Category Archives: Drugs (generic and brand names)


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                         

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

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 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
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
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.

Gilenya and PML: cause, effect and risk

Today the FDA followed up on a case of progressive multifocal leukoencephalopathy (PML) in a multiple sclerosis (MS) patient, first reported in July, by announcing an investigation. FiercePharma spelled it out as follows: 

Novartis’ MS drug Gilenya tied to rare brain infection FDA sends out alert
That’s a pretty scary headline, and the news drifted across twitter streams like a dry fly on a light tippet. Novartis quickly declared that there was no indication that Gilenya caused the rare brain infection, the patient was on co-medications, had been given intravenous steroid treatment, etc. etc. 

Lets back up. 

PML is caused by an infection of the JC virus within the central nervous system (CNS). PML is common and almost always benign, unless it occurs in a patient who in severely immunosuppressed. Of note, PML first came to public attention in the early days of the AIDs epidemic, appearing in HIV patients whose disease had progressed to the point that they had no more T cells in circulation. T cells are a critical arm of the immune system, that, along with B cells and other cells, control pathogen infections, including viral infections.   

MS, as readers know, is a chronic inflammatory autoimmune disease in which T cells, B cells and other components of the immune system engage in a deranged attack on the CNS, particularly targeting the myelin and other proteins that encase neurons in a sheath (thus, the myelin sheath). Neurons stripped of myelin do not signal properly and die off pretty quickly. The disease occurs in flares, geographically localized. The product of a flare is a “lesion” within the CNS, where the effect of demyelination and neuronal die back can be visualized by an MRI image. 

So, immune system cells, particularly T cells, are necessary for protection from JC-virus induced PML on the one hand, and cause MS flares and lesions on the other hand. It should be noted that more flares = more lesions = MS relapse or progression = more disability. 

The interplay of immune defense or immune surveillance and the pathology of MS first came to light with the development of two powerful immune modulating agents: Tysabritmand Rituxantm. Tysabri is a monoclonal antibody to the alpha4beta1 integrin (thus, a4b1) developed by Elan and licensed to Biogen. Tysabri is the single most potent agent developed to date for the treatment of MS, and its mechanism of action suggests why this is so. T cells use the a4b1 integrin to migrate out of circulation and across cell layers like endothelium. To gain access to the CNS, T cells must cross an endothelial cell membrane, a layer of basement membrane and then an epithelial cell membrane. This collection of barriers between the circulation and the CNS is called the blood-brain barrier. Importantly, a4b1 is necessary for efficient trafficking of T cells out of circulation and into the CNS (also into the lung, the gut mucosa and other tissues). When a4b1 is blocked by treatment with Tysabri, which binds and neutralizes a4b1, T cell movement out of circulation is effectively stopped. Indeed one of the first effects of Tysabri treatment is a rapid increase on the white blood cell count, as T cells excluded from tissues begin to accumulate in the bloodstream (and lymph). 

Tysabri treatment reduces signs and symptoms of MS, reduces relapses, number of flares, time to flare, number of lesions, and disease progression. Tysabri treatment also puts patients at a low, but still troubling, risk of developing PML, since the population of T cells excluded from the CNS also include those T cells that normally would control JC virus. In this case the mechanism of action (MOA) of Tysabri contributes to the risk of PML, and this can be seen in patients treated only with Tysabri (as monotherapy) as well as in patients taking multiple medications. The risk is handled in several ways: patients are monitored for the presence of antibodies to PML, that indicate exposure and likely the presence of quiescent virus in the patient, and by temporarily suspending Tysabri use for several months, usually after 2 years and intermittently thereafter. Its not a well defined art at this point, but because of the efficacy achieved with use of Tysabri, most patients and their physicians tolerate the risk, now estimated at about 1% across all patient groups. 

