AML Pipeline After the ORM-6151 and BL-M11D1 Exits: CD33 and CD123 Programs to Watch

Scope

Bristol Myers Squibb has discontinued BMS-986497/ORM-6151, a Phase 1 acute myeloid leukemia (AML) treatment candidate it acquired from Orum Therapeutics in November 2023 for $100 million upfront and up to an additional $80 million in milestones, after reviewing the Phase 1 clinical data.^[1][2] The ClinicalTrials.gov record for the study (NCT06419634) was updated on October 1, 2026 and lists the reason for termination as inability to meet protocol objectives.^[3]

Separately, the Phase 1 trial of SystImmune's BL-M11D1, the only new CD33 directed ADC with an open AML trial (now limited to the China study, NCT05924750), was terminated with a stated completion date of September 16, 2026. The registry gives sponsor prioritization of other development portfolio as the reason and does not cite safety or efficacy.^{[4][5][6][7][8]}

Executive summary

BMS's discontinuation of BMS-986497/ORM-6151 and the termination of the BL-M11D1 trial end one program and one trial within days of each other, in mid September 2026.^[1][4] Neither event is evidence that CD33 targeting, GSPT1 degradation, or antibody enabled payload delivery has failed as an approach. BMS has not disclosed the underlying Phase 1 data beyond the reason recorded on ClinicalTrials.gov, and no results are posted on the registry; the BL-M11D1 study's own record gives sponsor prioritization of other development portfolio as the reason and does not cite safety or efficacy.^[1][3][4]

The more relevant question for companies developing AML treatments is whether either event changes their competitive position. For some, one fewer active program may reduce crowding in a narrowly defined target or technology space. For others, it may raise the evidence needed to show clinical differentiation, a workable development pathway, or partnering relevance. The answer depends on target, modality, patient setting, development stage, and the data each company can show.

This paper reviews the active programs most relevant to that reassessment: ORM-1153 (Orum Therapeutics), a CD123 directed GSPT1 degrader antibody conjugate, first patient dosed October 14, 2026; mipletamig/APVO436 (Aptevo Therapeutics), a CD123 x CD3 bispecific with venetoclax and azacitidine; pivekimab sunirine (AbbVie), the CD123 conjugate approved in BPDCN, now in a Phase 2/3 AML trial; TRIO-863 (TRIO Pharmaceuticals), a preclinical CD33 x TRAIL-R2 bispecific; early CD33/CD123 dual target T-cell engager programs; and gemtuzumab ozogamicin (Pfizer), the approved CD33 benchmark.^{[9][10][11][12][13][14][15]} It also places the BMS exit within a broader late August and September 2026 period of pharma portfolio changes, distinguishing efficacy failures, futility calls, safety pauses and strategic discontinuations from one another.

Why a pharma exit can change the competitive question

Late August and September 2026 produced several visible pharma portfolio events across different therapy areas and development stages, and their common relevance is commercial rather than scientific. These events are not scientifically comparable: some reflect missed efficacy endpoints, some a futility decision, some a safety driven trial pause, and others a strategic discontinuation.^{[1][17][18][19][20][21][22][23]}

Once a significant program stops, companies still active around the same disease area, target, modality or treatment setting need to reassess whether the event changes competitive intensity, the clinical evidence required for differentiation, investor attention, or prospective partner appetite.

Note. This is a curated context scan based on public reporting, not an assertion of an exhaustive global census of all pipeline changes. The table excludes smaller company events and regulatory enrollment pauses that are not confirmed portfolio exits. Pfizer's transfer of discontinued Seagen originated PF-08046031 to Medicus Pharma is an asset recycling transaction rather than a new termination and is not included.

The BMS event belongs in this wider category of portfolio triggers, but its implications must be assessed within its own AML context. Unlike pelacarsen, ziltivekimab or rap-cel, BMS-986497 was an early clinical oncology program for which BMS has disclosed only a general reason, not the underlying data.^[1][3] The next question is which active AML assets need to be reassessed now that two visible programs have left the field within days of each other.

