Original Xie Ling Arterial New Medicine October 18, 2024 08:27 Chongqing

Yesterday (October 17th), Sanofi announced that it has reached an agreement with Orano Med, a subsidiary of the Orano Group, to further accelerate the development of next-generation radioligand therapy (RLT) by leveraging their expertise in combating rare cancers.

According to the agreement, Sanofi and Oueno will jointly invest in a new entity operated under the Oueno Medical brand, focusing on the discovery, design, and clinical development of next-generation radioligand therapy (RLT) based on lead-212 (①¹² Pb) alpha emitting isotopes. Sanofi will make an equity investment of 300 million euros (approximately 2.313 billion yuan), accounting for approximately 16% of the equity of the new entity Orano Medical, with a valuation of 1.9 billion euros (approximately 14.648 billion yuan).

At the beginning of last month, Sanofi announced a licensing agreement with RadioMedix and Orano Med for RLT, focusing on AlphaMedix, a rare cancer RLT therapy developed by RadioMedix ™ (①¹² Pb DOTAMATE). According to the agreement, Sanofi will pay a down payment of 100 million euros and up to 220 million euros in sales milestone fees (totaling 320 million euros, approximately 2.5 billion yuan) to RadioMedix and Orano Med, as well as tiered licensing fees. After the cooperation is reached, Sanofi will be responsible for the global commercialization of the project, and Orano Med will be responsible for producing AlphaMMedix through its global industrial platform ™。

Looking around the various sub sectors of biopharmaceuticals, nuclear medicine is gradually becoming a battleground for global pharmaceutical giants. In addition to Sanofi, multinational pharmaceutical companies such as Novartis, Bayer, AstraZeneca (AZ), Bristol Myers Squibb (BMS), and Eli Lilly have also laid out their presence, striving to occupy a favorable position in this innovative therapy track.

The collaboration with RadioMedix and Orano Med is Sanofi's first foray into the nuclear medicine sector. Although during the Q2 earnings conference call, Houman Ashrafian, the head of research and development at Sanofi, stated that the company currently does not have any radiation therapy projects. We are very cautious in this field and considering taking measures to truly differentiate therapies, "but within just one month, Sanofi's determination to layout the nuclear drug track, from pipeline cooperation to additional equity investment, is evident.

The focus of this additional equity investment is still on the clinical phase II nuclear drug AlphaMMedix.

AlphaMMedix is composed of a peptide complex labeled with Pb-212 that targets SSTR. This complex serves as an in vivo generator for alpha particles and is suitable for subjects with unresectable metastatic somatostatin receptor (SSTR) positive neuroendocrine tumors (NETs). Pb-212 isotope is particularly suitable for SSTR therapeutic applications due to its half-life, high energy, short decay path length, and irreversible damage to double stranded DNA. This therapy was granted Orphan Drug Designation (ODD) by the FDA in 2018 and received the TechConnect Innovation Award in 2020.

In February of this year, the FDA also granted AlphaMedix breakthrough therapy (BTD) for the treatment of unresectable or metastatic gastrointestinal pancreatic neuroendocrine tumors (GEP NETs) expressing somatostatin receptors in adult patients who can receive peptide receptor radionuclide therapy (PRRT).

The breakthrough therapy designation is based on the results of Phase I and ongoing Phase II clinical trials that evaluated the safety and efficacy of AlphaMMedix. In the Phase I study, AlphaMMedix showed good tolerability and significantly reduced tumor burden, with a persistent response rate (according to RECIST 1.1, ORR) of 62.5%.

Currently, a therapeutic radiopharmaceutical targeting SSTR has been approved for market worldwide, namely Novartis' Lutathera. Once AlphaMMedix therapy is launched, it will quickly compete with the radiopharmaceutical Lutathera sold by Novartis.

Lutathera is a beta particle radiation therapy based on lutetium 177, acquired by Novartis in 2017 for $3.9 billion through the acquisition of Advanced Accelerator Applications. As a peptide receptor radionuclide therapy (PRRT) drug, Lutathera can be used to treat growth hormone receptor (SSTR) positive gastrointestinal and pancreatic neuroendocrine tumors (GEP NETs).

However, compared to beta particle radiopharmaceuticals, alpha nuclide radiopharmaceuticals have unique advantages in tumor treatment. Specifically, alpha nuclides can emit alpha particles during their decay process, with an energy transfer line density (LET) nearly a hundred times higher than that of beta nuclides, and their tumor killing effect is significantly better than that of beta nuclides. On the other hand, beta isotopes can damage the single stranded DNA of tumor cells, which may lead to tumor cell repair and ultimately result in tumor recurrence. But alpha isotopes can directly destroy the double stranded DNA of tumor cells, leading to permanent killing of tumor cells, and are known as the "surgical knife like radiotherapy".