PML in Rituxan treated patients presents very differently. Rituxan is an antibody that binds to CD20 expressed on the surface of B cells, and this binding causes the B cells to be depleted. The antibody was developed by Idec and acquired by Biogen when those two companies merged to become Biogen Idec. Before Rituxan was essentially removed from the clinical MS landscape – a truly scandalous story for another time – it had undergone clinical trials in MS, showing excellent efficacy and limited toxicity, which did not include PML. Rituxan causes PML very rarely, and almost exclusively in lymphoma patients, who have been treated previously or concurrently with chemotherapy. In other words, PML was seen in heavily immunosuppressed cancer patients. Rituxan is also used in rheumatoid arthritis (RA) and a host of other inflammatory and autoimmune indications, and the risk of PML in these patients taking Rituxan is at least 10-fold lower than in lymphoma patients taking Rituxan. This is because RA patients are much less immunosuppressed than cancer patients. What we see then with the risk of PML from Rituxan is that the risk is really dependent on the prior immune status of the patient. In this sense you would not make the claim that Rituxan causes PML, but rather that it contributes to the risk of developing PML. IN the same way, Tysabri treatment doesn’t cause PML, but also contributes the risk of developing the disease. It is the case that the risk is higher with Tysabri than with Rituxan. 

Why Rituxan treatment allows JC viral escape and the occurrence of PML is a result of the depletion of the B cells that Rituxan targets. B cells make antibodies to pathogens, including anti-JCV antibodies, and this contributes to the control of virus by clearing both free viral particles and infected cells. Further, B cells supply “help” to T cells by secretion of cytokines and other factors that induce T cell survival, proliferation and function. So, T and B cells together are required for efficient JC virus control, although the available data suggest T cells are more directly critical. 

OK, back to Gilenya. I guess it was 4 or so years when the phase 3 data was coming out that I had a conversation with Jeff Browning, then at Biogen Idec and now at BU, about the results. He said something along the lines of, “sure, impressive results, but wait until they start to get PMLs.” 

Prescient, and certainly a well informed view. Jeff, myself, Paula Hochman (all from Biogen) and Reina Mebius (a key collaborator) along with a host of colleagues both inside and outside the company, had reinvigorated the study of lymph node biology in the mid-90s by unraveling the mechanisms by which these organs develop (search PubMed if interested), and as the field literally burst with new findings, attention turned to the control of lymphocyte (T cell and B cell) movement through the lymphatic system, within which lymph nodes are the critical organs. Lymph nodes (LN) provide the essential microenvironment for surveillance of tissues, including the CNS. Many labs unraveled the biology of cell traffic through LN, but it was Jason Cyster at UCSF who discovered that an agent in clinical trials called FTY720 functioned by shutting down the molecular pathway that allows T cells to exit LNs. The molecular pathway was driven by a bioactive lipid called sphingosine 1 phosphate (S1P). S1P bound and signaled through a class of receptors (the S1P receptors) and S1P receptor 1 was shown to be critical for T cell egress from LN. 

FTY720 became Gilenya. Thus, the mechanism of action of Gilenya is eerily similar to that of Tysabri – it controls the trafficking of T cells, in this case by trapping them inside of lymph nodes (B cells as well, although not so completely). The fact that Gilenya treated patients do not develop lymphadenopathy(LN enlargement) suggests that these trapped T cells die off. Gilenya treated patients experience a rapid drop in circulating white blood cell number – the opposite of what is seen in Tysabri treated patients – but the net effect is the same: T cells do not access the CNS, and therefore the signs and symptoms of MS are reduced, the relapse rate drops, the number of new lesions drops, etc, more or less similar to Tysabri treatment, albeit somewhat less effective. Gilenya has a host of non-immune system toxicities, which we won’t discuss here, but until July, Novartis, who developed the drug, had reported no patients with PML. 

Now, back to the headline. What Jeff Browning had recognized was that by its’ mechanism of action of Gilenya should increase the risk of PML, just as Tysabri increased that risk. Both stopped T cells from entering the CNS, by different mechanisms, and therefore both should prevent immune defense against JC virus in the CNS. Furthermore, the degree of risk should be proportional to the extent to which the exclusion of T cells was achieved. Since the efficacy of the drug should also be proportional to the extent to which t cells were excluded from the CNS . . . it follows that efficacy and risk of PML should be correlated. 

When Novartis states that Gilenya does not cause PML, they are being accurate, as accurate as when we state that Tysabri and Rituxan do not cause PML. More importantly and usefully, Gilenya is now hypothesized to be associated with the risk of developingPML, although it’s certainly a low risk. More specifically, the null hypothesis should be that Gilenya is associated with PML risk, based on its’ mechanism of action, and regulatory agencies and physicians should take note accordingly. 

We’ll watch out for other cases and comment as the clinical landscape develops. 

As always, stay tuned. 


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.