The AML question created by the BMS and BL-M11D1 exits

Neither event establishes a verdict on CD33, GSPT1 or conjugate based delivery; together they create a narrower competitive question about which active AML programs remain relevant because they pursue one or more elements of the same clinical and commercial opportunity through a different target, payload, modality or treatment setting.

BMS-986497/ORM-6151 was a Phase 1 CD33 directed degrader antibody conjugate being developed for relapsed or refractory AML or MDS.^[1][3] Its discontinuation removes a visible program at the intersection of CD33 targeting, antibody enabled payload delivery and GSPT1 degradation. It is also BMS's second GSPT1 exit in AML: the company's earlier small molecule GSPT1 degrader CC-90009 (eragidomide, developed by Celgene) had its study NCT02848001 terminated because of lack of efficacy in the short term acute phase, although a degrader antibody conjugate is a different delivery approach from an oral degrader.^[16]

That opportunity sits within a treatment landscape in which venetoclax plus azacitidine is the frontline backbone for patients unfit for intensive chemotherapy, menin inhibitors are approved in relapsed or refractory disease (revumenib for KMT2A translocated acute leukemia since November 15, 2024, and ziftomenib for NPM1 mutated AML since November 13, 2025), and FLT3 and IDH targeted therapies are used in mutation defined disease.^[12][25][26]

The table below compares the programs discussed in this paper on target, modality, stage and latest public status.

BL-M11D1 (SystImmune Inc.): a terminated trial, not necessarily a closed program

BL-M11D1 (SystImmune Inc.) was, until mid September 2026, the only new CD33 directed ADC with an open AML trial (now limited to the China study, NCT05924750), testing whether a new CD33 directed payload delivery construct could show a credible therapeutic profile in relapsed or refractory AML.^{[4][5][6][7][8]} Like BMS-986497/ORM-6151, it uses CD33 as the targeting anchor. Unlike BMS-986497/ORM-6151, it is an antibody drug conjugate carrying a topoisomerase I inhibitor payload on a stable, enzyme cleavable linker, rather than a GSPT1 degrader.^[27]

The Phase 1 study registered as NCT06714591 has been terminated: ClinicalTrials.gov lists a completion date of September 16, 2026, gives sponsor prioritization of other development portfolio as the reason, not a safety or efficacy finding, and recorded 52 participants.^[4] A separate, earlier registered BL-M11D1 study (NCT05924750) is sponsored by Sichuan Baili Pharmaceutical, part of SystImmune's Chinese parent group, at eight sites in China. Only one of those sites is recruiting; the other seven are not yet recruiting, and the record was last verified in September 2025, past the registry's 12 month verification interval.^[5]

The practical implication is narrower than "the program has ended." A single trial's termination for portfolio reasons does not establish that SystImmune's broader BL-M11D1 development, or the CD33 payload delivery approach generally, has been discontinued. What it removes, for now, is the clearest public source of new Phase 1 safety and efficacy data on this specific construct. Companies tracking this space should confirm current status directly with SystImmune, or through any new trial registration, rather than assume the asset remains in active clinical development.

Any financing or partnering move by SystImmune Inc. would also shape whether the program becomes more actionable for external innovation teams.

ORM-1153 (Orum Therapeutics): CD123 targeted GSPT1 degradation

ORM-1153 (Orum Therapeutics) is a CD123 directed degrader antibody conjugate designed to deliver a GSPT1 degrading payload into CD123 expressing hematologic cancer cells, and its first patient was dosed on October 14, 2026, as reported by RTTNews.^[9][32] The FDA cleared its IND on August 22, 2026.^[32] The Phase 1 study is registered as NCT07809906 under the official title "Phase 1 First-in-Human Multi-Region Clinical Trial of ORM-1153 in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML) or Other Hematological Malignancies With CD123 Expression"; the registry still lists the study as not yet recruiting, with the record last updated on September 9, 2026.^[28]

ORM-1153 tests a more specific alternative to BMS-986497/ORM-6151 rather than replacing it: whether substituting CD123 for CD33 can support a clinically workable target delivery context for GSPT1 degradation. The first study will be informative for its patient selection approach, dosing schedule, pharmacokinetic and pharmacodynamic plan, and early safety profile. Evidence of intracellular target engagement and a practical therapeutic window will be as important as early responses for determining its strategic relevance.

