Q&A with a PET Agent Expert
Michael Graham, MD, PhD, co-chair of the Society of Nuclear Medicine and Molecular Imaging’s Clinical Trials Network and a professor of radiology and radiation oncology at the University of Iowa Carver College of Medicine in Iowa City, Iowa, took some time to speak with Molecular Imaging Insight in an exclusive interview covering the latest developments in PET radiopharmaceuticals, from drugs just approved and blazing trail in clinical use, to compounds in the far reaches of research.Michael Graham, MD, PhD, co-chair of the Society of Nuclear Medicine and Molecular Imaging’s Clinical Trials Network and a professor of radiology and radiation oncology at the University of Iowa Carver College of Medicine in Iowa City, Iowa, took some time to speak with Molecular Imaging Insight in an exclusive interview covering the latest developments in PET radiopharmaceuticals, from drugs just approved and blazing trail in clinical use, to compounds in the far reaches of research.
SNMMI’s Clinical Trials Network was founded in 2008 in an effort to provide resources for and promote standardization of molecular imaging clinical trials in order to support new drug development from preliminary studies to clinical adoption.
Let’s start with dementia agents and the approval of F-18 Florbetaben (Neuraceq) this past March.
There are now three amyloid agents that have been [FDA] approved—Neuraceq, Vizamyl and Amyvid. They all have been shown to effectively image amyloid in the brain and amyloid content distribution and are useful in diagnosing Alzheimer’s disease and assessing its severity. They are terrific tools for use in clinical trials for therapeutic agents that reduce amyloid content, but in terms of clinical utility they are still rather limited, because the treatment options are limited. I think [Eli Lilly] has a clinical trial that is underway looking at a therapeutic agent using Amyvid. The hope is that these agents will allow identification of effective treatments for amyloid and, secondly, that these treatments are going to make a difference in terms of the progression of Alzheimer’s disease. That is a very reasonable hypothesis, but it’s important to understand that it is a hypothesis that hasn’t been proven. Lilly is betting big time that it’s going to work and that is why they bought Avid Radiopharmaceuticals. Most of us in the field think that it is likely that it’s going to work, but it has not yet been demonstrated.
What is your take on other mechanisms of Alzheimer’s imaging using biomarkers like tau protein and chitin-like polysaccharides in the brain?
It is essential that these be used in conjunction with some sort of a therapy. Simply accurately diagnosing Alzheimer’s without a therapy is of academic interest, but it is not going to be clinically useful and it is unlikely to be reimbursed. There is etalage in certain exciting directions, but it needs to point to a therapeutic option that is meaningful.
A few studies we’ve covered recently highlighted F-18 FLT. Where do you think these agents are standing?
FLT [F-18 39-deoxy-39-fluorothymidine] is used as a marker of DNA synthetic rate and it is thought to be a useful way to assess early response to therapy for chemotherapeutic agents. When I say early, I mean after just a few doses of the chemotherapeutic agent have been given. There have been a few small trials that have demonstrated that it works quite well in that setting. The problem is that the trials that have been published so far have been fairly small and they are all in different settings, with different chemotherapeutic agents and different tumors and timing. It has not yet matured to the point where we have clearly convinced the FDA that it is ready for approval. It is something we are grappling with, but it isn’t quite there yet.
What about F-18 FET, which also has gotten some headlines?
FET [F-18 fluroethyltyrosine] is an amino acid labeled with a PET agent and it falls into a class of a number of amino acid analogs. Interestingly, fluorodopa, which has been used in neuroimaging, is an analog of phenylalanine, and is taken up by the same amino acid transport as tyrosine. We are going to get very similar results with these agents.
Tumors, since they are growing, are taking up more protein and amino acids to make the protein. There are some amino acids that are promising for imaging because they make hormones or other proteins. One of them that I am rather interested in is the possibility of imaging myeloma with either fluroethyl-tyrosine or with fluorodopa. Myeloma is a disease where the tumor creates immunoglobulins—basically nonsense antibodies but in large quantities and that’s the kind of tumor that is very likely to be image-able. This is getting well outside of where we are today. It is still speculation, but there are other tumors that make protein and fall into the class of mucinous carcinoma. We can’t image those very effectively with FDG because of all this mucin. That, too, is another useful possibility. I’m just throwing this out there. Nobody has actually looked at this yet. Certainly in tumors that have been well characterized, like lung and colon cancer, it is likely that these amino acid analogs are going to work quite well.
There is a particular amino acid analog that has been quite effective in imaging prostate cancer and metastases, called FACBC [anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid]. There has been an increased interest for imaging prostate cancer. There are two reasons for that. One is that we don’t have an effective tool for imaging the disease and there is a large number of patients that have metastatic prostate cancer. There is an economic incentive for developing a prostate cancer imaging agent because there’s a potential profit to be made. FACBC is at the moment the most likely near-term agent that could be widely used in the U.S. Recently, the Mayo Clinic had C-11 choline approved, but the half-life of the agent is 20 minutes and you have to have a cyclotron right there. As a result, it is fairly inconvenient. An F-18 labeled agent would be like fluorodeoxyglucose in that it could be created at a central facility, distributed, and widely used. That is a particularly interesting direction that is now beginning to be explored and clinical trials are being planned.
