Bispecifics move beyond cancer

Hitting two targets with one molecule is all the rage in oncology, but Roche and others have taken this work into other disease areas.

Bispecific antibodies are continuing to attract deal interest, as two transactions this week showed. Oncology steals much of the limelight falling on such novel biological formats, but important progress is being made elsewhere too.

Two days ago Roche revealed that at least some of its future growth would be down to two novel dual-acting biologicals in non-cancer uses: Vabysmo in wet age-related macular degeneration and NXT007 in haemophilia. Evaluate Pharma reveals several other clinical-stage bispecifics outside oncology, including assets from Novo Nordisk, Moonlake and Provention Bio.

In wet AMD Roche’s recently launched Vabysmo, which targets VEGF and Ang-2, is taking market share from Regeneron’s Eylea, while in haemophilia A the Swiss group is taking forward NXT700, a Chugai-originated bispecific against factors IXa and X. The latter is a follow-on to the hugely successful Hemlibra, and the aim is for it to have higher potency, and possibly less frequent dosing.

Perhaps unsurprisingly, Roche is not the only company pursuing this mechanism: Novo Nordisk has Mim8 in phase 3, while Takeda inherited a Novimmune-originated preclinical anti-factor IXa/X, NIBX-2101, through its 2018 acquisition of Shire. However, NIBX-2101 does not yet appear to have been taken into clinical trials.

Structural approaches

Similarly to the oncology space the bispecifics in development here comprise a range of structural approaches, including full MAb formats, fusion proteins, Darts, MAb fragments like nanobodies and minibodies, and others.

This is well illustrated in lupus, where Astrazeneca/Amgen and Lilly have assets hitting the B cell survival protein BAFF. The former’s rozibafusp alfa combines an anti-BAFF MAb with a peptide against the co-stimulatory ligand ICOSL, while the latter’s tibulizumab is a tetravalent bispecific MAb that also hits IL-17, though it no longer appears in Lilly’s pipeline.

Among small players Provention Bio is also active in lupus with a bispecific Dart molecule, PRV-3279. Meanwhile, last year Merck KGaA sold to Moonlake Immunotherapies rights to sonelokimab, a nanobody it had studied in psoriasis, but which the licensee has taken forward in hidradenitis suppurativa.

Merck KGaA’s interest in sonelokimab stemmed from a deal with Ablynx, a Belgian company sold to Sanofi in 2018. It is largely through Ablynx, which was working on numerous camel-derived nanobodies, that Sanofi has a presence in bispecifics outside oncology, though vobarilizumab and ALX-0141 appear not to be in active clinical development.

Another Ablynx-derived asset, ozoralizumab, an anti-TNFα x human serum albumin nanobody, was licensed to Taisho, and last month was approved in Japan for rheumatoid arthritis as Nanozora.

Clinical-stage bispecific approaches excluding oncology
Project Company Pharmacology Status
Mim8 Novo Nordisk Anti-factor IXa & X bispecific MAb Ph3 in haemophilia A with/without inhibitors
NXT007 Roche/ Chugai Anti-factor IXa & X bispecific MAb Ph2 (Japan) for harmophilia A
Rozibafusp alfa (AMG 570) Amgen/ Astrazeneca Anti-BAFF x ICOSL MAb/peptide conjugate Ph2 for lupus
PRV-3279 Provention Bio Anti-CD32B x CD79B Dart Ph2 for lupus
Sonelokimab (M1095) Moonlake Immunotherapeutics (ex Merck KGaA) Anti IL-17A x IL-17F nanobody Ph2 for hidradenitis suppurativa
ALXN1820 Astrazeneca Anti-properdin bispecific minobody Ph2 for sickle cell disease
Fazpilodemab (RG7992/BFKB8488A) Roche Anti-FGFR1 x coreceptor β klotho MAb Ph2 for Nash
MEDI7352 Astrazeneca Anti-NGF x TNFR2 bispecific fusion protein Ph2 for osteoarthritis of the knee
Vobarilizumab Sanofi (ex Ablynx) Anti-IL-6R x HSA nanobody Mixed ph2 data in rheumatoid arthritis (Abbvie deal terminated)
SAR442999 Sanofi Anti-TNFα x IL-23 nanobody Ph1 for inflammatory/skin diseases
RG6120 Roche Anti-VEGF x Ang-2 dutaFab Ph1 for wet AMD (designed for port delivery system)
ALX-0141 Sanofi (ex Ablynx) Anti-RANKL x HSA nanobody Ph1 completed in postmenopausal women
Tibulizumab (LY3090106) Lilly Anti-BAFF x IL-17 bispecific MAb Various ph1 autoimmune trials completed
Note: HSA=human serum albumin; Source: Evaluate Pharma & clinicaltrials.gov.

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