Category Archives: ABT-199

The development of combination therapies for B cell lymphoma: ABT-199

The role of ABT-199 in the development of combination therapies in lymphoma.

Following yesterday’s blockbuster win for PCYC and JNJ – the Phase 3 trial versus Arezza was stopped early on clear PFS and OS benefit – it seems a little deflating to return to AbbVie, whose Bcl2 inhibitor ABT-199 has been dogged by Tumor Lysis Syndrome (TLS) problems, some fatal, and recent rumors of oversight problems at one clinical site. I stated the other day that ibrutinib would win the medical marketplace for B cell lymphoma treatment, based on its impressive suite of clinical trials, and the results announced yesterday support that opinion. I still believe that combo therapy is the critical path forward in this field, and ibrutinib and idelalisib are the clear leading candidates for combo treatment protocols.

However, ABT-199 remains a wildcard and could be transformative if developed carefully. The drug demonstrates ORR and CR responses in B cell lymphoma that are very dramatic, as detailed earlier. In the spirit of our earlier January posts, lets look at the clinical trial spectrum for ABT-199. There are five trials listed for ABT-199 monotherapy in oncology, including the phase 1 extension. These include trials in relapsed/resistant NHL, CLL, high-risk CLL (del17p), MM, and AML. The inclusion of acute myeloid leukemia (AML) distinguishes ABT-199 from the other lymphoma drugs, and is based on the mechanism of action and profiling of different tumor types for sensitivity to Bcl2 inhibition.

The combination trials are very narrow in scope and reflect the fact that the ABT-199 is partnered with Roche/Genentech, and therefore the anti-CD20 mAbs used are those developed by Roche, that is, rituximab and obinutuzumab (Gazyva). Obinutuzumab is already approved for the treatment of previously untreated CLL, i.e., as first line therapy. The obinutuzumab trial with ABT-199 is sponsored by Roche/Genentech, illustrating the depth of this collaborative effort. Roche has an ongoing preclinical BTK program, and it will be interesting to see if a combination trial with ABT-199 is eventually filed.

Here are the combination trials listed:

Trial Number
Phase
date filed
Combination
Indication
NCT0159422914/20/2012bendamustine/rituximabrrNHL and DLBCL
NCT0167190418/10/2012bendamustine/rituximabCLL (rr & untreated)
NCT016826161b6/26/2012rituximabrrCLL and SLL
NCT0168589219/12/2012ObinutuzumabCLL (rr & untreated)

The ultimate success of the program will depend in large measure on controlling the TLS issue. Its worth reminding ourselves that TLS did not suddenly become a toxicity concern in the treatment of B cell lymphoma. It occurs with anti-CD20 treatment and with chemotherapy treatment, as a result of triggering the death of a large number of tumor cells. The problem for ABBV and ABT-199 is that TLS does not seem to be related to dose given, remaining somewhat unpredictable (aside from worrying when patients present with bulky disease, which indicates huge number of tumor cells in the lymph nodes, bone marrow, etc). The recent outcry over moving one patient from one dose to another (150mg to 1200mg if I remember right) seems a little silly when a dose of 50mg can trigger TLS in a lymphoma patient. That said, the burden is on AbbVie to demonstrate that they can provide better efficacy than the competing drugs (ibrutinib and idelalisib), safely. If they can do this, I predict that ABT-199 will have a big role to play in the treatment of B cell lymphoma. If they continue to struggle then this drug will will still have a role, but may be relegated to second line or even salvage therapy status. Given the resources behind it, from both AbbVie and Roche, I imagine that a huge effort will be brought to bear on understanding and controlling the TLS toxicity.

Final ASH13 SnapShot: AbbVie’s ABT-199

Update on ABT-199. 12-3-2013, by @PDRennert 

I reviewed the status of ABT-199 back in August, following ASCO (see link). At the time I felt the drug was being overlooked in the hype around ibrutinib and idelalisib. This was based on impressive response rates and the sense that AbbVie had gotten a handle on how to dose safely. After all, tumor lysis syndrome (TLS) is not uncommon in the treatment of lymphomas, and can be dealt with by dose modification or intervention.

