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Sussing Out COVID-19 Severity

Can genetic variability explain why some people become seriously ill with COVID-19 while others have only mild illness?
The post Sussing Out COVID-19 Severity appeared first on Clinical OMICs – Molecular Diagnostics in Precision Medicine.

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A striking feature of the SARS-CoV-2 virus that has caused so much havoc around the world over the last year is how variable a response it elicits from those it infects, with some not even expressing symptoms and others becoming seriously ill. Could variation in our genetics be the answer to these differences?

With more than 150 million cases and 3 million deaths reported across the globe, COVID-19 remains a massive public health problem, despite the rapid rollout of vaccination campaigns in countries such as the U.S.

Around 85% of people infected with the virus experience mild-to-moderate flu like symptoms, or even no symptoms at all, and can recover at home. However, the remaining 15% of people experience more severe and potentially life threatening COVID-19 that requires them to be hospitalized.

Predicting who will fall into the more severe group has become the focus of many clinicians and researchers over the last year. Although a variety of factors such as increasing age, male gender, and presence of comorbidities such as diabetes, heart disease, or obesity have been shown to increase risk of being hospitalized due to SARS-CoV-2 infection, they do not account for all the observed variability in cases.

Variability in individual genetics, for example, whether someone carries certain immune system-related gene variants could help explain why some people who do not fit other risk profiles still become very ill. It could also explain why there is also variation in disease severity between those of the same age, gender, and with the same comorbidities.

Aurélie Cobat, M.D., Ph.D., INSERM

“Identification of the genes involved in the immune response to infection to SARS-CoV-2, in particular, has several immunological and medical implications,” Aurélie Cobat, M.D., Ph.D., a researcher at the Laboratory of Human Genetics of Infectious Diseases at INSERM in Paris, told Clinical OMICs.

“It can provide a better understanding of the function of the genes in natural conditions of infections. It may allow the identification of patients at risk of severe form of the disease and should help the development of specific preventive or therapeutic strategies.”

Investigating COVID-19 host genetics

One of the factors that differentiates severe COVID-19 from milder cases is an overreaction of the immune system to the virus. The resulting cytokine storm leads to damage in different tissues around the body, blood clots, and breathing difficulties that often require ventilation. It’s therefore not surprising that many of the genetic associations found so far are linked to immune system genes.

The COVID Human Genetic Effort is an international consortium aiming to discover genetic variants predisposing or protecting people from developing COVID-19-related pneumonia, as well as other aspects of the disease.

Cobat is a member of this consortium and was a co-author on two papers published in Science in October last year that linked type 1 interferon (IFN) genes, which play an important role in regulating the immune system, with severe COVID-19. One study showed that around 3.5% of patients with severe COVID-19 had a genetic defect in one of thirteen genes involved in the type 1 interferon circuit such as Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7).

“Patients with such defects are at very high risk of developing a severe form of the disease if they are infected,” says Cobat.

The other study she contributed to showed that at least 10% of people with severe COVID-19 had autoantibodies against type 1 interferon proteins IFN-α2 and IFN-ω, not found in individuals who were asymptomatic or had mild symptoms.

“Those autoantibodies were pre-existing and were a cause of severe disease rather than a consequence of infection,” notes Cobat. “Early detection of those autoantibodies could facilitate closer monitoring and allow the initiation of specific treatment as early as possible during, or even perhaps before infection.”

Another large, international group effort set up to investigate the genetics behind SARS-CoV-2 infection is the COVID-19 Host Genetics Initiative.  Authors from this collaboration published a genome wide association study (GWAS) in the NEJM last summer, which showed a genetic link between variants on chromosome 3 and COVID-19 related respiratory failure. They also confirmed a previously reported association with genes related to the ABO blood group system, suggesting people in blood group A may have a higher risk of infection than those in blood group O.

There has been some debate about the validity of the blood group association, as some studies seemed to show a link whereas others have not. But in a recent large meta-analysis study, also based on data collected by members of the COVID-19 Host Genetics Initiative and published as a preprint on the medRxiv server, the association was confirmed.

The researchers also confirmed other associations in the newer analysis including a link between severe disease and protein-altering variants in the genes TYK2 and PPP1R15A, which are involved in antiviral immunity and stress-induced cell death.

