This page contains the technology trend survey of senolytic drugs as of summer 2021. Except for a short explanation of the nature of senolytics, it contains an analysis of patents pertaining to senolytics and their major patent asignees. Please note that while the data analysis part illustrating the development of senolytics is based on actual patent data and can be thus considered reliable, the conclusions drawn here are my own, so they should be taken with a grain of salt.
Created: Oct 2021
Introduction to Senolytics
Senolytics are known as drugs that remove senescent cells from the body, while leaving the normal cells intact. Thus, senolytics are recognized as potential treatment for cancer, as well as a cancer prevention method. They could also find a use as anti-aging drugs.
Over half of cancer incidents occur in people over 70, and it is now said that aging is a significant risk factor in developing cancer. Both aging and cancer are associated with genomic instability, telomere attrition (shortening), epigenetic alterations, and cellular senescence. We now know that when the cells reach the Hayflick limit, they enter the state of cellular senescence though the action of Rb1 and p53. Cell division stops, and the cellular secretion profile changes. Cellular senescence can also be caused by oncogene activation or DNA damage response pathway.
Senescence is thought to prevent cancer by limiting the proliferation potential of cells that might become cancerous. However, senescence-associated secretory phenotype (SASP) that develops in senescent cells is linked to the secretion of proinflammatory cytokines and growth factors, which in turn promote cancer. While senescent cells tend to be eliminated by the immune system, solving the problem of SASP, they accumulate as the individual ages and the immune system gets weaker. Thus, finding ways to remove senescent cells from the human body and reducing the carcinogenic and other pathogenic effects associated with SASP has become an important challenge in the field of aging and cancer research. This can be achieved by several means, such as the use of senolytics, which selectively kill the senescent cells. By using senolytics, on top of treating the already existing disorders, we could prevent them.
The social impacts of senolytics therapies could be paramount. Currently, cancer is the 2nd leading cause of death worldwide, and the 1st in Japan. It has caused an economic loss of US$ 1.16 trillion in 2010 alone. It is thus in the best interest of the international community, especially of the aging societies, to develop effective senolytics in order to create better cancer therapies and prevention methods. This way, the healthy human lifespan can be extended, and economic losses associated with cancer treatment may be mitigated.
The Purpose of the Technology Trend Survey
Here, I conducted a patent survey of the senolytics field. The aims of this search are as follows:
I. Obtain up-to-date knowledge about the market development of senolytics.
II. Identify the companies with the largest patent share in senolytics industry.
III. Identify the areas and goals of senolytics development that one could focus on while researching senolytics
IV. Identify the potential threats to the development of senolytics
The patent search has been performed primarily using Google Patents, focusing on the keywords “senolytic”, “senescence”, “cancer”, and “removal” and including the common synonyms of those four terms. Cooperative Patent Classification system was used when analyzing the patents by type.
Results and Discussion
Senolytics Research is a Young, Fast-Developing Field
First, the development of the senolytics field has been assessed by analyzing the number of filed patent applications relating to those drugs by year. The results are presented in Figure 1.
According to the search results, there were around 207 patents filed until the end of 2020. This number relates to the more conservative search including the keyword “cancer” and its synonyms, which was included in order to focus the search on the application of senolytics as anticancer drugs.
As can be seen in Figure 1., the patents relating to the senolytics were only filed from 2013 onwards. This shows that senolytics are still a comparatively recent finding, and that the senolytic drug field is in fact very young.
Between 2013 and 2017, there was little growth in the field, indicating a slow start. However, 2018 saw a steep jump in the number of filed patent applications, which indicated a fast, promising growth of the senolytic drug field.
The growth continued in 2019 and 2020, although it was not as rapid compared to the preceding year as in the case of 2018. This could be at least partially attributed to the COVID-19 pandemic, which stalled researchers all over the world.
Overall, the fast-growing field of senolytic drugs could be a promising target research area. It is important to note that the field is still in a very early stage of development, and is thus fragile. It might collapse should there be any issues in the clinical trials of other senolytics due to e.g. social fears and investor’s uncertainty in whether the field is promising enough to endorse.
Most Senolytics Patents Include Biological Compounds with Therapeutic Activities
In the next step of the technology trend survey, I looked at the categories under which the senolytic patents were registered, and how those categories changed over the years. For this purpose, I took advantage of the Cooperative Patent Classification (CPC) system, in which every patent has one or more CPC term assigned to it. I focused on the CPC sub-class search. The results of the analysis are presented in Figure 2. Only subclasses with average prevalence of over 5% (average over the 2013-2020 period) are shown on the graph.
The subclasses which are consistently the most prevalent since the patents were started to be filed are A61K and A61P. A61K codes for preparations for medical, dental, or toilet purposes. This subclass includes drugs, biological compounds, and body treating compositions. Closely related to A61K is A61P, which is used to denote the therapeutic activity of the A61K preparations, as well as C12N preparations or C07 class.