PI3Kd isoform
PI3Kd/g isoforms
Partial response (PR) 

40%      (n = 5)
Complete response (CR) 

Overall response (OR = PR + CR) 

60% (n=5)
OR in 17p(del)
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







PI3Kd isoform
PI3Kd/g isoforms

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




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.

Syk inhibitors continue to struggle in the clinic

Syk inhibitors have had a rough ride, with both Rigel and Portola running into significant issues in clinical development.

Rigel and partner Astra Zeneca released data from a Phase 2 Rheumatoid Arthritis study, summarized here:

“In the study known as OSKIRA-1, two doses of fostamatinib significantly improved the signs and symptoms of rheumatoid arthritis compared to a placebo following 24 weeks of treatment. However, fostamatinib failed to show improvements over placebo in bone erosion and joint-space narrowing as measured by X-ray.” from

Sadly thats about all you need to know about fostamatinib, especially given that earlier data have been unimpressive as we discussed in December. There is no clear role for this drug in RA given the label granted to Pfizer for their JAK inhibitor tofacitinib, approved for use as second line therapy for RA. Tofacitinib also has shown clear evidence of protection from joint damage, something fostamatinib has failed to do.

Fostamatinib is apparently moving forward in multiple oncology indications, and therein may lie its future, if it has one.

Portola’s Syk inhibitor, licensed by Biogen Idec, is in development limbo, and the clinical trial in RA was withdrawn. Whether this is due to toxicity issues, efficacy concerns, or commercial strategy is not known, as Biogen has not provided an update on this drug.

In the meantime companies continue to focus on kinases that signal downstream of Syk, notably Btk and PI3K. While PI3K inhibition may carry too much toxicity for use outside of oncology, Btk inhibitors appear to be safe enough to develop in autoimmunity and inflammation. We will continue to watch the development of small molecule inhibitors in this space, and anticipate success for novel Btk inhibitors.

Interesting Dilemma for Genzyme and Other MS Players in Europe.

Guest Blog Post courtesy of Stephen Ames – Life Sciences Analyst

As Paul mentioned in the first paragraph of his post, Aubagio recently received positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the EMA. The committee is recommending the granting of marketing authorization for the treatment of adult patients with relapsing multiple sclerosis, which is by far the most common form of MS. Additional marketing applications for the drug are currently under review globally.

But there is a limitation in the recommendation that may have important consequences in the MS market, and was a very disappointing piece of news for Genzyme (a division of Sanofi). Although CHMP did recommend marketing authorization, they did NOT recommend that Aubagio receive a “new active substance” (NAS) designation. This was based on their opinion that the drug is simply a revamped version of a much older drug. The outcome means that Genzyme gets fewer years of market exclusivity than they would otherwise, which clearly erodes potential profits. Why? Because generics companies won’t have to wait as long as usual to enter the market with a less expensive, bioequivalent version of Aubagio which would result in “generic erosion”, a reduction in potential profits for Genzyme’s sales of the drug.
The relatively quick introduction of generic Aubagio in the European market would not only dig into Genzyme’s sales, it would also likely result in revenue erosion in European sales for MS therapies produced by Genzyme’s competitors. MS therapies are some of the most expensive in medicine, and over the years many of their price tags have actually increased. A lowering of prices in response to an oral generic would be a market first. Ironically, generic Aubagio would likely also erode potential sales of Genyzme’s own MS drug Lemtrada which is currently under review and if approved, would hit the market in 2014.
To keep things simple here, it is fair to say that Genzyme has two choices when considering the European market. They can launch Aubagio and try to earn as much revenue as they can during the relatively short period of market protection, or they can decide not to launch, which would then preclude the entrance of generics in the EU market (generic drug companies cannot market drugs in a country where there isn’t a “reference” drug – in this case Aubagio) which means the company doesn’t have to spend for a rollout, and means that they won’t have to compete with generic Aubagio. The latter is a safe play and is probably what the competition in Europe is hoping for. Biogen-Idec, for example, is expecting EU approval of their first oral MS drug Tecfidera, and would clearly prefer to play in a market space without a competing branded oral and certainly without a generic oral. 
In my opinion, the former approach (marketing) is more likely. Even if Genzyme is granted only one year of market protection, the actual length of this protection is likely to be extended given the usual delays that historically accompany the process of getting generics onto the market. In addition, this window of time will allow the company to develop relationships with MS prescribers across Europe. This latter point is crucial because establishing this network will grease the rails for Lemtrada if approved.