“If we find the genes and pathways involved in COVID-19 severity, this may point us to druggable targets and eventually lead to successful pharmaceutical interventions,” said Brooke Wolford, Ph.D., the Analysis Team Lead for the Michigan Genomics Initiative, one of the members of the COVID-19 Host Genetics Initiative.

“As of now, it’s less about predicting an individual’s genetic risk and more about finding clues that elucidate the biological mechanisms behind disease.”

Alessandra Renieri, M.D., Ph.D., is a professor at the University of Siena and is leading GEN-COVID a collaboration involving nearly 40 Italian hospitals, researchers, and clinicians, which aims to investigate the genetics behind COVID-19 and evaluate how these findings can help improve patient care.

Alessandra Renieri, M.D., Ph.D., (center) a professor at the University of Siena, Italy, poses with researchers from her lab.

 

One risk factor linked to more severe COVID-19 is gender, as men seem to be more at risk than women. In a recent paper in the journal eLife, Renieri and colleagues found that loss of function TLR7 gene variants seem to increase the risk of more severe disease in some men (around 2% of severely affected men).

Renieri acknowledged that while important, this still only accounts for a small number of affected individuals. “The next step is to identify more common variants,” she said.

Alessandra Renieri, M.D., Ph.D., a professor at the University of Siena is leading GEN-COVID a collaboration that is seeling to determine which genetic markers may predict more severe COVID-19 in some patients versus those markers that may indicate a milder form of the infection.

 

With this is mind, she and her co-workers are trying to develop a new kind of risk score combining common and rare genetic variants, as well as known clinical risk factors, to predict who is most likely to develop severe COVID-19. “The polygenic risk score, as you read in the papers today, is not enough to understand the whole picture… We are trying to find new strategies.”

When studying the genetics of infection with SARS-CoV-2 it is important to consider diversity, particularly as people of non-white origin seem to be disproportionately affected with more severe COVID-19. This is something that has been a problem with human genetic studies in the past as many large biobanks and GWAS studies have largely been based on data from Caucasian individuals of European descent.

Brazil has a very diverse population and has been hard hit by COVID-19. Iscia Lopes-Cendes, M.D., Ph.D., is a professor at the University of Campinas and published a paper in the journal Human Genome Variation in April assessing variability of COVID-19-related genes in the Brazilian population.

She and her team looked at exome sequencing data in almost 1,000 individuals. Six variants had previously been linked to COVID-19 in other studies, but an additional seven (thought to impact protein function) were exclusively found in the Brazilian population.

While its useful to know about these variants, they are very rare, said Lopes-Cendes. “If you want something that you’re going to use to make diagnosis and to inform people in terms of population about the risk, it has to be something that’s relatively common, because if it’s something that it’s too rare, it is going to be used for just a small percentage of patients,” she explained.

Diversity of sample collection is also something the COVID-19 Host Genetics Initiative, which Lopes-Cendes is contributing to, is encouraging. “We’re leading the charge into getting everyone to empower their own analysis to increase diversity and inclusion, because we are aware that genetics has been so focused on Caucasian European genetics, that it’s so hard to get anything else,” said Kumar Veerapen, Ph.D., a research fellow at the Broad Institute who is also working on the initiative.

Patient impact

One thing that seems clear from the research so far is that there is no simple answer to working out who is most likely to experience severe COVID-19. Similar to the multiple clinical factors that seem to play a role, such as gender and age, genetic risk also seems to be multifactorial.

Lopes-Cendes emphasizes that it’s important not to overplay the importance of genetic results. “Based on the data we currently have, the genetics has not yet offered an explanation in terms of risk factors that will overcome the [clinical] risk factors that we know already,” she noted.

“I think we have to be very careful about that…  we know it’s a complex phenotype with multiple predisposing genes, which might be very complex in terms of applying this in practice.”

Heping Zhang, Ph.D., is a professor at Yale School of Public Health. He recently published a study in the journal Human Genomics analysing data from the UK Biobank to search for genetic variants linked to risk of dying from COVID-19.

