Monthly Archives: November 2013

ASH 2013 preview: Myeloproliferative Neoplasms, New Targets

November 25, 2013. by P.D. Rennert (I keep forgetting to sign these entries)
Part 6b. Myelofibrosis and related Myeloproliferative Neoplasms: Phase 1 and preclinical updates from ASH 2013.

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
 
Back to it. In part 6a we looked at the phase 2/3 studies, and these are certainly focused on Jak inhibition, for reasons we discussed in part. Its worth noting that Jaks are a class of signaling proteins that hybridize shamelessly and because of this blocking any given Jak (Jak1, Jak2, Jak3, Tyk2) will necessarily block the activity of others in the context of signaling that requires hybridization. Conversely it has been demonstrated that blocking any given Jak may not be effective in settings where other family members can substitute. As always, it is complicated.
 
It has been mentioned that Jak inhibitors are not considered disease modifying or curative. They offer symptomatic relief, which relieve the pathological degradation of the bone marrow, and can do so for extended periods, as has been demonstrated with ruxolitinib. In this sense the treatment paradigm is not so different from some other targeted cancer therapies, where the name of the game is to keep the wolf from the door, at least for a time.
 
Regardless of the limited potential, Jak inhibitor development continues at a brisk pace, as demonstrated in the previous section. In earlier development we find yet more Jak inhibitors. Gilead will present data from the phase 1/2 trial (with extension) of the Jak1/2-selective inhibitor, momelotinib (Abstract #108). Confusingly, this trial used some new (to me) endpoints. One was a reduction in “palpable splenomegaly” which suggests the spleen was not imaged (?). Second (and useful I think) was “transfusion independence”. I like this because it clinically measures the impact of treatment on the most pathologically relevant endpoint, loss of RBCs and platelets in circulation. What is even more interesting about this trial is the extension data, showing a “median spleen response” of 324 days, with pretty huge variance. As noted with ruxolitinib, the variance cannot be traced to the presence or absence of Jak2 V617F mutation - I suspect Gilead will work to sort this out pretty quickly, so that bears watching unless of course the variance is due to the manner of measurement!
 
Early trial data will be reported for BMS911543, another Jak2-selective inhibitor (Abstract #664). Note that Jak3 and Tyk2 are hit with IC50s less than 100nM, so selectivity will depend on actual exposure, which is data not available yet. Anyway, the drug is given BID and the goal of the trial is to establish an MTD (not reached). Early efficacy data included analysis of responses of patients who had received a prior Jak inhibitor. Symptoms were well controlled and the spleen volume response (> 35% reduction in splenomegaly) was dose responsive – up to 70% of patients responded at the highest doses (note: small sample size). AEs were were the usual diarrhea, nausea and cytopenias. The investigators will update with data from 84 patients at the meeting.
 
Eli Lilly will present data from the LY2784544 phase 1 dose escalation trial (Abstract #665). Of note, this drug is described as being “selective” for the V617F mutant of Jak2. They are enrolling 38 patients (most MF, some PV) at 30 -300 mg per day, although at 200 mg and above they hit liver tox (grade 3 serum creatinine elevation) and the MTD is established at 120 mg/day. Other AEs are typical of the class and not severe. We are introduced to yet another way of measuring splenomegaly, this time as “spleen length”. There was a >50% improvement in 56% of the evaluable patients, furthermore, >50% of patients reported improved symptoms by TSS. An update is promised for the meeting.
 
Novel inhibitors are finally moving through preclincal and early clinical evaluation. Geron has a novel telomorase inhibitor, imetelstat, a lipid-conjugated oligonucleotide inhibitor of human telomerase (Abstract #662). Early data are impressive. AEs were modest, and responses (44%) included a fair number that appeared to be CRs or PRs. Here I quote: 
 
“The four (22%) CR patients experienced reversal of BM fibrosis and recovery of normal megakaryocyte morphology. Two CR patients were transfusion-dependent at baseline and became transfusion-independent … Among 13 patients with leukocytosis, 10 (77%) normalized their count or had >50% reduction. Eleven (61%) patients had complete or partial resolution of leukoerythroblastosis.”
 
Thats pretty impressive. The downside is that this was a small single center open label trial, so really, we just have to wait and see.
 
For an example of why such results can be so misleading, let look at a Phase 3 trial failure (Abstract #394). Here we have Celgene’s pomalidomide (approved under the name Pomalyst for the treatment of Multiple Myeloma). Phase 2 trials suggested that pomalidomide imporved severe anemia in MPN patients, including MF, PV and ET patients. The phase 3 trial enrolled 252 patients with MPN-associated MF who were dependent on RBC transfusions. There was no significant improvement in time to transfusion in drug-treated v placebo-treated cohorts.
 
So these early trials can be very misleading, but lets look even earlier, at some preclinical studies.
 
Novartis has some nice data showing elevation of Hedgehog signaling pathway targets in MF granulocytes (Abstract #666). Using in vitro and in vivo (mouse) models they demonstrate that Jak inhibition and Hedgehog inhibition have additive activity. The Jak inhibitor was INC424 and the Hedgehog inhibition was provided by Smoothened antagonism (sonidegib). Another novel approach is to target megakaryocytes, that contribute to MF pathogenesis. Using in vitro and in vivo models an academic collaboration (Abstract #109) shows that Aurora A kinase inhibition induces megakaryocyte arrest and this results in decreased bone marrow fibrosis, decreased infiltration of megakaryocytes and granulocytes into the liver and spleen, and decreased plasma TGFbeta, a potent pro-fibrotic growth factor.
Genetic analyses have demonstrated that certain signatures indicate risk for increased risk of leukemic conversion and decreased OS. These include ASXL1, EZH2, IDH1/2 and SRSF2 gene mutations (Abstract #104). EZH2 mutation accelerates the onset of primary MF (Abstract #110). However, patients carrying these mutations are not differentially impacted by ruxolitinib therapy, instead they have similar responses to patients without such mutations (Abstract #105). Novel pathways associated with MF include the arachidonate 5-lipoxygenase pathway (Abstract #111). An exciting new development is the identification of calreticulin mutations in patients that do not have Jak2 mutations, that is, the two appear to be mutually exclusive (Abtract #LBA1). This will spur investigation in novel drivers of MPN pathogenesis.
Obviously there is much more going on then can be covered here. The identification of the Jak2 mutation in MPN opened up a new era of drug development for these rare but nasty and lethal neoplasms. New findings will push us even further, and we can reasonably expect to see important advances over the next few years.
 
 

ASH13 SnapShots, part 6, Myelofibrosis: How Many Jak Inhibitors Are There?

November 25, 2013. by P.D. Rennert (I keep forgetting to sign these entries)

Part 6a. Myelofibrosis: Therapeutic agents in Phase 2/3.

