New Project Aims to Set Effectiveness Guidelines for Hemophilia Gene Therapy Trials

New Project Aims to Set Effectiveness Guidelines for Hemophilia Gene Therapy Trials

An international team has joined efforts to establish guidelines for effectiveness and outcome measurements regarding gene therapies in hemophilia.

The CoreHEM project will be led by researchers from McMaster University in Ontario, Canada, in collaboration with the National Hemophilia Foundation (NHF) in the U.S. and the Green Park Collaborative — a major initiative of the Center for Medical Technology Policy (CMTP), based in Baltimore, Maryland.

“With a growing pipeline of gene therapy products for hemophilia, it is an ideal time for this work,” Sean Tunis, president and CEO of CMTP, said in a news release. “This effort will potentially serve as a model for achieving consensus around outcomes to demonstrate effectiveness and value for promising emerging therapies in many other clinical areas, as well as for other rare conditions.”

Hemophilia is caused by a genetic defect that leads to low levels or the total absence of clotting factors — factor VIII in hemophilia A and factor IX in hemophilia B — which are necessary for effective bleeding control. Hemophilia patients need to receive routine injections of the missing clotting factors to control symptoms of the disease. This demanding therapy schedule can have an extreme impact on patients’ quality of life.

Scientific advances have led to the development of new treatments that may have the potential to cure hemophilia A and B by replacing the damaged gene. Clinical trials on these new gene therapies should provide enough evidence demonstrating their effectiveness, but also substantial improvements in reducing or eliminating burdens of the disease.

The CoreHEM project aims to define a core outcome, set through a consensus process, which should be considered when evaluating the effectiveness of gene therapies in patients with hemophilia.

Taking into consideration input from patients, clinicians, researchers, product manufacturers, public and private payers, and U.S. and international government agencies, the team will create a list of potential outcome domains and measurement approaches that will be reviewed by a steering committee.

This list will go through an online Delphi voting process and an in-person consensus meeting to prioritize and condense the list into the final core outcome set.

“These breakthroughs have the potential to be life-changing,” said Val Bias, CEO of the National Hemophilia Foundation. “This collaborative effort will bring a much needed voice from our patients, and the important role they play in identifying outcomes that are vital to their health.”

The final results of the CoreHEM project, expected early in 2018, will be published in a peer-reviewed article providing recommendations for important patient outcomes in clinical studies focused on gene therapies for hemophilia. In addition, an “effectiveness guidance document” will also be published.

Implementing these outcome-defined measures will not only help patients and clinicians to make better treatment-related decisions, but will also potentially improve the way clinical trials are conducted and assessed.

“The enthusiasm from so many stakeholders to becoming part of the project speaks volumes to the potential of this initiative,” said Alfonso Iorio, co-principal investigator and associate professor of health research methods, evidence, and impact at McMaster University.

Creating a consensus for implementation early in the development of breakthrough technology is a key to success, he added.

Hemophilia – Gene Therapy .

uniQure has built an exciting portfolio of clinical and pre-clinical programs focused on hemophilia.

uniQure has built an exciting portfolio of clinical and pre-clinical programs focused on hemophilia. This overall effort is well supported by uniQure’s proprietary position with our AAV5 viral vector, which has shown particular affinity for reaching the liver. AAV5 has the benefit of a low prevalence of pre-existing anti-AAV5 antibodies in patients screened to date in uniQure’s clinical trials and as indicated in medical literature. uniQure also has gained extensive experience in the development and regulatory approval of the first gene therapy approved in the Western world: Glybera.

Hemophilia B

uniQure is developing a gene therapy for hemophilia B, a severe orphan blood clotting disorder. The program’s gene therapy product candidate consists of an AAV5 vector carrying a therapeutic human Factor IX, or FIX, gene cassette that uniQure has exclusively licensed from St. Jude Children’s Research Hospital in Memphis, Tennessee. uniQure is currently conducting a Phase I/II study of AMT-060 in patients with severe hemophilia B and advanced joint disease.

In December 2016, the Company presented updated clinical data from our Phase I/II trial (view press release).  In January 2017, AMT-060 received Breakthrough Therapy designation from the U.S. Food and Drug Administration in January 2017 based on results from this ongoing, dose-ranging study (view press release).

The data from our Phase I/II study demonstrate AMT-060 is delivering sustained and significantly improved clinical benefits to patients suffering from severe hemophilia B by enabling them to discontinue bi-weekly infusions of FIX replacement therapy and to essentially eliminate the risk of spontaneous bleeding. We are observing a therapeutic benefit from AMT-060 that is clearly superior to their  previous prophylactic FIX  replacement therapy regimen, even in patients with advanced joint disease who still experienced many bleeds despite prophylaxis with FIX.