With regard to aptamer-based imaging, can you talk about how these agents work and what sets these apart from other agents?
Most of the ones that are used for imaging are RNA aptamers. These are relatively short sequences of RNA that might be 50 or so nucleotides. RNA has the characteristic that it will fold in different ways and some of these sequences potentially can fold in a way that would fit into a receptor site on a cell. The methodology involves SELEX [Systematic Evolution of Ligands by Exponential Enrichment] that allows taking large numbers of sequences and testing them against a receptor site and narrowing it down in a sequential fashion so that you get the one that best targets the receptor. It is a huge shotgun approach, but it has been very effective. Researchers have found these aptamers, RNA sequences that will target a specific receptor. For instance, this has been done for the PSMA [prostate specific membrane antigen] receptor in prostate cancer. They can be labeled and the label has to be put on at a distance from the active site. Of course there has to be all sorts of studies that show it is still targeting the site, these can work very effectively because they are small molecules that can rapidly distribute and bind to the sites. Some of them may be in phase I—that’s about as far as they’ve gotten and I’m not even exactly sure that they have gotten that far, but it’s a very powerful concept. The regulatory pathway is likely to be tricky, because if you just change one nucleotide in the sequence, you’ve got a new agent as far as the regulators are concerned and you have to start all over again in terms of toxicity and biodistribution and efficacy testing. It’s very challenging to bring these things to approval, but if you want to you can target almost anything if you worked at it. The people who are doing this are very skilled at coming up with one-in-a-million targets, but it is really in the animal study phase.
What PET radiopharmaceutical developments are happening for nuclear cardiology?
Lantheus has been working on a compound, F-18 Flurpiridaz. It has a very high extraction fraction. I know that the nuclear cardiology community has been rather excited about it. There have been some difficulties in bringing it to final approval…but it is in phase III trial. That agent appears to be the most interesting one in the cardiac realm. Another one is MIBG [metaiodobenzylguanidine]. This has been used for sometime for imaging pheochromocytoma [a type of neuroendocrine tumor]. There is excellent data now that MIBG imaging of the heart provides the best predictor for patients who need implantable defibrillators. The problem is one—getting it approved—and the other is educating the cardiology community about its utility. The talks I’ve heard on the subject suggest that it would be extraordinarily useful for congestive heart failure patients.
I have one more question related to the therapeutic side of the story. What developments are out there for agents that are used for both therapy and diagnostic imaging/treatment monitoring?
These are called companion agents. Another term is theranostics… the best example is in neuroendocrine tumor imaging and treatment. Up until recently, we have used Indium-111 octreotide to image neuroendocrine tumors, in particular carcinoids, the most common of that group. A therapeutic version of the molecule has been labeled with lutetium-177 and another with yttrium-90 and they have been used very successfully, particularly in Europe. There is one site in the United States that offers Lu-177 DOTATATE therapy and that is in Texas. The whole area of using gallium-68 DOTATOC and DOTATATE imaging to go along with Y-90 and Lu-177 labeled therapeutic agents is a very powerful concept that is catching on and has already caught on in Europe. This is an area where the Clinical Trials Network has been particularly active in working to move gallium-68 DOTATOC and DOTATATE forward.
How do these compare with DOTANOC?
DOTATOC and DOTATATE are very similar. There are at least one, if not two papers comparing them that show that you really cannot tell the difference. DOTANOC has a somewhat different receptor affinity profile than the other two. There are five receptor subtypes. They all target sub-type two, but DOTANOC also targets subtype five. There are some tumors that show up better with DOTANOC than the other ones. I think there are pluses and minuses. One of the issues with these agents is their intellectual property situation and availability. The number of people with neuroendocrine tumors is not very high, so the potential market is not very large. At least in the United States there has been very little commercial development. DOTATOC is just about to go off patent this year. DOTATATE goes off patent next year. DOTANOC doesn’t go off patent in the United States until 2022. Because of the uncertainty and IP issues with DOTANOC there has been less activity, at least in the United States. Currently the only places in North America doing DOTANOC studies are Edmonton in Alberta, Canada, and Indianapolis at the University of Indiana.
What else is on your radar?
Hypoxia imaging—one of my favorite areas. The standby in hypoxia imaging for the past two decades has been fluoromisonidazole and that has continued to be used as an experimental agent, but there has been no effort to bring that to approval. Our consensus is no. There are number of others and they are all variations on the same theme—they are all nitroimidazoles…There is another one called FAZA [fluoroazomycin arabinoside], and EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] and more recently there is a commercially developed agent called HX4 [flortanidazole] that was originally developed by Siemens and has been picked up by Threshold Pharmaceuticals. They are actually planning a clinical trial for this that could lead to its approval as a companion diagnostic agent. It’s an interesting concept because the chemotherapeutic agent they are testing is a hypoxia-activated chemotherapy. If they can find hypoxic tumors then this chemotherapy is likely to work and vice versa. It’s another nitroimidazole that has similar imaging characteristics.
Hypoxia imaging has been around for a long time but has never really made it. It is one that I am personally interested in and I am hoping to do some research studies with one of these agents in the near future when I have a little more time.