Text: Amino Observations
Nine deaths in one life is the best summary of the research and development of innovative drugs.
According to the report on the success rate of drug clinical development released by BIO and other organizations, after counting 12,700 clinical development projects of 9,704 drugs, it was found that in the ten years from 2011 to 2020, the success rate of drug development projects from phase 1 clinical trial to FDA approval was 7.9% on average, and the time required was 10.5 years on average.
The emergence of RNAi drugs has broken this life-and-death situation.
Due to the principle of base mutual protection pairing, RNAi drug development is similar to programming, and the success rate of biologics development such as small molecules or monoclonal antibodies is not half a point. The clinical translation success rate of RNAi leader Alnylam is as high as 64.3% (cumulative from Phase 1 to Phase 3), and the original research of the five RNAi drugs currently approved in the world are all from Alnylam.
RNAi is at the threshold of a new era. Of course, despite the game-changing mechanics and success rate, many more players are still in the process of proving themselves.
In other words, Alnylam's ultra-high clinical success rate is inseparable from the advantages of the RNAi drug mechanism itself, and even more inseparable from its own struggle.
As its founding CEO, Maraganore, summed it up, "The path to finding solutions is never a straight line, and the key to achieving the goals is resilience, science-based guidance, and nurturing an environment for innovation." ”
Ultra-high clinical conversion rate
"Alnilam" is the bright central star in Orion's belt and has been used for thousands of years as a "cosmic lighthouse" for nautical navigation, which is where the name Alnylam comes from.
After decades of R&D efforts, Alnylam has finally established itself as a beacon in the RNAi space.
Since its inception in 2002, Alnylam has not launched its first product until 2018. Since the launch of ONPATTRO, the world's first siRNA therapeutic, in 2018, Alnylam has achieved the approval of a new drug almost every year.
To date, Alnylam has received approval for five RNAi drugs, including patisiran, vutrisiran, givosiran, lumasiran (developed in collaboration with Novartis) and inclisiran.
On top of that, Alnylam has achieved extremely high clinical conversion rates. According to the data disclosed by it, in the phase 1 to phase 3 clinical trials, its cumulative conversion rate reached 64.4%, while the conversion rates in the field of targeted drugs and the pharmaceutical industry as a whole were only 10.3% and 5.7%, respectively.
In other words, it is 11 times higher than the cumulative conversion rate of 5.7% for the entire industry.
As shown in the figure below, Alnylam was able to achieve a conversion rate of more than 85% at different clinical stages. The success rate from phase 2 to phase 3 clinical trials is the lowest in the industry, only 27.4%, and the final cumulative conversion rate is only 5.7%. The research and development of innovative drugs is not just talking.
This set of data disclosed by Alnylam is also basically consistent with other studies on the success rate of transformation in the drug development stage. In 2021, BIO, one of the world's largest biotechnology industry organizations, Informa Pharma Intelligence, and QLS jointly released a report on the success rate of drug clinical development.
The report analyzed 12,700 clinical development projects of 9,704 drugs from 1,779 companies in the Biomedtracker database from 2011 to 2020, and found that the success rate from Phase 1 to Phase 2 clinical trials was 52.0%, the lowest success rate from Phase 2 to Phase 3 clinical trials was 28.9%, the success rate from Phase 3 clinical trials to NDA submission was 57.8%, and the success rate from NDA/BLA submission to FDA approval was 90.6%.
In total, only 7.9% of new drugs can successfully progress from Phase 1 clinical trials to the final FDA approval stage.
Whether it's 7.9% or 5.7%, Alnylam's clinical conversion rate is high enough.
In addition, in terms of R&D expenses, from 2013 to 2023, Alnylam has invested a total of 6.06 billion US dollars in 10 years. By comparison, Novavax and BioNTech have been the closest in R&D spending over the past 10 years, at $6.3 billion and $5.8 billion, respectively.
Among them, BioNTech is closer to Alnylam's mission, which is also exploring in an unknown and unproven field, but only mRNA new crown vaccines have been approved for marketing since its establishment.
However, BioNTech was also lucky. He has accumulated a huge fortune with the new crown vaccine, and the cash on hand is as high as 16.9 billion euros, which is enough to continue to burn money to buy and buy and open clinical trials.
So, how did Alnylam achieve a very high clinical conversion rate of 64.3%?
Dead-pound technology
This also starts with the mechanism of RNAi drugs.
In 1998, two scientists from the United States introduced double-stranded RNA into the nematode gene and found that double-stranded RNA was more efficient than single-stranded RNA in specifically blocking the expression of the corresponding gene, a phenomenon they called RNA interference (RNAi).