He thinks genetic studies can have a major impact on patient health, but cautioned that many studies still require replication and validation, as well as functional analyses. “It’s too early for us to say, ‘we’ll take this genetic marker and then design a particular drug for it.’… But I think that if we are able to identify genetic variants with hard solid evidence behind it, in the long term, it will have implications in terms of treatment design or even development of vaccines for this particular disease.”

nurse in protective gear examining a patient
A number of research groups around the world are examining genomic data in an attempt to better understand which people are more likely to suffer from a more severe form of COVID-19 in order to develop treatment strategies. [xavierarnau / Getty Images]

While she and her colleagues still have a way to go in developing a validated risk score to predict severe COVID-19, Renieri says genetic research can have a more immediate impact by helping to guide emergency drug treatments.

“For example, in our last paper on TLR7. These people are missing interferon, so you could use interferon to treat them. Of course, interferon is not the standard of care. To use interferon, or in general the appropriate drugs led by genetic markers, you have the possibility to use the drug off label. You can go to the local ethical committee and ask to use this specific drug, this could be done for single patients, or you can set up a clinical trial, we are exploring both possibilities right now.”

Genetics can also help explain the mixed responses seen with the use of drugs such as hydroxychloroquine for treatment of patients with severe disease. This off-label treatment was first recommended for treating COVID-19 patients, but this advice was later rescinded due to fears about adverse effects in patients given the drug. Renieri and colleagues have discovered that a polymorphism in the TLR3 gene, present in around 30% of Europeans, impacts the metabolism of hydroxychloroquine and is linked to poor outcomes in COVID-19 patients treated with this drug.

“Maybe hydroxychloroquine would be a good drug, but not for every patient,” said Renieri, “but you need to give it to the right patients based on their genetics.”

Cobat also said the research she and her colleagues have carried out can have a fast impact for patients. In those with IFN1 gene variants, “early administration of type I IFN in case of SARS-CoV2 infection may be beneficial in patients with such defects.”

Their discovery of autoantibodies in some patients with severe COVID-19 could also have an important impact on treatment of patients. For example, administration of convalescent plasma (one of the various treatments being tested for COVID-19 patients) could actually be harmful if it also contains autoantibodies. “Convalescent plasma should be tested to exclude those positive for autoantibodies against type I IFN,” said Cobat.

Predicting the future

It’s hard to predict how long the current pandemic will last. With vaccinations increasing around the world, and more vaccines soon to be approved, it’s tempting to be cautiously optimistic, but the widespread nature of SARS-CoV-2 suggests it is more likely to become endemic in the population than to disappear completely.

Either way, research into host genetics has a lot to offer in terms of predicting who will need the most medical care and also for developing suitable treatments and guiding the use of existing treatments in a more precise way. However, whether this research will have a meaningful impact on the current pandemic, or offer more long-term guidance into human response to SARS-CoV-2 and potentially other coronaviruses, is less certain.

“I think some of what we find may be useful to understand host viral response in general or coronavirus response in general, particularly when it comes to how our immune systems may over or under perform, thus leading to severe disease,” says Wolford.

Although many studies to date have focused on searching for gene variants linked to more severe disease using GWAS methodology. More recent efforts are also looking into the impact that epigenetic changes such as DNA methylation could have on severity of COVID-19.

Emerging science suggests that host genetics could also help explain why some people experience extended ‘long COVID’ symptoms and others do not—something that several groups are now looking into.

Large-scale genetic studies have not previously been known for their speed, as large amounts of data and analysis are needed to find meaningful information. One positive impact of the pandemic, has been the number of collaborative projects like the COVID Human Genetic Effort and COVID-19 Host Genetics Initiative that have sprung up as a result. These large collaborations are useful for speeding up the research, but also increasing the sample sizes and making results more statistically valid.

“They started being multi centric and involving the globe. To tackle a global public health problem, you have to go global in terms of the research, no single group will be able to answer the question. I think that was a very positive thing for the field,” says Lopes-Cendes.[/vc_column_text][/vc_column][/vc_row]

 

Impact of Epigenetics on COVID-19

lungs
[Source: Peter Zelei Images / Getty Images]

 

Host genetic variants are one factor that influences how people respond to COVID-19, but according to Spanish researchers at the ICREA institute in Barcelona, epigenetic factors can also play an important role.

