This report originally appeared in the June 2011 issue of DOTmed Business News

When the Food and Drug Administration held a public meeting on positron emission tomography drugs in early March, its organizers were pleasantly surprised by the number of participants.

Once the meeting reconvened after lunch, Jane Axelrad, the associate director with the Office of Regulatory Policy at the Center for Drug Evaluation and Research, announced that more than 200 people were taking part in the event, a significant jump from the previous PET meeting which hosted about 50.

Axelrad credited the attendance boost to “either changes in the industry or just the fact that now we’re really getting serious, people are paying more attention.”

Whatever the reason, it shows radiopharmaceutical developers are set to launch new PET drugs and doctors are eager to put them into practice.

To date, few agents have received a nod from the FDA, but industry experts predict that will change within the next few years.



Not only is the FDA now keen on closely working with manufacturers of imaging agents on the approval process, but the country’s PET infrastructure is also mature and strong -- encouraging factors for drug innovation.

“It may well be that the timing is finally right,” says Jonathan Allis, general manager of PET business with GE Healthcare.

Regulatory changes
Originally developed as research tools, PET radiopharmaceuticals only began to gain traction in clinical practice in the 1980s. The imaging agents caught FDA’s attention about a decade later and the agency began to consider regulating them.

In 1997, Congress enacted the FDA Modernization Act, which gave the agency the power to regulate PET drug manufacturing.

But Congress said the agency couldn’t require manufacturers to submit a New Drug Application or an Abbreviated New Drug Application for an agent for a period of two years after the law was enacted or two years after the completion of special approval procedures and current good manufacturing practices for PET drugs -- whichever took longer.

“They didn’t need to worry that we were going to be moving very speedily,” Axelrad joked at the meeting.

It took the FDA more than 12 years to provide the final rule and guidance on cGMP for PET radiopharmaceuticals, which were officially published in December 2009.

By the end of 2011, all PET drug manufacturers will have to comply with the cGMP and submit an NDA or ANDA in order to continue manufacturing agents for clinical use.

One PET drug producer got a jumpstart on the requirements. In early February, PETNET Solutions, Inc., a wholly owned subsidiary of Siemens Medical Solutions USA Inc., became the first commercial entity to file an application and receive FDA approval for a PET agent as mandated by FDAMA.

PETNET received FDA approval for its ANDA for Fludeoxyglucose F 18 injection, or FDG, a popular oncology agent. The company submitted the application more than three years ago, says Edward Plut, vice president, product management and marketing, with PETNET. “To date, we’re the only commercial manufacturer to even submit an application, let alone to be approved by the FDA,” he says.

More than a decade seems like a long time for establishing the regulations, but in many aspects, PET drugs were uncharted territory for the FDA. “Throughout these proceedings, we’ve tried to be sensitive to the fact that we are bringing under regulatory control an industry that had been largely unregulated and an industry with special characteristics,” Axelrad said at the meeting.

With more clarity from the FDA, industry experts hope to see novel PET agents glide through the regulatory process in the near future and pave the way for PET radiopharmaceuticals currently in development.

PET meets CAD
Lantheus Medical Imaging Inc., a North Billerica, Mass.-based diagnostic imaging company, is hoping to add a new PET cardiac imaging agent to the list of approved drugs. Lantheus is developing Flurpiridaz F 18, a myocardial perfusion agent for imaging of patients with coronary artery disease.

In early March, the company reached an agreement with the FDA on a Special Protocol Assessment on the design and planned analysis of the Phase 3 clinical trial for the drug.

“This is a significant milestone for Lantheus because it provides a very clear path towards the final approval of the agent and it gives us great clarity on what exactly we need to do to get there,” says Dr. Dana Washburn, the company’s vice president, clinical development and medical affairs. “From a development perspective, it lowers the overall risk to the program because we know exactly what we need to do as we proceed into Phase 3.”

Currently, SPECT is the dominant modality for noninvasive detection of CAD but the approval of Flurpiridaz can turn PET into a worthy competitor.

According to Washburn, PET has higher image quality than SPECT and offers certain technical features such as reduced attenuation and more robust attenuation correction, which reduces artifacts often prevalent in other modalities. PET also holds a lot of potential for novel applications, such as the ability to measure absolute quantitative blood flow in the heart. “I think the hope is that all of these characteristics lead to better diagnostics decisions and therefore better outcomes for patients,” says Washburn.

Just last month, Lantheus presented data on the full results from its Phase 2 clinical trial of Flurpiridaz at the International Conference of Non-Invasive Cardiovascular Imaging in Amsterdam.

[Read an exclusive Q & A with Dr. Jamshid Maddahi about the full results of Flurpiridaz's Phase 2 clinical trial]

And later this year, the company plans to launch the first part of its Phase 3 trial for the agent, which will be global and involve about 100 sites.

There are currently no similar cardiac PET imaging agents at the same advanced stages of development as Flurpiridaz.

