The Regeneron and Alnylam molecule has been applied in compassionate use against Creutzfeldt-Jakob disease, without clinical studies indicating efficacy. Preliminary data in mice shows a 15% reduction in the RNA that produces the prion protein, but no one knows whether this stops the disease.
By Poliana Casemiro, g1
Influencer Lito Sousa died this Thursday (1st), due to complications from Creutzfeldt-Jakob disease.
About two weeks earlier, he had received a substance that had never been administered to a person: ALN-6457, developed by the American pharmaceutical company Regeneron in partnership with Alnylam Pharmaceuticals, a bet against Creutzfeldt-Jakob disease, for which there is no treatment capable of stopping the progression.
The application was revealed by his wife, Mila Seidl, in a video released on September 14. She said that Lito was already admitted to the Intensive Care Unit (ICU) due to complications from the disease when he received the compound, the previous weekend, and that there was no adverse reaction, one of the risks of testing a new molecule on humans.
The medical team hoped that tests carried out six weeks later would indicate whether the condition had changed.
As the compound has not yet gone through the clinical testing phases, almost nothing has been published about it. What exists is preliminary, and g1 brought together this evidence to explain what is known about the substance.
— Photo: Reproduction/YouTube
What is compassionate use
ALN-6457 came to Lito through a regulatory mechanism called compassionate use. It authorizes patients with serious, debilitating or life-threatening illnesses to receive medicines, biological products or devices that are still experimental and without health registration, as long as there is no effective therapeutic alternative.
Permission for Lito's case was granted by the National Health Surveillance Agency (Anvisa). The "ALN" in the compound's name comes from Alnylam, which works with Regeneron on drugs targeting the central nervous system.
Alnylam's public documents show that prion diseases, a group that brings together Creutzfeldt-Jakob and others caused by the same protein, were among the targets of the collaboration from the beginning, alongside Alzheimer's and Parkinson's.
A brake on the protein factory
Lito's disease is born from a protein called a prion. In its normal form, it exists in the brain without causing problems. In Creutzfeldt-Jakob, an abnormally folded version starts to function as a template: when it touches healthy proteins, it forces them to fold in the same way, and the damage spreads throughout the brain tissue.
The treatment tries to act before this stage. It uses a small interfering RNA molecule (siRNA), which triggers a natural mechanism in cells and stops them producing a specific protein.
Understand Lito Sousa’s illness — Photo: Arte/g1
Inside the cell, the molecule is processed by a set of proteins that act as a search system, locate the copies of messenger RNA that carry the prion protein recipe and destroy them before the protein is manufactured. With fewer copies of the recipe, the cell produces fewer prions.
The logic is that, with less healthy protein available, there is less material left to be deformed. The strategy does not undo the damage already done or correct proteins that have already misfolded, but, in theory, it could slow the progression of the disease by reducing the production of new vulnerable proteins.
The challenge of reaching the brain and resisting there
Getting the molecule to the right place is the hardest part. The brain is protected by the blood-brain barrier, a type of natural filter that blocks most medications administered through the vein or taken orally.
Doctor in Biomedical Engineering and clinical research specialist Daniel Dahis explains that the difficulty of medications like this goes beyond reaching the organ. After entering the cell, the molecule falls into acidic compartments that the cell uses to digest what it receives, and, if it is not resistant, it is destroyed before it can act.
To overcome these obstacles, Alnylam's platform combines chemical modifications that preserve the siRNA with binding to a fatty chain called C16.
It works like a fatty anchor attached to the molecule and facilitates its passage through the cell membrane, a barrier that, without this feature, would block molecules with the characteristics of siRNA.
What the documents show
There is no clinical study on ALN-6457, so its effects on people are not known.
However, g1 located Alnylam's patent application for an siRNA conjugated to C16 and directed to the prion protein, a description that coincides with that of the substance authorized by Anvisa, in addition to presentation materials for the same technology applied to Alzheimer's.
Patents often cover an entire family of chemical variants developed over years, and ALN-6457 likely belongs to that group.
The document presents a test on mice: at the lowest dose evaluated, there was a reduction of around 15% in the messenger RNA responsible for the production of prion protein. For Dahis, the number is a positive biological sign, but it does not allow predicting whether a patient would feel a difference.
The experiment did not verify whether the drop in normal protein reduced the formation of the deformed version, nor did it show a gain in survival in animals, much less in humans.
According to the expert, the combination indicates that the strategy deserves to be investigated, especially in the face of a disease without treatment capable of stopping its progression, as long as safety uncertainties are considered and an individual assessment of risk and benefit is made.
Security: initial tests, still short
Alnylam's public presentations to investors in 2021 describe tests in rats and primates with the same C16 conjugation technology used in the central nervous system.
Clinical, neurological and examinations of organs such as the brain, spinal cord, liver and kidney showed no changes attributed to the substance.
The tests, however, were preliminary and short-lived. The most complete safety package, required by regulators before starting human studies, was completed by the company only for another program, aimed at Alzheimer's, and not for the candidate against the prion protein.
The path to an answer goes through clinical trials, a stage that ALN-6457 has not yet completed. Only with complete safety data and comparisons between many patients will it be possible to know whether reducing prion protein alters the course of a disease that, to date, has no treatment capable of stopping it.
