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.

Promising Gene Therapies Pose Million-Dollar Conundrum


Economists, investors and medical insurers can’t figure out how to pay for cutting-edge drugs

Drugs that act by modifying a patient’s genes are close to approval in the United States, and one is already available in Europe. The developments mark a triumph for the field of gene therapy, once considered controversial.

But with estimated price tags of at least US$1 million per patient, how will anyone pay for these treatments? The question is just one in a broader debate about how to finance a range of super-expensive drugs that are now available, thanks to an explosion in genetic and molecular-biology research over the past 20 years.

“Advances in science are presenting a social affordability question like never before,” says economist Mark Trusheim at the Massachusetts Institute of Technology in Cambridge. “Do we want to convert the science into therapies that we actually would have to pay for?”

Trusheim spoke at the Biotechnology Innovation Organization (BIO) meeting in San Francisco, California, on June 6–9, which featured much discussion about how society will pay for the rising costs of new drugs. At the American Society of Clinical Oncology meeting in Chicago, Illinois, on June 3–7, dozens of talks and abstracts focused specifically on the growing cost of cancer care.Cancer drugs that unleash the power of the immune system cost up to $40,000 per year.

Gene therapies that are close to US approval include treatments for haemophilia B, sickle-cell anaemia and the neurodegenerative disease cerebral adrenoleukodystrophy. A therapy under development at Spark Therapeutics in Philadelphia, Pennsylvania, for a type of blindness is considered the most advanced.

Many of the treatments deliver corrective genes using a modified virus that is considered safer than vectors used in earlier attempts. But many of the target disorders are rare, limiting the population that can be treated. And there are often no previously approved drugs that work similarly, removing the pressure on companies to lower their prices.

Such therapies could cost $1 million per patient, estimate haematologist Stuart Orkin of Harvard Medical School in Boston, Massa­chusetts, and Philip Reilly, an investor with Third Rock Ventures in Boston (S. H. Orkin and P. Reilly Science 352, 1059–1061; 2016). Reilly co-founded Cambridge-based Bluebird Bio, which is working on several of the gene therapies that are close to market.

That’s the same price as Glybera, the gene therapy given the green light by European regulators in 2012, which has been taken by only one person so far. Experts attribute this low uptake to the high price and to doubts about its efficacy. If newer gene therapies are to do better, they will have to produce convincing data that they are worth the money, Trusheim says.

For medicines that are already approved, one increasingly popular solution is a deal between insurers and drug companies that ties payments to how well medicines perform. Last November, for example, Boston-based Harvard Pilgrim Health Care, a major New England insurer, announced that it will cover treatment for its clients with Repatha (evolocumab), one of a new class of cholesterol-lowering medication that is made by Amgen and costs $14,000. But if patients don’t reach pre-agreed cholesterol levels, or if Harvard Pilgrim ends up paying more than it has budgeted for, Amgen will refund the insurer.

Networks set up by insurance companies to gather and share data from health centres make such deals possible, says Michael Sherman, chief medical officer at Harvard Pilgrim. And they are on the rise around the world: one study found ‘pay-for-performance’ deals across 14 countries in 2013, predominantly in Europe and the United States, but also in middle-income countries such as China and Brazil.

These deals may work for some conditions, such as haemophilia B, for which several drugs might be approved. But for others, such as adrenoleukodystrophy, only one company is developing a product, so there won’t be the incentive for companies to negotiate, Trusheim says.

At the BIO meeting, investors and economists discussed a range of alternative solutions, including the medical equivalent of a mortgage or annuity, in which insurance companies or governments might spread the cost of a one-time treatment over many years, as long as a patient continues to benefit from it. One complication of such arrangements in the United States is that patients often move between insurers, so it is unclear who would continue to make these payments on a patient’s behalf.

The difficulties of paying for the fruits of the biotechnology revolution are something that governments are already struggling with. The state of Arkansas last year settled a lawsuit filed by three people who said they had been denied access to the $300,000 cystic fibrosis drug Kalydeco (ivacaftor) because of the cost. And in April, the Japanese government imposed a 50% price cut on a new hepatitis C treatment, Sovaldi (sofosbuvir). A US federal judge in Seattle, Washington, ruled on May 27 that states cannot delay treatment with Sovaldi, which costs up to $84,000, because of price concerns.

But those working on gene therapy are confident that a solution is out there. “Let’s say that a gene therapy that really made a world of difference in the life of a small child should cost a million dollars for one event,” Reilly says. “I can think of many things in medicine that cost that much or more, and we don’t think twice about that.”

Germany poised to say yes to €1.1m a patient gene therapy drug


A laboratory technician examines blood samples
The western world’s first gene therapy drug is expected to go on sale in Germany next year.

The western world’s first gene therapy drug is set to go on sale in Germany, with a price tag that could amount to an £870,000 cost to treat a single patient.

Glybera, a treatment for the rare genetic condition lipoprotein lipase deficiency (LPLD), which clogs the blood with fat, has been developed by Dutch biotech firm UniQure and Italian MARKETING marketing partner Chiesi. It is undergoing an assessment of benefits by Germany’s federal joint committee, which will report by April 2015.

But the company is seeking a retail price of €53,000 (£42,000) per phial, which equates to €1.1m (£870,000) for a course of treatment for a typical LPLD patient. This price will be subject to a discount under Germany’s drug pricing system.

A Chiesi spokeswoman confirmed the launch price and added that a final figure would be set after the German authorities gave their verdict and negotiations are held with health insurance FUNDS. “First commercial treatments are expected in the first half of 2015,” she said.

UniQure, which will get a net royalty of between 23% and 30% on sales, said EU pricing was a matter for its Italian partner, although the Dutch firm does plan to discuss Glybera pricing during an investor meeting in New York next month.

With only 150 to 200 patients likely to be eligible for Glybera across Europe, the impact on healthcare budgets will be small, even at a very high price – but this case will be watched closely as a benchmark for future gene therapies.

UniQure also has plans to seek approval for Glybera in the United States, which it hopes to get in 2018.

Although there is already a gene therapy for cancer on the MARKETin China, that has not been rolled out to other countries, making Glybera a first for the west.

Proponents of the gene-fixing technology insist it stacks up as a cost-effective treatment, despite the high cost, as it could permanently cure many patients.

In the case of Glybera, Chiesi said the annualised cost was no morethan that charged for some expensive enzyme replacement therapies.

UniQure is also working on gene treatments for haemophilia and has an early-stage project in heart failure.

Assuming trials are successful, analysts expect gene medicines treating more common conditions to cost less, as manufacturers should be able to recoup their research and development INVESTMENT from a larger patient group.

Rivals in the gene therapy MARKET include privately-owned Spark Therapeutics, which has an eye drug in late-stage clinical tests, and Bluebird Bio, which is working on drugs for neurological and blood disorders.

Bluebird Bio and UniQure both staged successful floats on the Nasdaq MARKET in the past 18 months, reflecting growing investor interest in the field. Among major pharmaceutical companies, Bayer struck a gene therapy deal with Dimension Therapeutics in June, while Novartis recently established a new cell and gene therapies unit, and Sanofi has a long-standing tie-up with Oxford BioMedic.

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