For most companies, the discontinuation of their lead asset would be a body blow. But Aduro Biotech rose 5% yesterday despite news that it had canned CRS-207, an anti-mesothelin cancer vaccine that had been in phase II development in mesothelioma and ovarian and gastric cancers.
The sellside were quick to fight the fire, pointing to the rest of Aduro’s pipeline (see table below). And expectations for CRS-207 were likely low after the failure of Bayer’s antibody-drug conjugate anetumab ravtansine, which also targeted mesothelin. Still, there are reasons to be cautious about some of Aduro’s remaining projects.
And the company’s stock was down as much as 3% during trading this morning.
|Aduro's clinical pipeline|
|Project||Indication||Mechanism||Ongoing trial(s)||Primary completion||Notes|
|CRS-207||Mesothelioma, gastric and ovarian cancers||Anti-mesothelin vaccine||Discontinued||-||-|
|ADU-741||Prostate cancer||Vaccine against 4 prostate-specific antigens||NCT02625857||Jul 2017||Partnered with J&J|
|ADU-214||Lung cancer||Anti-EGFR/mesothelin cancer vaccine||NCT02592967||Mar 2020||Partnered with J&J|
|ADU-S100||Solid tumours, lymphoma||Sting cyclic dinucleotide activator||NCT03172936 (combo with PDR001), NCT02675439||Jan 2020, Mar 2020||Partnered with Novartis|
|pLADD||Microsatellite stable colorectal cancer||Personalised cancer vaccine||NCT03189030||Dec 2020|
|BION-1301||Multiple myeloma||Anti-April antibody||Phase I trial planned for Q4 2017||-||-|
|Source: Company website, Clinicaltrials.gov.|
The lung cancer vaccine ADU-214, also known as JNJ-64041757, also hits mesothelin – as well as EGFR – so could run into similar problems. Mesothelin is highly expressed in certain cancers but is also found on normal mesothelial cells, and difficulty finding a therapeutic window might explain why CRS-207 failed to show sufficient activity in mesothelioma and ovarian cancer.
Still, Aduro and its partner Johnson & Johnson are pressing on with the development of ADU-214, with a phase 1b/2 study of the project in combo with Bristol-Myers Squibb’s Opdivo in previously-treated NSCLC patients slated to start shortly.
However, another J&J-partnered project, ADU-741 or JNJ-64041809, requires additional preclinical work before development can continue.
All the aforementioned candidates are based on Aduro’s LADD platform, which uses a modified form of Listeria monocytogenes as a delivery vehicle. This technology has previously had issues, with CRS-207 already failing in pancreatic cancer, and Aduro reporting cases of listeria in clinical trials (Second time around, Aduro fails to shake off the listeria, October 24, 2016).
This does not appear to have been a problem this time around: Aduro’s chief medical officer Natalie Sacks said during a conference call that the decision to discontinue CRS-207 was not spurred by any safety concerns.
One of the LADDs
Despite the sellside’s protestations that CRS-207’s discontinuation should not affect the remaining LADD projects, the signs so far – plus the general difficulty in developing cancer vaccines – are not auspicious.
Aduro sees its final LADD project, the personalised vaccine pLADD, as differentiated from the rest of the platform. pLADD targets neoantigens, mutations unique to each tumour. “One expects stronger immune responses [with pLADD],” said Aduro’s chief executive Stephen Isaacs during the conference call, adding that this had been seen in animal studies.
A phase I proof-of-concept trial is currently enrolling; the company is looking for a meaningful immune response in multiple patients in order to continue development, and could have some data in 2018, according to Ms Sacks.
But Aduro is not alone here – other companies looking neoantigen-based cancer vaccines include Moderna and Biontech.
Sting and April
Luckily for Aduro, it has other irons in the fire. The project generating the most excitement is ADU-S100, generated via its Sting platform, which is partnered with Novartis (Pre-IPO Sting gives Novartis a stake in Aduro, March 30, 2015).
ADU-S100 is in two phase I trials, both in metastatic solid tumours and lymphoma: a dose-escalation monotherapy trial, and another trialling ADU-S100 in combination with Novartis’s PD-1 inhibitor PDR001. Aduro is also planning combination studies with other immuno-oncology agents, such as approved checkpoint inhibitors and investigational IDO inhibitors, Ms Sacks said, without disclosing which compounds these would be.
Another Aduro platform, B-Select, should produce its first clinical candidate next year in the form of an anti-April antibody for multiple myeloma.
With more projects, including an anti-CTLA4 agent and an anti-CD27 antibody, also set to enter the clinic soon, perhaps Aduro’s main issue is not running out of candidates, but a lack of focus. However, in the case of CRS-207, and perhaps the LADD platform in general, it is probably a good job that the company has other options to fall back on.