Gilead’s expansion plans get a kick in the gut

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Gilead’s success in viral diseases is incontrovertible, but it has not done so well in expanding into new indications. These efforts took another blow with the halt of a late-stage study of its matrix metalloproteinase (MMP) 9 inhibitor GS-5745 in ulcerative colitis on lack of efficacy.

True, the company still has a phase III trial ongoing with GS-5745 in gastric cancer, but the failure of various other MMP-targeting projects in oncology means this was always a long shot. Gilead’s non-viral pipeline looks increasingly uninspiring, which will only strengthen calls for it to do a deal (see table below).

At least Gilead still has its ageing hepatitis C franchise and its HIV drugs, with the latter the key to driving growth in the future (How Gilead could go back to basics, September 07, 2016). The UK-based biotech Abzena is not so lucky. GS-5745 is the most advanced candidate to include the group’s composite human antibody technology, and has been described as “an important aspect of the Abzena investment case” by Edison analysts.

Abzena’s shares fell 9% on the news while Gilead was largely unmoved, likely thanks to low expectations for GS-5745.

Souring sentiment

Despite muted hopes for GS-5745, though, the development is yet another blow to sentiment about Gilead’s R&D prospects. Outside HIV its pipeline is decidedly anaemic – and issues with its first cancer drug, Zydelig, will not have done anything to make investors confident of success beyond its core franchises.

Gilead’s late-stage non-viral pipeline
Project Mechanism Indications Status 2022e sales ($m)
Filgotinib Jak-1 inhibitor Rheumatoid arthritis, Crohn’s, ulcerative colitis Phase III 441
GS-5745 MMP9 MAb inhibitor Ulcerative colitis, gastric cancer Phase III 200
Eleclazine Sodium channel blocker Arrhythmia, cardiomyopathy Phase III 184
Momelotinib Jak-1/2 inhibitor Myelofibrosis, pancreatic cancer Phase III 95
Entospletinib Spleen tyrosine kinase inhibitor Haematological cancers Phase II -
GS-4997 ASK-1 inhibitor NASH, pulmonary hypertension, diabetic nephropathy Phase II -
GS-9674 Farnesoid X receptor agonist NASH Phase II -
Px-102 Farnesoid X receptor agonist NASH Phase II -
Simtuzumab LOXL2 MAb NASH, sclerosing cholangitis Phase II -
Source: Company website, EvaluatePharma.

The signs do not bode well for GS-5745. Four other MMP inhibitors have been abandoned in phase III, according to EvaluatePharma; three had been in development in cancer.

MMPs are a diverse group of enzymes responsible for processing a number of extracellular molecules, and are thought to play a role in various cell processes including cell proliferation and apoptosis. They have been implicated in a wide range of diseases, but in total over 50 MMP inhibitors have failed in a variety of indications for a variety of reasons, according to Leerink analysts.

And now GS-5745 seems likely to join them. The decision to halt the ulcerative colitis trial stemmed from a planned interim analysis after the first 150 of 1,600 patients had been treated for eight weeks. There were no safety concerns, according to the company.

While drug development always carries a risk of failure, Gilead now looks rash in its decision to plough forward into so many trials of GS-5745 on the basis of results from small phase I studies. The Leerink analysts pointed out that while phase I data were promising there were reasons for caution: in cancer they questioned the strength of the progression-free survival signal; and in ulcerative colitis they noted a decline in response at the highest dose, things that might have warranted further investigation.

If Gilead’s haste is indicative of a desperation to restock its late-stage pipeline, investors might have cause to worry. GS-5745 and MMP inhibition in general is beginning to look like a blind alley. With other areas of investment also on uncertain ground – NASH springs to mind – a bold move from Gilead is surely only a matter of time.

Study Trial ID Primary completion
Phase II/III in ulcerative colitis NCT02520284 Terminated
Phase III in gastric cancer NCT02545504     Jan 2019
Phase II in Crohn’s NCT02405442 Oct 2016
Phase II in rheumatoid arthritis NCT02862574 March 2018
Phase II in gastric cancer in combo with Opdivo NCT02864381 Sep 2018
Phase II in cystic fibrosis NCT02759562 Dec 2018

To contact the writer of this story email Madeleine Armstrong in London at madeleinea@epvantage.com or follow @medtech_ma on Twitter

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