Category Archives: TG Therapeutics

Some Adjacencies in Immuno-oncology

Some thoughts to fill the space between AACR and ASCO (and the attendant frenzied biopharma/biotech IO deals).

Classical immune responses are composed of both innate and adaptive arms that coordinate to drive productive immunity, immunological expansion, persistence and resolution, and in some cases, immunological memory. The differences depend on the “quality” of the immune response, in the sense that the immunity is influenced by different cell types, cytokines, growth factors and other mediators, all of which utilize diverse intracellular signaling cascades to (usually) coordinate and control the immune response. Examples of dysregulated immune responses include autoimmunity, chronic inflammation, and ineffective immunity. The latter underlies the failure of the immune system to identify and destroy tumor cells.

Let’s look at an immune response as seen by an immunologist, in this case to a viral infection:

 immune viral

Of note are the wide variety of cell types involved, a requirement for MHC class I and II responses, the presence of antibodies, the potential role of the complement cascade, direct lysis by NK cells, and the potentially complex roles played by macrophages and other myeloid cells.

In the immune checkpoint field we have seen the impact of very specific signals on the ability of the T cell immune response to remain productive. Thus, the protein CTLA4 serves to blunt de novo responses to (in this case) tumor antigens, while the protein PD-1 serves to halt ongoing immune responses by restricting B cell expansion in the secondary lymphoid organs (spleen, lymph nodes and Peyer’s Patches) and by restricting T cell activity at the site of the immune response, thus, in the tumor itself. Approved and late stage drugs in the immune checkpoint space are those that target the CTLA4 and PD-1 pathways, as has been reviewed ad nauseum. Since CTLA4 and PD-1 block T cell-mediated immune responses at different stages it is not surprising that they have additive or synergistic activity when both are targeted. Immune checkpoint combinations have been extensively reviewed as well.

We’ll not review those subjects again today.

If we step back from those approved drugs and look at other pathways, it is helpful to look for hints that we can reset a productive immune response by reengaging the innate and adaptive immune systems, perhaps by targeting the diverse cell types and/or pathways alluded to above.

One source of productive intelligence comes from the immune checkpoint field itself, and its’ never-ending quest to uncover new pathways that control immune responses. Indeed, entire companies are built on the promise of yet to be appreciated signals that modify immunity: Compugen may be the best known of these. It is fair to say however that we remain unclear how best to use the portfolio of checkpoint modulators we already have in hand, so perhaps we can look for hints there to start.

New targets to sift through include the activating TNF receptor (TNFR) family proteins, notably 4-1BB, OX40, and GITR; also CD40, CD27, TNFRSF25, HVEM and others. As discussed in earlier posts this is a tricky field, and antibodies to these receptors have to be made just so, otherwise they will have the capacity to signal aberrantly either because the bind to the wrong epitope, or they mediate inappropriate Fc-receptor engagement (more on FcRs later). At Biogen we showed many years ago that “fiddling” with the properties of anti-TNFR antibodies can profoundly alter their activity, and using simplistic screens of “agonist” activity often led to drug development disaster. Other groups (Immunex, Amgen, Zymogenetics, etc) made very similar findings. Careful work is now being done in the labs of companies who have taken the time to learn such lessons, including Amgen and Roche/Genentech, but also BioNovion in Amsterdam (the step-child of Organon, the company the originally created pembrolizumab), Enumeral in Cambridge US, Pelican Therapeutics, and perhaps Celldex and GITR Inc (I’ve not studied their signaling data). Of note, GITR Inc has been quietly advancing it’s agonist anti-GITR antibody in Phase 1, having recently completed their 8th dose cohort without any signs of toxicity. Of course this won’t mean much unless they see efficacy, but that will come in the expansion cohort and in Phase 2 trials. GITR is a popular target, with a new program out of Wayne Marasco’s lab at the Dana Farber Cancer Institute licensed to Coronado and Tg Therapeutics. There are many more programs remaining in stealth for now.

More worrisome are some of the legacy antibodies that made it into the clinic at pharma companies, as the mechanisms of action of some of these agonist antibodies are perhaps less well understood. But lets for the sake of argument assume that a correctly made anti-TNFR agonist antibody panel is at hand, where would we start, and why? One obvious issue we confront is that the functions of many of these receptors overlap, while the kinetics of their expression may differ. So I’d start by creating a product profile, and work backward from there.