A focus on a neurodegenerative disease
Another PET agent aims to change the grim statistics around the only cause of death among the top 10 in the United States that at this point cannot be prevented, cured or slowed in its progression.

Nationwide, 5.4 million people are living with Alzheimer’s disease and the care for those who are sick will cost Americans about $183 billion in 2011, according to the Alzheimer’s Association.

Avid Radiopharmaceuticals, Inc., bought by pharma giant Eli Lilly and Company last year, is looking to bring its agent Amyvid (a Florbetapir F 18 injection) to market.

Amyvid is currently under investigation for PET imaging of beta-amyloid plaque in the brain. The drug’s value is rooted in the amyloid hypothesis, which argues that accumulated levels of beta-amyloid in the brain lead to Alzheimer’s disease.

If approved, Amyvid will be the first drug to measure amyloid deposits in the brains of living patients, potentially providing clinicians with the means for early diagnosis and intervention.

The drug got its start in 1999 at the University of Pennsylvania, where Avid founder and CEO Dr. Daniel Skovronsky began working on its development.

Skovronsky and his team first looked at dyes that were used to stain cadaver tissue to see the amyloid plaque. They then worked on a way to translate the dyes into an imaging test.

After years of medicinal chemistry research, the scientists got to Florbetapir, “a small molecule that binds very avidly to the target of amyloid plaques,” says Skovronsky.

It’s no secret that drug development is a time-consuming, expensive and complex process but Amyvid also faced a unique challenge – the absence of a readily available truth standard to validate the newly developed test.

After a lot of discussion and work with the FDA, the researchers came up with a solution. They would image volunteers who are near the end of life and who had agreed to donate their brains to research upon death. “We would compare the amyloid actually found postmortem to the amyloid that we found in the scan, and thus develop a pathology truth standard,” says Skovronsky.

In the Phase 3 trial, about 150 people volunteered to be imaged. Not all of them died, but the first 35 who did formed the key data set for Amyvid. “We sometimes think of those 35 as pioneers, the individuals who made it possible to get to this point in the field,” Skovronsky says.

So how close is Amyvid to approval? In December, the FDA assigned priority review designation to the drug’s application. Then in January, an FDA advisory panel voted 3-13 against approval because of concerns around reader variability of the scans and a lack of a substantial training framework for clinicians.
But the panel also unanimously voted to approve Amyvid if the company created a rigorous program to train readers.

“The FDA asked us to establish a reader training program for market interpretation to help ensure reader accuracy and consistency of our scans,” Skovronsky explains. “And they asked us to validate the reader training program using the existing Amyvid scans which were obtained in Phase 2 and Phase 3 of our clinical trials.”

If approved, physicians will be able to use Amyvid to rule out Alzheimer’s disease. But the agent is far from becoming a screening tool.

It’s established that if there is no amyloid in the brain, the patient doesn’t have Alzheimer’s disease. However, the presence of amyloid doesn’t necessarily mean that the patient has the disease. “That is why it’s not a completely accurate diagnostic for Alzheimer's disease but it is a true representation of amyloid in the brain,” says Maria Carrillo, senior director, medical and scientific relations, with the Alzheimer's Association.

“Maybe in the future, there will be definite proof that patients with amyloid in the brain are going to get Alzheimer's, and drugs could be used to remove amyloid out of the brain,” Skovronsky says. “But we’re just not just there yet.”

Nonetheless, the potential approval of Amyvid is generating quite a buzz. This spring, for the first time in 27 years, three expert workgroups published new criteria and guidelines for the diagnosis of Alzheimer's disease. The new guidelines emphasize the importance of biomarkers, such as Amyvid, in the early diagnosis and research into the progression and intervention of Alzheimer's.

Of course, Amyvid will be considered a particularly useful tool in diagnosing Alzheimer's if pharma drugs that can halt the progression of the disease make it to the market. And according to Carrillo, several promising drugs are currently in Phase 3 trials, and many more are in Phase 2.

The most exciting thing about such pharmaceuticals is the potential to use them earlier in the progress of the disease. “That’s the shift in the therapeutic world that we’re probably going to see this decade,” says Carrillo.

Another company working on a PET imaging drug to detect amyloid plaque is GE Healthcare. Its flutemetamol agent is close to finishing the Phase 3 program and the company plans to file an application with the FDA later this year.
According to Allis, GE is looking at an integrated approach to Alzheimer’s disease. “We’re particularly interested in how PET and MRI will be used together in both the diagnosis of Alzheimer’s disease and also in therapy monitoring of the disease,” he says.

GE is also collaborating with Johnson & Johnson in developing a biosignature for Alzheimer’s, a project that’s in its early stages. The companies hope to develop a blood-based test that can help determine who should be specifically tested with a more complex imaging test for the disease, Allis says.

As for Amyvid, Skovronsky refrains from speculating on a timeline for the agent’s approval, only saying that Avid and Lilly are working with the FDA to complete the training program “as quickly as possible.”

