StemCell Therapy

As we prepare to enter a new decade, we look back on the major milestones and blunders within European biotech over the last 10 years.

Over the last decade, we have seen many biotech breakthroughs to come from Europe, including first-in-class therapies for cancer, the first approved in vivo gene therapy, as well as notable efforts to combat Covid-19. Some other areas have proven to fall behind expectations, such as Alzheimers or microbiome research, and will need a push over the next decade. Lets have a look back at what the biotech industry has accomplished in the decade were now leaving behind.

Few would disagree that this has been a game-changing decade within oncology. Weve seen the arrival of checkpoint inhibitor drugs, the first oncolytic viral therapy, and the approval of the first CAR-T cell therapies.

For Alexandra Bause, who leads a venture creation program at the investment firm Apollo Health Ventures, immuno-oncology was one of the most exciting things to happen during the last decade. Its not just one cancer and one drug for that specific cancer anymore, we can now activate, reactivate or replenish the bodys own immune response and we can potentially target malignant cells throughout the whole body.

This decade has witnessed the advent and establishment of checkpoint inhibitor drugs. These immunotherapies consist of therapeutic antibodies that block immune checkpoints proteins on the surface of immune cells that tumors use to evade the immune system.

The first checkpoint inhibitor, ipilimumab, was approved in 2011. Since then, six other checkpoint inhibitor drugs belonging to a new generation that blocks the PD-1/PD-L1 immune checkpoint have been approved. These drugs have made a big difference for a certain percentage of patients with difficult-to-treat forms of cancer.

Many good things came to cancer patients in the last decade, said Martin Bonde, CEO of Inthera Biosciences in Switzerland. For instance, we are now much better at treating multiple myeloma and malignant melanoma than we were 10 years ago. At the start of the decade, malignant melanoma had a 5% 5-year survival rate, now its over 50 % thanks to drugs like Opdivo (nivolumab) and Keytruda (pembrolizumab).

Since the initial approval of Opdivo and Keytruda as treatments for advanced melanoma in 2015, their indications have been expanded to include a range of blood and solid cancers. They are also used in combination with other checkpoint inhibitors as well as conventional chemotherapeutic agents. Sales-wise, Keytruda takes the lead as one of the worlds best-selling drugs.

The year 2015 also brought the approval of Imlygic, the first viral therapy for cancer in the Western world. The treatment acts by injecting melanoma tumors with a virus that infects and destroys cancerous cells. While Imlygic hasnt proved to be a blockbuster, viral therapies for cancer going forward could find a niche when combined with other cancer treatments such as checkpoint inhibitors.

In 2017, we saw the US approval of Kymriah, the worlds first CAR-T cell therapy. This treatment consists of engineering the patients own immune cells to make them better at identifying and attacking cancer cells. That same year, a second CAR-T therapy, Yescarta, was approved and a third one, Tecartus, received approval this year.

Despite concerns regarding severe side effects and prohibitive pricing, CAR-T cell therapy has made a big difference for patients with blood cancer that had not responded to other treatments, with remission rates above 90% in some cases. There are now over 1,000 clinical trials testing different forms of CAR-T technology aiming to improve its efficacy and safety and to extend its use to other forms of cancer, such as solid tumors.

The future of cancer treatment seems to be going in the direction of combining different approaches and selecting the most suitable for each patient. According to Bonde, combination therapy will continue to be refined with genomics technology.

I think its difficult to see combination therapy going away anytime soon because cancer is so complex and still difficult to treat, so we need to attack it from multiple angles. I think we will continue to see the search for new mechanisms of action, and research will help us to understand how we can best tackle a particular cancer in relation to its genetic makeup.

The last decade brought gene therapy to the market, offering a one-off treatment for patients suffering from genetic disorders. In Europe, the first gene therapy, Glybera, was approved in 2012. Although the treatment was withdrawn after a commercial failure, it set a precedent; there are now a total of 11 cell and gene therapies approved in the EU.

In 2018, the EMA approved Luxturna, a gene therapy developed by Novartis to treat blindness caused by a genetic mutation. This made Europe the first to approve an in vivo gene therapy, in which the genetic modification happens directly within the body rather than in cells extracted from the patient.

Despite these breakthroughs, the number of approved gene therapies in Europe is very modest compared to the over 1,200 gene therapy trials taking place across Europe. Meaning there is still a lot of space to grow.

Today we can get the entire human genome sequence in 24 hours for $500. This has opened up the possibility to design drugs using genetic information this is just starting and will be important in the next decade in gene therapy for cancer and elsewhere, said Bonde.

