Horizon still has a mountain to climb

But positive mid-stage Sjögren’s data raise hopes for others still plugging away at anti-CD40 assets.

The anti-CD40 ligand project dazodalibep might not have been the main driver behind Horizon’s $3bn purchase of Viela Bio. But the group has managed something the likes of Novartis failed to do, by getting a mid-stage win with this mechanism of action.

That win came in Sjögren’s syndrome, an autoimmune condition with no approved therapies that some on the sellside reckon could represent a $4bn market. Other CD40 hopefuls are also taking aim at the disease, so Horizon will have to make the most of its head start.

Sjögren’s hit

The phase 2 trial of dazodalibep enrolled two separate populations of Sjögren’s patients: those with moderate-to-high disease, based on ESSDAI score, and those with moderate-to-severe disease as per ESSPRI, another measure of disease activity.

The data yesterday came from the former group. Horizon said that, at week 24, dazodalibep-treated patients had a 6.3-point reduction in ESSDAI, compared with a 4.1-point reduction with placebo, which was statistically significant with a p value of 0.017.

The group added that numerical improvements were seen in various secondary endpoints, but the trial had not been powered to show statistical significance here.

Horizon did not give too many details on adverse events, but said the most common included Covid, diarrhoea and dizziness. Encouragingly, Stifel analysts wrote: “We note no incidence of thromboembolic events that have plagued earlier anti-CD40 programmes.”

Next up will be data from the ESSPRI-defined Sjögren’s patients, expected in the first half of next year. Horizon is already planning a phase 3 for 2023.

Dazodalibep recently returned positive results in another mid-stage study in rheumatoid arthritis; however, SVB analysts described these as only showing “moderate” efficacy.

Data are also expected soon from a trial in kidney transplant, but hopes are not high here following the failure of Novartis’s similarly acting project iscalimab last year (Novartis pushes on with iscalimab after transplant disappointment, September 6, 2021).

Long time

Work on projects targeting CD40 and its ligand has been going on for years, with little success; the likes of Abbvie, Boehringer and Astellas have all given up on such assets in the past couple of years. Novartis is still testing iscalimab for a raft of uses, including Sjögren’s, where results are due this year.

And there are plenty of others in the space. Some, like Eledon, reckon that targeting CD40 ligand, rather than the CD40 receptor, could provide better selectivity and efficacy. However, clinical efficacy data with that group’s contender, AT-1501, in ALS earlier this year were difficult to interpret.

Early next year, Eledon is set to report interim results in three more indications – but Sjögren’s is not one of them.

The disease, which involves the autoimmune destruction of patients’ saliva and tear glands, is thought to affect around 50,000 people in the US. SVB puts the market at $4bn, assuming pricing of $80,000 per year for any drug approved.

If dazodalibep succeeds this could go a long way towards justifying the price tag for Viela, which at the time looked steep.

Selected anti-CD40 & anti-CD40L projects in clinical development
Project Company Description Indication & trial details
Phase 3
Dapirolizumab pegol UCB/Biogen Anti-CD40L pegylated Fab SLE, Phoenycs Go
Phase 2
Dazodalibep (HZN-4920) Horizon Therapeutics (via Viela) Anti-CD40L-Tn3 fusion protein Positive topline results in RA May 2022 & Sjögren's Sep 2022; kidney transplant data due H2 2022, FSGS trial planned
Iscalimab (CFZ533) Novartis Anti-CD40 MAb Failed in kidney transplant Sep 2021; trials ongoing in Sjögren's; liver transplant; hidradenitis suppurativa; lupus nephritis; SLE, T1DM
Tegoprubart (AT-1501) Eledon Pharmaceuticals Anti-CD40L MAb ALS topline results reported May 2022; ph2 in IgAN & ph1/2 in kidney transplant & T1DM
SAR441344 Sanofi (via Immunext) Anti-CD40L MAb MS; Sjögren's; SLE
KPL-404 Kiniksa Pharmaceuticals Anti-CD40-CD154 interaction MAb RA
Phase 1
Letolizumab (BMS-986004) Bristol Myers Squibb Anti-CD40L MAb GvHD, academic trial
APB-A1 Lundbeck (via Aprilbio) Anti-CD40L MAb Healthy volunteer trial
FSGS=focal segmental glomerulosclerosis; IgAN=immunoglobulin A nephropathy; MS=multiple sclerosis; RA=rheumatoid arthritis; SLE=systemic lupus erythematosus; T1DM=type 1 diabetes mellitusSource: Evaluate Pharma & clinicaltrials.gov.

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