At both doses evaluated, AMT-060 appears to be safe and well-tolerated with no loss of FIX activity, no activation of T-cell response and no development of inhibitors for any of the 10 patients in the study.

The data from this ongoing study demonstrate clinically significant and sustained increases in FIX activity, substantial reductions in FIX replacement usage and a near cessation of spontaneous bleeding episodes.

AMT-060 has demonstrated a very low screening failure rate, with all patients screened in the study testing negative for pre-existing anti-AAV5 NABs, which suggests that a large proportion of the hemophilia patient population may be eligible for treatment with AMT-060.   The proprietary elements of AMT-060, including our fully-humanized FIX gene cassette and AAV5 vector, are the only gene therapy components clinically demonstrated in hemophilia B to be safe, effective, and durable for up to six and a half years.  These factors, along with our commercial-scale manufacturing capabilities, differentiate AMT-060 from other hemophilia gene therapies in development, and we look forward to advancing our program into a late-stage clinical study.


Hemophilia A

As another indication important to uniQure’s efforts in liver/metabolism, the Company is in pre-clinical evaluation for a gene therapy to treat hemophilia A.  We expect to provide an update on this program sometime in the first half of 2017.

Hemophilia B Treatment Refixia Passes Key EU Regulatory Hurdle

Hemophilia B Treatment Refixia Nears European Union Approval
Novo Nordisk’s hemophilia B treatment Refixia has cleared a major hurdle toward European Union approval.

An arm of the European Medicines Agency (EMA) known as the Committee for Medicinal Products for Human Use (CHMP) has recommended approving Refixin for preventing and treating patients 12 years and older with hemophilia B, or congenital factor IX deficiency. The European Commission will make the final decision on approval.

The EU designated Refixia (nonacog beta pegol, N9-GP) an orphan drug on May 15, 2009. The EMA said in a press release that the new recommendation covers Refixia as a powder and solvent for injection. The doses it covers include 500 IU, 1000 IU and 2000 IU.

Nonacog beta pegol, the active ingredient in Refixia, is a recombinant coagulation factor IX. It replaces the missing factor IX in patients with hemophilia B, helping the blood to clot and providing temporary bleeding control.

CHMP’s Refixia recommendation was based on the results of a Phase 3 clinical trial that enrolled 115 children and adults with moderately severe to severe hemophilia B.

Novo Nordisk reported in January 2016 that trial investigators found Refixia effective in preventing and treating bleeding episodes, and controlling bleeding in surgery. The treatment was well-tolerated, with no safety problems, the investigators said.

Refixia’s half-life was five times longer than that of other factor IX products, the trial results showed.  Participants achieved a higher level of factor IX in their blood than with other products, even with less frequent doses of Refixia. A drug’s half-life is the amount of time it takes for its effectiveness to drop in half.

The trial also found that 40 IU/kg of Refixia once per week kept patients’ factor IX levels above 15 percent, and reduced their median annualized bleeding rate (ABR) to 1.0. In addition, the treatment showed potential in preventing joint bleeding, and in improving patients’ quality of life.

“We are excited about the positive opinion obtained for Refixia, Mads Krogsgaard Thomsen, executive vice president and chief scientific officer of Novo Nordisk, said in a press release. It represents a significant milestone in our efforts to expand the treatment options for patients with haemophilia. We believe Refixia with its strong clinical profile provides hemophilia B patients better protection against bleeds, even into damaged joints, and an overall improved quality of life.”


St Judes’s newsletter:January

Gene therapy achieves early success against hemophilia B

St. Jude researchers have developed a treatment that offers hope to patients with the bleeding disorder hemophilia B. In a recent clinical trial conducted at the University College London (UCL), symptoms improved significantly in hemophilia B patients following a single gene therapy treatment.

The findings mark the first proof that gene therapy can safely reduce disabling, painful bleeding episodes in patients with the blood disorder. Results of the Phase I study appeared in the New England Journal of Medicine.

Hemophilia B is caused by an inherited mistake in the gene for making a protein called Factor IX, which is essential for normal blood clotting. Previous efforts to ease hemophilia B symptoms by introducing a correct copy of the gene had been unsuccessful. The current study used a harmless virus as the vector to deliver the Factor IX gene along with additional genetic material into each patient’s liver. The vector used in the study was produced at the Good Manufacturing Practices facility on the St. Jude campus. The approach was jointly pioneered by St. Jude and UCL, initially in the lab of study co-author Arthur Nienhuis, MD, of St. Jude Hematology.