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx

I’m splitting this into 2 parts because, well, lets just say there is always a lot to learn. Myelofibrosis is a proliferative cancer of myeloid lineage cells, characterized by bone marrow infiltration and fibrosis, splenomegaly and heptomegaly caused by extramedullary hematopoiesis, and overall disruption of hematopoiesis leading to cytopenic conditions such as anemia and thrombocytopenia. Patients experience diverse symptoms, which has led to the development of patient symptom scoring systems. They are at risk for transformation to acute myeloid leukemia, and in general have greatly reduced overall survival due to chronic anemia leading to bone marrow failure.

Myelofibrosis (MF) is one of a class of myeloproliferative neoplasms (MPN) that also includes Polycythemia Vera (PV) and Essential Thrombocytopenia (ET). In 2005 it was found that nearly all PV cases and about half of MF and ET cases had a mutation in Jak2 (V617F). This marked the beginning of novel drug development for MPN that culminated with the 2011 approval of ruxolitinib (Jakafi) for the treatment of intermediate risk (intermediate-2) or high risk MF. Ruxolitinib is a Jak1/Jak2-selective inhibitor.

The clinical landscape for MF remains dominated by Jak inhibitors, and to go through them is an exercise in duration. Lets spare you all that, and try to summarize quickly, hitting high and low points when they appear. At the outset its fair to make a few generalizations. First, Jak inhibitors are not curative and do not induce PRs or CRs in the way we have discussed in earlier sections. Second, Jak inhibitors themselves can cause cytopenias, and they are therefore dose or duration limited. So, this becomes a balancing act between efficacy (by inhibition of myeloid-lineage cell proliferation) and toxicity (due to inhibition of hematopoiesis). 

Lets sort these by clinical stage.

Sanofi is presenting results from a phase 3 trial of fedratinib, a Jak2-selective inhibitor (Abstract #393). In this trial of patients with high risk or primary (i.e. active) MF the primary endpoints are splenomegaly and patient reported symptoms. Patients have to present with platelet counts above 50 x 10^9/L. 67% of the patients were positive for the V617F Jak2 mutation. 40% of evaluable patients reached the spleen response rate of > 35% reduction in spleen volume as measured by MRI or CT. About the same percent recorded improvement in platelet counts and about 30% of patients reported improved symptoms. This is very much like the ruxolitinib results, as are the AEs reported, which include diarrhea, anemia, higher risk for infection, among others.

UPDATE: via FierceBiotech “A few days ago the pharma giant had to shutter a program for fedratinib after the FDA ordered a clinical halt when their myelofibrosis patients developed Wernicke’s encephalopathy–a neurological condition spurred by biochemical brain lesions.”

Well, thats the end of that drug (another abstract below, just to be thorough). This tox issue is clearly not a class effect, that is, not a Jak inhibitor issue. Instead this drug either hits another signaling or other protein target (that might be interesting). Alternatively, and perhaps more likely, this is compound specific toxicity. Either way, the fact that this tox issue was missed until now (phase 3) is remarkable.

Sanofi also has results (Abstract #661) from a phase 2 trial of fedratinib in MPN patients who were previously on ruxolitinib (so these are ruxolitinib resistant or intolerant). These patients presented with splenomegaly, as evidence of disease activity, and had to have platelet counts above 50 x 10^9/L. The presentation is of results obtained at the 12 week interim cutoff point. Somewhat remarkably (to me anyway) the spleen response rate (defined above) was about 40%. The patient reported outcome was modest, but measurable. This suggests that moving from one Jak inhibitor to another is not as silly as it might sound (we’ve seen this before: anti-TNFs in RA; IFN betas in MS). The downside was the toxicity: 26% of patients discontinued due to AEs that included some grade 3/4 (severe) diarrhea, and a very high rate of anemia and thrombocytopenia. It will be important to track patient outcomes and AEs going forward in this trial.

Incyte will report on a Jak1-selective inhibitor INCB039110 that is in an open-label MF Phase 2 trial (Abstract #663). The primary endpoint in this trial is patient reported symptom score (TSS). Inclusion/exclusion criteria were similar to what is described above. While there was a dose dependent improvement in TSS, there was only a modest improvement in the more objective endpoint of change in spleen volume. Importantly however, Hb level (a measure of RBC count) and platelet counts were preserved. This suggests that Jak1 inhibition might be useful, assuming that there is reasonable efficacy.

Just to remind us how confusing this all can be, Cell Therapeutics will present results obtained in a Phase 2 trial of its Jak2.Flt3 dual inhibitor, pacritinib (Abstract # 395). This trial enrolled patients with primary or secondary MF and included patients whose platelet counts were below 100,000/microliter. This low number is prognostic for transformation to a leukemic state and further, patients with such low counts were specifically excluded from the ruxolitinib registration trials (COMFORT III). 82% of patients had the Jak2 V617F mutation. So, Cell Therapeutics is trying to differentiate pacritinib here, and they are successful. Approximately 40% of patients achieved > 35% reduction in spleen volume. Most patients maintained stable platelet numbers if Hb levels. Notable also were the modest AEs reported. This is an interesting therapeutic to watch.

Next we’ll look at some earlier therapeutics, including novel (i.e. non-Jak targeting) therapies, coming up in part 6b.

