In the biopharma graveyard of Alzheimer’s disease it helps to have a back-up plan. Probiodrug’s name change to Vivoryon was quickly followed by news that it is getting into oncology with projects targeting the CD47 pathway.
The group’s chief executive, Ulrich Dauer, is adamant that the company’s main focus is still Alzheimer’s, and indeed Vivoryon has quickly moved to out-license its work in cancer. A deal with Morphosys announced today will see the German biotech take an option to Vivoryon’s family of QPCTL inhibitors and lead compound PQ912, in the field of oncology.
Speaking to Vantage ahead of the deal, Mr Dauer said that the cancer assets would be partnered to fund planned Alzheimer’s trials. However the Morphosys transaction did not involve any upfront cash; instead, the German biotech has committed to invest up to €15m in a fundraising that Vivoryon has planned for later this year.
An option fee will follow should Morphosys like what it sees, though presumably its assessments will take time, and Vivoryon has a more immediate need for cash. The company is pushing into phase IIb trials with its lead candidate, PQ912 in Alzheimer’s, despite the fact it does not have the funds to complete them (Probiodrug wins a market cap-sized grant for Alzheimer’s trial, March 20, 2019).
The group is in a better position than it was at the beginning of the year, at least. A $15m grant from the US NIH, to support its US phase IIb trial, was followed by an €8.2m ($9.3m) fundraising for its European phase IIb study, Saphir 2. The sum pledged by Morphosys presumably gives a more substantial cash call a better chance of succeeding.
Mr Dauer told Vantage that they plan to raise "at least" another €30m, which is the approximate cost of the 250-patient European trial. The US study will be larger, with a longer treatment duration, so will cost more, but he declined say exactly how much. Neither trial has started recruiting.
The company’s work in the CD47 space, meanwhile, is based on the finding that the CD47/SIRPα pathway is hijacked by some cancers to avoid destruction by the immune system. Vivoryon hopes that its research, now exclusively in the hands of Morphosys, can move quickly into human trials, particularly given the similarities between PQ912 and the CD47/SIRPα-targeting compounds it is developing for cancer applications.
PQ912 is a small-molecule inhibitor of glutaminyl cyclase, the enzyme that converts beta-amyloid into what the company calls the toxic pGlu-Abeta form.
In oncology, Vivoryon targeted an isomer known as the glutaminyl-peptide cyclotransferase-like (QPCTL) enzyme. The main difference, according to Mr Dauer, is that glutaminyl cyclase is expressed in the brain, while QPCTL is expressed in other tissues in the periphery.
QPCTL has been shown to be important in the interaction between the SIRPα protein and its CD47 ligand, so inhibiting the enzyme could silence this so-called “don’t eat me” signal and release the brakes on the immune system.
Mr Dauer admitted that this was a serendipitous finding for Vivoryon, adding that PQ912 could be used "as a kind of test compound to validate the principle clinically”. Follow-up compounds are probably around six months behind.
Mr Dauer claimed that Vivoryon is the only company with a small molecule in this space; all other CD47/SIRPα-targeting players use biologicals to hit either target.
|Selected industry assets targeting the CD47/SIRPα pathway|
|Project||Company||Mechanism of action||Note|
|Hu5F9-G4||Forty Seven||Anti-CD47 MAb||Phase I/II Erbitux & Rituxan combo trials (NCT02953782 & NCT02953509)|
|TTI-621||Trillium Therapeutics||Anti-SIRPα fusion protein||Soluble decoy receptor; Rituxan and PD-(L)1 combos (NCT02663518 & NCT02890368)|
|TTI-622||Trillium Therapeutics||Anti-SIRPα fusion protein||Uses IgG4 Fc instead of IgG1 Fc; phase I (NCT03530683) began in May 2018|
|ALX148||ALX Oncology||Anti-CD47 fusion protein||Keytruda, Herceptin or Rituxan combo (NCT03013218); company earlier known as Alexo|
|CC-90002/INBRX-103||Celgene/Inhibrx||Anti-CD47 MAb||Phase I in AML (NCT02641002) terminated in Oct 2018|
|SRF231||Surface Oncology||Anti-CD47 MAb||Project deprioritised in Dec 2018|
Apart from the obvious advantages of small molecules, such as their lower cost and oral availability, the Vivoryon approach might spare red blood cells, according to the chief exec.
This problem arises because CD47 is expressed on red blood cells as well as on cancer cells, so blocking this pathway could lead to anaemia. According to Mr Dauer, however, Vivoryon’s projects act specifically on cancer cells because QPCTL is not universally expressed, and so pre-existing CD47 binding remains untouchable; of course, this remains to be proven.
The RBC-sparing claim has been made by other CD47/SIRPα players, to no avail, and the issue probably goes to the heart of the rise and fall in interest in this pathway as an oncology approach.
Despite caution, such as developing MAbs based on the IgG4 immunoglobulin subclass in an attempt to send a more modest signal, recent setbacks include Celgene scrapping a trial of CC-90002, and Surface Oncology deprioritising SRF231 citing toxicities in dose escalation and the “evolving competitive landscape”.
Meanwhile, Forty Seven’s stock fell sharply in May despite this company reporting clinical remissions with Hu5F9-G4. And the stock of Canada’s Trillium imploded after a punitive fund raising was followed by the resignation of its chief executive in April.
Trillium tried a different, bolder approach, developing an anti-CD47 soluble decoy receptor, TTI-621, which it claimed did not bind RBCs despite being based on IgG1. However, neither TTI-621 nor Trillium’s IgG4-derived TTI-622 attracted partner interest, and the company is currently valued at less than $10m.
Vivoryon might have chosen a less risky sector than Alzheimer’s to move into. But recent developments with other CD47-targeting projects suggest that the company’s path forward in oncology might not be smooth, either.