Manel Esteller, Ph.D., a professor based at the University of Barcelo and ICREA and Aurora Pujol, M.D., Ph.D., also an ICREA professor, and their colleagues carried out an epigenome-wide association study of 407 individuals with confirmed COVID-19. Of those included, 194 had mild disease not requiring hospitalization and 213 had severe COVID-19 and were admitted to hospital where they received respiratory support.

The researchers assessed the DNA methylation status of 850,000 CpG sites on the DNA of these patients using blood samples. Overall, 44 CpG sites were significantly associated with COVID-19 disease severity, 23 of which were located in the coding sequence of genes.

Similar to studies of genetic variants linked to COVID-19 disease severity, many of these genes had functions linked to immune regulation and the release of interferon by the body in response to viral infection such as AIM2 and HLA-C.

The research team created an epigenetic score based on their findings, which they tested in the validation group of patients. They found it was able to predict disease severity with a specificity of 88.18% and a sensitivity of 77.78%.

Notably, when the scientists evaluated how many people in a population sample had this score, they found 13.3% of the group tested had this signature and 86.7% did not — a similar ratio to the number of people who seem to develop severe disease versus those who do not.

The post Sussing Out COVID-19 Severity appeared first on Clinical OMICs - Molecular Diagnostics in Precision Medicine.

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I created a ‘cosy game’ – and learned how they can change players’ lives

Cosy, personal games, as I discovered, can change the lives of the people who make them and those who play them.

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Cosy games exploded in popularity during the pandemic. Takoyaki Tech/Shutterstock

The COVID pandemic transformed our lives in ways many of us are still experiencing, four years later. One of these changes was the significant uptake in gaming as a hobby, chief among them being “cosy games” like Animal Crossing: New Horizons (2020).

Players sought comfort in these wholesome virtual worlds, many of which allowed them to socialise from the safety of their homes. Cosy games, with their comforting atmospheres, absence of winning or losing, simple gameplay, and often heartwarming storylines provided a perfect entry point for a new hobby. They also offered predictability and certainty at a time when there wasn’t much to go around.

Cosy games are often made by small, independent developers. “Indie games” have long been evangelised as the purest form of game development – something anyone can do, given enough perseverance. This means they can provide an entry point for creators who hadn’t made games before, but were nevertheless interested in it, enabling a new array of diverse voices and stories to be heard.

In May 2020, near the start of the pandemic, the small poetry game A Solitary Spacecraft, which was about its developer’s experience of their first few months in lockdown, was lauded as particularly poignant. Such games showcase a potential angle for effective cosy game development: a personal one.

Personal themes are often explored through cosy games. For instance, Chicory and Venba (both released in 2023) tackle difficult topics like depression and immigration, despite their gorgeous aesthetics. This showcases the diversity of experiences on display within the medium.

However, as the world emerges from the pandemic’s shadow, the games industry is facing significant challenges. Economic downturns and acquisitions have caused large layoffs across the sector.

Historically, restructurings like these, or discontent with working conditions, have led talented laid-off developers to create their own companies and explore indie development. In the wake of the pandemic and the cosy game boom, these developers may have more personal stories to tell.

Making my own cosy game

I developed my own cosy and personal game during the pandemic and quickly discovered that creating these games in a post-lockdown landscape is no mean feat.

What We Take With Us (2023) merges reality and gameplay across various digital formats: a website, a Discord server that housed an online alternate reality game and a physical escape room. I created the game during the pandemic as a way to reflect on my journey through it, told through the videos of game character Ana Kirlitz.

The trailer for my game, What We Take With Us.

Players would follow in Ana’s footsteps by completing a series of ten tasks in their real-world space, all centred on improving wellbeing – something I and many others desperately needed during the pandemic.

But creating What We Take With Us was far from straightforward. There were pandemic hurdles like creating a physical space for an escape room amid social distancing guidelines. And, of course, the emotional difficulties of wrestling with my pandemic journey through the game’s narrative.

The release fared poorly, and the game only garnered a small player base – a problem emblematic of the modern games industry.

These struggles were starkly contrasted by the feedback I received from players who played the game, however.