After A61K and A61P, C07K subclass has also initially enjoyed same prevalence as the other 2 terms, though it came up less often as time went by. Still, on average, C07K term was included in around 34% patent applications each year in the 2013-2020 period. C07K subclass stands for peptides, which includes shorter amino-acid strands as well as proteins. Since most bioactive compounds, such as drugs, are proteins, the prevalence of this subclass is also easily predictable. Closely related to C07K and also present in a fraction of patents are the C07D (heterocyclic compounds) and C07F (group of compounds containing some less-common elements). C07K and C07F relate broadly to the structure and composition of the senolytics.
Many patents were also assigned to C12N, which denotes microorganisms or enzymes. This could relate either to the senolytics themselves being the enzymes, or employing the microorganisms and enzymes for the production of senolytics. The related C12Q classifies the measuring or testing processes involving enzymes, nucleic acids or microorganisms, which hints that the microorganisms or enzymes might be perhaps used to measure the activity of the senolytics in the patents.
Lastly, the category G01N came up in over 10% of patent applications in several years. G01N denotes investigation or analysis of materials by determining their chemical or physical properties. This could refer to the senolytic drug search, including screening, and it can be tied to the most popular 2 categories: A61K and A61P.
The fact that, out of all subclasses, A61K and A61P came up in most patent applications shows that, as expected, most patents relating to senolytics describe biological compounds with therapeutic activity. However, as shown in Figure 2, the prevalence of both A61K and A61P subclasses has gradually decreased over time, which indicates less share of the therapeutic drug molecules in all filed patents in a given year. This could be attributed to the fact that there is probably a limited number of compounds with senolytic properties, so it becomes harder to discover or synthesize completely new senolytics that no one has described before as time passes and senolytics research proceeds. It is thus possible that as the senolytics patent number increases, potential inventors focus more on the method of delivery, or minor alterations to the drug, rather than on discovering brand-new compounds (or new properties of already known ones).
Senolytics Patents Field is Fragmented, but the Largest Assignees are Based in the US
In this section, I looked at assignees of the senolytics patents in the recent years. I analyzed data from 2018, when the senolytics patent number considerably increased, until present (August 2021). Figure 3 shows how the senolytics patents are distributed between different companies.
By far the biggest share of patent applications (15.6%) came from Unity Biotechnology. Respectively 2nd and 3rd share belongs to Buck Institute For Research On Aging (6.5%) and Mayo Foundation for Medical Education and Research (5.8%). All three companies are based in the United States. The 4th and 6th biggest assignees (Siwa Corporation and Bioventures) also have their headquarters in the US.
Among the assignees of over 3% of senolytics patents, only the 5th largest one- Insilico Medicine, is based outside of the US (in Hong Kong). This shows that the senolytics field’s largest players are concentrated in the US, and that the field might have the largest growth potential in there. Concerning the intellectual property rights, it is the US that controls the access to many senolytics patents at the moment. This must be taken into consideration while planning the research and potential commercialization of other senolytics. Should one wish to establish patent claims, they should pay particular attention to US companies during prior art search (including validity and clearance search).
However, this is not to say that the search should focus on US only, or on the largest assignees only. As shown in Figure 3, almost half (49.2%) of all senolytic patents were filed by the assignees who own below 1.9% of all senolytic patents (per assignee). Thus, one could theorize that the senolytics field is fragmented, the patents being filed by many different companies, without any single one getting a decisive control of the senolytics market yet. It seems that there is no single-company monopoly, or oligopoly when we look at the senolytics patent data, though one could argue that there is a trend of a forming of a single-country (US) monopoly. Also, Unity Biotechnology leaves it rivals far behind when it comes to filed senolytic patents, which hints that it might keep developing patents at high speed and eventually get to control the market. This prediction might come true mostly to the huge amount of money the company receives from investors such as Jeff Bezos, the founder of Amazon and currently the second richest man on Earth. However, Unity Biotechnology is not currently in full control, which is good news for smaller senolytic patent assignees, as it makes it easier to enter the patent “market”. This could be attributed to the very young age and relative lack of popularity of the senolytics field, which means that there was not enough time for any single company, or group of companies, to establish their dominance in the field yet.
This means that less popular senolytics might still be able to succeed among many other drugs available, though it will probably become harder with time, as Unity Biotechnology and others release more competitive patents. It seems that time will be key while researching new senolytic drugs.
Lastly, I analyzed several patents and research literature in order to assess the competition in senolytics market and establish a benchmark for evaluating senolytics research projects.