The gene therapies approved to date have mostly consisted of replacing a faulty gene with a functional copy delivered on viruses. Rapid technical advances within gene-editing technologies such as CRISPR-Cas9 are now making it possible to make precise edits to the genome, and many such therapies have entered clinical trials in Europe.

The orphan disease space has become much more crowded in recent years, with companies trying to target specific gene mutations behind a given rare disease, many of which incorporate gene therapy or gene-editing technologies, while others target downstream pathways with small molecules, said Bause.

The last decade has primarily been about tool-building within the gene therapy area and with the advent of CRISPR-Cas9 and related technologies, we are really only at the beginning of this era.

A therapeutic area that has seen huge investment, particularly in the second half of the last decade, is aging. Companies in this field seek to tackle aging-related diseases.

Why is this so important? According to Alexandra Bause, a wide range of diseases can be attributed to aging. In our 20s, 30s, and 40s, most of us are healthy, and then disease may creep up from the age of 50 years. The underlying aging process is causing the majority of known diseases that make up the major markets, such as Alzheimers, cancer, heart disease, chronic kidney disease, type 2 diabetes, metabolic disorders, and more.

Right now, much of the focus is on reverting age-related physiological damage. As research sheds light on the mechanisms underlying aging, many strategies to combat aging are being explored. Senolytics are a prominent example. These are small molecules that can simultaneously eliminate aged cells and promote tissue rejuvenation.

In recent years weve seen the creation of companies developing senolytics, including Senolytx in Barcelona and Velabs Therapeutics in Helsinki. However, a senolytic candidate developed by the US company Unity Biotechnology failed a key phase II trial in osteoarthritis earlier this year and the company is still suffering the fallout. Evidently, a lot more progress is still needed in the senolytics field before it can produce any marketed drugs.

Other strategies include drug repurposing, stem cells, and genomics. A major study called TAME is looking at whether the drug metformin can extend longevity and delay the onset of age-related chronic diseases such as heart disease, cancer, and dementia.

Metformin is widely used to treat type 2 diabetes but it also seems to have properties that may reduce Alzheimers and cancer risk. The TAME study will evaluate whether metformin doesnt just increase healthy lifespan by diminishing the risk of Alzheimers and cancer, but actually affects cellular pathways of aging as well. This is an important drug and an important study because it demonstrates how drugs can be repurposed to directly impact aging, said Greg Bailey, CEO of anti-aging company Juvenescence.

The organizers of the TAME trial also plan to launch a study into what biomarkers can best assess biological age, since its currently hard to measure how much a drug has slowed the aging process. Going forward, these trials will be a huge help to those working within aging, which is not currently seen as an official disease by the EMA or FDA. This means that companies are limited to targeting a specific age-related disease each time they want to test new treatments in clinical trials.

I think genetic modification of cellular pathways and epigenetics will play an enormous role. There is incredible ongoing work with Yamanaka factors; those transcription factors and gene modifications can reset cells to embryonic stage, potentially erasing the epigenetic changes of aging. Clearly the control of these factors and genes would be hugely transformational, said Bailey.

The field is coming fast and furious. We have the opportunity and ability to turn science fiction into science. In the last 10 years, scientists have truly begun to understand the cellular pathways involved with aging. And when we understand a cellular pathway, we can manipulate it. This was made possible by unlocking the human genome with computational biology, and advances in machine learning have literally opened the floodgates.

Although Covid-19 only appeared at the end of the decade, it has already made a huge impact on the biotech industry. If there is a positive in this crisis, the speed at which the biotech, pharma and research communities have come together in the face of Covid-19 is truly remarkable. It has probably accelerated scientific knowledge by years, said Bailey.

Covid-19 has focused the attention on biotech and healthcare and I believe that biotech is the ultimate superhero. It is the Modernas and the BioNTechs of this world that will kill Covid, said Antoine Papiernik, Managing Partner at life sciences VC firm Sofinnova Partners.

There are currently over 50 Covid-19 vaccines in clinical trials, with 12 of these in late-stage testing. One area in particular that has seen a big push because of the pandemic has been RNA therapeutics. In partnership with Pfizer, BioNTech in Germany has obtained approval in the UK and US for a Covid-19 vaccine, making it the first medicine using messenger RNA technology.

Although European diagnostics and vaccine development have seen a boost in funding this year thanks to Covid-19, funding for infectious diseases in general will still be an uphill battle. Its almost impossible to get funding for infectious diseases nowadays. Why? Because there are few patients in need, and a lot of drugs already out there, and treatment lasts a maximum of 2 weeks. How much can you charge for that compared to a cancer treatment? said Bonde.

There have been some efforts to boost the development of new antibiotics, such as the launch of the Antimicrobial Resistance Action Fund this year. Additionally, the UK began trialling a new payment policy to incentivize antibiotics development in 2019. However, this may still not be enough.