This is a crucial lesson for indie developers: the creator’s journey and the player’s experience are often worlds apart. Cosy, personal games, as I discovered, can change the lives of those who play them, no matter how few they reach. They can fundamentally change the way we think about games, allow us to reconnect with old friends, or even inspire us to change careers – all real player stories.

Lessons in cosy game development

I learned so much about how cosy game development can be made more sustainable for creators navigating the precarious post-lockdown landscape. This is my advice for other creators.

First, collaboration is key. Even though many cosy or personal games (like Stardew Valley) are made by solo creators, having a team can help share the often emotional load. Making games can be taxing, so practising self-care and establishing team-wide support protocols is crucial. Share your successes and failures with other developers and players. Fostering a supportive community is key to success in the indie game landscape.

Second, remember that your game, however personal, is a product – not a reflection of you or your team. Making this distinction will help you manage expectations and cope with feedback.

Third, while deeply considering your audience may seem antithetical to personal projects, your game will ultimately be played by others. Understanding them will help you make better games.

The pandemic reignited the interest in cosy games, but subsequent industry-wide troubles may change games, and the way we make them, forever. Understanding how we make game creation more sustainable in a post-lockdown, post-layoff world is critical for developers and players alike.

For developers, it’s a reminder that their stories, no matter how harrowing, can still meaningfully connect with people. For players, it’s an invitation to embrace the potential for games to tell such stories, fostering empathy and understanding in a world that greatly needs it.


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Adam Jerrett does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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KIMM finds solution to medical waste problem, which has become a major national issue

A medical waste treatment system, which is capable of 99.9999 percent sterilization by using high-temperature and high-pressure steam, has been developed…

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A medical waste treatment system, which is capable of 99.9999 percent sterilization by using high-temperature and high-pressure steam, has been developed for the first time in the country.

Credit: Korea Institute of Machinery and Materials (KIMM)

A medical waste treatment system, which is capable of 99.9999 percent sterilization by using high-temperature and high-pressure steam, has been developed for the first time in the country.

The Korea Institute of Machinery and Materials (President Seog-Hyeon Ryu, hereinafter referred to as KIMM), an institute under the jurisdiction of the Ministry of Science and ICT, has succeeded in developing an on-site-disposal type medical waste sterilization system that can help to resolve the problem caused by medical waste, which has become a national and social issue as the volume of medical waste continues to increase every year. This project was launched as a basic business support program of the KIMM and was expanded into a demonstration project of Daejeon Metropolitan City. Then, in collaboration with VITALS Co., Ltd., a technology transfer corporation, the medical waste treatment system was developed as a finished product capable of processing more than 100 kilograms of medical waste per hour, and was demonstrated at the Chungnam National University Hospital.

Moreover, the installation and use of this product have been approved by the Geumgang Basin Environmental Office of the Ministry of Environment. All certification-related work for the installation and operation of this product at the Chungnam National University Hospital has been completed, including the passage of an installation test for efficiency and stability conducted by the Korea Testing Laboratory.

Through collaboration with VITALS Co., Ltd., a corporation specializing in inhalation toxicity systems, the research team led by Principal Researcher Bangwoo Han of the Department of Urban Environment Research of the KIMM’s Eco-Friendly Energy Research Division developed a high-temperature, high-pressure steam sterilization-type medical waste treatment system by using a high-temperature antimicrobial technology capable of processing biologically hazardous substances such as virus and bacteria with high efficiency. After pulverizing medical waste into small pieces so that high-temperature steam can penetrate deep into the interior of the medical waste, steam was then compressed in order to raise the boiling point of the saturated steam to over 100 degrees Celsius, thereby further improving the sterilization effect of the steam.

Meanwhile, in the case of the high-pressure steam sterilization method, it is vitally important to allow the airtight, high-temperature and high-pressure steam to penetrate deep into the medical waste. Therefore, the research team aimed to improve the sterilization effect of medical waste by increasing the contact efficiency between the pulverized medical waste and the aerosolized steam.

By using this technology, the research team succeeded in processing medical waste at a temperature of 138 degrees Celsius for 10 minutes or at 145 degrees Celsius for more than five (5) minutes, which is the world’s highest level. By doing so, the research team achieved a sterilization performance of 99.9999 percent targeting biological indicator bacteria at five (5) different locations within the sterilization chamber. This technology received certification as an NET (New Excellent Technology) in 2023.

