Anticipating new therapeutics and forecasting treatment trends for acute myeloid leukemia – Part 2

Here is a quick recap of Part 1: we looked at some of the targeted small molecule drugs being developed for AML. That class of therapeutics can be binned into logical groups, as follows:

1) pan-signaling pathway inhibitors like sorafenib, sunitinib, even ponatinib

2) drugs that hit c-Kit (and various other receptor tyrosine kinases) like dasatinib and imatinib

3) drugs that target FLT3 (and usually hit other kinases) like quizartinib, midostaurin, lasartinib, and PLX3397

4) proteosome inhibitors like bortezomib and carfilzomib

5) epigenetic modulators like vorinostat, panobinostat, 5-azacitidine, decitabine and entinostat

6) miscellaneous. We discussed several of these in Part 1, and there are many more. One more of interest is AG-221 (Agios; AGIO) that targets the mutated IDH2 gene. IDH1 can also undergo mutation in AML. Such drugs are a nice idea, unlikely to work as monotherapy (just my view), but perhaps useful in combo. AG-221 is currently in early stage clinical development.

In the small molecule drug development landscape there is logic that is readily understandable, and the combinations of drugs being tried make good sense. In contrast the biologics side of AML drug development is pretty haphazard. On the other hand true breakthroughs leading to transformative changes in clinical practice very likely will be found here.

So lets move on to Part 2: Biologics, including cytotoxic monoclonal antibodies, ADCs, bi-specific antibodies, cell based therapy and few odds and ends.

An antibody that illustrates that haphazard nature of AML drug development is gentuzumab, a monoclonal antibody (mAb) directed to CD33, a protein expressed at high levels on AML cells. The mAb was coupled to a calicheamicin derivitive and developed as gentuzumab ozogamicin (GO). GO is therefore an antibody-drug conjugate (ADC). This drug was originally approved as Mylotargtm (Wyeth, now Pfizer; PFE) for the treatment of AML more than a decade ago based on a phase 2 trial data showing a CR + CRp rate of 30%. However the drug showed less benefit than expected in phase 3, plus unanticipated hepatic toxicity, and was pulled off market. GO continues to see use in clinical trials and off-label and has been shown to add to the effectiveness of chemo in AML patients carrying specific cytogenetic markers. A meta-analysis of large phase 3 trials was reported in the Annals of Oncology 2 weeks ago                           (http://annonc.oxfordjournals.org/content/25/2/455.abstract). Data from nearly 3600 patients (half treated, half controls) from five randomized phase 3 trials were analyzed. Compared with induction chemotherapy alone, adding GO significantly prolonged OS (HR 0.93, P = 0.05) and relapse free survival (HR 0.87, P = 0.003), decreased rates of resistance (OR 0.71, P = 0.01) and relapse (OR 0.75, P = 0.002), but oddly had no effect on CR rate, suggesting that complete response status was disconnected from longer term outcomes (this is actually very common). Subgroup analysis identified cytogenetic status as an important variable for response to GO. On the downside, the risks of grade 3–4 nausea/vomiting, diarrhea and liver aspartate transaminase (AST) elevation were increased in the GO arm.

Additional analysis is due this spring, and will likely be available at AACR or ASCO.

GO provided clear clinical POC that targeting CD33 could be an effective strategy for AML, and Seattle Genetics (SGEN) had also developed a naked antibody called SGN-33 (lintuzumab) that failed in phase 2b, demonstrating no efficacy benefit compared to chemo alone. Seattle Genetics has therefore developed a second-generation anti-CD33 targeting mAb, as an ADC. The mAb is coupled to pyrrolobenzodiazepine (BPD) a DNA minor groove-binding molecule that effectively stops tumor cell division and induces cell death. The resulting ADC is called SGN-CD33A. A phase 1 trial in AML just got underway (NCT01902329).

A very different mechanism for targeting CD33 is being developed by Amgen (AMGN) using technology acquired when they bought Micromet. Micromet developed a bi-specific antibody technology termed BiTE. BiTE antibodies fuse two single-chain mAbs, one that binds CD3 on T cells and a second that binds tumor cell antigens. The idea is to redirect T cells to selectively lyse tumor cells. AMG330 is a BiTE antibody with CD33 antigen recognition. This therapeutic is still in preclinical development.

A different bispecific modality is BiKE, in which an NK cell targeting mAb (anti-CD16) is coupled to anti-CD33. The idea is to trigger NK cells to degranulate thereby killing the tumor cells. Nice idea, probably a long shot, in preclinical development.

Yet another approach to targeting CD33 has been developed in the context of CAR-T technology. CAR-T technology is based on introducing a tumor-targeting construct to the patients own T cells ex vivo. A lentiviral vector expressing a chimeric antigen receptor with specificity for AML antigen CD33 is coupled with CD137 (4-1BB) and CD3-zeta signaling domains. A low dose of modified T cells are then re-infused into the patient. This technology is dubbed CART-33. The cells rapid proliferate and are activated in the presence of antigen (ie. the tumor cells), inducing a robust and long-lived anti-tumor response. A phase 1/2 trial has begun in Beijing (NCT01864902). We can expect additional trials to be added. This therapeutic approach has worked well in advanced lymphomas (with CD19 as the antigen). The technology, licensed by Novartis, is one to watch very closely.