Mipletamig / APVO436 (Aptevo Therapeutics): CD123 immune engagement

Mipletamig/APVO436 (Aptevo Therapeutics) is a CD123 x CD3 bispecific antibody being evaluated in the RAINIER Phase 1b/2 study with venetoclax and azacitidine in newly diagnosed AML patients who are not candidates for intensive chemotherapy.^[10][33] It does not use a conjugated payload or targeted protein degradation, and it is tested in the frontline setting, while BMS-986497 was tested in relapsed or refractory disease.^[3][10] Aptevo's second quarter 2026 business update, issued August 14, 2026, reported an 87 percent clinical benefit rate and an 81 percent complete or incomplete remission rate across 31 evaluable unfit frontline patients, including four from the completed dose expansion trial, with dose optimization expected to finish by year end 2026.^[10] A release of September 3, 2026 reported, in 14 evaluable TP53 mutated patients, a 93 percent clinical benefit rate (13 of 14) and a 79 percent complete or incomplete remission rate (11 of 14), with a Phase 2 regulatory interaction planned for the first half of 2027.^[29]

It belongs in this landscape because it provides a separate clinical route for using CD123 to direct treatment toward AML cells. The key issue is whether CD123 x CD3 engagement can be added to a venetoclax and azacitidine backbone with manageable cytokine release, cytopenia, infection and administration burdens, while producing a response signal strong enough to justify continued development. Its relevance is as a CD123 development readout, not a direct technical comparator to BMS-986497/ORM-6151 or BL-M11D1.

Pivekimab sunirine (AbbVie): the approved CD123 benchmark

Pivekimab sunirine (AbbVie) is the approved CD123 benchmark against which ORM-1153 and mipletamig will be judged. It is a CD123 directed antibody and alkylating agent conjugate that the FDA approved as Decnupaz on May 27, 2026 for adults with blastic plasmacytoid dendritic cell neoplasm (BPDCN), with a boxed warning for hepatotoxicity including veno occlusive disease.^[11]

In AML it is being tested in the same frontline setting as mipletamig: NCT07581002 is a randomized Phase 2/3 study of pivekimab sunirine plus venetoclax and azacitidine versus placebo plus venetoclax and azacitidine in newly diagnosed AML patients ineligible for intensive chemotherapy, recruiting about 660 participants.^[12] Its relevance here is twofold: it shows that a CD123 directed conjugate can reach approval, and its hepatotoxicity labeling sets the safety reference point that any new CD123 directed conjugate, including the GSPT1 degrader ORM-1153, will be compared against.^[11]

TRIO-863 (TRIO Pharmaceuticals): a non conjugate CD33 apoptosis strategy

TRIO-863 (TRIO Pharmaceuticals) is a preclinical CD33 x TRAIL-R2 bispecific antibody designed to bind CD33 and restrict TRAIL-R2 mediated apoptotic signaling to CD33 positive leukemia cells.^[34] In abstracts presented at AACR meetings in April and July 2026, TRIO reported that TRIO-863 "showed potent CD33-dependent killing of AML cells including high risk TP53-mutant and drug-resistant models, with over 3700-fold greater potency than Mylotarg" and that it "synergized with HMA/Ven"; ex vivo studies in primary human liver microtissues showed no liver toxicity, in contrast to monospecific anti TRAIL-R2 antibodies, which showed high toxicity in the assay.^[13][30] The abstract also reports ex vivo killing of patient blasts, sparing of normal CD34 positive progenitors, and planned clinical trials in relapsed or refractory AML, including TP53 mutated and drug resistant cases.^[13]

TRIO-863 belongs here as another attempt to use CD33 as the AML anchor while avoiding a conventional ADC or degrader payload, rather than as a near term clinical competitor to BL-M11D1 or ORM-1153. The important watchpoints are IND enabling toxicology and the start of the clinical trials TRIO says are planned, financing or licensing, and a credible transition into first in human development.

