Ash 2022 preview – Novartis has Apellis in its sights

Iptacopan looks as good as Empaveli in PNH, with the added bonus of being oral.

Solo launches are always tricky for biotechs, and Apellis has had a tougher task than most. Its paroxysmal nocturnal haemoglobinuria therapy, Empaveli, is up against an entrenched big pharma, Astrazeneca.

Now Apellis looks set to get squeezed from the other side, with a new PNH contender on the horizon from Novartis. The Swiss group’s oral project, iptacopan, has bagged a prestigious Ash late-breaker slot, showing that there is excitement over this novel approach.

The bad news for Apellis is that iptacopan looks as good, if not better than Empaveli on a cross-trial basis. Furthermore, iptacopan, being a twice-daily pill, is more convenient than Empaveli, which is given via a twice-weekly, 30-minute subcutaneous infusion.


The data being presented at Ash come from the Apply-PNH study, which evaluated iptacopan versus standard of care, Astra’s Soliris or Ultomiris, in patients who still had anaemia despite previously receiving standard of care. This was defined in the study as haemoglobin levels of less than 10g/dl.

This makes Apply-PNH broadly analogous to Pegasus, the phase 3 trial of Empaveli in treatment-experienced patients.

Apply-PNH met its two co-primary endpoints, showing superiority to standard of care, as Novartis had already disclosed – and the Ash abstract gives the magnitude of the benefit. After 24 weeks 82% of ipatcopan-treated patients had at least a 2g/dl increase in haemoglobin levels, versus 2% with standard of care. And 69% and 2% of patients respectively had haemoglobin levels of 12g/dl or more.

It is on secondary endpoints that the cross-trial comparison against Empaveli can be made, and here iptacopan looks to have a slight edge, although the usual caveats about carrying out these kinds of analyses apply.

Cross-trial comparison of iptacopan vs Empaveli
  Apply-PNH Pegasus
Project Iptacopan Placebo Empaveli Placebo
Change from baseline in Hb (g/dl)* +3.59 -0.04 +2.37 -1.47
Transfusion avoidance 96% 26% 85% 15%
*Primary endpoint of Pegasus. Apply-PNH at 24 weeks, Pegasus at 16 weeks. Source: Ash 2022 & product label.

As for adverse events, one patient on iptacopan had a transient ischaemic attack, but this was considered unrelated to the drug. The abstract reveals nothing else remarkable, with headache and diarrhoea more common with iptacopan, and infections more common with Soliris/Ultomiris. Both have a black-box warning for infection.

First vs second line

Empaveli is approved in treatment-naive as well as experienced patients, although so far sales have mainly been driven by the latter. Apellis carried out a treatment-naive trial, Prince, and is trying to get those data added to Empaveli’s label, which could help a shift towards newly diagnosed patients. The FDA is due to make a decision by February 2023.

Novartis, which estimates that around 40% of PNH patients remain under the haemoglobin 10g/dl threshold despite current therapy, also hopes that iptacopan will become a first-line PNH therapy. The group is carrying out the single-arm Appoint-PNH trial in treatment-naive patients; results are expected by year-end.

Novartis is far from alone in the PNH space. Astra also has an oral contender, danicopan, and said in September that it had hit in the Alpha trial, evaluating the project as an add-on to Soliris or Ultomiris.

Danicopan does not feature in this year’s Ash but Astra’s earlier-stage oral project, vemircopan (ALXN2050), does. Vemircopan is also a factor D inhibitor, but looks to be more potent than danicopan.

Biocryst is another oral player, but its project BCX9930 went on partial clinical hold earlier this year following cases of elevated serum creatinine levels. Trials have since resumed, but with a reduced dose.

Marketed/late-stage projects for PNH
Project Company Description Status
Soliris Astrazeneca (via Alexion) IV anti-complement C5 MAb (every 2 wks) Approved for PNH & aHUS, REMS programme
Ultomiris Astrazeneca (via Alexion) IV anti-complement C5 MAb (every 8 wks) Approved for PNH, REMS programme
Empaveli Apellis/Sobi Subcutaneous complement C3 inhibitor (twice weekly) Approved for PNH, REMS programme
Phase 3
Iptacopan (LNP023) Novartis Oral complement factor B inhibitor Data at Ash 2022 from Apply-PNH (treatment-experienced); data from Appoint-PNH (treatment-naive) due 2022
Crovalimab (RG6107) Roche Subcutaneous complement C5 inhibitor Data at Ash 2022 from Commodore-3 China study; global Commodore-1 (treatment-experienced) & Commodore-2 (treatment-naive) complete 2025 & 2023 respectively 
Danicopan (ALXN2040) Astrazeneca Oral complement factor D inhibitor Claimed topline hit in Alpha, Soliris/Ultomiris add-on, Sep 2022
ABP 959 Amgen Soliris biosimilar Claimed topline hit in Dahlia Aug 2022
BCX9930 Biocryst Oral complement factor D inhibitor Redeem-1 (treatment-experienced) & Redeem-2 (treatment-naive), clinical hold lifted Aug 2022
Cemdisiran Alnylam Subcutaneous siRNA complement C5 inhibitor Pozelimab combo; Access-1 (treatment-naive) & Access-2 (treatment-experienced); ph2 data at Ash 2022
Pozelimab Regeneron Subcutaneous anti-complement C5 antibody Cemdisiran combo; see above
Source: Evaluate Pharma &

The Ash conference is due to take on December 10-13 in New Orleans, Louisiana.

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