SnapShots from the 2013 American Society of Hematology Abstracts – Part 5

 
Part 5. Key Biologics in Clinical Trials.
November 20, 2013
The American Society of Hematology Meeting will take place in New Orleans,
December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
In parts 1-4 we meandered through the small molecule, mainly oral drugs,
highlighting a few key pathways and focusing mainly on CLL.
Biologic drugs are a different and equally important class of therapeutics for lymphoma
treatment, and really it is Rituxan, the antibody that depletes cells expressing CD20, that
ushered in the new era of non-chemotherapy-based drugs. Some of the small molecule
trials discussed earlier were done in combination with anti-CD20 antibodies with or
without added chemotherapy. This therapeutic trend toward combination therapy will
dominate the lymphoma landscape, with chemo, targeted small molecules, and antibodies available to mix and match, just so long as they are not too toxic when combined, provide additive efficacy, and we can afford to pay for them. One might also overlay immuno-
therapy approaches – checkpoint modifiers, CAR-T modified cells, even cancer vaccines -
and of course there is also the whole bone marrow or stem cell transplantation field.
There are notable new biologics being developed for the treatment of lymphoma, and a
few of these have new data available in the ASH 2013 abstracts.
The real question is whether anything will be able to compete with the novel anti-CD20
mAb obinutuzumab.
Obinutuzumab (GA101) is aglycoengineered antibody having 10-fold greater affinity 
for FcgammaR3A. This is receptor on cytotoxic NK cells that binds to the Fc domain 
of the antibody. The binding of the Fc domain to the FcR (receptor) triggers killing of 
the target (CD20+) cell by the interacting NK cell. Obinutuzumab was approved under 
the brand name Gazyva on November 1st for use in combination with chlorambucil to 
treat patients with previously untreated CLL. This was this first drug approved under 
the FDA’s new breakthrough therapy designation and wasbased on a Phase 3 study of 
previously untreated CLL patients (n = 365) comparing Obinutuzumab plus chlorambucil 
to chlorambucil alone. The PFS for the combination therapy was 23 months compared 
with 11.1 months with chlorambucil treatment. Additional data from the Phase 3 trials, 
comparing obinutuzumab pluschlorambucil (OB-c) to rituximab (Rituxan) plus 
chlorambucil (R-c), are to be presented during the plenary session at ASH (Abstract #6). 
Those data are summarized as follows:
ORR
CR
MRD*
PFS
OB-c
78%
21%
29.4%
26.7 months
R-c
65%
7%
2.5%
15.2 months
*: MRD is minimal residual disease, meaning that bone marrow and organs are negative 
for tumor cells.
AEs were higher in the obinutuzumab plus chlorambucil arm, although it appears that 
this was due to increased severe infusion-related reactions, which can be controlled.
Another study in previously untreated CLL patients will be presented at ASH (Abstract
#523). In this trial, obinutuzumab (OB) was combined with fludarabine/cyclophosphamide 
(FC) or bendamustine (B). There are 41 patients enrolled and the median reported followup 
time is nearly 12 months. 9 patients (22%) had to discontinue treatment due to AEs, mainly cytopenias. The investigators will report and update response data, summarized here (note 
that CRi, defined as complete response with incomplete bone marrow resolution, is included 
in this table with the %PR):
ORR
CR
PR
SD
PFS
OB-FC
62%
9.5%
47.6%
19%
not reached
OB-B
90%
20%
70%
0
not reached
No responding patients progressed and PFS was not reached. While the data look very good
for efficacy, the fact that a high percentage of patients had to discontinue due to AEs is
notable.
Two other studies will be presented at ASH. One is on the treatment of CD20+ Diffuse
Large B Cell Lymphoma (DLBCL) patients in a Phase 2 clinical trial (Abstract #1820).
DLBCL is an aggressive lymphoma, currently treated with combination chemotherapy
(CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone) or with rituximab plus combination chemotherapy (R-CHOP). In this trial, 80 previously untreated DLBCL
patients were treated with obinutuzumab plus CHOP. The ORR = 83%, consisting of
CR = 55% and PR = 28%. Of the 80 patients total, 11 patients discontinued treatment,
5 of these due to AEs (6.25%), but in general AEs were manageable. Nine patients had
PD, three died. These preliminary results are very encouraging, updated results including
analyses responses in DLBCL subsets (ABC v GC) and with reference to molecular
classification will be presented at the meeting. An earlier study (Abstract #1814) will
present data on the use of obinutuzumab as maintenance therapy after induction therapy
with chemo (either OB-CHOP or OB-FC). Patients had rrFL (follicular lymphoma). The
induction data was published by Radford et al. in Blood, 2013, volume 122, page 1137ff. 
CR rate was monitored at the start and end of maintenance therapy, with the maintenance 
period being a median of 35 months across the two cohorts. CR as a best overall response increased on maintenance with obinutuzumab in the OB-CHOP cohort (52%, PFS not 
reached) and in the OB-FC cohort (82%, median PFS = 46 months). Finally, a combination 
trial of obinutuzumab and ABT-199 is currently in phase Ib (NCT01685892).
These studies show benefit of obinutuzumab therapy in different lymphoma populations
using a variety of treatment paradigms, and point to the importance of this biologic
therapy in B cell lymphoma treatment.
There are a large number of new biologics competing for attention; just a few are discussed
here.
Another anti-CD20 antibody with breakthrough status is ofatumumab (Arezza). Approved in
2009 for use in rrCLL patients, this antibody is moving toward use earlier (i.e. in newly
diagnosed CLL) and in other patient subsets.
In May of this year, positive phase 3 data for ofatumumab were announced by GSK. Patients
with previously untreated CLL (n = 447) received ofatumumab plus chlorambucil (OF-C) or chlorambucil (C) alone. The study found that patients in the ofatumumab cohort experienced
a longer median PFS. That study will be updated at ASH (Abstract #528). Top line data is
here:
PFS
ORR
CR
MRD
OF-C
22 months
82%
12%
4%
C
13 months
69%
1%
0
Other studies on ofatumumab being presented at ASH include a phase 2 trial in combination
with dexamethasone, to treat high risk rrCLL patients (Abstract #2877). This study presents
a CR = 16% and PFS = 10 months, although the infection risk was quite high. Another
phase 2 study is testing the efficacy of ofatumumab in combination with the AKT inhibitor afuresertib (Abstract # 4175) in the treatment of high-risk rrCLL patients. In this small
study (n = 19) AEs were manageable (neutropenia, GI complications) but responses were
low: ORR = 42%, CR = 0, PR = 42%; 58% of patients had SD, and 26% of patients
progressed. Several other trials will also be updated (Abstracts #1645 and 4177).
An example of the high bar set by obinutuzumab therapy can be seen in several trials of
other biologics. Pfizer has developed an antibody/drug conjugate (ADC) called inotuzumab ozogamicin (InO). This is a humanized anti-CD22 antibody conjugated with calicheamicin, 
a potent cytotoxic. CD22 is expressed on most forms of NHL. The trial (Abstract #1821) 
is a phase 1 dose escalation trial designed to identify the MTD in combination with 
rituximab plus chemo (gemcitabine, dexamethasone, and cisplatin). AEs, mostly
cytopenias, causing dose reductions and dose delays established the MTD. Patients had 
rrNHL, with 21 DLBCL, 14 FL, 12 MCL, 4 SLL, 1 MZL, and 3 other indolent B-NHL.
At the MTD dose the ORR = 45% and the CR = 22%. Of the 55 patients enrolled, 12
(22%) discontinued due to AEs and 12 (22%) discontinued due to PD. These numbers
are a little worrisome although this is a difficult patient population to treat. It will be
important to see PFS and OS numbers as clinical development of this therapy continues.
An intriguing target for antibody development is CD37. CD37 is tetraspan protein expressed
on a variety of hematopoietic cells, and can transmit a cell death signal through its SHP-1
domain. Trubion engineered a modified antibody called TRU-016, now being developed by Emergent (see the 14 November issue of Blood – volume 122, p 3397 – for a brief description 
of this and other anti-CD37 targeting agents). Phase 2 data on TRU-016, now called 
otlertuzumab, will be presented at ASH. Otlertuzumab induces cell death directly (ie. by 
signaling cell death) and also through Fc-mediated cytotoxicity. The phase 2 trial recruited 
65 rrCLL patients who had failed between 1 and 3 prior therapies. The Abstract (#2860) 
presents data on 44 evaluable patients treated with otlertuzumab (OTL) or with otlertuzumab
plus bendamustine (OTL-b). The data are as follows:
treatment
ORR
CR
% progression
OTL
42%
4%
46
OTL-b
80%
20%
10
The % progression data refers to the responding patients only. AEs were in line with the chemotherapy treatment. A second study (Abstract #4165) provides preliminary data on
patients treated with otlertuzumab plus the anti-CD20 antibody rituximab (Rituxan). This
dual antibody therapy was given to previously untreated CLL patients. Preliminary data
suggest an ORR = 88%, and modest AEs. This trial will be updated at the meeting. These
early studies suggest that targeting CD37 is an attractive approach for CLL therapy.
BITE antibodies are bi-specific antibodies originally developed by Micromet. They have
received a lot of press following the 1.2 billion dollar acquisition of Micromet by Amgen. Blinatumomab binds to CD3 on T cells and CD19 on lymphoma cells, helping to direct the
T cells to recognize and destroy the tumor cell (BITE stands for BI-specific T cell Engager). Abstract #1811 has some very early data on blinatumomab treatment of rrDLBCL patients.
Lets be clear upfront that this is a tough patient group to treat. At the time of abstract
submission, 11 patients were enrolled with initial ORR = 57%. It will be very interesting
to hear updated results from this trial at ASH, including both efficacy and AEs, which at
first glance seem tolerable if unpleasant (including CNS toxicity).
MEDI-551 is an afucosyl-anti-CD19 antibody with augmented cytotoxic activity (due to the
lack of fucosylation of the antibody). An 83 patient Phase 1 trial (Abstract #1810) enrolled heavily pretreated rr CLL, DLBCL, FL, or MM (multiple myeloma). All of these B cell lymphoma types are CD19 positive. The ORR = 25%, with CR = 10.8% and PR = 14.5%.
50.1% of patients were characterized as SD. PFS was calculated to be 9 months. At first
glance the single agent responses are substandard; MedImmune is continuing development
of MEDI-551 in combination with chemotherapy.
A CD19 ADC has advanced to phase 2, in a combination trial with rituximab (Rituxan).
SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a cytotoxic
agent. It is under development by Sanofi and was licensed from ImmunoGen. This ADC
was given along with rituximab (Rituxan) to rrDLBLC patients (refractory to first line
therapy or relapsed after a prior therapy; Abstract #4395). ORR was low at 31% and 36%
of responders progressed by the end of the study. Sanofi plans to move this agent into
patient populations that may be more responsive.
So, here we have seen two anti-CD19 antibody therapeutics with rather poor efficacy
profiles.
I want to end with an old dog/new trick story concerning alemtuzumab. First studied many
years ago in the context of transplant rejection therapy, this anti-CD52 antibody lives on as
a treatment for hematological malignancies (CD52 is widely expressed) and, under the
brand name Lemtrada, as a therapy for multiple sclerosis. The long strange trip of this
nasty antibody (the side effect profile is not good) is the subject for another day. Of interest
at ASH however is a nice study looking at the utility of alemtuzumab for very high risk
treatment naive CLL patients (Abstract #2861). High risk is defined here genetically – these
are patients with genetic deletions or mutations known to be associated with poor prognosis. Without diving into the details, the investigators have shown that TP53 mutations had an
adverse prognostic impact and shorter PFS and this was overcome by alemtuzumab treatment. This then presents itself as a potential therapeutic for patients known to have this poor risk
factor.
If time allows I want to discuss the CAR-T technology, perhaps in the next section.