At ASH we get a further look at this drug. Abstract #872, to be presented by J. Seymour, introduces a modified dosing regimen. Patients (rrCLL/SLL, n = 56) were given single doses of ABT-199 at day -3 or day -7, then started on daily dosing after that. This is a Phase 1 monotherapy trial designed to determine MTD. The efficacy readouts were pretty dramatic. ORR = 84% with CR = 21% and PR = 63%. Within the CR group (n = 12), 8 patients had no or very low minimal residual disease. There were 12 discontinuations due to progressive disease (21%). The response rate was not related to del(17p) status but the PR rate was lower in fludarabine-refractory patients (these patients are all at high risk).

Notably, among the usual AEs (diarrhea, neutropenia, URIs, etc) there was an 11% grade 3/4 TLS rate. This is 6 patients. Problematically, TLS was not clearly dose associated: 2 @ 50mg, 1 @ 100mg, 2 @ 200mg and 1 @ 1200mg, this last one resulting in sudden death. So dose optimization remains in progress.

The observation that response was not related to del(17q) status or other aberrations in the TP53 locus in rrCLL patients will be discussed in more detail by M.A. Anderson (Abstract #1304).

M. Davids (Abstract #1789) will present a similar study in a variety of rrNHL patients, including MZL, MCL, DLBCL, FL and WG. Of the 32 patients enrolled and followed for a median time of 6 months, 18 discontinued due to progressive disease (that’s 56%). AEs were typical (nausea, diarrhea, cytopenias, URIs). There were 2 mild episodes of TLS. For FL and DLBCL, doses of 600mg or higher were required for efficacy. The responses were good given this difficult mix of patients. Note that the text and table in this abstract don’t entirely line up, so best to hear the current results at the meeting. The implication here however is that ABT-199 is safer in these patient populations than in rrCLL, a theme we also heard at ASCO.

Aside from the clinical data there is an awful lot of preclinical modeling using cell lines or patient derived cells in vitro or in vivo (mouse). The point of all this nice work is to show the potential of combination therapy using ABT-199 along with other drugs. A few examples:

-  2-DG + ABT-199 kills all Myeloma subtypes (#1921)

-  ibrutinib + ABT-199 is effective against MCL cells and CLL cells (#645 and # 3080)

-  imatinib + ABT-199 kills chronic phase CML cells

-  BTK inhibitor R406 + ABT-199 kills DLBCL cells

   etc, etc

The CML observation points to another trend, which is efficacy of ABT-199 in settings beyond NHL, including ALL (#3919), AML (#885) and MM (#4453). There are others…

On balance this remains an exciting and potentially important drug. The issue of TLS in certain subtypes of NHL remains to be solved, while in other, difficult NHLs there appears to be clear and compelling efficacy with less toxicity.

LINKS TO THE #ASH13 ABSTRACT PREVIEW CHAPTERS @ SUGAR CONE BIO

ASH13 previews

Part 8.   ABT-199
Part 7.   CAR-T tech                        

Part 6b. new targets for Myelofibrosis           

Part 6a. Jak inhibitors in Myelofibrosis                       

Part 5.   Biologics for Non-Hodgkin Lymphomas              

Part 4.   New & noteworthy: CLL etc             

Part 3.   Btk and PI3K inhibitors for CLL      

Part 2.   Ibrutinib                              

Part 1.   Idelalisib

pre-ASH post on ADC technology:  here                         

Apoptosis Induction for the Treatment of B Cell Lymphomas: Update on AbbVie’s Bcl-2 Inhibitor ABT-199.

