Imagine a product so profitable, it makes printing money look like child’s play. Enter Ac-225, a radioactive drug with the potential to revolutionize cancer treatment. This tiny powerhouse packs a punch with its high energy and short tissue range, making it a formidable weapon against tumors. But here’s the catch: producing Ac-225 is no walk in the park. It’s a complex, expensive process that only a handful of countries can pull off.
In the past few years, the pharmaceutical industry has seen a flurry of major acquisitions centered around this coveted substance. Companies are scrambling to secure their slice of the Ac-225 pie, with deals totaling over a hundred billion dollars. The stakes are high, and the competition is fierce.
So, why all the fuss? Ac-225’s unique properties make it a game-changer in cancer treatment. Its high linear energy transfer (LET) means it can deliver a lethal dose to cancer cells while sparing healthy tissue. Plus, its longer half-life compared to other isotopes like Lu-177 means it can be produced and stored more efficiently, expanding its potential reach and impact.
But here’s the kicker: the global supply of Ac-225 is extremely limited. The production process relies on the decay of Th-229, which is itself a rare and expensive material. Only a few laboratories worldwide have the capability to produce Th-229, making Ac-225 one of the rarest and most valuable substances on the planet.
Despite these challenges, the potential rewards are astronomical. The return on investment for producing Ac-225 is a staggering 510 times, rivaling the profitability of printing money. But this lucrative future hinges on the ability to secure a steady supply of Th-229 and develop the advanced technology needed for production.
As the world watches, Chinese companies are poised to enter the fray. With their technological prowess and the high demand for Ac-225, they have the potential to become major players in this high-stakes game. The race is on, and the winners will not only reap immense financial rewards but also make a significant impact on the future of cancer treatment.
Ac-225 is more than just a profitable product; it’s a beacon of hope for cancer patients worldwide. The journey to harness its full potential is fraught with challenges, but the rewards are worth the effort. As the competition heats up, one thing is clear: the future of cancer treatment is bright, and Ac-225 is leading the charge.
In the past three years, perhaps no nuclide is more scarce than “it”, and no nuclide has attracted more attention than “it”. In less than half a year, there have been four major acquisitions in this field, with a total transaction amount of more than 10 billion US dollars.
- In December 2023, Eli Lilly acquired Point pharma for US$1.4 billion;
- In February 2024, Bristol-Myers Squibb (BMS) acquired RayzeBio for US$4.1 billion;
- In March 2024, AstraZeneca acquired Fusion Pharmaceuticals for US$2.4 billion;
- In May 2024, Novartis acquired Mariana for US$1.75 billion;
Behind the frequent moves of MNC, a large pharmaceutical company, is the competition for the leading position of the next generation of alpha nuclide radiopharmaceuticals (nuclear drugs based on Ac-225/Act-225). This includes both the competition for the “progress” of pipeline research and development, and The competition for the “supply” of the nuclide Ac-225.
Compared with β nuclide (Lu-177), α nuclide (Ac-225) has greater application potential and advantages in radioimmunoassay and tumor treatment. The LET energy of α nuclide is high (>100KeV/μm) but The tissue range is short (<100μm) and can be blocked by a piece of paper The radiation from alpha nuclides can basically only cause damage to a few surrounding cells after entering the human body. Therefore, nuclear drugs based on alpha nuclides can irradiate normal tissues at low doses and achieve a high cancer cell killing rate. In theory, the Ac-225 will have advantages over the Lu-177 in terms of effectiveness and safety.
Moreover, the half-life of Ac-225 is 9.9 days, which is longer than the 6.6 days of Lu-177. Its production and treatment time are more sufficient, and the storage time of nuclear drugs will be longer. Therefore, a “centralized production + outpatient supply” model can be adopted. , not only expands the supply range of nuclear medicines, but also doubles sales.
However, such a bright future is based on an unreliable assumption:
The nuclide Ac-225 can be fully supplied
01 The output is not even enough for R&D
The first to break this window was Bristol-Myers Squibb (BMS). In June 2024, BMS announced that it would suspend the recruitment of new patients in the Phase III clinical trials of its RYZ101 pipeline because of the nuclide Ac-225 (actinium-225). supply shortage.
Ac-225 is known as “the rarest nuclide on earth”. It is extremely rare in nature and relies entirely on artificial synthesis. Ac-225 currently used in clinical research or drug synthesis mainly comes from Th-229/Ac-225 generators made after the decay of U-233. The entire decay process is:
U-233 → Th-229 → Ra-225 → Ac-225
Restricted by the Nuclear Non-Proliferation Treaty, Th-229 is expensive and in short supply. There are only three laboratories in the world that can supply Th-229: Oak Ridge National Laboratory (ORNL) in the United States (5.55GBq, 150mCi), Karlsruhe Laboratory in Germany Institute of Uranium (ITU) (1.7GBq, 46mCi) and Obninsk Institute of Physics and Power Engineering (IPPE), Russia (5.55GBq, 150mCi).