An ideal TNFR target would complement the immune checkpoint inhibitors, an anti-CTLA4 antibody or a PD-1 pathway antagonist, and also broaden the immune response, because, as stated above, the immune system has multiple arms and systems, and we want the most productive response to the tumor that we can generate. While cogent arguments can be made for all of the targets mentioned, at the moment 4-1BB stands as a clear frontrunner for our attention.

4-1BB is an activating receptor for not only T cells but also NK cells, and in this regard the target provides us with an opportunity to recruit NK cells to the immune response. Of note, it has been demonstrated by Ron Levy and Holbrook Khort at Stanford that engagement of activating Fc receptors on NK cells upregulates 4-1BB expression on those cells. This gives us a hint of how to productively combine antibody therapy with anti-4-1BB agonism. Stanford is already conducting such trials. Furthermore we can look to the adjacent field of CAR T therapeutics and find that CAR T constructs containing 4-1BB signaling motifs (that will engage the relevant signaling pathway) confer upon those CAR T cells persistence, longevity and T cell memory – that jewel in the crown of anti-tumor immunity that can promise a cure. 4-1BB-containing CAR T constructs developed at the University of Pennsylvania by Carl June and colleagues are the backbone of the Novartis CAR T platform. It is a stretch to claim that the artificial CAR T construct will predict similar activity for an appropriately engineered anti-4-1BB agonist antibody, but it is suggestive enough to give us some hope that we may see the innate immune system (via NK cells) and an adaptive memory immune response (via activated T cells) both engaged in controlling a tumor. Pfizer and Bristol Myers Squibb have the most advanced anti-4-1BB agonist antibody programs; we’ll see if these are indeed best-in-class therapeutics as other programs advance.

Agonism of OX40, GITR, CD27, TNFRSF25 and HVEM will also activate T cells, and some careful work has been done by Taylor Schreiber at Pelican to rank order the impact of these receptors of CD8+ T cell memory (the kind we want to attack tumors). In these studies TNFRSF25 clearly is critical to support CD8 T cell recall responses, and may provide yet another means of inducing immune memory in the tumor setting. Similar claims have been made for OX40 and CD27. Jedd Wolchok and colleagues recently reviewed the field for Clinical Cancer Research if you wish to read further.

Looking again beyond T cells another very intriguing candidate TNFR is CD40. This activating receptor is expressed on B cells, dendritic cells, macrophages and other cell types involved in immune responses – it’s ligand (CD40L) is normally expressed on activated T cells. Roche/Genentech and Pfizer have clinical stage agonist anti-CD40 programs in their immuno-oncology portfolios. Agonist anti-CD40 antibodies would be expected to activated macrophages and dendritic cells, thus increasing the expression of MHC molecules, costimulatory proteins (e.g. B7-1 and B7-2) and adhesion proteins like VCAM-1 and ICAM-1 that facilitate cell:cell interactions and promote robust immune responses.

I mentioned above that interaction of antibodies with Fc receptors modulates immune cell activity. In the case of anti-CD40 antibodies, Pfizer and Roche have made IgG2 isotype antibodies, meaning they will have only weak interaction with FcRs and will not activate the complement cascade. Thus all of the activity of the antibody should be mediated by it’s binding to CD40. Two other agonist anti-CD40 antibodies in development are weaker agonists, although it is unclear why this is so; much remains to be learned regarding the ideal epitope(s) to target and the best possible FcR engagement on human cells. Robert Vonderheide and Martin Glennie tackled this subject in a nice review in Clinical Cancer Research in 2013 and Ross Stewart from Medimmune did likewise for the Journal of ImmunoTherapy of Cancer, so I won’t go on about it here except to say that it has been hypothesized that crosslinking via FcgRIIb mediates agonist activity (in the mouse). Vonderheide has also shown that anti-CD40 antibodies can synergize with chemotherapy, likely due to the stimulation of macrophages and dendritic cells in the presence of tumor antigens. Synergy with anti-CTLA4 has been demonstrated in preclinical models.

One of the more interesting CD40 agonist antibodies recently developed comes from Alligator Biosciences of Lund, Sweden. This antibody, ADC-1013, is beautifully characterized in their published work and various posters, including selection for picomolar affinity and activity at the low pH characteristic of the tumor microenvironment (see work by Thomas Tötterman, Peter Ellmark and colleagues). In conversation the Alligator scientists have stated that the antibody signals canonically, i.e. through the expected NF-kB signaling cascade. That would be a physiologic signal and a good sign indeed that the antibody was selected appropriately. Not surprisingly, this company is in discussion with biopharma/biotech companies about partnering the program.