Snapshots, 2013 American Society of Hematology Abstracts – New & Noteworthy

Part 4. Novel and exciting new pathways, drugs and combinations.

November 18, 2013

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx

OK, finally coming to the end of our review of the small molecule, mostly oral, CLL drugs, highlighting a few impressive studies.

First, the Idelalisib plus Rituxan (Rtx) phase 3 results were posted to late-breaking abstracts (Abstract LBA6). The trial was run in high-risk rrCLL patients, comparing placebo/Rituxan to Idelalisib/Rituxan. The data are summarized here:

The trial was stopped early based on the impressive data, including doubling of survival at 24 weeks. Detailed results should be presented at ASH.

Back to the abstracts:

Karyopharm is presenting Phase 1 results of KPT-330 (Selinexor) in NHL/CLL patients (Abstract #90) and AML patients (Abstract #1440). KPT-330 is an inhibitor of the Exportin/Xpo1 protein, whose normal function is to export tumor suppressor proteins from the cell nucleus. Blocking export of tumor suppressor proteins keeps them active in the nucleus, and induces the death of tumor cells. Xpo1 is mutated in some lymphoma patients, and mutated Xpo1 is associated with poor patient outcome.

Patients with advanced NHL or rrCLL, having failed therapy with all available drug classes, were dosed with oral Selinexor. The cohorts include patients refractory to Ibrutinib therapy and refractory to Rituxan plus chemotherapy (R-CHOP). Patients were dosed between 3 – 30 mg/m2 for 8-10 doses per 4-week cycle (NCT01607892). Grade 3/4 AEs were common, including cytopenias. No MTD has been established and dose escalation is continuing. Remarkably, ORR = 80% for all patients that could be evaluated; 20% of patients had PD. These preliminary results in such a high-risk rrNHL/CLL patient population investigators are very encouraging and the investigators will present updated results at the meeting.

Vorinostat, the HDAC inhibitor from Merck, is worthy of notice. What we see in the Phase 1/2 trial is an approach similar to the one Merck used for the AKT inhibitor MK2206. In both cases, combination therapy is initiated very early in the clinical trial process. Abstract #4191 outlines a trial design in which previously untreated CLL/SLL patients are given Vorinostat plus fludarabine, cyclophosphamide and Rituxan (FCR) for 4-6 cycles of therapy, followed by treatment with Vorinostat plus Rituxan alone. Analysis of 22 patients that had completed the treatment cycle is presented. The ORR = 100%, with CR= 73%, PR = 22% and SD = 4.5%. AEs are generally cytopenias, and GI complications.

A second study (Abstract #3063) examines the effect of Vorinostat in the context of Rituxan and cladribine therapy. The investigators will update previous results of a 40 patient Phase 1 study in newly diagnosed MCL patients. The abstract details the impact of a cyclin D1 allele on response to therapy, which has been reported as an ORR = 100% and CR= 87%.

Vorinostat has been around for a long time (aka SAHA) and it is encouraging to see these applications. What is interesting about these studies is that intervention is early (i.e. these are previously untreated patients) and aggressive. In will be useful to look at the comparative data for FRC treatment alone in these patient populations, but the available (and preliminary) data suggest that the Vorinostat combinations are very effective.

Of interest will be data from studies in which more selective HDAC inhibitors are used in place of Vorinostat, and data from other classes of epigenetic modulators.

We will turn next to Biologics, coming up in Part 5.

SnapShots, American Society of Hematology Abstracts – Part 3

Part 3. Additional studies featuring small molecule inhibitors for Chronic Lymphocytic Leukemia and other B cell lymphomas.

