The end of 2020 saw several big pharma acquisitions of companies developing antibody-drug conjugate drugs for the treatment of cancer.
Unfazed by the Covid-19 pandemic, companies developing antibody-drug conjugates (ADCs) for cancer have flourished over the last year. For example, Gilead closed a colossal €17.8B acquisition of the US ADC developer Immunomedics in September, and in November, Merck took over the US ADC firm Velos Bio for €2.2B.
The last month of 2020 saw a flurry of European deals in the same field. The most impressive was Boehringer Ingelheim purchasing the Swiss ADC company NBE Therapeutics for a neat €1.2B.
Additionally, the UK firm ADC Bio announced an impending acquisition by the contract manufacturing heavyweight Sterling Pharma Solutions while the Swiss biotech ADC Therapeutics, which raised €215M in a Nasdaq IPO last year, teamed up with the Chinese company Overland Pharmaceuticals to commercialize its pipeline in the Greater China region.
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 attaching chemotherapy drugs to anti-cancer antibodies, which function like a ‘guided missile’ system.
Another reason for the big investor interest is that the ADC field has gained a steady foothold in the industry. In August, the FDA approval of GSK’s Blenrep moved the tally up to 13 approved ADC treatments globally. ADC Therapeutics could get an FDA approval of its lead candidate this year and the Dutch ADC player Byondis expects phase III data for its own lead candidate around the summer.
“We’ve recently seen growing interest in the field with pharma companies in-licensing the first generation of ADCs in billion-dollar deals because they have seen real advances in clinical efficacy,” said Bertrand Damour, CEO of NBE Therapeutics. “Historically, the ADC space has seen several cycles of success and failure, and it finally appears to have entered a period of maturation.”
European ADC startups also reaped a big funding harvest last year, including seed rounds from Emergence Therapeutics, the Cambridge spinout Spirea, and the Swiss company Araris, as well as a Series A round raised by the German company Tubulis.
“There is excitement in the ADC field due to the many acquisitions of ADC companies and licensing deals that happened during 2020, in particular during the last quarter,” said Philipp Spycher, CEO and co-founder of Araris.
In a maturing field, 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. It was potentially the reason why the Danish company Genmab abandoned one of its ADC candidates in November.
“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 explanation for the small therapeutic window seen in current ADC drugs concerns the molecules that join 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 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 at the tumor site, the toxic drugs make their way into the blood. Because they can’t be broken down fast enough, they accumulate in the bloodstream, causing 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.
“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 whom current ADCs can’t 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 which can show you how much better our candidates are compared to approved drugs.”
While the ADC market 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’s probably 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 into 2021, ADC fundraising will likely build momentum as more investors see the potential of ADC technology for cancer treatment. Byondis, for instance, expects to launch a commercialization partnering deal and file for US and EU approval of its lead candidate this year if its phase III trial succeeds.
Additionally, startups may add new bright ideas into the mix. Anticipated innovations on the ADC horizon include antibodies that are more selective to tumors than current ones, drugs that are able to treat a wider range of cancers, 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.”
This is an updated version of an article published on the 27th of October, 2020
Image from Elena Resko