Lost in the fanfare surrounding the BTK inhibitor Ibrutinib and the PI3Kdelta inhibitor Idelalisib at this year’s American Society of Clinical Oncology meeting (ASCO 2013) was some rather stunning data from AbbVie on their Bcl-2 selective inhibitor ABT-199.
ABT-199 binds to Bcl-2 in such a manner as to prevent this protein from interacting with pro-apoptotic proteins such as BAX and BID, thereby allowing them to attach to the mitochondrial membrane, induce cytochrome-c release and trigger apoptotic cell death. Tumors disable the Bcl-2 pathway in a number of clever ways. Many tumor types delete p53, a protein that normally up-regulates expression of BAX and BID and down-regulates expression of Bcl-2 and related proteins (BclxL, Mcl-1, Bcl-w, etc). Tumors with this deletion phenotype are termed 17p(del) referring to the site of chromosomal alteration. Such tumors are generally very aggressive, resistant to chemotherapy and radiation, and associated with poor prognosis.
B cell lymphomas constitute a diverse collection of lymphomas and some leukemias (the distinctions have become blurred). B cell lymphomas have historically been classified as Hodgkin lymphomas or the very diverse Non Hodgkin lymphomas (NHL). The term NHL is confusing as this covers chronic lymphocytic lymphoma (CLL), mantle cell lymphoma (MCL), diffuse large B cell lymphomas of 2 subtypes (DLBCL-ABC and DLBCL-GCB), indolent Non Hodgkin lymphoma (iNHL) and a host of other tumor types. A baffling mix of biology and acronyms, but simply put, all of these tumor types are derived from various stages of B cell development, and most require signaling through the B cell receptor (BCR) to survive. The BCR triggers proliferative and survival (anti-apoptotic) signals, and therefore Bcl-2 becomes a relevant target in NHL.
Not surprisingly, genetic evaluation of B cell lymphomas has revealed mutations in Bcl-2 or downstream of Bcl-2 that foster lymphoma cell survival. Examples include constitutive activation of Bcl-2 in follicular lymphoma (FL) and CLL, amplification of Bcl-2 in MCL, down-regulation of NOXA (another pro-apoptotic protein) and BIM (a protein that regulates Bcl-2 activity) in iNHL and CLL, and down-regulation of expression of the caspases, part of the apoptotic machinery triggered by mitochondrial cytochrome-c release, in CLL.
ABT-199 was developed as a follow-on to the earlier Abbott compound navitoclax (ABT-263). Navitoclax inhibited multiple Bcl-2 family members, including BclxL, and was associated with severe thrombocytopenia (platelet loss) in clinical trials. Bcl-xL is an obligate pro-survival protein for platelets and thrombocytopenia became a dose limiting toxicity in navitoclax clinical trials. ABT-199 has a much lower affinity for BclxL than for Bcl-2, and spares other proteins in this family, as shown in this data reproduced from a recent AbbVie paper (Souers et al. 2013. Nat Med 19: 202-210):
                                 TR-FRET Ki (nM)
                      Bcl-2    Bcl-xL    Mcl-1    Bcl-w
navitoclax       0.044    0.055      > 224     > 7
ABT-199      < 0.01     48          > 444     245
What is important to note here is the relative difference in potency of ABT-199 against Bcl-2 (less than 10 picomolar, an unbelievable potency number) vs 48nM against BclxL. Taken at face value this is a 4800 fold difference in target potency. As noted below however, the number may be deceiving given the drug exposure achieved in patients.
AbbVie presented several studies at ASCO, including their Phase 1b trial in CLL. What is striking about the data is the response rates, as these compare favorably with similar data shown recently for BTK inhibitors and PI3K inhibitors, from Gilead (Idelalisib), Infinity (IPI-145), Celgene (CC-292) and J&J (ibrutinib). A snapshot of results from the CLL trials is shown below.
drug 

ABT-199 

Ibrutinib 

CC-292 

Idelalisib 

IPI-145 

pathway 

Bcl-2
BTK
BTK
PI3Kd isoform
PI3Kd/g isoforms
Partial response (PR) 

65%
68%
40%      (n = 5)
39%
55%
Complete response (CR) 

18%
2%
0%
0%
0%
Overall response (OR = PR + CR) 

84%
71%
60% (n=5)
39%
55%
OR in 17p(del)
81%
68%
NA
NA
50%
The table is adapted from results presented at ASH 2012, ASCO 2013 and this year’s European Hematology Association meeting (EHA 2013), as generously posted on Twitter by @andybiotech. ABT-199 differentiates from the competing drugs in several critical ways. First the OR rate reached 84% and was not statistically different between CLL patients having or not having the p53 deletion, ie.17p(del). Second, the CR rate was 18%, meaning that this many patients absolutely cleared disease from the bloodstream, lymphatic fluid, and lymph nodes. In addition AbbVie stated at ASCO that in the CR group, 11% had complete recovery of the bone marrow and 7% had partial bone marrow recovery – these are responses that are not seen with BTK or PI3Kg/d or PI3Kd inhibitors.
So why did the fanfare around NHL treatment coming out of Chicago in May during ASCO 2013 not include ABT-199? The answer was toxicity, and this toxicity came in 2 distinct forms. One has been addressed recently, the other is somewhat complex.
Tumor Lysis Syndrome (TLS) is a drastic physiological response to the sudden and acute destruction of massive numbers of tumor cells, more or less simultaneously. The disgorging of massive quantities of intracellular material triggers acute physiologic response as the heart, kidney, spleen and other organs cope with a titanic overload of potassium, calcium, phosphate, and uric acid. Organs fail and circulation collapses the patient drops quickly toward death. ABT-199 caused this syndrome in the first 3 patients that were dosed, each having been given 200mg of drug. One died. Faced with this spectacular disaster AbbVie immediately halted all ABT-199 clinical trials. That was back in January or February of this year. So the update at the end of May was tempered by this ongoing toxicity issue, and what AbbVie had to say at that point didn’t help. Starting with a lower dose of 50 mg they had restarted all trials, and gotten the drug into 34 CLL patients. Three experienced TLS, 1 died, 1 lost renal function (acute renal failure, generally meaning a lifetime of dialysis or a transplant). In addition, other toxicities were present, as seen in the next table showing severe toxicities (grade 3+) in CLL clinical trials. URI: upper respiratory infection. NA: data not available
drug 

