Wall Street Trader schreef op 16 augustus 2020 16:36:
What do we know about the TOLEDO program of particular interest for investors so far;TOLEDO rebalances inflammatory and anti-inflammatory cytokines by hitting an as yet unrevealed target.
Gilead & TOLEDO: Gilead will have opt-in options developed by GLPG over the next 10 years.
For each asset where GILD opts-in, GLPG will receive $150M and will be eligible to receive 20-24% tiered royalties on all future ex-European sales, with GLPG retaining full commercial rights in Europe.
Each TOLEDO molecule will be considered a separate asset, with each having its own $150M opt-in fee.
This could be an important source of future value!A significant proportion of the c.$5bn from Gilead is to be used to accelerate GLPG's secretive Toledo programme in order to maximise first-mover advantage with this undisclosed mechanism of action.
Galapagos would have accepted a lower upfront payment if it excluded the Toledo program, which was a potential no-go on the part of Gilead since it may have prompted Galapagos to committing the best human and technical resources to the Toledo platform at Gilead's detriment.
2027 is the projected launch year for TOLEDO.As of December last year Galapagos is currently committing over 110 R&D personnel to the TOLEDO project, including over 70 discovery scientists and over 40 chemists (out of about 250 total R&D employees).
The intent is to move as rapidly as possible to establish the preclinical science and to build out legal protection prior to revealing the identity of the TOLEDO target.GLPG envisions development of
the TOLEDO molecules is taking place in three waves.• Wave 1: will include initial Phase 1 dosing studies followed by small PoC trials.
• Wave 2: will include dose-finding and larger PoC studies that probably will trigger opt-in decisions from Gilead.
• Wave 3: will investigate TOLEDO in indications outside of inflammation. GLPG is currently working to better understand the science surrounding these molecules and their implications outside of inflammation.
The goal of developing multiple TOLEDO molecules is to leverage targeting of different combinations of TOL1, 2, and 3. Targeting different combinations will produce different safety/efficacy profiles that may provide distinct advantages in particular indications.
Phase 1 studies were completed in healthy volunteers with GLPG3312 and GLPG3970. Given the superior profile of GLPG3970, this asset will be prioritized. The start of several POC trials with GLPG3970 is expected in 2H20, with top-line results expected in 1H21.
GLPG3970 is a 2nd generation TOLEDO molecule that selectively inhibits TOL2 and TOL3 while sparing TOL1.
The company indicated that whilst it very much hopes that the ISABELA readout will be in 1Q21, given the COVID-19 driven slowdown seen at some sites, Galapagos wanted to build in a bit more time into its guidance. Encouragingly, sites in Asia are picking back up again as the region recovers from its initial outbreak. Regarding Toledo, the profile seen from the phase 1 data in ‘3970 was just “all around better” than '3312 and this it makes sense to take the former forward and discontinue the latter.
GLPG4399 is a selective TOL3 inhibitor with potential applications in RA and PsA. This is the only TOLEDO molecule thus far that has not demonstrated efficacy in IBD, presumably due to its lack of influence on IL-10 expression. Instead, GLPG will initially develop this molecule in RA.
‘4399 has demonstrated potential in joint models.
www.iex.nl/Forum/Upload/2020/12576727...GLPG intends to reveal 4th and 5th generation TOLEDO molecules in 2020.GLPG already filed a patent see:
www.freepatentsonline.com/WO201910588...The patent refers to a class of compounds that inhibit
salt-inducible kinases (SIK kinases) that could be used for the prophylaxis and/or treatment of inflammatory, autoinflammatory, autoimmune, proliferative, fibrotic and cartilage/bone related diseases associated with hypersecretion of TNFa, interferons, IL-6, IL-12 and/or IL-23. More specifically, the patent gives examples of SLE, CLE, lupus nephritis, dermatomyositis, Sjogren's, psoriasis, RA, PsA, MS, trisomy 21, UC and/or CD as hypersecretory diseases, but plenty of other disease examples are given.
Quite some list, with significant overlap with Filgotinib.SIKs are multifunctional proteins, widely expressed that are particular involved in cellular energy homeostasis with three isoforms (SIK1-3). SIKs have been noted to control the localisation and phosphorylation of a number of two key classes of transcriptional regulatory factors - histone deacetylases (HDACs) and cAMP-regulated transcriptional coactivators (CRTCs), which amongst other activities, also controls macrophage phenotype. One recent paper noted that small molecule SIK inhibition could mimic cAMP-induced signals in
IBD, osteoporosis and skin pigmentation;www.cell.com/trends/endocrinology-met...another noted their impact on pancreatic ß-cells
suggesting a role in diabetes and obesitywww.cell.com/trends/endocrinology-met... and another noted
a role in oncologywww.frontiersin.org/articles/10.3389/...Clearly, there is a wide ranging potential from this target (if indeed this is Toledo!)
Onno van de Stolpe;Toledo is really a once-in-a-lifetime opportunity. There are some academic articles about the mechanism, but pharma hasn’t really picked up on it.
We have invested massively in research over the past couple of years and the project is now ready to move into the clinic (we’ll start our first Phase II studies this year).
If Toledo is successful (and we’re all convinced that it will be),
it will work even better than current drugs like the JAK inhibitors or the TNFs. This is the biggest pharma market in the world, and we might have a new mechanism that turns everything upside down. That is so exhilarating.
Binnen Toledo, ons nieuwe programma in ontstekingsziekten, verwachten we nog steeds om meerdere proof-ofconcept-studies met GLPG3970 bij patiënten te starten in de tweede helft van dit jaar, met topline resultaten in de eerste helft van 2021.
In afwachting van de succesvolle start van deze studies zijn we van plan om voor het einde van dit jaar meer informatie te delen over het Toledo-programma, inclusief de target en meer preklinische gegevens.
Toledo development strategywww.iex.nl/Forum/Upload/2020/12511952...Onno promised that he will disclose a target this year, so that's a promise from Galapagos to all of the investors. So the mystery will be there for a couple of months...