Early dual target programs: CD33/CD123 coverage

CD33/CD123 dual target T-cell engager programs (multiple developers) are earlier stage but relevant to this landscape because they address antigen heterogeneity and potential escape from single target treatment. Published preclinical work on a CD33/CD123 Nanobody T-cell engager reported killing of AML cells expressing one or both antigens.^[14]

These programs connect to BMS-986497/ORM-6151 and BL-M11D1 through the treatment objective rather than the construct: broader and potentially more selective AML cell targeting. They should be monitored selectively as named sponsors advance toward IND enabling work or first in human testing. The meaningful signals will be target expression requirements, cytokine release mitigation, myeloid toxicity, dosing strategy, and evidence that dual targeting improves coverage without sacrificing therapeutic feasibility.

Gemtuzumab ozogamicin (Pfizer): the CD33 reference point

Gemtuzumab ozogamicin (Pfizer) is the approved CD33 directed benchmark that every new CD33 program must measure itself against. It is an approved CD33 directed calicheamicin ADC.^[15] ClinicalTrials.gov listed 24 recruiting or active studies of gemtuzumab ozogamicin as of October 16, 2026 (19 recruiting and 5 active, not recruiting), spanning adult, pediatric, measurable residual disease and relapsed settings.^[31] Its relevance is practical: a new CD33 program must establish why it can add value relative to the efficacy, toxicity and operational experience already associated with gemtuzumab ozogamicin.

For emerging CD33 constructs, the differentiation burden could be better tolerability, a different payload mechanism, activity in resistant or post venetoclax disease, a superior combination position, more practical dosing, or a clearer biomarker defined role. Tracking new gemtuzumab combination and sequencing evidence matters because it continuously resets the benchmark for later generations of CD33 directed therapies.

Other CD33 and CD123 programs in the clinic

Several other CD33 and CD123 directed programs remain in the clinic, with mixed status. On CD33, Actimab-A (lintuzumab Ac-225), a CD33 radioconjugate, has its NCI trial NCT06802523 suspended for drug supply issues; GTB-3650, a CD33 NK cell engager (TriKE), is recruiting in Phase 1 (NCT06594445); and CD33 CAR-T programs such as City of Hope's NCT05672147 are recruiting.^[6][7][8]

On CD123, tagraxofusp (Stemline), the first approved CD123 directed therapy, in BPDCN, is in a Phase 2 study with venetoclax and azacitidine in AML (NCT06456463) that is active but no longer recruiting, while Sanofi's CD123 NK cell engager SAR443579 had its study NCT05086315 terminated on a strategic sponsor decision not driven by any safety concerns.^[11][35][36] The pattern across these programs is that CD33 and CD123 remain active targets while the delivery and effector approaches are still being sorted out, which is the same question the ORM-6151 and BL-M11D1 exits raise.

When a competitor event requires primary research

A competitor discontinuation, clinical readout, regulatory action, or partnership change does not have one self evident implication for companies still active in the same treatment space.

Public sources can confirm the event and identify relevant active assets. They cannot reliably establish whether AML clinicians and investigators view the event as specific to one molecule, a payload, a target, a modality, a trial design, or a broader treatment hypothesis. Nor can desk research determine whether the event changes the evidence required for differentiation, trial site interest, recruitment prospects, or pharma partner appetite.

The question for a company developing an AML therapy is therefore how the event has changed the competitive and clinical context for its own asset.