November 18, 2013

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx

Lets start with other compounds targeting Btk, PI3K and related kinases in the BCR signaling cascade. In part 1 of this series we looked at Idelalisib, a PI3Kdelta (d) inhibitor, and in part 2 we reviewed Ibrutinib, a Btk inhibitor. In both of those reviews we focused on data from CLL trials, as CLL is the most common B cell malignancy.

Other Btk inhibitors are moving through the clinical development process. Abstract #1630 presents Phase 1 data for relapsing/refractory Non-Hodgkin’s Lymphoma (NHL) patients, including CLL and SLL patients. CC-292 is a covalent inhibitor of Btk developed by Avila and acquired, along with that company, by Celgene. The Phase 1 is a dose escalation/dose schedule trial, with various doses between 125 and 1000 mg given once (qd) or twice (bid) a day. The maximum tolerated dose (MTD) was not reached and AEs were as usual in these trials, with cytopenias being the most common toxicity. The patients enrolled were rrCLL/SLL with high-risk characteristics, as were outlined in Part 1. Of 83 patients enrolled, response data are shown for the 55 efficacy-evaluable patients who had at least a PR (so, 66%). These patients were treated at the highest 4 dose levels: 750 mg qd, 1000 mg qd, 375 mg bid and 500 mg bid (qd = once daily and bid = twice a day). Across these 4 dose groups the ORR = 60% and all responses were PR. Some patients showed evidence of reduction of nodal (lymph node) disease as seen by a reduction in size of the nodes. Abstract #4169 lays out the pharmacodynamic (PD) assays that will likely be used in support of further optimization of this drug’s PK/PD profile. The assays include the familiar Btk autophosphorylation and PLC-g2 phosphorylation assays. Applied to the Phase 1 trial, the PK/PD analysis shows that BID dosing is preferable for CC-292, with 94% target coverage achieved at trough over 24 hours vs 83% target coverage (+/- 17%) at trough with qd dosing. This is important data that has already been applied to further clinical trials underway.

I’m hopeful that optimized dosing will allow CC-292 to achieve higher response rates. Looking beyond lymphomas, Celgene investigators will present preclinical data showing that CC-292 given in combination with a proteosome inhibitor carfilzomib had activity in Multiple Myeloma models (Abstract #682) suggesting other therapeutic areas for the development of Btk inhibitors.

Ono Pharmaceuticals will be presenting Phase 1 clinical data for ONO-4059, a covalent BTK inhibitor (Abstract #676). The trial enrolled 16 high risk rrCLL patients for a dose escalation study (20 – 320 mg). ONO-4059 is shown to have a half-life in circulation (T1/2) of 6 hours. Remarkably, PD analyses shows Btk target coverage of 100% at 24 hours at all doses tested. AEs were typical and not dose limiting. All patients initially responded. ORR is given as 70%, and 1 of 16 patients progressed. Notably, 15/16 patients are reportedly still on treatment. A second Phase 1 study (Abstract #4397), enrolled 14 patients (mantle cell lymphoma n=7, follicular lymphoma n=3, plasmablastic DLBCL n=1, ABC-DLBCL n=1, small lymphocytic lymphoma n=1 and Waldenstrom’s macroglobulinaemia n=1) using the same dose escalation design. This is a complex and difficult group of patients. ONO-4059 induced an initial response in all patients. The ORR (all patients) = 42% and for MCL patient ORR = 50%. AEs are similar to other Btk and P13K inhibitors.

The limited available data suggest that ONO-4059 is highly potent and will be an interesting drug candidate to watch. Preclinical data show synergistic efficacy with anti-CD20 antibody Obinutuzumab/GA-101 treatment, anticipating next steps (Abstract #3069).

Gilead is bringing forward a new Syk inhibitor, now in phase 2 clinical trials. Syk is the kinase just upstream of Btk and is required for Btk activation (see the model shown in Part 1). Early Syk inhibitors from Rigel and Portola were not selective and did poorly in the clinic, as discussed previously: http://sugarconebiotech.blogspot.com/2013/04/syk-inhibitors-continue-to-struggle-in.html. Gilead’s new inhibitor GS-9973 (Abstract #1634) is presented as having 7.6 nM activity against Syk with no other kinase being inhibited below 100nM. The abstract presents early activity data, with most patients responding to therapy within 4 weeks. AEs are mild except for grade 3/4 liver transaminase elevations in a small number of patients. Gilead will give a fuller picture of this phase 2 trial at the meeting. Gilead is developing GS-9973 as a single agent and also in combination with Idelalisib – the latter trial is recruiting patients with diverse types of B cell lymphomas (NCT01796470). Here again we are seeing the development of a rational combination – targeting two key elements of the signaling cascades that support lymphoma proliferation and survival.

Certainly there appears to be room for the development of additional BTK inhibitors, as this space is hardly crowded, and it will be important for companies to control their own compounds, for use in combination studies.

New PI3K inhibitors will report data at ASH, with IPI-145 from Infinity Pharmaceuticals updating a Phase 1 trial in B cell lymphomas, including rrCLL. IPI-145 is a potent PI3Kgamma/delta inhibitor, and impacts signaling through both of these isoforms at a sub-nM KD. The Abstract #677 reveals a maximum tolerated dose of 75 mg bid and also suggests that 25 mg bid is sufficient for target coverage by PK/PD analyses. The PK/PD analysis is shown in abstract #1633. These are the data that support the dosing regimen used in the ongoing Phase 3 clinical trials. The preliminary ORR for the rrCLL patients in the Phase 1 trial (19 patients) = 53%, and it appears there were a high number of discontinuations. Importantly, AEs appear to be in line with other drugs in this class. At the meeting, Infinity will present updates data from treatment-naïve CLL patients who received IPI-145 at 25 mg bid and R/R CLL patients who received IPI-145 at 25 or 75 mg bid.

Amgen is developing AMG 319, a selective PI3Kdelta inhibitor. Results from the Phase 1 dose escalation trial are shown in Abstract #678. Doses were 25 – 400 mg qd. AEs were diverse and included colitis in some patients at the 400mg dose. Ex vivo analysis of the phosphorylation of AKT (downstream of PI3K) showed nearly 100% inhibition 24 hours after dosing at 400 mg. Clinical activity was seen in all patients at all doses, with dose dependent activity observed.

Gilead has a 2nd generation PI3Kd inhibitor in clinical development, GS-9820. In Abstract #2881 dose escalation results from the Phase 1b trial are shown for doses ranging from 50 – 400 mg bid. No MTD was observed, there was no liver toxicity and 9/12 patients showed some response to therapy.

Bayer has a very interesting presentation of phase 2 data with BAY 80-6946, a selective PI3Kalpha/delta inhibitor. This drug is given IV at 0.8 mg/kg. There are notable toxicities (neutropenia, hyperglycemia, hypertension) but the efficacy is impressive at least at this early stage of development. I calculated %ORR and %CR by B cell lymphoma type, as follows (note that the sample sizes are small):



The hypertension AE is being studied in a sub-study of the ongoing Phase 2 trial (NCT01660451).