As is often the case with experimental therapies, this study was conducted in adults to ensure the treatment was safe and effective. Plans are to include children in future trials. Because they have not yet experienced the joint damage and other complications of the disease, children undergoing gene therapy will likely benefit even more than adults do.

“These results are highly encouraging and support continued research. More patients are scheduled to be enrolled in future trials scheduled to begin later this year,” said the study’s senior author, Andrew Davidoff, MD, St. Jude Surgery chair.


In-house screening reduces stroke risk

Gail Fortner, RN, uses an ultrasound to measure blood flow in arteries leading to a child’s brain. The procedure, known as transcranial Doppler (TCD) ultrasound, is the most effective tool for predicting primary stroke in patients with sickle cell anemia.

Gail Fortner uses ultrasoundSickle cell patients at St. Jude undergo annual TCD screenings at their regular clinic visits. Most sickle cell centers require patients to go to radiology or neurology appointments to have the test done.

With the knowledge obtained from TCD screenings and the treatment offered to those considered to be at high-risk for strokes, clinicians are able to prevent stroke in many children with sickle cell anemia.

“Today, 99 percent of our high-risk patients ages 2 to 16 are screened for stroke. In published data from other institutions, that number is from 49 to 58 percent,” Fortner said.

She and Beth McCarville, MD, Radiological Sciences, are training Brazilian and Jamaican physicians who will be collaborating with St. Jude and Baylor College of Medicine on a future multicenter trial. This will be the first NIH-funded international sickle cell disease clinical trial and the latest example of the hospital’s collaboration on research that helps to improve the quality of life for sickle cell patients.


Molecule serves as key in some protein interactions

St. Jude structural biologists Brenda Schulman, PhD, Daniel Scott, PhD, and Julie Monda have identified a mechanism that facilitates some protein interactions that are workhorses of cells. In the process, they have also found a potential new cancer drug development target.

Brenda Schulman, PhD, Daniel Scott, PhD, and Julie MondaThe discovery involves a chemical known as an acetyl group. About 40 to 80 percent of human proteins have this chemical added to the amino acid at one end of the protein during a process known as N-terminal acetylation. Although it has long been recognized that proteins are N-terminally acetylated, until now it was unknown how that process could serve specific functions.

The researchers showed that much like a key must fit precisely to work a lock, the acetylated end of one enzyme fits perfectly into a deep pocket on the surface of another protein. The connection helps accelerate the activity of a protein complex that is involved in regulating cell division and that has been linked to cancer. The research appeared in the journal Science.

The findings have potential implications for drug discovery and for understanding basic mechanisms governing the interaction of possibly thousands of proteins, said Schulman, who is also a Howard Hughes Medical Institute investigator.

“The work presents a major new concept in protein-protein interactions,” she said. “This raises the question of whether similar ‘keys’ on thousands of different proteins also unlock doors to allow them to function.”

Brain tumor research yields new treatment options

St. Jude investigators have pioneered a new approach to drug development and have identified dozens of potential new treatments for ependymoma, a rare tumor of the brain and spine.

The new system combines the latest drug screening technology with the first accurate laboratory model of the tumor.

Using the method, researchers have identified new and existing drugs as possible ependymoma treatment candidates. The drugs were identified by screening 5,303 existing medicines, natural products and other compounds for activity against the tumor, which affects children and adults.

The list of candidate drugs included 5-fluorouracil (5-FU), which has been widely used to treat adult cancers but has not been formally tested against ependymoma.

Based on study results, St. Jude is now planning a clinical trial of 5-FU in young ependymoma patients, said senior author Richard Gilbertson, MD, PhD, Comprehensive Cancer Center director.

The work was published recently in the scientific journal Cancer Cell.

Researchers hope to use the same system to expand chemotherapy options for patients with other cancers. Rather than waiting years for clinical trial results, this system promises to take just months to provide key information about a drug’s effectiveness and optimal administration.


Study addresses survivors’ neuromuscular problems

Kirsten Ness, PhD, of St. Jude Epidemiology and Cancer Control, is principal investigator of research that is spurring efforts to address the neuromuscular problems of some cancer survivors.

Kirsten Ness, PhDIn a study recently published in the journal Cancer, Ness and her colleagues found that high doses of two drugs widely used to treat children with acute lymphoblastic leukemia (ALL) left nearly half of adult survivors in their mid-30s with walking, balance and other limitations typical of someone decades older.

