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Pharma Companies Navigate Their Way through Ac-225 amidst Supply Constraints by EOS Intelligence
by EOS Intelligence EOS Intelligence No Comments

Pharma Companies Navigate Their Way through Ac-225 amidst Supply Constraints

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Pharma companies have been increasingly investing in developing targeted alpha therapies for cancer treatment, using alpha-emitting isotopes such as Ac-225. However, the current supply for Ac-225 is limited, and thus, companies are working towards securing their supply chain. The recent investment by Eli Lilly in isotope manufacturer Ionetix brings to light the increasing interest of large pharmaceutical companies in Ac-225 and its uninterrupted supply for their pipelines. Similar to Eli Lilly, several other companies have strategically invested in or partnered with manufacturers to ensure a guaranteed supply.

Ac-225 is pegged as a promising isotope for next-generation cancer treatment

Among the recent advances in cancer therapies, only a few have shown as much promise as targeted alpha therapies have. Targeted alpha therapies (TAT) involve using alpha-emitting isotopes to selectively target and destroy cancerous tissue without causing significant damage to surrounding healthy tissue. This is facilitated by the short range of alpha radiation in human tissue (less than 0.1 mm), which corresponds to less than 10 cell diameters. Moreover, they are characterized by high energy levels (5-9 MeV), which results in the selective destruction of malignant cells.

Several alpha-emitting isotopes are currently being explored for TAT, the most common among them being Ac-225, At-211, Pb-212, and Bi-213. Of these, Ac-225 (actinium-225) is considered the most potent medical-grade radioisotope as it has a high decay energy of 5.9 MeV and a half-life of 10 days. It is the isotope of choice in several clinical trials, with about 15 Ac-225-based ongoing clinical trials currently in the USA. However, despite having substantial potential for developing next-generation treatments in the cancer space, their adoption has been slow, given the short supply of the isotope.

Ac-225 is not naturally available and is derived from Th-229 (thorium-229), a byproduct of uranium-233 (U-233), which is a leftover from the production of atomic weapons in the 1950s and 1960s. The initial batch of Ac-225 has been supplied by the US Department of Energy (DOE). However, the supply cannot keep up with the growing demand for trials.

Isotope producers invest to accelerate Ac-225 supply in the future

Currently, there are two commercialized routes to produce Ac-225. As mentioned above, the first and traditional route involves separating Ac-225 from Th-229, derived from the US government’s legacy reserves of U-233. The US government holds about 453kg of U-233, of which only about 256kg is of high quality and will produce about 24g of medical-grade thorium.

The government had previously started a program that extracted a small amount (150mCi) of Th-229, which produced about 1.2 Ci of Ac-225 per annum, enough to treat 1,200 patients. However, in 2019, the US DOE entered into a public-private partnership with Terra Power and Isotek to downblend its stock of U-233 to extract Th-229, which can further be used to develop Ac-225. In 2021, TerraPower entered into an agreement with Cardinal Health, a US-based commercial alpha contract manufacturing organization (CMO), to develop and produce Ac-225 for drug development commercial sales. This will likely significantly improve the supply of Ac-225 in the long run.

The other route to produce Ac-225 is through cyclotron production, which involves irradiating a Ra-226 (Radium-226) target with a proton and knocking off two neutrons. Several isotope manufacturers are adopting this technology and are working on increasing their manufacturing capacity.

Niowave, a US-based supplier of medical and industrial radioisotopes, uses a closed-loop cycle to produce high-purity Ac-225 and other alpha emitters from Ra-226 using a superconducting electron linear accelerator. Similarly, Ionetix, a leading cyclotron technology innovator and isotope manufacturer, uses the same technology to produce Ac-225 and managed to produce its first batch of Ac-225 in June 2024. The company commissioned its first cyclotron at its current facility in 2023, while it aims to install and commission a second cyclotron there in early 2025. By 2025, it is expected that the company will be able to produce about 1Ci per week. The company also aims to establish another site in the USA for Ac-225 production in 2026.

While isotope manufacturers are strategically working to enhance the production of Ac-225 in the long run, the current supply, which is required to fuel the ongoing clinical trials using Ac-225, is quite limited. In 2024, the worldwide supply of Ac-225 is estimated to be about 2Ci per annum, which is merely enough to treat 2,000 patients.