Until now, medical waste has been sterilized by heating the exposed moisture using microwaves. However, this method requires caution because workers are likely to be exposed to electromagnetic waves and the entrance of foreign substances such as metals may lead to accidents.

In Korea, medical waste is mostly processed at exclusive medical waste incinerators and must be discharged in strict isolation from general waste. Hence, professional efforts are required to prevent the risk of infection during the transportation and incineration of medical waste, which requires a loss of cost and manpower.

If medical waste is processed directly at hospitals and converted into general waste by applying the newly developed technology, this can help to eliminate the risk of infection during the loading and transportation processes and significantly reduce waste disposal costs. By processing 30 percent of medical waste generated annually, hospitals can save costs worth KRW 71.8 billion. Moreover, it can significantly contribute to the ESG (environmental, social, and governance) management of hospitals by reducing the amount of incinerated waste and shortening the transportation distance of medical waste.

[*Allbaro System (statistical data from 2021): Unit cost of treatment for each type of waste for the calculation of performance guarantee insurance money for abandoned wastes (Ministry of Environment Public Notification No. 2021-259, amended on December 3, 2021). Amount of medical waste generated on an annual basis: 217,915 tons; Medical waste: KRW 1,397 per ton; General waste from business sites subject to incineration: KRW 299 per ton]

As the size and structure of the installation space varies for each hospital, installing a standardized commercial equipment can be a challenge. However, during the demonstration process at the Chungnam National University Hospital, the new system was developed in a way that allows the size and arrangement thereof to be easily adjusted depending on the installation site. Therefore, it can be highly advantageous in terms of on-site applicability.

Principal Researcher Bangwoo Han of the KIMM was quoted as saying, “The high-temperature, high-pressure steam sterilization technology for medical waste involves the eradication of almost all infectious bacteria in a completely sealed environment. Therefore, close cooperation with participating companies that have the capacity to develop airtight chamber technology is very important in materializing this technology.” He added, “We will make all-out efforts to expand this technology to the sterilization treatment of infected animal carcasses in the future.”

 

President Seog-Hyeon Ryu of the KIMM was quoted as saying, “The latest research outcome is significantly meaningful in that it shows the important role played by government-contributed research institutes in resolving national challenges. The latest technology, which has been developed through the KIMM’s business support program, has been expanded to a demonstration project through cooperation among the industry, academia, research institutes, and the government of Daejeon Metropolitan City.” President Ryu added, “We will continue to proactively support these regional projects and strive to develop technologies that contribute to the health and safety of the public.”

 

Meanwhile, this research was conducted with the support of the project for the “development of ultra-high performance infectious waste treatment system capable of eliminating 99.9999 percent of viruses in response to the post-coronavirus era,” one of the basic business support programs of the KIMM, as well as the project for the “demonstration and development of a safety design convergence-type high-pressure steam sterilization system for on-site treatment of medical waste,” part of Daejeon Metropolitan City’s “Daejeon-type New Convergence Industry Creation Special Zone Technology Demonstration Project.”

###

The Korea Institute of Machinery and Materials (KIMM) is a non-profit government-funded research institute under the Ministry of Science and ICT. Since its foundation in 1976, KIMM is contributing to economic growth of the nation by performing R&D on key technologies in machinery and materials, conducting reliability test evaluation, and commercializing the developed products and technologies.

 

This research was conducted with the support of the project for the “development of ultra-high performance infectious waste treatment system capable of eliminating 99.9999 percent of viruses in response to the post-coronavirus era,” one of the basic business support programs of the KIMM, as well as the project for the “demonstration and development of a safety design convergence-type high-pressure steam sterilization system for on-site treatment of medical waste,” part of Daejeon Metropolitan City’s “Daejeon-type New Convergence Industry Creation Special Zone Technology Demonstration Project.”


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IFM’s Hat Trick and Reflections On Option-To-Buy M&A

Today IFM Therapeutics announced the acquisition of IFM Due, one of its subsidiaries, by Novartis. Back in Sept 2019, IFM granted Novartis the right to…

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Today IFM Therapeutics announced the acquisition of IFM Due, one of its subsidiaries, by Novartis. Back in Sept 2019, IFM granted Novartis the right to acquire IFM Due as part of an “option to buy” collaboration around cGAS-STING antagonists for autoimmune disease.

