The market appetite is growing for antibody-drug conjugate drugs for the treatment of cancer. In a space traditionally dominated by big pharma, European biotechs are starting to move the field forward.
Unfazed by the Covid-19 pandemic, the field of antibody-drug conjugate drugs (ADCs) for cancer seems to be flourishing. The ADC market is projected to grow at an estimated 3% per year. In the US, the FDA approved GSK’s ADC drug Blenrep for the treatment of cancer in August this year and, in September, the biotech giant Gilead purchased the US ADC developer Immunomedics for a colossal €17.8B.
Across the pond, European ADC developers are also in a flurry of activity. Following a busy year of fundraising via a €215M IPO in April and a €172M share offering in September, the Swiss biotech ADC Therapeutics applied for FDA approval of its lead ADC candidate. The Dutch ADC player Synthon Biopharmaceuticals, freshly rebranded as Byondis, is running a phase III trial of its lead candidate ADC and has launched a string of trials of other candidates in the past few months.
Furthermore, the German upstart Tubulis landed a €10.7M Series A round in July and the Basel-based NBE-Therapeutics formed an alliance with the US Exelixis last month to develop ADC treatments for cancer. Most recently, the Swiss startup Araris closed a €14M seed round last week with the aim of taking its lead candidate ADC into phase I trials by 2023.
“There is strong interest in the ADC space right now and an appreciation by investors for what our technology can bring to the table,” said Philipp Spycher, CEO and co-founder of Araris.
ADCs are drawing investor attention because of their potential to hit tumors more selectively than classical chemotherapy drugs and minimize side effects such as fatigue and nausea. ADC companies do this by sticking chemotherapy drugs to anti-cancer antibodies, which function like a ‘guided missile’ system.
With 13 ADCs approved in the cancer treatment space globally, what room do startups have to make improvements? A lot, as it turns out. One issue with current ADC drugs is that it is difficult to find a dose that will be high enough to be effective but low enough to prevent side effects such as nausea. In technical circles, this is known as having a narrow therapeutic window.
“If you look at the ADCs that have been approved thus far, to be honest, most of them have only a very limited improvement in the therapeutic window compared to the classical chemotherapeutics,” said Marco Timmers, CEO of Byondis.
One reason for the small therapeutic window seen in current ADC drugs concerns the molecules that stick together the antibody and its chemotherapy drug payload, called linkers.
“One challenge has been the lack of stability of ADCs in the body because the chemical linker connecting the antibody to the payload discharges the payload prematurely due to chemical interactions in the body,” said Jonas Helma-Smets, co-founder and CSO at the German ADC startup Tubulis. He added that this causes adverse side effects and can reduce the benefits of the drugs.
Another reason is that, once the ADC drops its payload in the tumor, the toxic drugs make their way into the blood. Because they can’t be broken down fast enough, they accumulate in the bloodstream, causing chemotherapy side effects.
European companies are working on this problem in a variety of ways. Byondis focuses on developing a payload drug that breaks down much faster in the blood than current payload drugs do, with a half-life of around 20 minutes.
“We actually see hardly any toxicity for blood cells, which is the most common toxicity for all other ADC platforms,” noted Timmers.
Araris is developing better linkers, which could improve the therapeutic window of ADC drugs.
“We know from preclinical data in cancer models that with the same dose, we see better treatment response rates compared to conventional ADCs. Additionally, early data suggests that our ADCs are much better tolerated in animals, so we can dose much higher,” said Spycher.
ADC Therapeutics, on the other hand, aims its cancer treatments at different populations of patients than current ADCs can treat.
“The clinical trials are being carried out with patients who are relapsing or not responding to current treatment regimens, therefore addressing an unmet medical need,” said Chris Martin, ADC Therapeutics’ CEO. “There are no head-to-head studies that can show you how much better our candidates are compared to approved drugs.”
While the ADC landscape seems to be dominated by big pharma companies, the reality is that small biotech companies such as Seattle Genetics were the root of much of the technology to begin with. Small biotech innovation will likely continue to shape the progress of the field.
“There is growing activity in the ADC sector generally; biotech and pharmaceutical companies all have a role to play in this increasingly important field of cancer therapy,” said Martin.
As to why the European ADC scene is thriving, it seems like it’s part of a global acceleration in the technology.
“The trend is coincidental, possibly. Europe has many old-guard companies developing ADCs like Heidelberg Pharma and ADC Therapeutics, but it seems to be evolving,” said Timmers. “I think what is really going on is new insights into types of payloads, refinements that we put forward in making the payload … and things like molecular engineering of old concepts. We’re good at that in Europe.”
Going forward, the glut of ADC fundraising this year could attract more startups with new bright ideas into the herd. For example, Timmers sees major innovations on the ADC horizon such as antibodies that are more selective to tumors than current ones and payloads that can overcome drug resistance in cancer.
Further into the future, ADCs could expand beyond cancer treatment and tackle other conditions such as autoimmune disorders.
“You would be able to really selectively target a blood cell or an immune cell that is involved in an autoimmune reaction and basically attacking your own healthy cells,” said Timmers. “If you were able to reach that specific immune cell that’s doing a bad job, you would be able to reprogram that cell or selectively kill that cell.”
Image from Elena Resko