In the Th-229/Ac-225 generator, such changes occur all the time:
Th-229 → Ra-225 → Ac-225
Th-229 with a half-life of 7917 years decays into Ra-225 with a half-life of 14 days
Ra-225, which has a half-life of 14 days, continues to decay into Ac-225, which has a half-life of 10 days.
Ac-225, which has a half-life of 10 days, continues to have a half-life of other nuclides.
Ac-225 is produced all the time and decays all the time. The accumulated amount reaches a peak every three months, so Ac-225 can be eluted every three months.
The existing Th-229 in the world is about 12.8GBq (ORNL+ITU+IPPE). According to the frequency of collecting Ac-225 once every three months, the annual production of global Ac-225 is about 63GBq (1700mCi).
During treatment, the dosage of Ac-225 is generally determined according to the patient’s weight, which is approximately 2~5 μCi/kg. Therefore, the Ac-225 consumed by each patient per treatment is approximately 160~640 μCi.
Assuming that the average patient weight is 70kg and the dosage per kilogram is 4 μCi, the average Ac-225 consumed by each patient per treatment is 280 μCi (0.28mCi). If 4 treatments are one course of treatment, the average dosage per patient is 1.12mCi.
Calculated based on the global annual production of Ac-225 of 1700mCi (1700mCi/1.12mCi≈1500 people), it is only enough to treat 1500 patients.
Such a small amount of output, let alone large-scale supply, cannot even meet the needs of drug research and development and clinical research. No wonder it has hit an ultra-high price of 1 million US dollars/mCi (millicurie), and is known as “the rarest on earth.” of drugs”.
02 Under heavy rewards, there must be brave men
At first (in 2004) in Russia, the Ac-225 with 1 milliCu was only $800. I was silent because I was not in Russia;
Then (in 2007) in the United States, the price of Ac-225 at 1 millicurie rose to 1,500 US dollars. I was silent because I was not in the United States;
Finally (in 2020), when the price of Ac-225 at 1 milliCue rose to 1 million US dollars, no one stood up to speak for me anymore.
Because they all went to study new methods of preparing Ac-225
Note: In 2004, Isonic Company of the United States imported Ac-225 from Russian IPPE with a unit price of USD 800/mCi; in 2007, St George Hospital of Australia imported Ac-225 from Oak Ridge National Laboratory (ORNL) of the United States with a unit price of USD 1500/mCi. mCi.Figure 3: 2004, IPPE (Russia), USD 800/mCi
There are currently three new methods for preparing Ac-225:
(1) Preparation of Ac-225 by irradiating Th-232 with high-energy proton accelerator
(2) Preparation of Ac-225 by irradiating Ra-226 with medium and low energy (>16 MeV) proton accelerator
(3) High-energy electron accelerator (generating high-energy γ) irradiates Ra-226 to prepare Ac-225,
Ac-225 is prepared from Th-232 . Although the target preparation and irradiation have been verified and the preparation process is relatively complete, the irradiation process will be accompanied by the production of trace amounts of highly toxic and long half-life Ac-227 (half-life 21.8a ), and Ac-227 and Ac-225 cannot be chemically separated, so the separation operation is very demanding.
At the same time, this technical route also has very high requirements for proton accelerators. The proton energy must reach more than 70 MeV, preferably 200 MeV. However, there are very few cyclotrons in the world that can meet this beam condition. Even if there are, the cost is ridiculously high.
Therefore, the vast majority of commercial manufacturers will choose “proton accelerator irradiation of Ra-226” and “high-energy electron accelerator (generating high-energy γ) irradiation of Ra-226” as the technical path for preparing Ac-225.
There are currently eight major commercial manufacturers, concentrated in the United States, Europe and China. Only three of them have accelerator manufacturing capabilities, including PanTera, Actineer, and Deru Optoelectronics.
03 Profits comparable to printing dollar bills
When chatting with investors before, I always like to describe the profit margin of “preparation of nuclides with accelerator” as “turning stone into gold”. However, after carefully calculating the profit of “preparation of Ac-225 with high-energy electron accelerator”, I feel that I am still too To be conservative, the ROI of 510 times, the only thing that can be comparable to it may be the printed dollar, and it has to be the kind with a face value of 100 US dollars.