Given the impact of various antibody/FcR engagement on the activity of antibodies, it is worth a quick mention that Roghanian et al have just published a paper in Cancer Cell showing that antibodies designed to block the inhibitory FcR, FcgRIIB, enhance the activity of depleting antibodies such as rituximab. Thus we again highlight the importance of this sometimes overlooked feature of antibody activity. Here is their graphical abstract:

 graphical abstract

The idea is that engagement of the inhibitory FcR reduces the effectiveness of the (in this case) depleting antibody.

Ok, moving on.

Not all signaling has to be canonical to be effective, and in the case of CD40 we see this when we again turn to CAR T cells. Just to be clear, T cells do not normally express CD40, and so it is somewhat unusual to see a CAR T construct containing CD3 (that’s normal) but also CD40. We might guess that there is a novel patent strategy at work here by Bellicum, the company that is developing the CAR construct. The stated goal of having a CD40 intracellular domain is precisely to recruit NF-kB, as we just discussed for 4-1BB. Furthermore, the Bellicum CAR T construct contains a signaling domain from MYD88, and signaling molecule downstream of innate immune receptors such as the TLRs that signal via IRAK1 and IRAK4 to trigger downstream signaling via NF-kB and other pathways.

Here is Bellicum’s cartoon:

 cidecar

If we look through Bellicum’s presentations (see their website) we see that they claim increased T cell proliferation, cytokine secretion, persistence, and the development of long-term memory T cells. That’s a long detour around 4-1BB but appears very effective.

The impact of innate immune signaling via typical TLR-triggered cascades brings us to the world of pattern-recognition receptors, and an area of research explored extensively by use of TLR agonists in tumor therapy. Perhaps the most notable recent entrant in this field is the protein STING. This pathway of innate immune response led to adaptive T cell responses in a manner dependent on type I interferons, which are innate immune system cytokines. STING signals through IRF3 and TBK1, not MYD88, so it is a parallel innate response pathway. Much of the work has come out of a multi-lab effort at the University of Chicago and has stimulated great interest in a therapeutic that might be induce T cell priming and also engage innate immunity. STING agonists have been identified by the University of Chicago, Aduro Biotech, Tekmira and others; the Aduro program is already partnered with Novartis. They published very interesting data on a STING agonist formulated as a vaccine in Science Translational Medicine on April 15th (2 weeks ago). Let’s remember however that we spent several decades waiting for TLR agonists to become useful, so integration of these novel pathways may take a bit of time.

This emerging mass of data suggest that the best combinations will not necessarily be those that combine T cell immune checkpoints (anti-CTLA4 + anti-PD-1 + anti-XYZ) but rather those that combine modulators of distinct arms of the immune system. Recent moves by biopharma to secure various mediators of innate immunity (see Innate Pharma’s recent deals) and mediators of the immunosuppressive tumor microenvironment (see the IDO deals and the interest in Halozyme’s enzymatic approach) suggest that biopharma and biotech strategists are thinking along the same lines.

Oncology drug development questions for 2014: Combination therapies for B cell lymphoma

Part 1 – Ibrutinib and the development of combination therapies for B cell lymphoma

For physicians, patients, investors etc, major medical conferences are a way to check in on the progress of a company’s drugs in the context of the medical communities response to the data, i.e. the buzz. Negative buzz is generally pretty straightforward, reflecting poor results or unexpected toxicity in a clinical trial. Positive buzz should be (and often isn’t) more nuanced, as positive data, while great to see, need to be placed into the context of evolving clinical practice and the ever-present competition for patients. Results, positive or negative, need to be vetted for robustness: clinical trial stage, sample size, design; endpoint design; therapeutic window (the dose range between efficacy and toxicity); and duration of response.

Last year saw extraordinary advances in the treatment of B cell lymphoma, particularly the Non-Hodgkin Lymphomas (NHL) that include well known cancers like Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), indolent NHL (iNHL) and many others. This advances included small molecule therapeutics that target critical drivers of lymphoma cell proliferation and survival, novel antibodies (“naked”, enhanced, payload carrying), ex vivo modified patient T cells that attack lymphomas upon reinjection, and a variety of other modalities. It was interesting to see that the companies getting the most buzz varied during the year, with different companies “winning” different conferences. Be assured that in this context, winning reflects wins for the stock price! Winning in the medical marketplace is a whole different story.