Pharma companies invest in securing their Ac-225 supply chain

Given its currently limited availability and immense potential, leading pharmaceutical players are adopting various strategies to secure their Ac-225 supply to support their targeted alpha therapies drug pipelines. Several leading players, such as Fusion Pharmaceuticals, Telix Pharmaceuticals, and Bayer, are actively working on partnering with companies producing Ac-225 to overcome supply-related challenges for their trials. Recently, a leading pharmaceutical company, Eli Lilly, also joined the bandwagon and secured its supply of the actinium isotope.

Fusion, which has three Ac-225-based drugs currently under trial, was one of the first movers in this regard and has inked several partner agreements to ensure a smooth supply.

In December 2020, Fusion entered into a partnership with TRIUMF, Canada’s national particle accelerator center. In this partnership, Fusion would provide the latter with up to US$18.5 million (CA$25 million) to upgrade its production facilities and scale up production of Ac-225. In return, Fusion would receive preferred access and pricing to the resulting isotope.

In June 2022, Fusion collaborated with Niowave, a US radioisotope manufacturer. Under the agreement, Fusion would invest up to US$5 million in Niowave to further develop their technology to increase their production capacity of Ac-225. In return, Fusion will be guaranteed access to a pre-determined percentage of Niowave’s capacity of the resulting Ac-225, as well as preferred access to any excess stock produced.

In November 2023, Fusion entered into an agreement with BWXT Medical, a US-based supplier of nuclear components and a subsidiary of BWX Technologies. Under the agreement, the latter agreed to provide Fusion with a preferential supply of Ra-225 (parent isotope of Ac-225) and access to high-specific activity generator technology. This would enable Fusion to produce Ac-225 at its own manufacturing facility for use in clinical trials. In addition, BMXT Medical provides Fusion with predetermined amounts of its actinium supply needs under a preferred partner agreement.

Another leading radiopharmaceutical player, Telix Pharmaceuticals, entered into an agreement with Cardinal Health in May 2024 to supply Ac-225 globally.

Similarly, in February 2024, Bayer signed an agreement with PanTera (a Belgian radioisotope production JV created by Ion Beam Applications and SCK CEN) to secure large-scale production of Ac-225. PanTera uses both the Ra-226 and Th-229 production mechanisms to produce Ac-225. It is collaborating with TerraPower to supply Th-229.

Eli Lilly, the largest pharmaceutical company globally, has also recently invested in a nuclear isotope manufacturing company, Ionetix, in August 2024. Eli Lilly has made a US$10 million convertible loan investment in the company to secure its supply of Ac-225. Moreover, PointBiopharma, which was acquired by Eli Lilly in 2023, also had a previous US$10 million investment in Ionetix, resulting in Eli Lilly holding a total of US$20 million debt facility with Ionetix. The pharma giant has the option to convert this debt into equity when Ionetix’s valuation exceeds US$300 million.

These investments by Eli Lilly and Fusion Pharmaceuticals are rare cases where major pharmaceutical companies are investing up the supply chain to secure actinium availability for their cutting-edge drug pipelines.

EOS Perspective

While targeted alpha therapies are emerging as high-potential next-generation cancer drugs, they are plagued by supply constraints of alpha-emitting isotopes, especially Ac-225. Thus, companies seeing great promise in these therapies must work towards securing their supply of these isotopes to ensure the smooth running of their clinical trials.

In the past, large pharmaceutical companies such as BMS have had to halt enrolment in their clinical trials due to the non-availability of Ac-225. Such interruptions not only delay the entire clinical trial but also have significant cost implications and could jeopardize its overall success.

Considering these limitations, it is imperative that pharmaceutical companies with ongoing or planned Ac-225-based trials invest in ensuring a guaranteed supply of the isotope for the entirety of their trial and future production of the drug once approved. While several companies are merely entering into supply agreements with isotope manufacturers, others are taking it one step ahead and investing in their upstream suppliers. Moreover, some companies, such as Fusion and now BMS, are advancing towards building on-site production of Ac-225.

That being said, establishing a secure supply chain of Ac-225 comes with its own set of costs and risks. Most pharmaceutical companies are undertaking significant investments (ranging between US$5-25 million) to guarantee their supply of Ac-225.

