The RDC track is heating up, and the ADC challenger is coming?

Image source @ Visual China

Wen 丨 Amino Finance

A century ago, the bacteriologist Paul Ehrlich came up with the concept of the magic bullet. At that time, Paul Ehrlich may not have expected that the concept of "magic bullet" would be widely used today.

In addition to the "ADC" (antibody conjugated drugs), Novartis Pluvuicto was approved for marketing on March 23, making the RDC (nuclear conjugated drug) of another family member of the "Magic Bullet" family a new hot spot.

RDC drugs are structurally similar to ADC drugs and appear to be more powerful, not only for treatment, but also for diagnosis, combining the two into one.

Although RDC drug development is more difficult, it is difficult to replicate the glory of ADC drugs in the short term due to multiple factors such as unstable nuclide sources, strict supervision, and short half-life of nuclides.

But it's man-made. The success of the first and third totals has made ADC drug development in full swing, becoming the hottest track in the field of oncology; the approval of Novartis Pluvuicto has added a fire to the RDC track.

As more and more RDC drugs are approved and enter the clinic, the RDC track will gradually begin to heat up. So, can RDC drugs take over the ADC and become the next rising star for conjugated drugs?

01, similarly structured twin brothers

Structurally, RDCs are very similar to ADCs.

We know that ADC is composed of three parts: antibody + linker + toxin, and RDC also has "three major pieces", specifically antibodies / small molecules + connectons + nuclides.

In simple terms, the antibody part of RDC has more choices, which can be both antibodies and small molecule drugs, but the principle is similar, and they are all targets that are low expression in normal cells and high expression in cancer cells.

The biggest difference between the two is the "toxin". The "toxin" small molecule drug at the ADC site becomes a nuclide here in the RDC.

Nuclides, or radioisotopes, are metallic or non-metallic elements that can produce α, β, or γ radiation. These nuclides can decay to produce radioactive rays that destroy the chromosomes of the cell and stop the cell from growing, thus destroying the proliferating cancer cells.

However, some people may wonder how radiation rays enter the human body choose to only kill tumor cells and not normal cells.

In fact, under the same radiation conditions, different cells are not equally sensitive to radiation. Specifically, cells in the division phase are the most sensitive to radiation, while those in the DNA synthesis phase are the least sensitive to rays.

For tumor aggregation sites, most tumor cells are in the division phase due to the need to continue to proliferate, while normal cells are in the stable phase. This difference also allows the rays to be targeted at tumor cells in differentiated strikes.

The structure is similar, and the mechanism of action of the two is also similar, both are accurate to the beginning of the tumor cell precision strike, but the RDC's strike weapon has changed from a chemical weapon to a nuclear weapon.

Back to Novartis' Pluvuicto, it chose PSMA, which was overexpressed in prostate cancer, as a target, and the previous development of this target was not smooth, and many drugs have folded at this target. This time, Pluvicto broke through the failure spell of the PSMA target.

In phase III clinical trials, the median overall survival with Pluvuicto+ standard therapy was 15.3 months, the control group using standard therapy was 11.3 months, and the median overall survival was extended by 4 months; in terms of objective response rate, Pluvuicto+ standard therapy was 30% and the control group was 2%.

Judging from the clinical data, Novartis' Pluvuicto has indeed lived up to expectations.

02, the broad future of RDC: diagnosis + treatment

In fact, in the field of RDC, Novartis has many layouts, and in 2018, Novartis lutethate octreotide was approved by the FDA, becoming the first radiopharmaceutical drug to treat gastrointestinal and pancreatic neuroendocrine tumors.

Not just Novartis. In June 2021, Bayer acquired a 225Ac radiation therapy targeting PSMA through an acquisition. In china, Broad Pharmaceutical is also actively deploying and introducing a number of RDC products.

Why are many pharmaceutical companies so optimistic about RDC drugs? The reason may be that RDC has a large imagination space.

Due to different kinds of nuclides, they have different functions. Therefore, for RDC drugs, by selecting different nuclides, they can play different roles, which can be treatment or diagnosis.

