etentamig intravenous (ABBV-383 IV)

P1, N=180, Recruiting, TeneoOne Inc. | N=120 --> 180 | Trial completion date: Jul 2026 --> Mar 2027 | Trial primary completion date: Jul 2026 --> Mar 2027

P1, N=8, Active, not recruiting, AbbVie | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

P1, N=55, Recruiting, AbbVie | Not yet recruiting --> Recruiting | Initiation date: Mar 2024 --> Jun 2024

P3, N=380, Recruiting, AbbVie | Not yet recruiting --> Recruiting

P1/2, N=76, Recruiting, AbbVie | Not yet recruiting --> Recruiting

P1/2, N=76, Not yet recruiting, AbbVie | Phase classification: P1 --> P1/2

P1, N=270, Recruiting, TeneoOne Inc. | Trial completion date: Nov 2028 --> Jul 2031

P1, N=55, Not yet recruiting, AbbVie

P3, N=380, Not yet recruiting, AbbVie

P1, N=76, Not yet recruiting, AbbVie

Overall, sBCMA impacted (reduced) the ‘free’ ABBV-383 (pharmacologically active component) PK exposures only, with pronounced effect at lower doses and the effect is consistent with understanding of treatment dependent sBCMA dynamics over time. Determination of both ‘total’ and ‘free’ ABBV-383 serum concentrations allowed to demonstrate such underlying impact of sBCMA on PK.

P1, N=120, Recruiting, TeneoOne Inc. | Phase classification: P1b --> P1 | N=80 --> 120

High avidity BCMA binding coupled to low affinity T-cell engagement distinguishes the resulting mechanism of action for ABBV-383 in MM. Here, we show that the presence of bivalent-BCMA reduced the negative impact of soluble BCMA, reduced inflammatory cytokine production, and dampened the emergence of TOX+ CD8+ T-cells indicating that ABBV-383 structure maximizes its clinical potential as a safe and effective MM therapy.

At 40 mg and 60 mg, ABBV-383 monotherapy yielded deep and durable responses with mPFS of 13.7 mo and 11.2 mo, and 12-month DOR of 70% and 66% (mDOR NR in pts with ≥CR), respectively. These results in heavily pretreated RRMM pts support further clinical evaluation.

This activity is supported by educational grants from AbbVie Inc, Genentech, a member of the Roche Group, Genmab US Inc, Karyopharm Therapeutics, Lilly, Regeneron Pharmaceuticals Inc, Sanofi, and Seagen Inc. Clinical and biological factors affecting the selection of up-front therapy for patients with MMLong-term findings with daratumumab-containing regimens for newly diagnosed MM; role for transplant-eligible and ineligible patientsPublished data with novel daratumumab-based quadruplet regimens for transplant-eligible patients with newly diagnosed MMSimilarities and differences between daratumumab and isatuximabKey findings from the Phase III GMMG HD7 trial comparing isatuximab with RVd to RVd alone for transplant-eligible patients with newly diagnosed MMOngoing Phase III studies of isatuximab as a part of induction therapy for transplant-eligible and ineligible patientsAvailable data with and current role of minimal residual disease assessment in therapeutic decision-makingOptimal maintenance approach for transplant-eligible and ineligible patientsResults from Phase III trials evaluating isatuximab-based combination regimens for relapsed/refractory (R/R) MMKey results from the Phase III BOSTON trial leading to the FDA approval of selinexor in combination with bortezomib/dexamethasone for R/R MM; available data with other selinexor-based combinationsStructural makeup and manufacturing of available B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell platformsEfficacy and safety findings from the KarMMa (idecabtagene vicleucel) and CARTITUDE-1 (ciltacabtagene autoleucel) trials for R/R MMAvailable and emerging data with and ongoing studies of BCMA-targeted CAR T-cell therapies in earlier lines of treatmentSimilarities and differences in the cellular targets and mechanisms of action of bispecific antibodies in MMActivity and responses observed with available (teclistamab) and investigational (elranatamab, linvoseltamab, ABBV-383) BCMA-targeted bispecific antibodies in R/R MMBiological rationale for and available data with non-BCMA-targeted bispecific antibodies (eg, talquetamab, cevostamab, forimtamig); FDA breakthrough therapy designation for talquetamabSpectrum, incidence and severity of toxicities, including cytokine release syndrome and neurotoxicity, with bispecific antibodies in patients with MM; mitigation and management protocolsPublished data with and current role of venetoclax-based therapy for patients with MM and t(11;14) or Bcl-2 overexpressionOther promising novel strategies in clinical development for patients with MM

Aims: This open-label, multi-center, Phase 1b, dose-escalation and expansion study (NCT05259839) will evaluate the safety profile, tolerability, preliminary efficacy, pharmacokinetics and recommend Phase 2 dose of ABBV-383 in combination with pomalidomide-dexamethasone (Pd), lenalidomide-dexamethasone (Rd), daratumumab- dexamethasone (Dd) or nirogacestat (Niro) in patients with RRMM. Efficacy endpoints include ORR, PFS, DOR, time to progression and minimal residual disease negativity. Summary/

Despite promising efficacy in MM, BsAbs may come with substantial infection risk, warranting more detailed analysis of infections and immune phenotyping to guide targeted supportive care. Table – Summary of included studiesAgent Target Source Phase Enrolment (mm/yy) N Median prior lines All- Grade Infection N (%) Grade ≥3 Infection N (%) Alnuctamab (CC-93269) BCMA Wong 2022 I 03/18- 68 4 23 (34) 6 (9) ABBV-383 BCMA Voorhees 2022 I 10/22- 174 5 61/124 (50) 39/124 (22) Elranatamab BCMA Raje 2022 I 10/21- 123 5 82 (67) 43 (35) Linvoseltamab (REGN545) BCMA Bumma 2022 Ib/II 1/19- 252 5 136 (54) 73 (29) Pacanalotamab (AMG-420) BCMA Topp 2020 I 3/19 – 4/22 42 5 14 (33) 10 (24) Teclistamab BCMA Moreau 2022 I/II 09/20- 165 5 126 (77) 57 (45) Teclistamab + daratumumab BCMA + CD38 Rodriguez- Otero 2022 II 03/21- 46 5 29 (63) 8 (17) Forimtamig (RG6234) GPRC5D Carlo- Stella 2022 I 11/20- IV: 51 SC: 57 IV: 5 SC: 4 IV: 31 (61) SC: 26 (46) IV:11 (22) SC:15 (27) Talquetamab GPRC5D Chari 2022 I/II 02/21- 288 5 153 (53) 46 (16) Talquetamab + daratumumab GPRC5D + CD38 Van de Donk 2022 II 09/21- 46 5 23 (50) 6 (13) Cevostamab (BFCR4350A) FcRH5 Trudel 2021 I 07/21- 161 6 68 (43) 18 (11) Bispecific, Multiple myeloma, Cellular therapy

ABBV-383 monotherapy is associated with a manageable safety profile at doses of 40 and 60mg, with low incidence of TEAEs leading to discontinuation. CRS was predictable and resolved quickly with standard supportive care. Promising efficacy of ABBV-383 monotherapy was observed, with similar ORR in 40 (58%) and 60mg (61%) cohorts.