The study is the first to document the association between high doses of methotrexate and the muscle, joint and nerve problems that affect some long-term survivors of childhood ALL. Adult survivors whose treatment included high cumulative doses of the drug vincristine were also identified as being at increased risk of reduced ankle flexibility, reduced leg strength and difficulty walking.

The information was collected as part of the St. Jude LIFE study that provides ongoing clinical follow-up to thousands of St. Jude cancer survivors.

“These survivors do not complain of pain or numbness, but many have evidence of a mild motor neuropathy that affects their ability to walk and leaves them at risk for a variety of problems later in life,” Ness said.

Simple stretching and strengthening exercises may help ease the problems, she added.


Nasal flu vaccine safe for young cancer patients

New St. Jude research demonstrates that both the flu shot and the nasal vaccine are safe for use in young cancer patients. The finding is important because the influenza virus poses a severe risk to cancer patients with immune systems weakened by their disease and treatment. Flu can also cause life-threatening illness and delay chemotherapy.

The new findings will not change recommendations that pediatric cancer patients receive flu shots, which deliver a vaccine made from killed flu viruses, rather than nasal vaccines, which use a different form of influenza virus to trigger a protective immune response. But the research should ease any lingering concerns that pediatric cancer patients will contract flu following direct or indirect exposure to the nasal vaccine.

The vaccine, which is marketed as FluMist, uses live, but weakened flu virus to trigger protection.

The study is the largest yet to compare the safety of the two flu vaccines. Patricia Flynn, MD, Infectious Diseases, was senior author of a paper on this topic, which appeared in the Journal of Infectious Diseases.

Cover of inaugural issue of Promise magazine

Let us eat cake

Both Promise magazine and St. Jude Children’s Research Hospital are celebrating anniversaries. This is the 50th issue of Promise, which was launched in 1998. This year, the hospital also celebrates a monumental milestone—five decades of finding cures and saving children. Look for a special issue marking the hospital’s anniversary in April of this year…and go ahead: Celebrate!

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Outreach program is national model

A marquee outreach program developed at St. Jude is a national model for raising awareness about sickle cell disease, the world’s most prevalent genetic disorder.

Approximately one in 12 African Americans has sickle cell trait. Sickle cell disease is also prevalent among those of Caribbean, Latin American, Mediterranean or Middle Eastern descent.

The Know Your Sickle Status program, or K.Y.S.S., provides free educational programs and screenings to families affected by sickle cell trait and sickle cell disease. K.Y.S.S. offers awareness education to at-risk populations, particularly teenagers and young adults.

“If one parent has sickle cell trait and the other parent has sickle cell trait or any other abnormal hemoglobin trait, the couple has a one-in-four chance of having a child with sickle cell disease. That’s why it is important for people to know their status,” said Yvonne Carroll, RN, director of Patient Services in St. Jude Hematology.

Coordinated by Charlotte Hoyle of Hematology, the peer education component of K.Y.S.S. targets African-American teenagers and young adults who are at risk for having children with sickle cell disease. St. Jude has one of the largest sickle cell centers in the country. Approximately 800 patients, from infants to teenagers, are treated at the center.

To access sickle cell resources and materials at St. Jude, visit


Hormone research may lead to more targeted drug development

Research led by St. Jude scientists advances a strategy for taming the side effects and enhancing the benefits of steroids and other medications that work by disrupting the activity of certain hormones.

The approach relies on a small molecule developed at St. Jude. In this study, scientists showed that a compound known as SJ-AK selectively blocked the activity of genes in a cell signaling pathway regulated by thyroid hormone. SJ-AK also affected cells growing in the laboratory, reducing cell proliferation as well as the production and secretion of a growth hormone regulated by thyroid hormone.

The research appeared in the journal ACS Chemical Biology.

The findings raise hope that compounds like SJ-AK will lead to drugs with more tailored effects by selectively controlling signaling pathways that switch genes on and off.

“This study offers the first evidence that it is possible to shut down a portion of the signaling network activated by a particular hormone,” said the study’s senior author, R. Kiplin Guy, PhD, chair of Chemical Biology and Therapeutics at St. Jude.

Such selectivity could lead to a new generation of medications with greater effectiveness and fewer side effects. The new treatments could include steroids that fight leukemia or suppress the inflammation associated with autoimmune disorders without affecting metabolism or bone strength.

Source: St Judes’s newsletter