In addition, clinical trial data also shows that alpha isotopes can kill cancer cells while triggering tumor immune responses, which have a mutually reinforcing effect with immunotherapy, achieving a "one plus one greater than two" effect in tumor treatment. In terms of safety: Alpha isotopes have a short range, only a few cells' range, minimal damage to normal tissues, and almost no side effects, making them safer.

This also means that in theory, AlphaMMedix has the potential for high efficacy and selectivity in tumor treatment, which may make it more advantageous than beta particle therapy in certain situations. However, the specific efficacy still depends on subsequent clinical data.

Orano Med: Launching the establishment of the world's first industrial scale Pb radiopharmaceutical manufacturing plant

AlphaMMedix is the result of a collaboration between RadioMedix and Orano Med, with RadioMedix responsible for drug development and Orano Med responsible for production.

RadioMedix was founded in 2006 and has collaborated with multiple pharmaceutical companies to develop multiple pipelines as a "water seller" of nuclear drugs. Including the company's first diagnostic product, 64Cu DOTATATE (Detectnet), which was approved by the FDA in September 2020 ®） And AlphaMMedix, which collaborates with Orano Med. In addition, RadioMedix is also developing painkillers for the treatment of brain tumors and pancreatic ductal adenocarcinoma (PDAC).

The most outstanding achievement of Orano Med, which has obtained equity investment this time, is the establishment of a Pb-212 based radioactive ligand production facility in France in early 2024, and the launch of the world's first industrial scale Pb radiopharmaceutical manufacturing plant in Brownsburg near Indianapolis, Indiana in the middle of the year. By 2025, this will enable Orano Med to produce 10000 doses annually globally, with the goal of producing 10 times this quantity by ten years; And ensured the reliable transportation of radioactive drug products by being close to major domestic and international distribution networks. This directly demonstrates Sanofi's ambition to layout the nuclear drug track.

On the one hand, radioactive isotope raw materials are facing a global shortage problem. At present, isotopes are mainly produced through two methods: reactors and accelerators, with a large number of reactors concentrated in Europe and America. It is expected that by 2030, multiple active reactors around the world will be shut down, which will lead to a tight supply of medical isotopes worldwide. The global shortage of nuclides is approaching faster than expected.

On the other hand, due to the half-life of radioactive isotopes, drug activity will weaken within a specific period of time, so timely delivery and administration to patients are necessary. Due to the limited time window for administration, these drugs are usually produced in single dose form, taking into account transportation distance and drug delivery cycle. Not only does it require mature and complete upstream and downstream industries, as well as supporting facilities for nuclear pharmacies, but it also requires the existence of medical institutions with clinical use qualifications for nuclear drugs within a certain range.

In this context, even Novartis, known as the "nuclear drug leader," has faced production capacity and supply chain issues. In the first half of 2023, Pluvicto's global production and supply encountered problems, resulting in distribution delays, drug supply disruptions, patient medication delays, and promotion obstacles, leading to a situation of "waiting in line for medication". It was not until the end of October that the FDA removed Pluvicto from the list of drug shortages.

In order to address the urgent production capacity issue, Novartis has accelerated the layout of production bases in the past five years, including setting up nuclear drug production bases in Italy, Spain, the United States, China, and other countries. In January of this year, the FDA approved Novartis' commercial production of Pluvicto at its production site in Indianapolis, which is currently Novartis' largest nuclear drug production site and can reach patients across the United States within 12 hours. CEO Vas Narasimhan stated that Novartis aims to deliver over 250000 doses of drugs annually by 2024 through the construction of four facilities.

When Sanofi announced its entry into the nuclear medicine field in September, according to the Medical Economics News, industry insiders analyzed that based on the down payment amount and proportion at that time, it was not particularly high compared to AlphaMMedix being in phase II clinical stage. This strategy also reflects Sanofi's cautious layout in the field of nuclear medicine, as well as its rational evaluation of the future commercial potential of the AlphaMedix project.

Now, for Sanofi, which wants to challenge Novartis' position in the nuclear medicine field, adding equity investment in Orano Med can not only indirectly solve the potential production capacity and supply chain problems of AlphaMedix, but also "buy insurance" for Sanofi in the nuclear medicine field - even if AlphaMedix is not successful enough, Sanofi can occupy a place in the nuclear medicine field by indirectly controlling the nuclear medicine production base. Picture