Operating costs
The cost of producing Ac-225 includes: target raw materials, equipment operation and maintenance, water and electricity expenses, labor expenses, and equipment depreciation. Except for “target raw materials“, the prices of other cost factors are relatively fixed, of which equipment operation and maintenance is about 2 million/ Annual water and electricity costs are about 40 0 million/year, labor expenditure is about 2 million/year, and equipment depreciation is about 5 million/year. In addition to target raw materials, the total is about 13 million/year. Calculated based on 50 production cycles a year, the average operating cost of one cycle is 260,000 yuan (approximately US$40,000)
Ra-226 cost
High-energy electron accelerators prepare Ac-225, and the target material used is Ra-226. Ra-226 mainly comes from the nuclear fuel cycle. The output is low and the price is opaque. There is no market price at all.
A researcher from New Haven Hospital said that they had “donated” 0.75 g of Ra-226 to a company, which cost about US$82,000 including shipping costs; another British scholar said that purchasing 1 mg of Ra-226 in Europe would cost about $82,000. It costs 15,000 euros and comes in a variety of prices, with huge differences.
A relatively reliable clue comes from a company that uses cyclotrons to produce Ac-225. The price of Ra-226 it purchases ranges from 250,000 to 2 million US dollars/g . We can make a conservative estimate and take the highest value of 2 million. USD /g.
Ac-225 production value
Similar to Ra-226, the price of Ac-225 is not transparent. There is no market price. After searching the literature and asking through multiple channels, I finally learned that the price range of Ac-225 is about US$30,000 to US$70,000/mCi. Taking a conservative The average value is US$40,000/mCi.
Assuming that the yield of Ac-225 prepared by high-energy electron accelerator is about 550 Bq/(μA·h·mg 226Ra), the recovery rate of Ra-226 is 95%, and the input of a production cycle is:
- Ra-226 target 1g
- Irradiation time 150h
- The accelerator current is 1000μA,
- Accelerator energy 50 MeV
Then the theoretical yield of Ac-225 is 2.2297 Ci, and the calculation formula is as follows:
550Bq/(μA·h·mg 226Ra) x 1000 μA x 150h x 1000mg =8.25 ×10^10 Bq =2.2297 Ci
Assuming that the operating loss is 20%, the actual output is 1.7838 Ci. Calculated based on the unit price of US$40,000/mCi, the output Ac-225 is worth US$71.35 million.
- 1.7838 Ci x $40,000/mCi = $71.35 million.
The output of Ac-225 in one production cycle is 1.7838 Ci. Calculated based on 50 production cycles a year, that is 89.19 Ci, worth 3.5676 billion U.S. dollars, equivalent to about 25 billion yuan.
ROI calculation
1.7838 Ci per production Ac-225 requires 1g of Ra-226, but the recovery rate of Ra-226 is 95%. Therefore, the actual consumption of Ra-226 in each production is only 0.05g. Calculated at 2 million US dollars /g, each time The cost of raw materials (Ra-226) produced is US$100,000, plus other operating costs of US$40,000, totaling US$140,000. From this, it can be calculated that the ROI of producing Ac-225 is 510 times.
- ROI (Ac-225) = 71.35 million US dollars / 140,000 US dollars ≈ 510
According to the latest data released by the Federal Reserve in 2021, the production cost of a $100 bill is 19.6 cents. After calculation, the ROI of printing U.S. dollars is also 510 times.
- ROI (printed US dollars) = 100 US dollars / 0.196 US dollars ≈ 510
510 times VS 510 times , the profit margin of making Ac-225 is really comparable to printing money.
04 Not everyone can play the poker table
The principle of using a high-current electron accelerator to prepare Ac-225 is very simple. It is to use the high-energy electron beam generated by the accelerator to hit the conversion target to produce γ-rays, and then use γ-rays to irradiate the Ra-226 target material to induce (γ, n) photonuclear reaction. This produces Ra-225, and finally Ra-225 undergoes beta decay (natural decay) to produce Ac-225.
226Ra(γ,n)225Ra→225Ac
Therefore, just like preparing other nuclides, a team that wants to prepare Ac-225 also needs to solve three problems: accelerator, target raw materials and separation and purification process.
Although it is said that if you want to mass-produce the Ac-225, all three are indispensable, but as long as you master one of them, you will be qualified to play on the poker table.
There are currently four teams using “high-energy electron accelerator irradiation Ra-226” as a technical path. Among them, PanTera and NorthStar have the shadow of the same company behind them, that is, IBA.
Although the accelerators used by the two nuclide companies are IBA’s TT300HE, to IBA PanTera is their biological son, while NorthStar is just a surrogate mother.