RNAi drugs mimic this process by providing specially designed small interfering RNAs (siRNAs) that bind to disease-causing mRNAs as part of RISC (RNA-induced silencing complexes). Once the targeted mRNA is found, like a pair of molecular scissors, the siRNA works with the RISC to cleave the "unwanted" gene, allowing it to be degraded.
To put it simply, siRNA disrupts the original gene expression process, resulting in the blocking of some gene expression, and naturally cannot continue to exert any pathogenic functions.
Compared with small molecules and monoclonal antibodies, RNAi drugs can target and silence any gene in the genome, with a strong and long-lasting mechanism of action, which can solve the problem of "undruggable" pathogenic proteins; In terms of drug synthesis, it may be simpler than screening small molecules or generating biologics, and it only needs to lock the sequence of disease-causing genes and complete Watson–Crick base pairing with mRNA to achieve its function, without fitting into the complex structure of the protein, so the success rate of development is relatively high.
Theoretically, but the development of the industry is not going to be smooth sailing. RNAi once faced problems such as poor stability, low delivery efficiency, and poor safety, among which the most fatal is the delivery problem, once the siRNA is delivered into the body, it will be quickly destroyed by enzymes in the blood, and cannot be successfully delivered to the target tissue cells to play a role.
Since its inception in 2003, Alnylam has focused more than 80% of its R&D investment on siRNA delivery. A multi-pronged strategy is employed, including multiple delivery modalities such as conjugates, lipid nanoparticles, and biomaterials.
It took several years to evaluate dozens of delivery systems targeting external sources across a range of tissues, but the results were disappointing. Subsequently, Alnylam partnered with Arbutus to obtain a license agreement for the latter's lipid nanoparticle technology (LNP), which Alnylam uses to deliver its first RNAi therapeutic, patisiran.
It was not until 2012 that Alnylam's "key weapon" GalNAc coupling was successful. Alnylam is well aware that the development technology is the core barrier, and even though GalNAc has become the primary technology for the delivery of oligonucleotides to the liver, the company is not satisfied with just solving the barriers to siRNA delivery, and continues to modify the siRNA sequence, which has led to the creation of enhanced stable chemistry (ESC) and later ESC+ technology, which continues to improve the targeting and efficacy of GalNac through different RNA modifications.
It can be said that the persistence and breakthrough of technology is the basis for all clinical transformations of Alnylam. Without Alnylam's breakthrough in delivery technology, perhaps the RNAi field would have been in the middle of a few years away.
Product-oriented
In the decade that Alnylam has been grappling with the delivery problem, the enthusiasm for the RNAi space has exploded and then evaporated at an equally rapid rate.
In 2010, big pharmaceutical companies such as Roche, Pfizer, and Merck withdrew from the RNAi field one after another, and RNAi therapeutics entered the "darkest era". Alnylam's share price also fell to freezing point, and in order to survive, he had to lay off employees significantly.
When the industry was hit hard, Alnylam decided to shift its focus from the platform to the pipeline, because the only way to restore confidence in RNAi was to come up with unassailable human clinical data.
In January 2011, Alnylam launched the "Alnylam 5x15" strategic plan to advance five RNAi therapeutics to the clinical stage by the end of 2015.
Despite the opposition of the R&D team, because the company only had one liver-targeted program in development at that time, and had not yet obtained human clinical data, Alnylam still threw this slogan to the outside world at the insistence of the CEO at the time.
In the fall of 2011, the first important results from the Alnylam study were released, in a Phase 1 clinical trial of ALN-TTR01, patients 50-03 showed significant TTR silencing. This result is the first demonstration of the ability to harness RNAi in humans, which is a landmark moment for Alnylam. At the same time, it also heralds the beginning of a series of significant clinical translational results of RNAi drugs.
At the end of 2015, Alnylam successfully advanced 8 projects into clinical development. Three years later, the RNAi drug Onpattro was approved by the FDA for the treatment of hATTR (hereditary transthyretin amyloidosis neuropathy). It is also the world's first RNAi drug.
To date, Alnylam has 5 approved RNAi drugs.
In addition to the aforementioned insistence and breakthrough in the research and development of delivery technology, more importantly, Alnylam's product orientation.
The so-called product orientation, Alnylam has explained in its financial report. In simple terms, Alnylam development focuses on those with a high unmet need, genetically validated targets, clinical indications for early-stage biomarkers to be assessed for clinical activity in Phase 1 clinical studies, and clear pathways to drug development, regulatory approval, patient access, and commercialization.
In fact, all of Alnylam's current approved programs are based on genetically validated targets. Typical example is the PCSK9 target. In 2003, researchers found that mutations in the PCSK9 gene lead to increased expression of PCSK9 protein and promote an increase in LDL-C levels, leading to familial hypercholesterolemia.