One could argue that the biggest threat to any given senolytic is the development of other senolytic drugs that work better. This can be drugs with higher specificity, higher toxicity for senescent cells, or lower toxicity to normal cells. For example, in 2017 researchers identified Heat Resistance Protein 90 (HSP90) inhibitors as a new class of senolytics that seem to regulate autophagy. One HSP90 inhibitor called 17-DMAG was shown to extend lifespan and delay the appearance of age-related symptoms in mouse models of human progeroid (early ageing-like) syndrome. Compounds called ABT263, A1331852 and A1155463, which are inhibitors of Bcl-2 family members, also have senolytic activity in some cell types. Senolytics mentioned in the patents by Unity Biotechnology are, among others, pi3-kinase, hdac, and p97 inhibitors (WO2019133904A1), as well as peptide-based proteasome inhibitors (EP3548504A1) where the latter can be used both to remove senescent cells and treat cancer.
The problem is that it would take incredible amount of time, people, and money to measure the efficacy of all the senolytics mentioned above, and numerous other in existence, against any new senolytics that we might might to develop. This is why many publications only compare the efficacy of a few drugs side-to-side. Therefore, it is virtually impossible to assess whether the performance of a new senolytic would exceed that of numerous other senolytics in clinical trials. Unfortunately, as is the case in basic research, a risk will have to be taken when researching any given senolytic over other compounds, and the success cannot be predicted or guaranteed.
This is exemplified by the famous failure in phase II clinical trials conducted by Unity Biotechnology. The company used its novel, promising top candidate senolytic called UBX0101 (MDM2 inhibitor) to treat knee osteoarthritis in human subjects. However, UBX0101 produced no therapeutic effect compared to the placebo treatment. This event caused a 60% drop in the stock price of Unity Biotechnology and increased the skepticism about the usefulness of senolytics among the investors and members of the public alike. Just like in the case of Unity Biotechnology, other senolytic research might not lead to the development of a viable drug that will be commercialized, so one must weigh the risk against the potential benefits while conducting research. On the other hand, the mishap of Unity Biotechnology means that its development and expansion could be stalled for a while before it rebuilds its position and reputation. This is to say that, for a while, it might be easier to enter the senolytics market for smaller companies and organizations.
Summary of Threats
As the senolytics field is still very young, it is also quite unstable and prone to changing moods of the investors. Therefore, even if one's senolytic research was successful and their drug could be commercialized, one has to be aware that there is a risk that the whole field will sustain a great damage or collapse entirely should any controversy, such as harm to human subject, arise with time. This could happen no matter where the fault for the controversy lies. This risk should be weighed into any senolytics research.
Unity Technology seems to be the biggest rival in the field, as it boasts huge monetary support from the powerful and influential investors and will thus probably grow at a great pace after it recovers from the recent clinical trials mishap. Should Unity Technology release a successful senolytic in the coming years, it could completely outshine other senolytic research.
Regardless of the releasing company, the main threat for any new senolytic would be the development of a senolytic drug with better efficacy and lower toxicity. Though Unity Biotechnology’s UBX0101 is no longer a concern, there is a constant risk that someone will develop a senolytic of better efficacy than one is working on.
That being said, patients and their wellbeing should always be the priority while developing any drugs or therapies, so the establishment of senolytics that work better than your own should not be considered bad news, though this is easier said than done. Establishment of one famously successful senolytic could mean the interest and trust in those drugs will increase, which in turn could attract investors and promote the growth of the entire senolytics field. One could also treat the development of a better senolytic (than the one currently researched) as a chance to build and improve on the newly established drug (patent rights allowing), for example by tweaking the delivery method, dosage, therapy timeframe, or testing co-administration with other drugs or additives to increase efficacy. It is also possible to learn from the success of your competitor, studying their research/market strategy as well as the properties and structure of their patented senolytic molecule to potentially come up with an even better drug. Finally, establishment of better senolytics (than your own) prevents stagnation of the field, serving as a motivation to improve existing senolytics, which is advantageous to patients.
Summary of the Research Development Strategy
To summarize the points made throughout the previous sections, because senolytics development is still a young field which has recently gained considerable pace, it could be easier for smaller organizations to establish patents in the field, as the probability of passing the novelty check could be higher.
Analyzing senolytics patent categories showed that the share of the therapeutic drug molecules in all filed patents has been decreasing over time, which might reflect difficulty in finding novel senolytics as time goes by due to limited number of existing molecules with senolytic properties. This might suggest that rather than finding new senolytics, one should focus on improving the existing ones. For example, one could try to improve the delivery method of a given senolytic or try to combine it with another supporting drug to increase its efficacy.
Analyzing the companies holding the senolytics patents showed that the largest patent assignees are based in the US, which means one should pay enough attention to this country while doing prior art search. Results showed that senolytics field is somewhat fragmented, which means that it is not virtually impossible for smaller assignees to enter the field. However, it is important to perform senolytic research possibly fast, as major patent assignees are expected to grow more powerful with time.
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