This secures for IFM what is a rarity for a single biotech company: a liquidity hat trick, as this milestone represents the third successful exit of an IFM Therapeutics subsidiary since its inception in 2015.

Back in 2017, BMS purchased IFM’s  NLRP3 and STING agonists for cancer.  In early 2019, Novartis acquired IFM Tre for NLRP3 antagonists for autoimmune disease, which are now being studied in multiple Phase 2 studies. Then, later in 2019, Novartis secured the right to acquire IFM Due after their lead program entered clinical development. Since inception, across the three exits, IFM has secured over $700M in upfront cash payments and north of $3B in biobucks.

Kudos to the team, led by CEO Martin Seidel since 2019, for their impressive and continued R&D and BD success.

Option-to-Acquire Deals

These days option-based M&A deals aren’t in vogue: in large part because capital generally remains abundant despite the contraction, and there’s still a focus on “going big” for most startup companies.  That said, lean capital efficiency around asset-centric product development with a partner can still drive great returns. In different settings or stages of the market cycle, different deal configurations can make sense.

During the pandemic boom, when the world was awash in capital chasing deals, “going long” as independent company was an easy choice for most teams. But in tighter markets, taking painful levels of equity dilution may be less compelling than securing a lucrative option-based M&A deal.

For historical context, these option-based M&A deals were largely borne out of necessity in far more challenging capital markets (2010-2012) on the venture front, when both the paucity of private financing and the tepid exit environment for early stage deals posed real risks to biotech investment theses. Pharma was willing to engage on early clinical or even preclinical assets with these risk-sharing structures as a way to secure optionality for their emerging pipelines.

As a comparison, in 2012, total venture capital funding into biotech was less than quarter of what it is now, even post bubble contraction, and back then we had witnessed only a couple dozen IPOs in the prior 3 years combined. And most of those IPOs were later stage assets in 2010-2012.  Times were tough for biotech venture capital.  Option-based deals and capital efficient business models were part of ecosystem’s need for experimentation and external R&D innovation.

Many flavors of these option-based deals continued to get done for the rest of the decade, and indeed some are still getting done, albeit at a much less frequent cadence.  Today, the availability of capital on the supply side, and the reduced appetite for preclinical or early stage acquisitions on the demand side, have limited the role of these option to buy transactions in the current ecosystem.

But if the circumstances are right, these deals can still make some sense: a constructive combination of corporate strategy, funding needs, risk mitigation, and collaborative expertise must come together. In fact, Arkuda Therapeutics, one of our neuroscience companies, just announced a new option deal with Janssen.

Stepping back, it’ s worth asking what has been the industry’s success rate with these “option to buy” deals.

Positive anecdotes of acquisition options being exercised over the past few years are easy to find. We’ve seen Takeda exercise its right to acquire Maverick for T-cell engagers and GammaDelta for its cellular immunotherapy, among other deals. AbbVie recently did the same with Mitokinin for a Parkinson’s drug. On the negative side, in a high profile story last month, Gilead bailed on purchasing Tizona after securing that expensive $300M option a few years ago.

But these are indeed just a few anecdotes; what about data since these deal structures emerged circa 2010? Unfortunately, as these are mostly private deals with undisclosed terms, often small enough to be less material to the large Pharma buyer, there’s really no great source of comprehensive data on the subject. But a reasonable guess is that the proportion of these deals where the acquisition right is exercised is likely 30%.

This estimate comes from triangulating from a few sources. A quick and dirty dataset from DealForma, courtesy of Tim Opler at Stifel, suggests 30% or so for deals 2010-2020.  Talking to lawyers from Goodwin and Cooley, they also suggest ballpark of 30-50% in their experience.  The shareholder representatives at SRS Acquiom (who manage post-M&A milestones and escrows) also shared with me that about 33%+ of the option deals they tracked had converted positively to an acquisition.  As you might expect, this number is not that different than milestone payouts after an outright acquisition, or future payments in licensing deals. R&D failure rates and aggregate PoS will frequently dictate that within a few years, only a third of programs will remain alive and well.