However, as a cancer therapy, TAT is in the nascent stages of development, and most trials utilizing Ac-225 are still in either phase 1 or phase 1/2, far from FDA approval. Moreover, the only Ac-225-based trial in phase 3 is being conducted by BMS for neuroendocrine cancer and is currently halted due to supply issues. Given the nascency and early stages of development of this treatment, it is too soon to predict if these heavy investments into Ac-225 would result in the development of FDA-approved drugs and bring sufficient returns. This risk can have particularly dire consequences for small players.

Thus, while companies looking to develop targeted alpha therapies using Ac-225 must work to secure their supply, their level of investment must remain in sober relation to their size, pipeline, and financial position.

Gut Matter - Will FMT Change How We Look at Disease Treatments by EOS Intelligence
by EOS Intelligence EOS Intelligence No Comments

Gut Matter: Will FMT Change How We Look at Disease Treatments?

Converting poop to pills was something unimaginable a few years ago, but now Fecal Microbiota Transplant (FMT) is taking the medical world by storm. This revolutionary technique, which promises to treat a wide range of diseases, from GI disorders to mental health issues, is becoming popular due to its success in treating recurrent clostridioides difficile infection (CDI), a serious infection that can damage the colon. FMT offers tremendous opportunities but also has challenges that players should consider if they want to thrive in this industry.

FMT is a procedure in which feces from a screened, healthy donor are transplanted into a recipient to balance the gut microbiota. This procedure can help treat certain infections and lessen the severity of some gut health issues.

Gut infections are usually treated using antibiotics, which can occasionally destroy beneficial bacteria. A 2000 study published in the Journal of Microbiology, a delayed open-access journal of the American Society for Microbiology, indicated that CDI recurring in around 15% to 35% of people is caused by antibiotics disrupting the gut microbiota and its balance (gut dysbiosis). Dysbiosis has been linked to several chronic illnesses, such as cardiovascular disease, inflammatory bowel disease (IBD), diabetes, and colorectal cancer (CRC).

FMT is highly efficient in treating recurrent CDI, with a cure rate of 90%, according to a 2015 study published in the American Journal of Gastroenterology. Numerous trials to understand the efficacy of FMT in treating conditions such as obesity, liver disease, ulcerative colitis, Crohn’s disease, Parkinson’s disease (PD), and IBS are underway. There are also some pre-clinical studies in progress to understand the potential of FMT in treating illnesses such as diabetes, skin issues, lung diseases, and autism.

This article is the second in EOS Perspectives' coverage 
of Fecal Microbiota Transplantation in animals and humans.

Read our related Perspective:
 Poop to Pills: Is FMT the Future of Veterinary Medicine?

FMT is showing promising growth

The human FMT sector is expected to grow at a CAGR of 5.1% and reach US$3.15 billion by 2031, according to a 2023 report published by India-based market research company The Brainy Insights.

The key factor influencing this growth is the rising incidence of GI disorders. According to the GI Alliance, a US-based network of gastroenterology providers, around 20 million Americans have chronic digestive disorders. Similarly, the CDC estimates that there are around 500,000 cases of CDI reported annually in the USA, and about 9% of elderly patients die within a month of contracting healthcare-associated CDI. All these have influenced the growth of FMT, which offers a promising solution to several conditions.

Other factors influencing the FMT sector growth are the rising patient awareness and interest in preventive healthcare and the emergence of effective probiotic strains.

There are several biotechnology companies currently involved in R&D and product development. Australia-based BiomeBank became the first company to get approval from a competent authority to market its FMT-based CDI solution called Biomictra Faecal Microbiota (colonoscopic, enema, and upper GI delivery) in November 2022. This was followed by the FDA approval of US-based Rebiotix-Ferring Pharmaceuticals’ REBYOTA (rectally administered) in the same month. Seres Therapeutics, a US-based company, has also received FDA approval for its orally delivered product Vowst (SER-109) for treating CDI in April 2023. Following Seres’ footsteps, Rebiotix-Ferring is now conducting trials to develop an oral alternative, RVX7455.

US-based Finch Therapeutics is another major company developing solutions presently undergoing phase-3 studies for diseases such as chronic hepatitis B and autism. Its solution, CP101, for treating CDI, has been discontinued.

