Looking for winners in geographic atrophy

NGM’s NGM621 now looks like a dead end, but there are plenty of others hoping for a piece of this market, including Roche and Lineage.

After a couple of recent successes in geographic atrophy, investors were reminded last week that the eye disease is still a tough nut to crack, with the failure of NGM Biopharmaceuticals’ NGM621. Like Apellis’s pegcetacoplan, NGM621 targets complement C3, raising the question of why the former worked – to an extent – while the latter did not.

A look at the geographic atrophy pipeline shows that many players are pinning their hopes on hitting the complement cascade. However, there are also some different mechanisms in development, and Roche – which has had its own setbacks in the disorder – stands out with several shots here. However, one of these, the mid-stage project galegenimab, recently fell by the wayside.

Another of Roche’s bets, the cell therapy known as OpRegen, comes courtesy of a $50m deal last year with Lineage Cell Therapeutics. Despite the dismal track record of other stem cell projects, Lineage’s chief executive officer, Brian Culley, insists that this time it is different.

He admits that undifferentiated stem cells have not been effective. But he tells Evaluate Vantage that what is new is that Lineage – and a couple of other groups – are using differentiated retinal pigment epithelium cells, “which are integral to the function of vision”.

Mr Culley points to early data suggesting that OpRegen could improve vision: the project has shown an average 7.6-letter gain in BCVA among 12 patients in a phase 1/2 trial. This is something that the likes of Apellis and, more recently, Iveric, have been unable to do with their complement inhibitors.

Still, OpRegen has a long way to go. Roche is now responsible for development, and although it dedicated a slide to the project at a recent R&D day it has not yet detailed its phase 2 plans.

This does not mean a lack of enthusiasm on the big pharma’s part, Mr Culley says. “They appear to be very committed to this programme and investing a lot of resources in getting ready for the next study.” However, he admits: “It's very frustrating as the licensor that I'm not able to talk about what [Roche’s] plans are – but when it does go public, I'll be shouting it from the rooftops.”

Backhanded complement

As for the promise of complement inhibition, he says: “I think it's pretty clear that there's a benefit there. It's just so small.”

He sees the upcoming approval decision Apellis’s pegcetacoplan as a win for Lineage either way. “If the FDA does approve based on an anatomical change I'm going to be the happiest person in the world, because the anatomical change that we have is so much larger.

“But if they do not, I'm still very happy because it says that all the complement inhibitors need to move to the side because they do not have an effect on function. And that's not going to change if you're tickling the pathway in a different place.”

NGM’s NGM621, like pegcetacoplan, targets C3, so it is unclear why this failed when Apellis’s project succeeded – at least in one of its phase 3 trials.

Wells Fargo analysts noted that NGM621 only blocks C3 and not C3b convertase, while pegcetacoplan inhibits both, and suggested that the latter might also be responsible for GA pathology.

Whatever the reason, there now looks to be one less contender in the pipeline, although NGM still appears to see some hope for NGM621. And, despite the discontinuation of Roche's galegenimab during that group's third-quarter results last week, the pipeline still looks fairly crowded.

Cell therapy rivals

A couple of other companies are also testing retinal pigment epithelium cells, including Regenerative Patch Technologies. That group found an improvement in BCVA in a phase 1/2 trial of its implant, known as CPCB-RPE1 – data that Lineage’s Mr Culley describes as “encouraging”.

Meanwhile, Astellas gained ASP7317 through its 2015 purchase of Ocata, but development has not been smooth; the Japanese group put a phase 1 trial on hold last year owing to manufacturing changes, but recently restarted enrolment.

Other interesting approaches include gene therapy, with Novartis active here through last year’s purchase of Gyroscope. Johnson & Johnson also has a gene therapy project that it bought from Hemera in 2020. It recently reported phase 1 data at the American Academy of Ophthalmology conference, concluding that the asset warranted further investigation, although J&J does not appear to have started phase 2 yet.

Selected projects in development for geographic atrophy pipeline
Project Company Description Trial details/note
Intravitreal pegcetacoplan Apellis Pharmaceuticals Complement factor C3 inhibitor Pdufa date Nov 26, 2022
Phase 3
Zimura Iveric bio Complement factor C5 inhibitor Pivotal Gather2 trial hit Sep 2022; filing planned Q1 2023
ALK-001 Alkeus Pharmaceuticals Modified form of vitamin A Saga completes Aug 2023 (from Dec 2021)
Phase 2
ANX007 Annexon Bioscience Anti-complement factor C1q antibody Archer initial data due H1 2023
PPY988 (GT005) Novartis (via Gyroscope) Complement factor I gene therapy Explore & Horizon complete Feb 2023 & Oct 2024
IONIS-FB-LRX (RG6299) Ionis/Roche Complement factor B antisense Golden completes Jan 2024 (from Oct 2022)
Danicopan (ALXN2040) Astrazeneca Complement factor D inhibitor NCT05019521 completes May 2024
Elamipretide  Stealth Biotherapeutics Mitochondria targeted therapy Reclaim-2 failed May 2022, development continues
NGM621 NGM Biopharmaceuticals* Anti-complement factor C3 antibody Catalina failed Oct 2022, next steps unclear
Galegenimab (RG6147) Roche Anti-HtrA1 antibody-binding fragment Removed from Roche's pipeline Oct 2022
Phase 1/2
CPCB-RPE1 Regenerative Patch Technologies Retinal pigment epithelial cell therapy NCT02590692 data reported
RG6501 (OpRegen) Lineage Cell Therapeutics/Roche Retinal pigment epithelial cell therapy NCT02286089 data reported
VOY-101 Perceive Biotherapeutics Unclear NCT05380492 completes Oct 2025
Phase 1
JNJ-1887 (formerly HMR59/AAVCAGsCD59) Johnson & Johnson (via Hemera) CD59 gene therapy NCT03144999 data reported
ONL1204  ONL Therapeutics Fatty acid synthase inhibitor NCT04744662 completes Dec 2022
RG6312 (RO7303359) Roche Unclear NCT04615325 completes Jan 2023
ASP7317 Astellas Pharma Retinal pigment epithelial cell therapy NCT03178149 completes Aug 2024
BI 754132 Boehringer Ingelheim Unclear NCT04002310 terminated, risk/benefit balance cited
*Merck & Co has option. Source: Evaluate Pharma & clinicaltrials.gov.

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