventive treatment.

The frequent dosing of the intravenous blood clotting factors understandably makes prophylactic treatment a hassle, lowering the quality of life in patients. New products designed to stay longer in the blood so that they can be administered at longer intervals are increasingly gaining ground. In 2014, a factor IX Fc fusion protein was approved for hemophilia B, and it was soon followed by a factor VIII Fc fusion protein for hemophilia A.

Another approach to prolong the activity of the blood clotting factors was to link them to so-called PEG molecules. A PEGylated factor VIII was approved in 2015, and a factor IX is undergoing clinical trials. Other approaches, such as linking factors to the blood protein albumin, or using compounds stabilizing clotting factors, are also being explored.

On the other end of the therapeutic spectrum is gene therapy, which aims to cure hemophilia by introducing new genes into the body. Phase 1 and 2 clinical trials exploring factor IX are currently ongoing, while attempts with factor VIII gene therapy have not yet reached human studies. This is in part caused by the larger size of the gene mutated in hemophilia A, making it difficult to find suitable carriers for delivery of the gene into cells.

Although prophylactic treatment has been shown to prevent bleeding and complications, several barriers continue to prevent the use of such an approach. The most important obstacle to good care is the development of antibodies against the factors used. Clotting factors are biological structures, and could be identified by the immune system as a threat.

Other limitations might be in the form of varying effects of replacement therapy linked to individual differences in how patients break down the factors they receive. This is an obstacle that could be overcome to some extent through tailored treatment programs.

Studies also show that patients often don’t continue with their treatment. Increasing awareness through educational initiatives in children and adults would likely improve treatment adherence — and long term outcomes.

High cost of factor replacement therapy might contribute to nonadherence, and studies are needed to explore if the high cost of preventive treatment is outweighed by costs linked to inadequate treatment later in life.

Therefore, more research is needed to overcome these barriers to further improve the lives of hemophilia patients.

source: http://hemophilianewstoday.com/2016/08/10/prophylactic-hemophilia-treatment-still-faces-obstacles/

Gene-Therapy Cure Has Money-Back Guarantee

The most expensive drugs in history, or medicine’s biggest bargains? Gene therapy could be both.

by Antonio Regalado 

August 9, 2016

A gene therapy will be offered for sale in Europe with a money-back  

guarantee, according to GlaxoSmithKline, the company commercializing it.

The treatment, called Strimvelis, is the first outright cure for a rare disorder to emerge from gene therapy, and its price tag of 594,000 euros ($665,000), announced last week, makes it one of the most expensive one-time treatments ever sold by a drug firm.

Now, we’ve learned, it’s also the first genetic fix to come with a warranty.

“The drug has to deliver what you say or we don’t pay,” says Luca Pani, director general of the Italian Medicines Agency, known as AIFA, which set the price and terms during negotiations with the British drug giant. “If it does not work, they will return the money.”

The treatment employs a virus to add a missing gene to the bone marrow of children with ADA-SCID, a sometimes fatal inability to fight infections. In a study involving eighteen children, carried out at a Milan hospital, all but three were cured outright.

GSK bought rights to the treatment in 2010 and won approval earlier this year to sell it in Europe, but because of its complexity the company will offer it only in Milan, requiring families to travel and spend weeks there. That means the Italian price will apply to all of Europe, says Pani. He also said that GSK would also be paid in installments over a period of years.

By some measures, Strimvelis’s price counts as a bargain. The cost of a bone marrow transplant from another person—the established way to treat ADA-SCID—can reach $1 million. Some other patients get treated with enzyme injections that cost $250,000 a year. The expense of these drugs and the care needed for a sick child quickly add up to millions.

“I was expecting a higher price,” says Christian Hill, managing director with Map Biopharma, a consultancy in Cambridge, U.K. “My initial gut feeling was ‘Hmmm, that’s really surprising.’”

According to Pani, GSK approached the Italian agency with a price “nearly double” what was eventually settled on—or of about $1 million. But AIFA was in a strong negotiating position because the therapy had been developed in Italy with charitable donations. GSK declined to comment on the negotiations. “It’s really difficult, because everyone’s [economic] models involve regular drugs and these are not regular drugs,” says Pani. “It’s a symbol of the future, absolutely.”

The idea behind gene therapy is that a one-time correction to a patient’s DNA will lead to a lifelong cure. Strimvelis is the first treatment to be commercialized that lives up to the promise. But potential cures for hemophilia, a rare eye disease, and a fatal brain illness could reach the market next, and they could be similarly expensive.

The Italian agency is unusual in that it already imposes pay-for-performance rules on some cancer drugs. It maintains 135 patient registries to track how well they work and Pani says Italy has collected more than 250 million euros in refunds. Patients receiving GSK’s gene therapy will also be tracked in a registry, the company confirmed. Based on experience gained so far, GSK might end up refunding about one in six treatments.

But the big question isn’t whether gene therapy costs too much—it’s whether companies can make any money at it, especially treating ultra-rare diseases. Only about a dozen children are born with ADA-SCID each year in Europe. Treating all of them would generate about $8 million in revenue—barely a blip for GSK, which sells $30 billion worth of drugs a year.

“Treating 12 kids a year—it’s just not commercially viable, at any price,” says Phil Reilly, a partner at Third Rock Ventures in Boston, who invests in gene-therapy companies. “But there are hundreds if not thousands of disorders that fall into this category. We need a new model for ultra-rare disorders, because we are going to develop these treatments.” Reilly says money-back guarantees and pay-as-you-go schemes are two ways to make high sticker prices palatable.

GSK says it won’t make much money off Strimvelis. Instead, it sees the treatment as a way to help patients and gain experience with treatments involving cells and genes. It’s also working with a small company, Adaptimmune, to genetically alter immune cells to battle cancer. “We do not expect to recover all of the costs of building a platform to deliver gene and cell therapy from Strimvelis alone,” says Anna Padula, a spokesperson for GSK’s rare-diseases group. “We hope that Strimvelis will be the first of a number of innovative gene-therapy medicines that we will bring to patients.” The company recognizes, she adds, “that the industry will need to adapt the way in which medicines are priced and funded.”

source:https://www.technologyreview.com/s/602113/gene-therapy-cure-has-money-back-guarantee/