PCSK9 became the third gene to be found to be involved in cholesterol metabolism. Shortly thereafter, another research team reported the presence of naturally occurring genetic mutations that inhibit PCSK9 expression in a small number of people. These individuals had very low LDL-C and a significant reduction in the incidence of cardiovascular disease, showing no other adverse effects.
In addition to being genetically validated in humans, the PCSK9 target is appealing because the PCSK9 protein is primarily expressed in the liver, making it a highly validated target in the right tissues. In line with Alnylam's technical route, Leqvio, a long-acting lipid-lowering injection developed in cooperation with Novartis, directly prevents the liver from producing PCSK9 protein through gene silencing to achieve a long-lasting therapeutic effect. In 2023, Leqvio's annual sales will be 355 million US dollars, a year-on-year increase of 2.17 times.
Greater certainty, combined with the high success rate unique to the RNAi mechanism, results in an extremely high clinical conversion rate. These key features still play an important role in the development of Alnylam to this day.
Chance or necessity
Although Alnylam believes that 5x15 is the foundation of its transformation from a platform company to a product company. But in essence, RNAi drug development is the result of the transformation of platform technology.
In other words, RNAi drugs are platform-based. Just like ADC and mRNA technology platforms, after validation, they can continuously incubate new pipelines. This is one of the core reasons for Alnylam's high clinical conversion rate.
As the CEO of Arrowhead, the second company in the industry, said, making only one drug is gambling, and it is necessary to use the advantages of the RNAi platform to make more drugs and strive for breakthroughs.
This is a good explanation why most start-up biotechs have 3-5 projects in development, while Alnylam, IONIS or Arrowhead can have a full pipeline of screens, almost all of which start with 10.
On June 24, Alnylam disclosed the results of a Phase III clinical trial of its RNAi therapy Amuvttra (vutrisiran) for the treatment of patients with ATTR-CM. In all populations, vutrisiran was statistically significant for the primary endpoint and all secondary endpoints. It plans to submit a supplemental new drug application to the FDA by the end of the year using the priority review voucher.
Once successfully expanded into the ATTR-CM field, it means that Alnylam will enter a vast blue ocean. Data shows that 200,000-300,000 people worldwide suffer from ATTR-CM, and the only approved drug is Pfizer's small molecule stabilizer Tafamidis, which sold more than $3.3 billion last year.
What's more, the company can continue to expand its pipeline with the real money from the approval of this indication, including cardiovascular diseases, neurological diseases, autoimmune diseases and even cancer. With the advantages of RNAi over small molecules and antibody drugs, including efficacy, dosing interval, safety, and the very high clinical success of RNAi drugs, Alnylam will enter a new situation.
There is an uncertain chance and even luck behind Alnylam's achievement today, after all, the RNAi mechanism is universal, but other RNAi players are still in the stage of proving themselves. But it's always the accident, and there is the necessity behind it.
For Alnylam, this necessity lies not only in the technical and product orientation mentioned above, but also in its adherence to and practice some simple business principles.
For example, the importance and respect for talents. The founding team includes Nobel Prize winner in biomedicine Phillip Sharp, biophysical chemist Paul Schimmel, molecular biologist David Bartel, biochemist Thomas Tuschl and molecular biologist Phillip Zamore.
At the same time, Alnylam attaches great importance to the independent innovation of scientists at the company level, and has established a "20% time rule" to provide some freedom for the research team and encourage scientists to spend 20% of their time to realize their ideas, even in the case of gradually increasing company operating costs.
In fact, several of the company's important breakthroughs have been made in this atmosphere that encourages innovation. Including the core GalNAc conjugation technology, as well as C16 conjugated siRNA delivery technology targeting the central nervous system.
Many people take innovation as a result, but in fact, innovation is a process. Understand this, and you'll understand why some businesses struggle to spark innovation.
On top of that, at the lowest point in 2010, Alnylam decided to stick with it. The toughest one was in 2016, when a pivotal clinical trial went wrong and had to be stopped.
After the announcement, Alnylam's market value evaporated by $7 billion on the same day, and investors were worried about broader platform security issues, affecting the entire product pipeline and even the entire RNAi space.
This was a very big test for Alnylam, but fortunately, the company withstood the pressure, which led to the approval of the first RNAi drug in 2018 and the actual validation of RNAi therapeutics.
Whether it's the emphasis on talent, the culture that encourages innovation, or perseverance in the face of adversity, these principles are not new to innovative pharmaceutical companies, but few can actually implement them consistently. This is perhaps the biggest revelation that Alnylam has brought to the industry.