TG Therapeutics will show early data for TGR-1202 a novel orally available PI3Kdelta inhibitor. Patients have been dosed from 50 – 400 mg qd. DLT was not observed and at the 200 mg dose about half the patients had stable disease and half had progressed. The company plans to present updated results at the meeting.

Sanofi will present phase 2 results of its pan-PI3K inhibitor SAR245409, using the MTD as defined in solid tumor studies. This drug also targets the downstream signaling proteins mTORC1 and mTORC2. Data are presented in Abstract #4170. Focusing just on the CLL patients (n=10) 5 patients have SD, PFS ~ 6 months and 5 patients have a PR, PFS ~ 16.5 months.  That’s not a bad result, except that AEs are notable – all patients have cytopenias, GI complications, and hypotension. An update will be presented at the meeting. Follicular lymphoma (FL) patient data from the same trial is shown in Abstract #86. rrFL patients were given SAR245409 at 50 mg bid until disease progression (PD) or withdrawal. 36% of patients were lost to PD and 7% to AEs. 24 patients were available for evaluation, as they had responses as follows: ORR = 50%, PR = 36%, CR = 7%. For those 28 patients PFS had not been reached at 8 months.

As we can see from this Sanofi drug, moving to a pan-inhibitor and also moving further down the signaling pathways (mTORC1/2) doesn’t necessarily translate to better mono-therapeutic efficacy.

A different approach is seen with the Merck drug MK2206, an allosteric AKT inhibitor. Abstract #2882 presents a very interesting Phase 1 study. There is a 1 week “run-in” with MK2206 alone, sufficient to demonstrate a PD effect. After the first week, MK2206 is given along with bendamustine (B) and Rituxan (R). The MTD is shown to be 90 mg/week. Early results show an ORR = 89% and CR = 22% in the small Phase 1 study (n=9). These results compare favorably to BR alone (9% CR and 59% ORR) in rrCLL patients.

Other PI3K, AKT, mTOR and related drugs are in the pipeline for hematologic malignancies, and this is an area that should evolve quickly.

Next we will look at few promising pathways and drugs, coming up in Part 4.

SnapShots from the 2013 American Society of Hematology Abstracts – PART 2

Part 2. Small molecule BTK inhibitor Ibrutinib in the treatment of Chronic Lymphocytic Leukemia (CLL).
November 15, 2013
The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
Note that I’ve defined most of the terms we are using in Part 1, so please refer to that section for help with any abbreviations. In Part 1 is also some background on CLL and the signaling pathways downstream of the B Cell Receptor, which are targeted by these drugs. Finally, I introduced the patient populations typically encountered in CLL clinical trials.
So now we come to the Btk inhibitors and specifically to Ibrutinib, the Pharmacylics compound partnered with the Janssen arm of Johnson & Johnson. This soon-to-be blockbuster drug has been approved for the treatment of Mantle Cell Lymphoma (MCL) at an anticipated cost of 150,000 USD/year.
As mentioned in Part 1, CLL is the most common of the B cell lymphomas, so it is of keen interest to see how Ibrutinib performs in that patient population, especially given the efficacy seen with Idelalisib from Gilead.
Abstract #675 presents data from a 40 patient phase 2 trial in which Ibrutinib (IBRU, 420mg/day) was given with Rituxan anti-CD20 antibody (Rtx). The trial is notable for the inclusion criteria that enrolled patients only if they had high-risk disease: del(17p) or TP53 mutation (treated or untreated), PFS < 36 months after frontline chemotherapy + anti-CD20 treatment, or relapsed CLL with del(11q). Most patients responded well (see the table), very few patients were lost to followup and AEs were well tolerated.
Abstract #525 presents data from a small phase 1b trial in high-risk rrCLL/SLL patients (SLL is a form of CLL called small lymphocytic lymphoma, in which most of the cancer cells are located in lymph nodes). In this trial patients received IBRU + Rtx + B (bendamustine, see part 1). The response rate was very high (see the table) although the authors do note that 30% of patients eventually discontinued treatment, 10% due to progressive disease. Responses appeared to be independent of specific high-risk cytogenetic factors. Grade 3 or higher AEs were GI related, cytopenias (including 6.7% febrile neutropenia), and infections. The data from these 2 abstracts are shown below, and compared to published data (Byrd et al. 2013 NEJM 369:32-42). Note the caveats described above when reading these response percentages.
 
 
It is a little hard to directly compare these results with the Idelalisib data, partially reproduced here from Part 1, with one correction to the table (column 3: DOT = median duration of treatment):
 
 
It is tempting to conclude that the response rates with Ibrutinib are a little higher, but such comparisons will required much larger data sets. At the moment it is fair to say that these therapeutics both provide superb novel options for rrCLL patients.
Returning to Ibrutinib, there will be additional data from monotherapy studies shown at ASH. Abstract #4163 reports on an extension study of Ibrutinib monotherapy in treatment-naive CLL and in rrCLL patients. An important parameter of this study is that it included treatment-naive (likely newly diagnosed) patients; the data for discontinuation due to disease progression (PD) shows that nearly all of these early-treated patients maintain a response for at least the DOT.
After 2.5 years, 76% of this patient population was still alive, an impressive number.
Abstract #673 also examined the impact of Ibrutinib monotherapy, in this case in elderly patients with or without the del(17p) cytogenetic factor indicating high risk for progression. In this study there was a significant difference in the PR percentage, with 81% of patients with wild-type 17p responding while only 53% of patients with a deletion of 17p responded (p = 0.04). This suggests more (or larger) studies will be required to sort out the best patients for Ibrutinib therapy.
A very nice study will be presented by investigators at The Ohio State University (Abstract # 2872). Using multivariate analyses of patient response, progression and survival, these investigators compare Ibrutinib monotherapy to checkpoint-inhibitor therapy (alvocidib, dinaciclib, or TG02) to “other” therapy, in del(17p) rrCLL patients. “Other” is unfortunately not identified, but must include standard-of-care, which would normally be chemotherapy plus Rituxan. Here is a snapshot of the data at 24 months (the analysis is beautiful and I won’t reproduce their graphs here):
These data really drive home the importance of the new therapeutics and new therapeutic combinations, where we are seeing improvement in PFS.
There are a swarm of newer small molecule drugs coming up, and these will be covered in Part 3.