ABT-199 

Ibrutinib 

CC-292 

Idelalisib 

IPI-145 

pathway 

Bcl-2
BTK
BTK
PI3Kd isoform
PI3Kd/g isoforms
Infections 

2% (URI)
18% (pneumonia
NA
19% (pneumonia)
NA
Liver damage (AST/ALT) 

NA
NA
NA
4%
6%
thrombocytopenia 

11%
5%
0%
NA
NA
neutropenia 

38%
18%
18%
NA
26%
anemia 

7%
5%
9%
NA
0%
The table is adapted from results presented at ASH 2012, ASCO 2013 and EHA 2013, as generously posted on Twitter by @andybiotech.
Where really jumps out here is at the level of thrombocytopenia and neutropenia seen in patients receiving ABT-199. Its worth noting that patients taking any of these new drugs are already at risk for decreased cellularity due to chemotherapy, and so adding to this burden complicates their subsequent care. Neutropenia is a bona fide pathway toxicity as demonstrated by defective expression of Bcl-2 in Kostmann syndrome (severe congenital neutropenia) and so there is nothing to do about this but lower drug exposure, potentially at the expense of efficacy. An interesting question in this regard is whether the thrombocytopenia and anemia seen are due to residual inhibition of BclxL. If you look at the PK data presented from the CLL trial, its pretty clear the effective concentrations of drug are far in excess of what is needed to inhibit BclxL. Taking data presented by Seymour et al. at ASCO 2013, abstract #7018, its clear that the maximum concentration achieved after multiple doses (Cmax(ss)) is up to 2mg/ml, which is going to give low mM exposure. So, at Cmax and for some time thereafter, drug concentration exceeds that required to inhibit BclxL by as much as 50-fold. Whether the duration of inhibition is sufficient to induce thrombocytopenia and anemia in patients is not known.
Lets go back to TLS, as this is the real show-stopper. On their July 26, 2013 earnings call, AbbVie stated that the dosing regimen has been further modified (details not clear). AbbVie further stated “With regard to tumor lysis syndrome which is a direct consequence of the explicit potency of 199 we have been enrolling CLL patients with a revised dosing schedule where we start at a lower dose and ramp up at a more slow rate, and so far so good with regard to the patients that we have been treating under that new protocol.” It is beginning to look as if AbbVie is learning how to manage TLS, and therefore have the potential to get their drug back in the fast lane.
Why does all this matter? Selective Bcl-2 inhibition is a unique strategy and ABT-199 illustrates compelling activity. In the era of rapidly advancing combination therapy for NHL, this could be an important component of the evolving treatment paradigm. With a lower dose they will try to avoid TLS and perhaps blunt thrombocytopenia and neutropenia. In the near term this drug may play a prominent role in patients who are at high risk (17p(del) or who are refractory to other targeted therapies. More interestingly, Bcl-2 inhibition in combination therapy may be a breakthrough treatment paradigm, and in this regard, AbbVie is swinging for the fences with trials combining ABT-199 with R-CHOP (Rituxan + chemotherapy) in pursuit of achieving outright cures. Combine this with genetic profiling of Bcl-2 and related proteins across many tumor types, and you have a very interesting story. 

This is a drug to watch, and just, perhaps, to improve upon.
As always, stay tuned, and follow us on Twitter @PDRennert.