Genzyme is planning to request a re-examination of the NAS decision, and so we’ll have to wait and see what comes of that step. This is an interesting story to be sure, and one that the field will be following very closely as it evolves.

By the way, Biogen-Idec received FDA approval to market Tecfidera in the US today.

A Science-Side Guide to the New Oral Multiple Sclerosis Drugs

Back to the blog now that I’ve settled into a new career (more on this another day).

Last week brought a wave of commentary on the evolving Multiple Sclerosis (MS) marketplace, as the European Medicines Agency (EMA) rendered positive opinions for two new oral drugs for the treatment of relapsing and remitting MS: Tecfidera (dimethyl fumarate or BG-12) and Aubagio (teriflunomide). FDA approval of Tecfidera is expected this week; Aubagio won FDA approval in September 2012. The focus of much of the discussion was the impact these new drugs would have on the companies that dominate the MS market: Biogen Idec, Novartis, Sanofi/Genzyme, Teva, EMD-Serono, and Takeda/Millenium. A summary of last week’s approvals can be found at FierceBiotech:

The consensus is that these new drugs will very quickly impact MS treatment paradigms and alter the fortunes of companies operating in this market. This is therefore a particularly good time to have a look behind the hype, and review the scientific rationale behind some of these new therapies. I’ll address the landscape with one eye on drug efficacy and one on known and potential side-effects of this new class of MS therapeutics.

The current stage was set in September 2010 with the approval of Gilenya (fingolimod), an S1P receptor modulator developed by Novartis. S1P receptors regulate a bewildering array of biological and pathological responses. Gilenya acts on at least 4 different S1P receptors, so formally speaking its’ mechanism of action in MS is undefined. It does appear however that the basis for the efficacy of this drugs lies in its ability to down-regulate the activity of the S1P receptor 1 (S1P1). S1P1 has many functions, including regulating the exit of lymphocytes, particularly T cells, from lymph nodes. Since all T cells that are in circulation will move through both the bloodstream and the lymphatic system, they all move through lymph nodes, which are organs that lie within lymphatic circulation. As T cells become trapped in lymph nodes, the number of circulating T cells in the bloodstream drops precipitously. In MS, autoreactive T cells use the blood circulatory system to gain access to the central nervous system (CNS) and attack myelin and other CNS antigens, thereby causing the disease. Gilenya is effective in MS because it prevents T cells from reaching the CNS, instead trapping them inside lymph nodes. This mechanism of action (MOA) is superficially similar to that of Biogen Idec’s Tysabri (natalizumab), a biologic drug that acts on T cells by preventing their exit from the bloodstream into the CNS (and other tissues). Both drugs therefore impact MS via effects on T cell movement. Tysabri is the single most efficacious drug developed for MS capable of reducing the annualized relapse rate by 68%. However, use of this biologic drug requires intravenous infusion (IV) and extended therapy is associated with a variety of side-effects, including the very dangerous disease PML. Its fair to say that Biogen-Idec has worked very hard at defining and managing PML risk associated with Tysabri use, and Tysabri continues to be a dominant drug in this market. I’ll come back to the efficacy and side-effect profiles of Gilenya in a bit, but first lets introduce the newer drugs.

Tecfidera was developed by Biogen Idec and is their first oral drug for MS. On March 20th the EMA’s Committee for Medicinal Products for Human Use (CHMP) issued a positive review of Tecfidera as a first-line therapeutic for the treatment of relapsing remitting MS. A positive CHMP opinion means that the drug is likely to be approved by the EMA for sale in the EU within a few months. FDA approval for use in the US is expected on March 28th. Tecfidera, like Gilenya, does not have a formally defined MOA, although there is good evidence to support the hypothesis that this drug primarily acts as an NRF2 activator. This is a compelling MOA, as NRF2 is a master regulator of the oxidative stress response. The drug may very well act on both the inflammatory response to myelin and other CNS proteins, blunting its intensity and impact, and directly on cells within the CNS, via cytoprotective effects. The efficacy of this drug was demonstrated in 2 large phase III studies (DEFINE and CONFIRM) and is impressive. Pooled phase III data showed reduced disease burden as measured by annual relapse rate (reduced by 49%) and identification of new or enlarged MS lesions (reduced by 78%) among other favorable outcomes. Equally compelling is the safety profile of this drug, with side-effects generally limited by unpleasant gastrointestinal (GI) symptoms including nausea, diarrhea and abdominal pain. For many patients these side effects wane after the first month.

