The generous licensing deal between Hanmi and Lilly for the Korean company’s phase I BTK inhibitor reveals the scarcity in this class – $50m up front was required to corner HM71224, one of only four clinical-stage projects to remain in small companies' hands (see table below).
The ultimate potential seen in this mechanism was of course amply demonstrated by AbbVie’s $21bn move on Pharmacyclics, but despite Imbruvica’s successes in recent years no other BTK has really made much clinical progress. This has seemingly left the path clear for follow-on compounds and, interestingly for the other independent developers in this space, Lilly does not seem to be focused on chasing Imbruvica into oncology.
In a press release Lilly chose to emphasise HM71224’s potential in autoimmune diseases, although the licensing deal does not preclude work in other areas. The project is ready to enter phase II, and the parties plan to investigate RA, lupus, lupus nephritis, Sjögren's syndrome and other related conditions, they said.
The role of BTK makes a case for investigation in these fields. Bruton’s tyrosine kinase plays a role in B-cell development, and mutations in the gene that code for the protein are implicated in immunodeficiency disease. BTK is also thought to play a role in activation of mast cells; these have various roles in the immune system and have been linked to the pathology of autoimmune joint disorders.
|BTKs in the pipeline|
|Phase II||CC-292 (spebrutinib)||Celgene||Avila Therapeutics||NCT01975610|
|ACP-196||Acerta Pharma||Merck & Co||NCT02387762|
|Phase I||ONO-4059/ GS-4059||Gilead Sciences/Ono Pharmaceutical||Ono Pharmaceutical|
|MSC 2364447||Merck KGaA||Merck KGaA|
|HM71224||Eli Lilly||Hanmi Pharmaceutical|
|PRN1008||Principia Biopharma||Principia Biopharma|
|Preclinical||BTK Inhibitor Program||ArQule||ArQule|
|SNS-062||Sunesis Pharmaceuticals||Biogen Idec|
|BTK Inhibitor Program||Carna Biosciences||Carna Biosciences|
|Bruton's Tyrosine Kinase Inhibitor Program||Pharmascience||Pharmascience|
|BTK Inhibitor Program||CrystalGenomics||CrystalGenomics|
|BTK Inhibitor Program||Principia Biopharma||Principia Biopharma|
|MKC4659||Tolero Pharmaceuticals||Tolero Pharmaceuticals|
This has not escaped others working in this field.
Acerta Pharma has listed a 70-patient RA study for its candidate, ACP-196, on clinicaltrials.gov, although this does not appear to be recruiting patients yet. Most of the company’s attention is directed at blood cancers, moving the asset directly into Imbruvica territory, although interestingly the clinical trial registry indicates that it is also planning studies in bladder and pancreatic cancers.
ACP-196 appears to be the most heavily investigated BTK inhibitor outside ibrutinib, though very little is known about either the compound or the company. It certainly has pedigree, having been founded in 2013 by Ahmed Hamdy, the ex-chief medical officer of Pharmacyclics. And ACP-196 was licensed from Merck & Co, possibly sometime in 2014.
Celgene is also testing CC-292 in an 80-patient RA study, with data due next year, although again the company has said little about its progress with this candidate since it was bought in 2012, via the takeover of Avila. Its main focus has been cancer indications.
However, work elsewhere is very early and could feasibly veer in either direction. Gilead, for example, has yet to reveal its plans for ONO-4059, a project it has now dubbed GS-4059, and to which it licensed rights from Ono Pharmaceuticals last December; terms were not disclosed.
For Lilly, autoimmune conditions make much more sense than oncology, given the focus of the group's R&D efforts. It recently started an extensive pivotal programme of baricitinib; the Jak inhibitors represent the first class of kinase inhibitor that were thought likely to capture the significant potential of an oral RA therapy, but they have yet to really prove themselves (Therapeutic focus – Jaks still need to prove worth in rheumatoid arthritis, December 12, 2014).
Of course AbbVie, another dominant player in the autoimmune space, is also well aware of this opportunity and is likely to decide this year whether to throw its hat into the Jak ring, with a decision pending on the Galapagos candidate GLPG0634 (Event – Galapagos looks to AbbVie to secure its evolution, February 18, 2015). It is also investigating other mechanisms for Humira follow-ons, and the potential to move Imbruvica into autoimmune indications cannot have escaped its notice, although this was not highlighted at the time of the Pharmacyclics move.
Either way, for the independent companies left with BTK inhibitors, it is clear that big pharma is interested in this space. And adding another avenue for clinical investigation should only mean more to talk about around the negotiating table.