NorthStar is the seed customer of TT300HE and the only demander in the early stage. It can be said that without the demand put forward by NorthStar, there would be no birth of TT300HE. However, if the cooperation between the two only stays at the “procurement-supply” level, If there is no deep bonding in equity, it is not surprising that they eventually separated, because their long-term interests are not consistent.
In the early stage, the risk of failure of the “Nuclide Preparation by High Current Electron Accelerator” project was very high. For IBA, there was no need to take risks and bet on the future as an accelerator supplier.
However, no one expected that NorthStar would actually create nuclides. This news completely verified the feasibility of “preparation of nuclides by high-current electron accelerator” in industrialization.
If you participate before, it is risky
Then participating now is just picking up money.
If IBA only participates in this wave as a supplier of accelerator equipment, although it can get a piece of the pie, it will not be able to make a living for a long time.
Although the price of high-current electron accelerators is high, the product life cycle is also long, generally more than 20 years, or even 30 years of operation. Therefore, the market space for high-current electron accelerators is destined to not be very large.
If the downstream interests cannot be shared, there will naturally be no motivation for “long-term cooperation.”
Therefore, after 2022, IBA will no longer continue to provide accelerators to NorthStar. Instead, it established a joint venture with SCK CEN to produce Ac-225 nuclide-PanTera. To protect the joint venture, IBA related the TT300HE accelerator The technology was transferred to PanTera, and the TT300HE accelerator was no longer sold externally.
05 Summarize
IBA is to the nuclide industry just like Nvidia is to the AI industry. It uses its monopoly position to cut off the supply of “high-current electron accelerators” and chokes the necks of pursuers, forcing everyone to either develop their own accelerators. Or switch technical paths.
However, I believe that in the face of a market space of more than 10 billion US dollars and the temptation of 510 times ROI, there is no monopoly that cannot be overcome. It is just a matter of spending more time.
Accelerators, target raw materials and separation and purification processes, if you get one out of three in the world, you will have the qualifications to be on the poker table and aspire to IPO.
We must know that our country’s technical reserves are not weak. “High-current electron accelerators” have been used in many major scientific research devices. However, there were no commercial application scenarios before, so there have been no relevant commercial companies.
But now that PanTera and NorthStar have verified that this path is feasible, more Chinese teams will inevitably emerge in the future. It is said that projects in the primary market are like production capacity in the manufacturing industry. Excellent projects are always scarce and mediocre projects are always in excess . As far as I know, in addition to the self-developed “40MeV high-current electron accelerator” by Derui Optical Nuclear, The Ninth Academy is also developing this type of accelerator for a nuclide/nuclear medicine company.
Now that we have mastered the “Accelerator” card, there is no reason to play the card table.
The fight against cancer is constantly evolving, and a new weapon is emerging from the realm of nuclear medicine: Ac-225. This rare earth element, one of the most scarce isotopes on Earth, is poised to revolutionize cancer treatment, offering a powerful new approach to fighting this devastating disease.
The Power of Alpha Radiation:
Ac-225 emits alpha particles, which are highly energetic and can effectively destroy cancer cells. Unlike beta particles, which have a longer range and can damage healthy tissue, alpha particles have a short range, making them ideal for targeted therapy. Think of it like a precision strike, targeting cancer cells with minimal collateral damage.
A Game-Changer in Radioactive Immunotherapy:
Ac-225 is particularly promising for radioactive immunotherapy, a cutting-edge approach that uses antibodies to deliver radioactive isotopes directly to cancer cells. These antibodies act like homing missiles, guiding the Ac-225 to its target, where it unleashes its destructive power.
Facing the Challenges:
While Ac-225 holds immense potential, its production and supply face significant challenges. The scarcity of this isotope makes it incredibly expensive, and the technical hurdles of synthesis and purification are complex. But researchers and companies are working tirelessly to overcome these obstacles, paving the way for wider availability.
A Race for Innovation:
The global nuclear medicine market is booming, and the race for innovation is heating up, especially in the field of alpha nuclide drugs. Companies are investing heavily in research and development, striving to bring Ac-225-based therapies to market.
The Future is Bright:
Despite the challenges, the future of Ac-225 is bright. The successful commercial production of Ac-225 by several companies demonstrates the feasibility of this technology. More research and development are underway, and it’s only a matter of time before Ac-225-based therapies become a standard treatment option for a range of cancers.
The Takeaway: A New Era of Cancer Treatment:
Ac-225 represents a new era in cancer treatment, offering a powerful and targeted approach to fighting this disease. While challenges remain, the potential benefits are immense, and the future of Ac-225 is filled with hope for patients and their families. This rare earth element could be the key to unlocking a new era of precision medicine, where cancer is treated with greater effectiveness and fewer side effects.