Aubagio was developed by Sanofi and its’ subsidiary Genzyme. Aubagio is the teriflunomide metabolite of leflunomide, an approved drug for rheumatoid arthritis. These drugs are pyrimidine synthesis inhibitors that function by targeting the mitochondrial enzyme dihydro-orotate dehydrogenase. Inhibition of pyrimidine synthesis blocks DNA replication and causes cell death of dividing cells like activated T cells and B cells, thereby reducing lymphocyte proliferation. Not surprisingly, this class of cytotoxic drugs was first developed in the context of cancer therapy.

So with Aubagio we are back to effects on lymphocytes, presumably impacting activated T cell survival and function, reminiscent of Tysabri and Gilenya that also target T cell activity. Aubagio has a rather different efficacy/toxicity profile than the other drugs we have discussed so far. With a risk reduction of approximately 30% in annualized relapse rate, Aubagio has an efficacy profile similar to the beta interferons (Avonex, Betaseron, Rebif) and Copaxone, drugs that are delivered by cutaneous injection. On this basis, Aubagio would benefit from the fact that it is an oral medication, not requiring injection. The safety profile for Aubagio is perhaps more problematic, as this drug carries a black box warning for liver toxicity and is contraindicated in women who are pregnant or are likely to become pregnant due to concerns about teratogenicity. Also Aubagio is associated with increased susceptibility to infections, alopecia (hair loss) and GI effects.

Despite the safety concerns, Aubagio has attracted use among US neurologists whose patients want an oral medication, and this is despite the modest efficacy profile. This brings us back to Gilenya, the first oral MS drug approved in the US and EU. Gilenya is certainly efficacious, with a reduction in the annualized relapse rate of 54%, which is very similar to Tecfidera. Gilenya has a challenging risk profile, with a still poorly understood cardiovascular risk and a high rate of opportunistic infections. Recently, 15 unexplained patient deaths have triggered a review by the EMA that could lead to new safety warnings. Bradycardia continues to be an issue with Gilenya use, requiring patient monitoring after the first dose for at least 6 hours. Despite this safety profile, the efficacy of Gilenya has driven substantial use, and Novartis reported at the American Association of Neurologists meeting last week that no new toxicities have been seen in long-term extension studies.

It’s worth briefly mentioning two other potential oral medications for MS. Laquinimod is an immunomodulator from Teva and Active Biotech. Laquinimod’s MOA is not well understood. The drug has given mixed results in 2 phase III MS clinical trials, with pooled data showing only a 21% reduction in annualized relapse rate. A third trial is underway. The drug appears to be relatively safe, and may be appropriate for some patients although the limited efficacy will make wide use of this drug difficult to justify. Cladribine, from Merck Serono, is another drug that interferes with DNA metabolism and is broadly cytotoxic. It was withdrawn from consideration for use in MS after FDA rejection and negative EMA guidance. Cladribine was associated with an array of severe toxicities consistent with its cytotoxic MOA, including high risk of infection, neutropenia, liver toxicity, effects on the CNS and other side effects.

What we see then among the class of oral MS drugs is a spectrum of efficacy and toxicity profiles that will determine the evolution of their use in the context of existing injectable drugs. We see distinct mechanisms of action that will allow for class differentiation and, perhaps, for combination therapy. This latter goal, likely to be a critical development to stopping MS progression completely, will be achieved if, and only if, the toxicity profiles of potential combination therapies allow. In this regard the use of injectable beta interferons may be most compatible with the use novel orals like Tecfidera. A few combination therapy trials are underway.

Watch this space for further updates on developments in autoimmunity and oncology, my favorite subjects in drug development.

Please follow the author on Twitter @PDRennert and connect on LinkedIn.