With the medical marketplace in mind, a reasonable question for 2014 pops up when you step back and look at the breadth of the B cell lymphoma therapeutic landscape.

How will biopharmaceutical companies, physicians, and payers develop and use combinations of these therapies?

Lets think about the possible combinations. The most obvious are those that we are already seeing widely used, such as the combination of a small molecule inhibitor with a tumor-targeting antibody. One example is the combination of ibrutinib, a BTK inhibitor, and rituximab, an anti-CD20 monoclonal antibody. Ibrutinib was approved for treatment of relapsed/treatment refractory (rr) MCL in November 2013 under the brand name Imbruvica, and approval for rrCLL is expected soon (these indications were filed for approval together, in August 2013). Patients with relapsed/refractory small lymphocytic lymphoma (SLL) were included in the CLL arm of the clinical trial.

CLL is a good example of the power of combination therapy. Rituximab monotherapy in rrCLL/SLL produced overall response rates (ORR) in the range of 55% and a complete response rate (CR) of somewhere under 10%, depending on the trial. Note here that ORR and CR refer to assessments of tumor burden at a specific and predetermined time after treatment is initiated. A CR does not indicate a cure but rather is a measure of the degree of efficacy. The ORR and CR measurements are most meaningful when presented in the context of duration of response (DOR) or in the context of progression-free survival (PFS) or overall survival (OS).

Monotherapy of rrCLL/SLL with ibrutinib produced ORRs ranging from 70-80%, with CRs ranging from 0 – 10%. Duration of response was good, and there was a measurable impact on PFS. There are different classes of rrCLL patients, based on cytogenetic status. High risk CLL patients commonly carry a deletion on chromosome 17 (del17p) and/or other abnormalities. Such mutations predict poor prognosis for these patients. Last April, the FDA granted Ibrutinib Breakthrough Therapy Designation for high-risk rrCLL/SLL del17p patients based on achievement of a 50% ORR in these patients when given ibrutinib monotherapy.

Now to the combination of ibrutinib and rituximab (and a chemo agent, bendamustine). As discussed in earlier coverage of the American Society of Hematology Annual Meeting (ASH), linked here, treatment of high-risk CLL patients with the combination therapy produced an ORR of 95%, with 78% maintaining response through 18 months. While only 10% of the responses were designated CR, the long duration of the partial responses (PR) was a dramatic result.

The cost of Rituxan treatment for B cell lymphoma is generally quoted at ~10K/month but billed to insurance at about 5K monthly, so we are somewhere between 60-120K per year per patient in the US. Imbruvica will cost 130K per year per patient in the US. Note here that neither therapy, given alone, is considered curative. We don’t know yet what the durable remission rate will be for the combination therapy, where we define durable remission as no detectable disease (in the blood, lymph nodes, bone marrow) without maintenance therapy. Curative treatment means no disease in a patient who no longer requires drugs.

So it’s fair to say that these combination therapies will be very expensive and may need to be used for a long time. Given the current climate of cost control, especially outside of the US, what are companies doing to anticipate eventual pushback on premium pricing?

Just a quick reminder that Imbruvica (ibrutinib) is a Pharmacyclics/Johnson&Johnson (J&J) product and the Rituxan is a Roche product and further, that Roche has a next generation anti-CD20 antibody, obinutuzumab, recently approved for the treatment of CLL (including as first line treatment), under the brand name Gazyva. This antibody given in combination with a cheap chemotherapy agent, chlorambucil, produced an ORR = 78% and a CR of 28% in the phase 3 trial. This antibody was significantly better than Rituxan (rituximab) plus chlorambucil in the same clinical trial (ORR = 65%, CR = 7%). The trial was done in rrCLL patients including high-risk patients defined as del17p.

Another anti-CD20 antibody, ofatumumab from GSK, has been approved for second-line use in rrCLL. This drug, priced at 120K yearly, ran into reimbursement pressure in Europe and the UK as not showing sufficient benefit to justify the price. This is a hint of price pressures to come.

This is where I think things get really interesting. I spent some quality time on clinicaltrials.gov, trying to understand how companies competing in the B cell lymphoma space are looking ahead, the assumption being that one can do this by looking at the trials planned or underway for the top tier drugs. Many of the oral drugs in advanced development for B cell lymphomas are reviewed here.