SnapShots from the American Society of Hematology Abstracts, Part 1

November 15, 2013
The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
Part 1. Small molecule PI3Kdelta inhibitor Idelalisib in the treatment of Chronic Lymphocytic Leukemia (CLL).
It is useful to remember that most CLL patients have indolent disease and are in a “watch and wait” mode with their physicians, who will not initiate treatment unless they see signs that the cancer is becoming active and/or the patient has one or more risk factors. Therefore in clinical trials the CLL patients are those at high risk. Typically “relapsed or refractory” CLL (rrCLL) patients have cytogenetic markers of poor prognosis (mutated p53, del(17p), del(11q), trisomy 12, mutated NOTCH1), or are patients who have failed multiple prior therapies (chemotherapy and/or antibody therapy such as Rituximab treatment), patients with “bulky” disease indicating lymph node and other lymphoid organ involvement, and patients with unmutated IGVH sequences. Often these high risk markers occur together. It is important to realize that at this time CLL is not considered a curable disease, and that the goal is therefore to increase median progression-free survival (PFS) and median overall survival (OS), the latter referring to time until death.
That said, we are witnessing a remarkable time. Terrific new therapies are being developed, and physicians look forward to offering their patients a chance at a cure.
Lets start with a drug class I think has great promise, inhibitors that act downstream of B cell receptor (BCR) signaling. CLL is a B cell lymphoma, and is dependent on chronic activation of these signaling pathways. Here is a model to get us oriented, from the Onclive website:
Note that Syk, Btk and PI3K are upstream (relative to the cell surface and BCR) and therefore are critical components of the pathway. Drugs targeting each of these signaling kinases have been developed. AKT, mTOR and others, generally more familiar to us from the solid tumor literature, are further downstream.
There are four isoforms of PI3K relevant to the drug class: alpha, beta, delta and gamma. Different drugs have selectivity for one or more of the isoforms.
For treatment of CLL, the lead therapeutic in the class Idelalisib is a PI3Kdelta(d) selective inhibitor from Gilead. PI3Kd signaling is known to be essential for the activation, proliferation, survival and tissue homing activity of lymphoma cells. On October 9th a phase 3 CLL clinical trial of this drug was stopped ahead of schedule based on a positive risk/benefit assessment. The drug is also under New Drug Application (NDA) review for indolent Non-Hodgkin’s Lymphoma iNHL) based on results from multiple phase 3 trials. Idelalisib is trailing just a step behind Ibrutinib, a BTK inhibitor, in the approval process – Ibrutinib was approved for Mantle Cell Lymphoma (MCL) on November 12th. Neither drug is approved for CLL, the most common lymphoma.
Both drugs have moved aggressively into combination therapy trials. Some of the early trials (phase 1 and 2) will report out interim data at ASH.
Abstract #4176 presents analyses of Idelalisib (IDELA) given in combination with Rituximab (Rtx) antibody therapy plus chemotherapy (B: bendamustine or C: chlorambucil) in high-risk rrCLL patients. Results are encouraging and shown in Table 1, where ORR = stable disease (SD) + partial response (PR) + complete response (CR). Its important to note that these are clinical trial terms and do not reflect outcomes, just observations at specific timepoints. Regardless we are looking for high % ORR, PR and CR. Importantly, the median duration of exposure was 18 months at the time of analysis, meaning that 18 months is the median amount of time patients have been exposed to drug without withdrawing due to toxicity, disease progression, or death. More importantly, the median duration of response (DOR) to therapy had not been reached within the 18 months (so that’s good, patients are still on drug and are still responding) nor had the median PFS been reached (so more patients have survived than have not survived). The IDELA-Rtx-C data are similar, just of shorter average duration with a median exposure = 7.7 months (I’m guessing here that this arm of the trial enrolled later). Also notable is the toxicity data from this trial, which tracked pretty consistently with the chemotherapy regimen. When the combination therapy included bendamustine, neutropenia was the defining toxicity, with > 60% of patients experiencing grade 3-4 neutropenia. When the combination therapy included chlorambucil, liver transaminase elevation was the defining toxicity, with > 21% of patients experiencing grade 3-4 liver toxicity. Its important to realize that these are severe, but manageable, toxicities for most patients.
Abstract 2878 presents a similar study, but in this case the combination therapy given with Idelalisib was limited to chemotherapy. Chemotherapy consisted of B: bendamustine, F: fludarabine or C: chlorambucil, given in standard doses. This trial was run in a heavily pre-treated patient population having a very poor prognosis. The data are very encouraging given the composition of the enrolled patient population (Table 1). The adverse events (AEs) were cytopenias and gastrointestinal tract (GI) disorders. This study demonstrates that Idelalisib has potent activity in combination with chemotherapy.
Abstract 4180 gives us data from an additional study, in which Idelalisib is paired with anti-CD20 antibody therapy (Table 1). As in the other studies the cohorts were comprised of a high risk patient population. This was a small phase 1 study with an extension arm, enrolling 40 patients. This study produced some sobering results that remind us how serious a disease aggressive CLL is, and how potent the drugs treating this disease have to be. Notably, 25% of patients did not enter the extension study due to disease progression, 6 patients died. A further 23% did not enter the extension study due to AEs. These data remind us that response rates readout at a specific pre-determined time during the trial, and do not reflect outcomes. Regardless the median PFS and DOR for all patients (N=40) and were 20 and 19 months, respectively. Median overall survival (OS) had not been reached.
The phase 3 study mentioned at the outset, which was stopped early due to significant evidence of clinical benefit, was very similar to, if much larger then, the Phase 1 study presented in abstract 4180. We don’t know much about the trial data yet, but Gilead’s press release states that the “Phase 3 study … evaluating idelalisib in previously-treated … CLL patients who are not fit for chemotherapy will be stopped early  … based on a predefined interim analysis showing highly statistically significant efficacy for the primary endpoint of progression-free survival in patients receiving idelalisib plus rituximab compared to those receiving rituximab alone. The safety profile of idelalisib was acceptable and consistent with prior experience in combination with rituximab in previously treated CLL.”
I think the general takeaway here is that a high proportion of those patients who respond did well over time. The fact that they did so without additional chemotherapy is very encouraging. PFS in either not being reached or is reached at 20 months or so. This suggests that impact on OS will be significant for all of the drug combinations presented. 
 
Additional analyses from Phase 1b and 2 studies were presented in abstract #1632. This abstract presents data comparing responses among CLL patients with high risk prognostic markers (del(17p) or TP53 mutation, del(11q), IGHV mutation and NOTCH1 mutation) to CLL patients without these markers. rrCLL patients given Idelalisib monotherapy or combination therapies responded equally well to treatment regardless of the presence or absence of these critical genetic markers of disease aggressiveness. That is a very important result that suggests great potential for CLL therapy with Idelalisib. The table is below.
 
Note that the response rates in the phase 2 Idelalisib + Rtx trial in previously untreated (i.e. newly diagnosed) patients are quite high, and this is exactly what you want to see as to drug moves to treat patients earlier in their disease course.
Next up is a review the Ibrutinib data in the same disease, and also a quick look at the other therapies in these drug classes.

