OK … so it took us a couple of days to work out why only two centers (at UCSF and UCLA) had been approved to administer the new (to the US) gallium-68 PSMA-11 scans. It wasn’t very smart of us. We should have realized immediately!
The answer is very simple. Each dose of Ga-68 PSMA-11 has to be made on site at the particular center using the drug to carry out the PET/CT scans because the half-life of gallium-68 is only 68 minutes. You therefore can’t transport and store this drug in a “ready to use” manner. We had seen this before in relation to the development and use of the choline C-11 PET/CT scans first developed and initially only approved for use at the Mayo Clinic in Rochester, MN.
The good news, however, is that there may to be ways to make it easier (than it is at the moment) to actually create each batch of Ga-68 PSMA-11, and so we expect that it may not be too long before any institution with a PET/CT scanning capability and a good nuclear medicine department will be able to carry out this type of scan, but each institution will probably have to demonstrate to the FDA that they actually have the manufacturing capabilities to make the product consistently and with high enough quality levels from the relatively readily available base components.
Filed under: Management | Tagged: gallium-68, maunfacture, PSMA, scan |
THE "NEW" PROSTATE CANCER INFOLINK 
England, Netherlands and Argentina have PSMA PET/CT. While the US catches up, far too many men — one is too many — will progress to incurable metastasis.
AnCan’s thinking is a little different on this FDA approval.
We see it as the first FDA endorsement of PSMA “technology”. We are well aware there are many PSMA “drugs” in the pipeline being trialed, some of which may already have been submitted for FDA approval — for example, PSMA 617 that can also be attached to Lu177, and the Blue Earth version.
Before long we believe other more transportable PSMA agents will be approved so ultimately PSMA-11 will not be the most widely used product.
The “breakthrough” here is FDA acceptance of proof of concept rather than clinical application. And we realize each agent has to be individually assessed for safety.
A little of the chemistry for those who are interested ….
Gallium-68 (Ga-68; half-life = 68 minutes) is a major decay product of germanium-68 (Ge-68; half-life = 271 days). Ge-68 is made by proton bombardment in large cyclotrons at one of the US National Laboratories. Ga-68 is easily separated out when needed from its Ge-68 source by chromatography. It is then easily combined by a relatively loose chemical bond (called a coordination complex) to the PSMA-11 ligand. (It is also chelated to the DOTATATE ligand when it is used for detection of gastric neuroendocrine cancer.)
The chelation makes it easy to produce on-site, but it also is a relatively unstable bond. It can be replaced by other metals, by other chelates (look at the label on a bottle of multivitamins), or perhaps by other biological chelates. Vitamin B12 is a coordination complex with cobalt; hemoglobin is a coordination complex with iron.
A more strongly bonded positron-emitter occurs when fluorine-18 (F-18; half-life = 110 minutes) is incorporated into the DCFPyL molecule. F-18 is easily produced from proton bombardment of oxygen-18 in an on-site linear accelerator — a large cyclotron is not required. Oxygen-18 is a stable, naturally occurring isotope. It is about 0.2% of water, and it is easily separated from oxygen-16 in water by distillation or a semi-porous membrane. F-18 easily replaces the hydroxyl moiety in organic molecules, and the covalent bond produced is very tight and stable. It is commonly used in FDG PET scans. When the DCFPyL PET scan is approved next year (a New Drug Application was submitted to the FDA in October), any site that offers an FDG PET will be capable of offering it.
Choline PETs are a unique problem. When F-18 replaces the hydroxyl moiety in choline, the fluorine atom is so tightly bonded that it changes choline’s biochemistry. A choline C-11 PET scan only works because the choline molecule is metabolically active in prostate cancer cells. When it is changed so that it cannot be metabolized, it isn’t as sensitive to the cancer. Mayo solved the problem by using carbon 11 (C-11) instead. Carbon is part of the backbone of the organic choline molecule. There were some problems: (1) The C-11 half-life is only 20 minutes, and (2) incorporating C-11 into the choline backbone meant that it had to be synthesized from C-11-enriched carbon dioxide. The short half-life means there has to be an on-site cyclotron. The organic synthesis starting with C-11-enriched carbon dioxide has to be automated, and done very quickly — it is an expensive and very low yield process. Mayo holds the patent and invested a lot in it. It is no wonder that they continue to push it even after the more sensitive Axumin PET scan became widely available.
From something I recently read … evidently these scans are almost standard of care and widely available in Australia … but a big deal in the world’s most expensive medical system?