Nearly all advanced oral drugs for B cell lymphoma have trials underway or planned with an anti-CD20 antibody. Most of these trials are done with rituximab, probably just reflecting the wide availability of this antibody. Perhaps some companies are sticking with rituximab in the belief that generic biosimilar forms of this antibody will become available in Europe (where it is now off-patent) and in the US (where patent protection expires in 2018), which may make combination therapy more widely available. The rituximab trials are not done in collaboration with Roche, with one notable exception which we will get to later.

There are 11 clinical trials listed as active that include ibrutinib with rituximab either alone or with various other agents. Some of these trials have already read out results:

TRIAL NUMBER
PHASE
DATE FILED
IBRUTINIB WITH
INDICATION
NCT01980654210/24/2013rituximabuntreated FL
NCT0188056726/4/2013rituximabrrMCL
NCT0152051921/25/2012rituximabhigh risk CLL, SCL
NCT0161109035/15/2012rituximab/bendamustinerrCLL, rrSCL
NCT0177684031/24/2013rituximab/bendamustineuntreated MCL
NCT01479842111/1/2011rituximab/bendamustinerr DLBCL,MCL,iNHL
NCT0185575035/14/2013R-CHOPDLBCL-ABC
NCT0188687236/24/2013noneuntreated CLL
rituximab
v rituximab/bendamustine
NCT01974440310/28/2013R-CHOPrr iNHL
v rituximab/bendamustine
NCT0188685916/24/2013lenalidomiderrCLL, rrSCL
NCT0182956814/9/2013lenalidomide & rituximabrrFL
NCT0195549919/27/2013lenalidomide & rituximabrr iNHL

Note that FL is follicular lymphoma and DLBCL is diffuse large B cell lymphoma. DLBCL-ABC is a subtype. These are all types of B cell lymphomas. R-CHOP is rituximab plus a standard mixture of chemotherapeutic agents, and I may or may not have defined this correctly, suffice to say if it says CHOP then there is a potent mix of chemo being given; “v” means versus, that is, it is a comparator arm.

There are another seven or eight single agent ibrutinib trials also, but I did not include those here, so what we see all together is a full court press of clinical trials designed to show benefit of ibrutinib in multiple different B cell lymphomas, as first line or second line therapy. These trials will produce a tidal wave of data that, if positive, will by their sheer volume place ibrutinib at the top of the heap of B cell lymphoma oral agents. So, yes, I’m betting on Pharmacyclics (stock symbol PCYC) and J&J to win the marketplace, at least for the near term.

Ibrutinib development does not stop there. There are three trials with lenalidomide, also known as Revlimid, approved as second line therapy for multiple myeloma (MM). A monotherapy trial of lenalidomide in CLL was halted last year due to an increase in deaths seen in the active arm. Even at a reduced dose (I’m guessing here) the use of this agent plus ibrutinib plus rituximab seems risky. Also, the drug is owned by Celgene. So why conduct trials with lenalidomide at all? The answer to that question will be found in the list of clinical trials for CC-292, Celgene’s BTK inhibitor under development for B cell lymphoma.

But just to finish with ibrutinib. Here are the rest of the active clinical trials I could find:

TRIAL NUMBER
PHASE
DATE FILED
IBRUTINIB WITH
INDICATION
NCT020131281,212/11/2013ublituximabCLL, MCL
NCT0157870734/11/2012v ofatumumabrrCLL
NCT012177491,210/7/2010ofatumumabCLL
NCT01478581211/18/2011nonerrMM
NCT0184172321/24/2013noner Hairy Cell leukemia
NCT019627921,29/27/2013carfilzomibMM

Ublituximab is a new anti-CD20 antibidy from TG Therapeutics and the clinical trial is being run by that company, not by J&J/PCYC. In contrast the ofatumumab trials, which are “active but not recruiting” are sponsored by Pharmacyclics.

Finally, just some tidbits. Ibrutinib presentations recently have included studies in some interesting new indications, particularly MM. There are two MM trials shown here, the second one being run in collaboration with Onyx Pharmaceuticals, whose proteosome inhibitor carfilzomib, has been approved for treatment of rrMM under the name Kyprolis.

I suspect we will see many more such collaborative efforts as the field matures.

Next up we will look at the efforts of two of the compounds seeking to compete with ibrutinib, Gilead’s idelalisib and Celgene’s CC-292.

Stay tuned.

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.