In development for oncology
In addition to neurodegeneration, GE is also working on several PET agents for imaging cancer. One of its drugs, fluciclatide, could be used for imaging angiogenesis, and is currently in Phase 2 trials.

There is a huge class of anti-angiogenic drugs, says Allis, worth about $8 billion. If and when GE’s angiogenesis agent gains approval, it can be used to track changes in response to a specific therapy.

Instead of having a patient take a particular drug for months only to find it’s not effective, a PET exam with the agent can determine the response within weeks, explains Allis, thus reducing both the potential of unpleasant side effects for the patients and the associated costs.

GE plans to progress fluciclatide into Phase 3 next year.

Researchers within Siemens’ Molecular Imaging Biomarker Research facility are also developing a number of novel oncology PET biomarkers “that image the key hallmarks of cancer,” says PETNET’s Plut. Several Siemens’ agents are currently in Phase 1 or 2 clinical trials, with a cellular proliferation agent preparing to start Phase 3 trials.

A class of their own?
Although many PET drugs are currently on track to FDA approval, the journey is complicated and, increasingly, costly.

Dr. Mark Hibberd, senior medical director, global medical affairs and pharmacovigilance with Lantheus, has been in the clinical trial research industry for about 20 years. He says drug development costs have gone up and are likely to keep climbing.

“Some of the drivers for the increasing costs have been increased regulatory standards for the demonstration of safety and the efficacy of new products,” he explains, which call for additional partnerships and longer, larger trials.

To bring Amyvid to where it is today, Avid raised $70 million from venture capital investors as a startup company, and that’s before the Eli Lilly deal enabled access to additional resources.

And yet, compared to a pharma product, bringing a PET drug to market is relatively inexpensive and quick. “But because there are so few precedents, the challenge with an imaging drug is that it’s more difficult to understand what the market outlook is for it and how it will be used by doctors,” says Skovronsky.

Plut also says that although it’s somewhat cheaper to develop an imaging agent compared to a therapeutic drug, the volume of utilization for most therapeutic products would far exceed that of a PET drug once approved. “When compared to therapeutic drug products, there’s a mismatch between the development costs for an imaging agent and the potential volume or procedures that will be performed in the marketplace with that imaging product once approved,” he says.

The fact that imaging agents are held to the nearly same standard as classic therapeutic products drives this mismatch between development costs and potential procedure volumes.

For instance, classic outcome studies performed with traditional pharmaceutical products, measuring an improvement in overall survival, are quite challenging with diagnostic imaging, explains Plut. But an imaging agent can be shown to improve diagnostic accuracy, stratify patients and influence change in patient management.

That’s why there should be an “equitable development pathway” specific for imaging agents, “that takes the unique properties of molecular imaging biomarkers and the distributed manufacturing requirements of PET into account,” says Plut.

“There are molecular imaging agents which are very close to approval and we’re eagerly looking to them as precedents,” he adds.

Making it personal
One of the biggest promises of molecular imaging is its ability to drive the care model towards personalized medicine. Experts say that additional PET drugs will aid clinicians in identifying the right patients for particular therapies, and do so early and accurately.

“A lot of the hope for personalized medicine and molecular imaging biomarker development is to use molecular imaging to help stratify patients, to help determine which patients might benefit from particular types of therapy, rather than one size fits all treatment,” says Plut.

To turn that hope into reality will require developers of biomarkers and pharma products to collaborate on R&D initiatives, a growing trend in the market.

And the industry has no intentions of slowing down. “We’ve only seen the tip of the iceberg of what molecular imaging can accomplish for patients,” says Avid’s Skovronsky.

EXTRA

Agent Update: Sodium Fluoride F 18
Sodium fluoride F 18, the PET agent for bone imaging, has been deemed safe and effective by the FDA, but its utilization has been relatively limited for a long time.

What’s standing in its way? According to Edward Plut, vice president, product management & marketing with PETNET Solutions, it’s a lack of reimbursement.

However, the company is collaborating with the imaging community to change that. To satisfy Medicare’s requirement for a large clinical trial in order to support reimbursement, PETNET is working with the Academy of Molecular Imaging to carry out a trial that compares sodium fluoride to traditional bone imaging tests. (To date, the trial is about halfway through.)

In 2010, the Centers for Medicare and Medicaid Services decided to cover PET with sodium fluoride under the CMS Coverage with Evidence Development program. The National Oncology PET Registry then established a registry for the agent, creating a pathway for clinicians to get reimbursed for using sodium fluoride for PET.

“Since that time, we’ve seen a pretty significant growth in utilization for sodium fluoride and there’s a lot of excitement in the community around PET bone imaging,” says Plut.

The next step is to use the combined results of the CED program through NOPR and the AMI clinical trial to petition CMS for a broad coverage decision on the agent, which the imaging community hopes to do in the next year or two, according to Plut.

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