Dear Rick:
With respect, the FDA would have approved a PSMA-based imaging agent years ago if anyone had submitted an appropriate application to them. There is no “breakthrough” with respect to the FDA being willing to approve such products. Numerous other countries had already approved such generic agents!
The other issue is going to be price. The cost may be much lower for this generic agent than for other patented agents still in development. There is going to be a big question around whether any newer forms of such imaging agents — even using lutetium-177 — will be significantly “better” than the most recently approved generic agent.
“”With respect the FDA would have approved a PSMA-based imaging agent years ago if anyone had submitted an appropriate application to them.”
We could say that about absolutely any approval, Sitemaster. If someone had submitted an application for an anti-PD1 a few years earlier it may have been approved earlier …… as they say “no S***, Sherlock!” Unfortunately the developers of the technology were not ready to submit. I suspect they did so at the earliest possible time they considered feasible.
Maybe I need to better define what I mean by breakthrough.
This is an approval breakthrough in the USA. Several agents have been submitted to the FDA – R2, 617 etc etc. This is the first to gain approval – that’s a breakthrough since we now know the FDA will approve the concept of attaching a radiionuclide molecule to a PSMA receptor, though it has to test and approve other agents for safety and efficacy.
PSMA has been widely available in Australia and Germany for some time as others have commented. And PSMA trials have been going on in this country for around 5 years. Back in 2013 a friend of ours pocket- funded Tom Hope ….. but we had to wait until a trial was submitted, filled and completed before the Ga68 PSMA 11 application could be submitted. The technology is not a breakthrough – the FDA approval definitely is given the number of PSMA drugs in line.
The ligand that has been approved for Ga-68-PSMA-11 is PSMA-11 (which is a simplified name for PSMA-HBED-CC). It is not a generic approval – only this specific molecule has been FDA-approved so far. There are several other ligands in the pipeline (e.g., PSMA-1007, PSMA-I&T, CTT1057, rhPSMA-7.3, and PSMA-J591). My understanding is that the ligand approved at UCLA and UCSF was developed by Uwe Haberkorn at the University of Heidelberg, which made it available without royalties.
PSMA detection has been around for a long time. Some of us may remember Prostascint (Indium capromab pendetide), which was an FDA-approved In-111- radiolabeled monoclonal antibody to PSMA. It was used to detect prostate cancer, but wasn’t very good (low specificity, poor inter-observer agreement) and was discontinued in 2018. It was used with SPECT (In-111 is a gamma emitter) rather than PET scans.
Dear Rick:
You are missing my point entirely … this particular form of Ga-68 PSMA (a generic drug) has been widely available in Europe and Australia for some years now because studies were done rapidly (with “public money”) a while ago to gain such approval. The situation with regard to things like anti-PD1 agents is utterly different. There was no generic equivalent.
The primary problem in the US was that there was no commercial motivator for a drug company to make and test this agent, which meant that raising the money to plan and conduct the trials was hard and there was no meaningful, significant source of “public money” to facilitate this (e.g., through the NIH or similar).
I do understand the various potential uses of the term “breakthrough”.
Hi Allen. My error. I was under the impression that PSMA-11 had been around for so long that it was off-patent, but if it’s academic developers are waiving royalties it comes to the same thing anyway. PSMA molecules have been around since the early 1990s.
The fundamental point remains the same. There was no commercial motivation in the USA to develop the combination product (Ga-68 PSMA-11) because no drug company could make significant money from it.
For sure there is commercial motivation, Sitemaster. Otherwise why are companies like Blue Earth and other privte entities developing it!
The commercial motivation is to sell the ‘drug’ widely. Each time a screening is carried out, it requires the agent – and someone has to be produce and sell that. At this time the agent is expensive and scarce – that’s the reason centers like UCLA and elsewhere have been charging several thousand dollars to particpate in screening trials as well as therapeutic trials for Lu177 in Houston and elsewhere.
Personally, I suspect there will be several PSMA agents (drugs) available before long. That said, competition will hopefully bring the cost down.
As to why UCSF and UCLA have made PSMA 11 open source ….. probably because they raised research costs through grants and they are eager to make this game changing, breakthrough technology widely available in the US. Also, Heidelberg has set a precedent.
And yes – I guess I am missing your point entirely, SItemaster. When you say that the FDA would have approved a PSMA drug earlier had it been submitted earlier, that is tautologous. Of course ….! It wasn’t submitted earlier becasue the evidence was ready for prime time.