Gut Matter Will FMT Change How We Look at Disease Treatments by EOS Intelligence

Gut Matter Will FMT Change How We Look at Disease Treatments by EOS Intelligence

The FMT sector is grappling with a multitude of pressing challenges

The FMT sector has the potential to treat numerous GI and other related disorders effectively. However, the business landscape is still marred by several challenges that players must consider.

Lack of consensus about policies is making development challenging

Regulatory hurdles are one major roadblock players face. The FDA currently regulates FMT as an unapproved biologic medicine. There is a lack of uniform guidelines for FMT, causing variations in processes, such as donor screening and processing.

The FDA took its first step toward FMT regulation in 2013. It released a set of guidelines removing the need for investigational new drug (IND) applications when FMT is used for treating CDI unresponsive to standard treatments if medical practitioners secure informed consent. However, this application is needed when FMT is used for other reasons, including safety studies.

The FDA drafted new guidance in 2016, which was finalized in November 2022. In this guidance, the FMTs acquired from stool banks are exempt from regulatory discretion. Also, the IND requirements will be waived if some conditions are fulfilled, such as getting informed consent from patients or authorized representatives and screening and testing stool under the supervision of competent healthcare professionals. There should also be no known potentially serious safety concerns, such as issues with improper handling or storage, or issues with administering product collection without the proper testing or screening. All these increase the procedural burden for healthcare practitioners. However, the FDA has indicated no regulatory policies for stool banks to reduce the administrative burden of private practice settings without the support of research staff.

Due to the significant variation in gut microbial composition among samples, FMT fails to satisfy EU drug classification requirements. Also, since human cells are not an active component of fecal matter, FMT is not covered by EU Directive 2004/23, which deals with the safety and quality of human tissues and cells. Therefore, the European Medicines Agency (EMA) has authorized the member states to regulate FMT however they see fit.

This lack of consensus has led to diverging regulatory policies, causing uncertainties for interested players and making developmental activities challenging, particularly in Europe. But despite this, many companies, such as Rebiotix-Ferring Pharmaceuticals, are making leaps in R&D.

Donor selection has social, ethical, and financial challenges

Another bottleneck that needs to be addressed is the availability and selection of suitable donors. There is a debate regarding whether the patient should know the donor or not. Also, the ideal donor should be free from chronic illnesses or infections and willing to donate. The donor is screened for obesity, antibiotic resistance, microbiome diversity, oncogenic potential, a history of antibiotic use, and risky behaviors such as drug abuse.

Stool banks require donors to follow several restrictions, such as maintaining BMI, abstaining from unhealthy eating habits such as spicy foods or saturated fatty acids, and avoiding travel to infection-prone tropical regions for an extended period. With that, donor dropout is high due to the considerable commitment needed, according to a 2019 study published in Gastroenterology, the official journal of the American Gastroenterological Association (AGA).

FMT implementation is also facing several social and ethical challenges with questions such as donor compensation, gender of the donor, donor and patient vulnerability, and commercial use of fecal matter.

Companies can launch educational drives targeted at patients and ideal donors to raise their awareness about FMT, tackle social resistance towards the procedure, and build trust with prospective donor candidates and patients. This can help reduce people’s reluctance to participate in FMT procedures.

The procedure remains risky, especially for vulnerable population

FMT is associated with an increased risk of transmitting infections such as Shiga toxin-producing E. coli (STEC) and enteropathogenic E. coli (EPEC) from the donor to the receiver. Immunocompromised patients are at a higher risk of developing side effects, according to a 2020 study published in Digestive Diseases and Sciences, a peer-reviewed journal. Similarly, a 2019 case study published in the New England Journal of Medicine, a journal of the Massachusetts Medical Society, showed a fatal infection contracted by an elderly immunocompromised individual following an FMT procedure.

Another challenge is the very few pediatric clinical trials, which makes it difficult for physicians to make the best judgments for when to initiate FMT therapy in children.

To tackle safety-related challenges, the FDA released safety advice in 2019 and 2020 regarding the possible risk of severe, potentially fatal infections associated with the procedure. Companies such as Boston-based OpenBiome have promptly modified their sample screening methodology to identify such infections.