Finally, radioactively labeled anti-CD33 mAbs have been developed, including conjugates of anti-CD33 mAb M195 to 131-I and 213-Bi. The latter conjugate was run in a Phase 1 trial but the clinical trial literature here is sparse. Other radiolabeled mAbs used for AML treatment include a 131-I-conjugated anti-CD33 mAb BC8 and a Y90-conjugated anti-CD45 mAb. Both are undergoing clinical testing at the Fred Hutchinson Cancer Center, apparently with very promising results. In general, radiolabeled mAbs that emit β-particles, such as I131-anti-CD33, Y90-anti-CD33, and I131-anti-CD45, deliver high doses of radiation to the bone marrow and are used as pre-conditioning prior to SCT. Re188-anti-CD66c also falls in this catagory. Short-ranged α-particle emitters like Bi213 Bi-anti-CD33, are used to treat low-volume or residual disease.

Another company that is using bispecific technology to target AML to activated T cells is Macrogenics (MGNX). They have developed an anti-CD3/anti-CD123 DART mAb MGD006, partnered with Servier. This Dual Affinity Re-Targeting (DART) construct is built from 2 different polypeptides, each comprising the VH of one antibody in tandem with the VL of the other antibody, creating a heterodimer that is stabilized by disulfide binding. This construct binds to both CD123 and to CD3 in the human T-cell receptor complex. A phase 1 trial should begin this year.

CD123 is the IL-3 receptor, expressed on myeloid lineage cells and elsewhere, highly expressed on AML cells. It also is expressed on leukemic stem cells, leading to the hypothesis that targeting CD123 might prevent relapses by eliminating residual tumor progenitor cells from the bone marrow niche. Recent data suggest that mutations in the signaling chain of CD123 may contribute to oncogenesis in some lymphomas and leukemias, including AML. Early POC was provided by the mAb 7G3, which showed potent in vitro and in vivo killing of human AML cells. This mAb did not undergo further development, although it appears occasionally in the radio-immunotherapy literature, e.g. as In-111-NLS-7G3 where NLS is a 13-peptide linker.

An anti-CD123 mAb already in Phase 1 is CSL362, a novel monoclonal antibody therapy. This antibody has been engineered antibody to efficiently recruit NK via the Fc portion of the antibody, so this is a classic antibody-mediated cytotoxicity approach. The mAb is being developed by CSL LLC and is partnered with Janssen.

 Stemline Therapeutics (STML) is developing SL-401, which is comprised of the IL-3 protein conjugated to a truncated diphtheria toxin, a potent inhibitor of protein synthesis. This construct reportedly has anti-tumor potency against tumor cell lines and primary tumor cells in the femtomolar (10-15 M) range. SL-401 is in Phase 2a in AML. That trial should report out preliminary data this year.

Of great interest is the CAR-T technology as applied to CD123 (CART-123). The technology is the same as discussed above for CART-33, and is in preclinical development. Again this is technology developed at U Penn and licensed to Novartis. We won’t get into the competitive landscape of modified T cell technologies, nor the intellectual property wars, a subject perhaps for another time.

A few other biologics to keep an eye on:

- Trebananib (AMG386) is a peptibody targeting the Angiopoietin 1/2 proteins. These are ligands for Tie2, a receptor on endothelial cells that promotes tumor angiogenesis. Peptibodies are petides fused to the Fc domain of an antibody. The peptide provides the parget recognition. A phase 1 reported at ASH that the therapeutic was safe and showed preliminary signs of efficacy in adult AML (Abstract #2710).

- Igenica is a private company that just received Series D funding of 14MM USD to advance IGN523 into the clinic. The funding round was led by Third Rock Ventures. IGN523 is an anti-CD98 antibody that targets both the tumor cells and tumor stem cells. CD98 is the neutral amina acid transported expressed on dividing lymphocytes, and it has been argued that IGN523 functions not only by inducing antibody-mediated cytotoxicity (by NK cells and CD8+ T cells) but also by blocking activity of the receptor.

- CXCR4 has emerged as an attractive target in AML, beyond the standard application of CXCR4 to mobilize stems cells. More recent work has focused on using CXCR4 antagonists like plerixafor (a small molecule) for chemo-sensitization (see ASH 2013 abstract #2680). More direct targeting is being pursued by Bristol Myers Squibb (BMS), with the antibody BMS-936564 (ASH abstract #3882), currently in phase 1 for AML (NCT01120457). Other CXCR4 agents are in development.

- other antigens have been recently identified.

If we look broadly at the biologics being developed for AML a few things jump out. First, there are no home runs, as we have seen in other lymhomas such as Non-Hodgkin’s lymphoma, where the anti-CD20 mAb rituximab showed dramatic response rates early in clinical development. Second, it’s still early for nearly all of these agents, with the exception of the GO ADC. Third, and this is a very common theme, combination therapies will be required to control this brutal disease. We saw in the review of small molecule therapeutics that companies and the NCI are co-sponsoring trials in order to move clinical practice forward, and we should expect similar collaboration as the biologics move ahead (indeed we already see this with the GO combo trial).

Tomorrow we’ll talk about the role of immune-checkpoint therapeutics in AML, a field with great promise.