ImmunoGen’s ADC Platform and Toxicity – Not So Simple After All

November 11th, 2013
Last week ImmunoGen’s candidate Antibody-Drug Complex (ADC) IMGN901 (aka lorvotuzumab mertansine)blew up in a Small Cell Lung Cancer (SCLC) phase 2 clinical trial. ADCs are designed to bind to proteins expressed at a high level on tumor cells. Upon binding these antibodies are internalized and release their payload, a cytotoxic drug. The idea is to load the tumor cells with a lethal poison while sparing normal cells.
The problem with IMGN901 seems a simple one. The antibody recognizes and binds to its target (called CD56) expressed on tumor cells including SCLC, Multiple Myeloma (MM), and Merkel Cell Carcinoma. In the SCLC trial the ADC was given either alone or with standard-of-care chemotherapy, which is the combination of etoposide and carboplatin (E/C).
It can be inferred from the press release that the ADC treatment, either alone or in combination therapy (ADC plus E/C) did not work: tumor cells were not killed off to a degree that resulted in measureable clinical benefit. Further, “an imbalance in the rate of infection and infection-related deaths was noted between the arms” and it was “recommended that all patients discontinue IMGN901 treatment. Infection-related death is a recognized risk in SCLC trials, including trials with E/C. Among the 198 patients receiving IMGN901 as a single agent in early trials, there was one incidence of infection-related death; it was deemed possibly drug related”. The quotes here are from the Business Wire version of the press release.
The tumor protein targeted by ’901, CD56, is also expressed on immune cells called NK cells. NK cells are essential for immune responses to infection, and it is possible that they were diminished enough by ’901 treatment to allow infections to occur at a rate higher than normal. CD56 expression on human NK cells is bright by flow cytometric analysis, generally giving a 2-log shift in staining intensity with standard reagents. This suggests somewhere between 10,000 and 50,000 copies of CD56 on each NK cell. This is similar to the expression of CD56 on multiple myeloma cells. We do not have comparative data for SCLC but immunohistochemical staining on these solid tumors shows extremely dark CD56 reactivity, implying robust expression. On balance it is plausible that there was enough expression of CD56 on human NK cells to cause their depletion, and this might have been associated with a higher infection rate. However, proving this is the case is currently not possible.
The combination of lack of efficacy and high rate of infections led the company to suspend the clinical trial.
Of note, a high infection rate was not noted in the ’901 MM phase 1 trial. This is from the presentation given at ASH in 2012, as summarized by The Myeloma Beacon web site: “Of the 39 patients evaluated for response, 57 percent of the participants responded to the combination therapy, including 3 percent who achieved a stringent complete response, 28 percent a very good partial response, and 26 percent a partial response. The most common side effects of all grades (both moderate and severe) included peripheral neuropathy (56 percent), fatigue (42 percent), low white blood cell counts (32 percent), and low platelet counts (32 percent).” In this trial the combination therapeutics used were Revlimid (lenalidomide) and dexamethasone, and the side effect profile is consistent with the use of those agents.
On top of the increased infection observed in the ’901 SCLC trial, there is also the larger question of whether ImmunoGen’s ADCs are inherently unsafe. This hypothesis has been brought forward based on multiple reports of ocular toxicity associated with ImmunoGen’s drugs, thought to be related to the “linkers” used by ImmunoGen to attach its antibodies to the toxin. The linker is a biochemical construct – these are designed to be stable while in circulation, and then cleaved once the ADC is internalized by the target tumor cell. Much has been made of the hypothesis that some linkers are “leaky”, that is, they undergo some cleavage even while in circulation and that this leakiness contributes to toxicity. This is a very difficult hypothesis to evaluate, as ImmunoGen has used multiple different linkers for different ADCs. Also there is anecdotal reference to ocular toxicity seen with Seattle Genetics ADCs, which use a different linker and toxin combination.
Some insight can be gleaned from ImmunoGen’s recent patents in the area of linker development. US 2012/0282282 “relates to charged or pro-charged cross-linking moieties and conjugates of cell binding agents and drugs comprising the charged or pro-charged cross-linking moieties and method of using the same to reduce ocular toxicity associated with administration of antibody drug conjugates”. The benefit of charged groups in the linker appears to be to increase solubility, which implies that the ocular toxicity is a drug precipitation or drug aggregation effect seen at higher doses. Example 8 of the patent states that  “administration of the substituted charged sulfo-SPDB linker for the uncharged SPDB linker greatly decreases ocular toxicity in a rabbit model.” Example 9 of the patent further states that “MGN242 is an antibody drug conjugate for the treatment of CanAg-expressing tumors … Forty-five patients have been treated with IMGN242 at 8 different dose levels (18 to 297 mg/m2) in two clinical trials. Dose limiting toxicities (DLTs) included decreased visual acuity, corneal deposits and keratitis, which appeared to improve in patients where follow-up data is available. A two-phase pharmacokinetic profile was observed for IMGN242 in plasma from patients with low circulating CanAg levels (1000 U/mL) compared to patients with low levels (
So, at least in this case, a high level of circulating drug is associated with ocular toxicity.
Similarly, ImmunoGen reported ocular toxicity associated with IMGN853, an ADC targeting folate receptor alpha on diverse tumor types. Toxicity was managed by dose reduction (from 7mg/kg to 5mg/kg, as reported at ASCO this year – abstract #2573). Related to this observation is the finding that changing the dose schedule can reduce ocular toxicity, as reported for with SAR3419, an ADC targeting CD19 (Beck et al. 2012. mAbs 4: 637-647).
ImmunoGen appears to have suffered a perfect storm of negative publicity on the heels of the ’901 efficacy/toxicity results. The data relevant to a specific drug (’901) in a specific cancer (SCLC) have been extrapolated to reflect on the entire pipeline. As we’ve seen from even this brief look under the hood, it’s not that simple. The bigger issue of ocular toxicity may be addressable by adjusting dose and dosing schedule, although I’ll grant this is not an ideal situation. ImmunoGen is continuing the development of next generation linkers as discussed above. Finally, ImmunoGen is seeing continuing success with T-DM1/Kadcyla, an earlier generation ADC with its own issues and history, approved for treatment of Her2-positive breast cancer. However, StartUp, writing in 2011, disclosed that ImmunoGen’s upside from the Kadcyla deal with Genentech/Roche was very limited, with single digit royalties following the payment of ~50MM in milestones. At total worldwide current Kadcyla sales of ~200MM per annum this will not amount to much cash. I have no idea what ImmunoGen’s broader financial picture looks like, but investor’s were clearly spooked by last week’s news, driving the stock down over 20% on November 4th. It has regained about half of that ground since.
 
With at least 10 ADCs using 4 different linkers already in the clinic, trial results may inform ImmunoGen’s developmental strategy in a timely manner, and at the end of the day this technology may be refined to a point that it achieves broader application. In the meantime we should anticipate a bumpy ride, to be expected I think when innovation is the driver. ImmunoGen aside, Seattle Genetics, Roche, BMS, Takeda etc have programs running in this space, with 32 clinical programs listed by Credit Suisse in November 2012. A host of small companies (and investor’s dollars) are competing to add value, whether at the level of antibody technology, alternative scaffolds, novel linker technology or new ways to couple toxins in ADCs. Identifying the best chances for adding value is a discussion for another day.