For example, when using isotopes such as F-18 and Ga-68, RDC can be used as a diagnostic product and has an advantage over existing products.

At present, the commonly used tumor diagnosis is first imaging examination by CT and PET-CT, and after the initial determination of the tumor location, a small piece of pathological tissue is removed for biopsy. This method takes a long time, not to mention, it may also cause tissue rupture and tumor metastasis risk.

If diagnosed by RDC drugs, the situation is different. RDC delivers drugs to the body and binds to specific tumors, a process in which radionuclides can spontaneously decay into stable nuclides and emit particles or photons during a very short half-life period.

These particles or photons, after being detected by PET (Positron Emission Tomography) or SPECT (Single Photon Emission Computed Tomography) instruments, can convert the received signal into an image of the structure or function of an organ or tissue and reflect the sensitivity of tumor cells.

When the nuclide was replaced with isotopes such as Lu-177, Ac-225, 89Sr, and 90Y, RDC became a therapeutic agent again.

Due to the cross-fire effect of nuclides, neither the drug nor the antibody needs to be internalized to exert its therapeutic effect. This results in only a smaller amount of the drug required to produce the desired therapeutic effect, which also reduces the possible adverse reactions of the drug to some extent.

In addition, because the nuclide does not need contact with cells to work, there is no need for lysable connectons for RDCs, which also makes RDCs less off-target and more stable and safe.

Since the same ligands are used for diagnosis and treatment, they can also achieve consistent targeted effects.

03, take over the three major mountains facing the ADC

Although RDC seems to have a wide range of effects and good results, for a long time, RDC was not cared for. Why?

First of all, the source of nuclides has stumped many heroes.

It is also difficult for RDC drugs, if the supply of nuclides cannot be guaranteed, then the development and production of RDC drugs have become empty talk.

At present, the current nuclides of the mainland are not self-sufficient. According to the data of arterial new medicine, in recent years, the mainland's independent production of I-131 and Sr-89 only meets 20% of domestic demand, Lu-177 only meets 5% of domestic demand, and other commonly used medical isotopes rely on imports.

However, in May 2021, many ministries and commissions of the state issued the "Medium- and Long-term Development Plan for Medical Isotopes", in which the development of medical isotopes was put on the agenda, and this problem may be solved in the future.

Secondly, the distribution after the completion of drug development is also a big problem.

Unlike ordinary drugs, which can be stored for a long time, RDC drugs have a very short nuclide half-life. The so-called half-life of a nuclide refers to the time it takes to reduce the "power" of radionuclides by half. This means that the shorter the half-life of the nuclide, the easier it is for RDC drugs to lose efficacy.

How short is that? Some are only a few tens of minutes. Take the radionuclides commonly used in clinical trials today, I-131 half-life of 8 days, Y-90 half-life of 2.7 days, Lu-177 half-life of 6.7 days, Bi-213 half-life of 45.6 minutes.

This makes it impossible for RDC to be mass-produced in advance and transported over long distances. This also puts forward higher requirements for R & D enterprises, not only to be able to produce, but also to ensure timely distribution.

In fact, even for a large pharmaceutical company like Novartis, it is difficult to ensure the continuous release of nuclear drugs. Novartis' nuclear drug Lutathera, approved in 2018, although sales grew rapidly in the first two years, from $167 million in 2018 to $441 million in 2019. However, since then, its sales in 2020 and 2021 will be 445 million US dollars and 475 million US dollars respectively, and the growth rate will slow down significantly.

In the mainland, when drugs enter clinical use, medical institutions also need to have relevant qualifications.

In 2019, I had 770 nuclear medicine departments working on nuclear therapy, but there were only 2,544 nuclide treatment beds. This is far from meeting the needs of patients, and even if the production capacity of drugs keeps up, it is a problem for patients to find no designated agency to use drugs.

Due to the high entry threshold and high research and development requirements, there are not many domestic RDC players at present.

However, with the successful approval of Novartis RDC drugs, coupled with the support of national policies, it is believed that more players in China will join the research and development of RDC drugs. Will this give birth to RDC giants?