Lack of studies on long-term effects

The lack of understanding of the long-term changes FMT can cause in a patient’s microbiota is another challenge. Several studies reveal that liver diseases, cancer, cardiovascular diseases, etc., can develop due to microbiota dysbiosis. Investment in R&D by interested and capable players can help medical professionals understand the long-term implications and complications of FMT and identify feasible solutions, which can pave the way for widespread treatment acceptance.

The sector’s future appears bright, underpinned by extensive development

FMT is a highly effective treatment for recurrent CDI. New developments have been taking place in many areas, such as administration modes, stool collection, and storage, and interested players can find opportunities in these areas. The FDA is also becoming more accepting of FMT-based treatments that show good results. This is shown by the approval of Rebyota and Vowst, both of which were more effective in reducing recurrent CDI compared to placebo in randomized controlled trials.

Stool banking and processing is another area ripe with opportunities for interested players. Conventionally, fresh stool is used for FMT, but this can increase the cost of the procedure. Stool banks are being developed to facilitate cost-effective and safe treatment. An example is OpenBiome, the USA’s first and biggest public stool bank. Stool banks can also make the standardization of stool processing and donor selection easier, according to a 2019 report published by the European Helicobacter and Microbiota Study Group.

Players can also form collaborations with healthcare professionals and research institutions to offer FMT treatments and support microbiome research. Many government organizations are also showing interest in the development of FMT therapies. The GBP500,000 grant awarded by the Biotechnology and Biological Sciences Research Council (BBSRC), a part of UK Research and Innovation, in 2022 to Norwich-based Quadram Institute (QI) to build and equip a new FMT research facility is an indication of this.

Investing in the development of FMT treatments can revolutionize the treatment of several diseases, and companies that can invest in research can gain a head start in the competition. Rigorous R&D is going on to develop FMT solutions for conditions such as obesity, depression, cancer, pediatric diseases, and autoimmune disorders such as Crohn’s disease.

A 2023 trial conducted by the US-based Emory University School of Medicine also showed that FMT can reduce the colonization of multidrug-resistant organisms in kidney transplant patients. Investigators believe more research in this field can help improve transplant success rates and decrease the chances of infection. Individual case studies have shown great improvement in cure rates for certain diseases, including mental health conditions, but more research is needed to present a solid case for product development.

EOS Perspective

FMT is gradually establishing itself as a promising solution for recurrent CDI and is expected to create waves in the treatment of numerous physical and mental health conditions despite facing several challenges.

Improvements in donor selection, early identification of certain conditions with better risk assessment, and increased treatment efficiency can be expected with ongoing research expanding the knowledge base of the medical community.

Experts are also looking into FMT’s potential as an adjunct therapy in treating diseases such as tuberculosis, and it is expected to open the door to interested players to create personalized and targeted FMT-based treatments for various diseases.

Studies are also being done to understand and substantiate the potential of gut microbiota to anticipate diseases such as IBD and CRC using AI (Artificial Intelligence) and ML (Machine Learning). ML can be used to identify biomarkers in the gut microbiota to aid in the early detection of CRC. These studies, when extended to FMT, are expected to help medical professionals identify ideal donors and improve treatment efficiency.

The Brainy Insights, in its 2023 report, predicts a growth in the probiotic infusion segment owing to the increasing studies on diabetes management. Therefore, competitive players interested in FMT can also diversify their portfolios by including consortia (multi-population systems with a broad spectrum of microbial species) and probiotic products that have the potential to offer regulated, standardized treatments. This can help them get an edge over their competitors.

Several oral FMT solutions are currently in phase-1 and phase-2 clinical trials, and many are geared toward treating conditions other than recurrent CDI. For example, US-based Vedanta Biosciences is developing FMT therapeutics for IBD, food allergies, solid tumors, etc. As research continues, it is expected that investigators will be able to identify the bacterial strains that can treat different diseases and isolate and mass-produce them, leading to a decrease in stool collection and processing and a reduction in stool transplant-related infections, but this development is expected to occur very far in the future.

Although marred by several challenges, FMT is well-positioned in the microbiome industry to obtain FDA approval and (with time) widespread acceptance. Right now, interested players can expect good returns by investing in oral FMT development, stool banking, and R&D.

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