Targeted kinase inhibition in inflammation & oncology: lots of gambling, and some winners

We’ve had a lot of news in the last 6 weeks from ACR, ASH and the release of clinical trial results. Here’s what we’ve learned in, and some thoughts on what might come next:
1) Rigel and partner AstraZeneca threw craps in the RA game. Syk inhibition is less effective than Jak inhibition in Rheumatoid arthritis (RA), per ACR presentations on Jak inhibitor tofacintinib and clinical trial data released on Syk inhibitor fostamatinib. Whether the difference in efficacy is due to suboptimal dosing of the Syk inhibitor fosta’nib, or reflects distinct biological readouts is a critical question, particularly as fosta’nib has off-target activity on Jak1 and other relevant kinases. It is interesting that Pfizer’s tofacitinib, widely viewed as a pan-Jak inhibitor with potential toxicity issues, has scored approval in DMARD-IR patients, and can therefore be prescribed before biologic therapy.  I’ll admit I did not see this coming and felt tofa’nib would get approval, to start, in TNF-IR patients only. AZN is clearly running the clinical trials needed to show a clean safety profile for fosta’nib, but may now lose out in the marketplace on the basis of efficacy. It remains to be seen how this will play out as Rheumatologists weigh the safety/efficacy profiles of these drugs, but clearly in a “treat to target” regimen, where the target is no clinical sign of disease and no advance in joint degradation, fosta’nib has a tough road ahead. They may yet persevere but it will take a combination of squeaky-clean safety data and a clear demonstration of protection from joint damage. The compound is also moving forward in B cell malignancies (see below).

            We will not learn anytime soon if better Syk inhibitors would be better RA drugs, as Biogen Idec may have lost its bet on Portola’s Syk inhibitor. Biogen has quietly withdrawn its phase 2 clinical trial for PRT062607, aka BIIB057 ( The withdrawal occurred prior to the recent data coming out on fosta’nib and seems more likely to be related to the specific compound than to the pathway. Looking more widely at drug development in this space, the only other clinical stage compound is the inhaled Syk inhibitor R343, for asthma and other lung diseases, currently in phase 2 and unlikely to provide any insight into the systemic inhibition of the pathway in RA. We may have to wait for clinical readouts in RA following inhibition of Btk – this is the next kinase downstream of Syk – before we understand the utility of targeting this pathway. More on Btk to follow.
2) Jak inhibitors: does three of a kind equal two pair? There are actually four Jak kinases: Jaks 1,2,3 and Tyk2. People used to spend a lot of time discussing the specificity of different Jak inhibitors and the toxicity/efficacy expectations of targeting Jak3 vs Jak2 vs Jak1. The reality is that all Jaks are obligate hybridizers: distinct Jaks hybridize to transduce signals from cell surface receptors. It is very likely that different Jak specificities matter less than we think and that the current crop of Jak inhibitors are more alike than they are different, off target specificity aside. That being said, the Jak inhibitors appear to be poised to reap hefty winnings, in wildly distinct diseases. Novartis’ and Incyte’s ruxolitinib (Jakafitm),first-in-class “Jak2-selective” inhibitor, was approved for use in myelofibrosis in early 2011 and in 2012 is already poised to take in $100MM in sales as patients move onto this drug earlier in the treatment paradigm. The therapeutic rationale of Jak inhibitor use was well understood from genetic analysis of myelofibrosis, and the commercial and clinical validation is now clear, prompting Gilead to recently pay ~$400MM to buy the phase 1 Jak1/2 inhibitor CYT387 along with the rest of YM Biosciences. Other Jak2-selective inhibitors in development include the Sanofi Aventis compound SAR302503, currently in phase 2, and the Cell Therapeutics compound pacritinib. While myelofibrosis is the clear POC arena for these compounds, look for companies to begin moving these into new therapeutic areas as the compounds advance.

 3) Jaks are wild in RA. I’ve already mentioned the success of Pfizer’s pan-Jak inhibitor tofacitinib (brand name Xeljanztm), recently approved for use in RA patients who have an inadequate response to DMARDs such as methotrexate. Other Jak inhibitors being developed to compete in the inflammation area include the Jak1-specific inhibitor GLPG0634 from Galapagos, licensed in early 2012 by Abbott (now AbbVie), who paid $150MM upfront for rights to the Phase 1 compound. It should be noted that GLPG0634 does appear to have a different side effect profile than the other Jak inhibitors, in that no impact on lipid levels were seen, nor signs of anemia and neutropenia. These side effects have been seen in clinical trials of ruxolitinib and with tofa’nib and are generally ascribed to Jak2 inhibition. Given the promiscuous nature of Jak heterodimerization this differentiation remains somewhat surprising. Indeed, Cell Therapeutics, who is developing S*BIO’s Jak2-inhibitor pacritinib in myelofibrosis, claims not to see anemia or thrombocytopenia (another class side effect) in the clinic. Finally, Vertex has moved its Jak3-selective inhibitor VX-509 into phase 2b following decent results in a phase 2a RA trial. No matter how you look at it, the data suggest that hitting any combination of Jaks, or just one if we believe the Galapagos selectivity data, is sufficient for efficacy in RA. This is almost certainly due to the prevalence of heterodimerization, as mentioned, but also due to the sheer number of pathogenic pathways impacted by Jak inhibition, including numerous cytokine and growth factor pathways. Despite the risk of side effects from such broad blunting of the immune system, this approach so far appears to be more efficacious, and at least as safe, as inhibition of Syk. On the basis of efficacy in RA, one might be tempted to move Jak inhibitors into stubborn and complex diseases like systemic lupus erythematosis. That’s another bet altogether but I’ll be looking for those investigator trials!