Atlas’ experience with Option-based M&A deals

Looking back, we’ve done nearly a dozen of these option-to-buy deals since 2010. These took many flavors, from strategic venture co-creation where the option was granted at inception (e.g., built-to-buy deals like Arteaus and Annovation) to other deals where the option was sold as part of BD transaction for a maturing company (e.g., Lysosomal Therapeutics for GBA-PD).

Our hit rate with the initial option holder has been about 40%; these are cases where the initial Pharma that bought the option moves ahead and exercises that right to purchase the company. Most of these initial deals were done around pre- or peri-clinical stage assets.  But equally interesting, if not more so, is that in situations where the option expired without being exercised, but the asset continued forward into development, all of these were subsequently acquired by other Pharma buyers – and all eight of these investments generated positive returns for Atlas funds. For example, Rodin and Ataxion had option deals with Biogen (here, here) that weren’t exercised, and went on to be acquired by Alkermes and Novartis (here, here). And Nimbus Lakshmi for TYK2 was originally an option deal with Celgene, and went on to be purchased by Takeda.

For the two that weren’t acquired via the option or later, science was the driving factor. Spero was originally an LLC holding company model, and Roche had a right to purchase a subsidiary with a quorum-sensing antibacterial program (MvfR).  And Quartet had a non-opioid pain program where Merck had acquired an option.  Both of these latter programs were terminated for failing to advance in R&D.

Option deals are often criticized for “capping the upside” or creating “captive companies” – and there’s certainly some truth to that. These deals are structured, typically with pre-specified return curves, so there is a dollar value that one is locked into and the presence of the option right typically precludes a frothy IPO scenario. But in aggregate across milestones and royalties, these deals can still secure significant “Top 1%” venture upside though if negotiated properly and when the asset reaches the market: for example, based only on public disclosures, Arteaus generated north of $300M in payments across the upfront, milestones, and royalties, after spending less than $18M in equity capital. The key is to make sure the right-side of the return tail are included in the deal configuration – so if the drug progresses to the market, everyone wins.

Importantly, once in place, these deals largely protect both the founders and early stage investors from further equity dilution. While management teams that are getting reloaded with new stock with every financing may be indifferent to dilution, existing shareholders (founders and investors alike) often aren’t – so they may find these deals, when negotiated favorably, to be attractive relative to the alternative of being washed out of the cap table. This is obviously less of a risk in a world where the cost of capital is low and funding widely available.

These deal structures also have some other meaningful benefits worth considering though: they reduce financing risk in challenging equity capital markets, as the buyer often funds the entity with an option payment through the M&A trigger event, and they reduce exit risk, as they have a pre-specified path to realizing liquidity. Further, the idea that the assets are “tainted” if the buyer walks hasn’t been borne out in our experience, where all of the entities with active assets after the original option deal expired were subsequently acquired by other players, as noted above.

In addition, an outright sale often puts our prized programs in the hands of large and plodding bureaucracies before they’ve been brought to patients or later points in development. This can obviously frustrate development progress. For many capable teams, keeping the asset in their stewardship even while being “captive”, so they can move it quickly down the R&D path themselves, is an appealing alternative to an outright sale – especially if there’s greater appreciation of value with that option point.

Option-based M&A deals aren’t right for every company or every situation, and in recent years have been used only sparingly across the sector. They obviously only work in practice for private companies, often as alternative to larger dilutive financings on the road to an IPO. But for asset-centric stories with clear development paths and known capital requirements, they can still be a useful tool in the BD toolbox – and can generate attractive venture-like returns for shareholders.

Like others in the biotech ecosystem, Atlas hasn’t done many of these deals in recent funds. And it’s unlikely these deals will come back in vogue with what appears to be 2024’s more constructive fundraising environment (one that’s willing to fund early stage stories), but if things get tighter or Pharma re-engages earlier in the asset continuum, these could return to being important BD tools. It will be interesting to see what role they may play in the broader external R&D landscape over the next few years.

Most importantly, circling back to point of the blog, kudos to the team at IFM and our partners at Novartis!

The post IFM’s Hat Trick and Reflections On Option-To-Buy M&A appeared first on LifeSciVC.

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