Its a broken business model, and its going to hurt us because an estimated 10 million people will die over the next 10 years or so, from multi-resistant bacteria. But theres no incentive in the market for companies to go after it. I think this should and will end as a state matter. The state will make sure that we have enough options to deal with deadly bacteria.

The last decade saw hundreds of clinical trials for Alzheimers disease, yet not a single drug is able to stop or slow down its progression. Clinical trials are failing one after the other, in most cases because of a lack of convincing therapeutic efficacy when tested in large groups of patients.

For the last decade, research and clinical strategies within the Alzheimers field have largely focused on the beta amyloid protein, which accumulates in the brains of Alzheimers patients years before they experience cognitive symptoms. These findings led to the hypothesis that these beta amyloid plaques were responsible for cognitive decline, but the failure of clinical trials targeting beta amyloid seems to indicate the solution may lay elsewhere. The biggest challenge is that no consensus exists on the underlying mechanisms of the disease, which is now the 6th leading cause of death worldwide.

Poor disease models and an incomplete understanding of the mechanisms of disease are a big part of the problem. Beta amyloid might be more of a biomarker or a symptom, than the mechanism, said Bause.

Companies dont talk to each other enough to share knowledge about what doesnt work. How many amyloid drugs do you have to put into trials before you realize that this isnt working? This is one of the biggest blunders of the last decade from my perspective, added Bailey.

Even for companies following other approaches, the results have been mixed so far. One example is an antibody drug developed by the Swiss company AC Immune and US partner Genentech to tackle Alzheimers disease by blocking a protein called tau. However, this drug proved a dud on a debut phase II trial this year.

However, the French company AB Science provided a glimmer of hope at the end of the decade. Its drug designed to reduce inflammation in the brain reportedly reduced the number of mild Alzheimers cases that progressed to being severe cases in a phase IIb/III trial this month.

Alzheimers isnt the only field to suffer from inadequate animal models. Other notable disease areas that lack translatable animal models include infectious diseases, bacterial sepsis, psychiatric disorders and immunological disorders.

Alexandra Bause points out that the problem with animal studies is not only due to an incomplete understanding of the underlying mechanisms of disease, but also to the fact that there are intrinsic problems with the way animals are tested. Most companies or most research programs are looking at young animals, and theyre artificially making these young animals sick. Then they are giving them the drug to target whatever made them sick, and they recover. But that doesnt mean that an old animal can recover equally.

Other factors that limit the predictive power of animal models are assumptions that animals and humans use the same or highly similar cellular pathways in response to specific diseases, as well as gender-biases and the use of germ-free animals that dont reflect the potential impact of our microbiome on health and disease.

For the next decade, the biotech industry will have to face the challenge of improving animal models or even replacing them with alternatives such as organs on chips or tissue bioprinting.

In the last decade, the study of the microbiome has gained a lot of attention. The human microbiome, which comprises the collection of microorganisms that live in and on our bodies has been linked to almost every disease imaginable. There are currently more than 1,000 clinical trials listed worldwide testing microbiome-related therapies.

This created huge expectations that are taking longer than expected to pan out. Technological advances have resulted in the generation of mountains of data that is often extremely complex and difficult to interpret. We still dont really understand the dynamic complexity of the microbiome or how to manipulate it for therapeutic benefit.

I think theres a long way to go, said Bonde. Im not sure were ever going to fully understand it.

We aggressively looked at a number of microbiome companies and its fascinating but chaotic. We know what we can do with lactobacilli, but what do we do with everything else? You can change one factor, but what does it do to the other billion or trillion entities that constitute the microbiome? said Bailey.

Overall, the biotech industry in Europe has matured over the last decade and strengthened its position in the global market. If the biotech market in Europe was born around 25 years ago, then by now we have learned from the best during our childhood as well as our adolescent years. Today, as an industry, we are now young adults in our prime, ready to forge our own paths, said Antoine Papiernik, Managing Partner at the French life sciences investment firm Sofinnova Partners.

During this pandemic, Europe has demonstrated its strength, resilience, and scientific prowess, he added. Europe has strong scientific and technological output, it has cultivated talent and built highly experienced management teams, and more than ever before, we are capable of funding young biotechs and medtech to success.

The last decade has brought incredible levels of progress to the biotech industry, while also opening up new challenges to tackle in the coming years. Stay tuned for part two next week, where well look in more detail into what the next decade has in store.

More:
A Look Back at the Past Decade of European... - Labiotech.eu

This entry was posted on December 30, 2020 at 8:51 pm and is filed under Gene therapy. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed. |