4) PCI’s Btk inhibitor shows its hand. The recent American Society of Hematology (ASH) meeting was a showcase for Pharmacyclics’ (PCI) and JNJ’s Btk inhibitor ibrutinib, aka ib’nib. This Btk inhibitor produced remarkable efficacy in several B cell lymphomas, including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and Mantle Cell Lymphoma, the latter being generally viewed as a very intractable disease. The data have been reviewed in detail elsewhere (e.g. fiercebiotech story), but clearly ib’nib has validated Btk inhibition as a therapy with broad application in B lymphoma oncology. The field is still young, with the next closest drug in development Avila’s AVL-292, who reported phase 1b data at ASH. AVL-292 demonstrated efficacy in Non-Hodgkin’s Lymphoma (NHL), CLL, multiple myeloma (MM) and other indications. Avila was acquired by Celgene earlier this year, further highlighting the interest in Btk inhibition in oncology. Ib’nib and AVL-292 covalently bind to the kinase domain of Btk, forming an irreversible bond that prevents substrate from accessing the active site of the enzyme. Historically, covalent inhibition has been associated with off-target toxicity, as it is possible for the drug to link irreversibly to unwanted targets. Happily, this does not appear to be an issue with this new class of covalent inhibitors, and toxicity is generally considered mild. Regardless, non-covalent inhibitors are being developed by several companies, perhaps with the goal of differentiating from the leading compounds. The CGI compound GDC-0834, now held by Genentech, in a non-covalent active site inhibitor under development for inflammatory disease, as is the Roche compound RN486.  Given the current status of the Syk inhibitor fosta’nib in RA, it will be interesting to see if these companies stay the course, or move their inhibitors onto new disease targets. It was the success of Syk inhibition in early RA and B cell lymphoma trials that stirred interest in Btk, and the field will respond accordingly to any new Syk inhibitor data.

This is a lot of information to absorb, but it stimulates the obvious question: What’s next? Here are just a couple of thoughts:

– What is considered safe and efficacious today will change tomorrow. As combination therapy takes hold in B cell oncology, additive toxicity may become problematic. If we consider the obvious combination of a Btk inhibitor with other kinase inhibition, or with biologic therapy, the safety/efficacy profile of these compounds will evolve. This is even more true in RA, where toxicity will drive physicians away from drugs.

– Escape is possible (or inevitable). As has already been described in myelofibrosis, patients needing chronic therapy may select for drug resistance. In myelofibrosis, such resistance is associated with the recruitment of other Jaks to take over for Jak2. Having a well-stocked armory may allow continued control over the disease, even as signaling pathways shift – in the context of B cell lymphomas this may mean Syk inhibitors, Btk inhibitors, PI3K inhibitors, mTOR inhibitors, in succession or in tolerable combination therapies.

– In RA the success of tofa’nib heralds a new wave of oral medications that can challenge biologic therapies, in particular the anti-TNF biologics. This is no surprise, and it will be of considerable interest to watch how clinical practice evolves. I’m hoping that diligence is being applied to the collection of samples for analysis of response and non-response in patients receiving the new, targeted orals as it will be fascinating to understand why some patients fail while some succeed – something not yet adequately understood in RA.

– Finally its important to remember that “success” in RA still means that most patients fail to reach ACR 50 and ACR 70 scores, suggesting that they are continuing to experience disease despite treatment. Until these numbers come up, perhaps in the context of personalized medicine, we cannot declare that the work in RA is done. We note in passing that there are a plethora of diseases that could benefit from these new kinase inhibitors, and expect to see their use tested more widely.