Monthly Archives: February 2014

Immune checkpoint inhibitors – Part 2

In part 1 our focus was primarily on the PD-1 and CTLA4 pathways, where the biology is well understood and the drug development advanced. See that post here. In part 2 we look at drug development for some newer immune checkpoint targets, and this will drive us a little deeper into the scientific rationale for some of the less known pathways.

 I would argue that a good deal of the excitement around some recent deals (Novartis/CoStim and Agenus/4-Antibody) really is driven by the opportunity to get in early with novel targets. While the CoStim portfolio included PD-1 pathway related IP, I think the fact that this deal was so early stage suggests that novel LAG-3 and TIM-3 IP had a lot to do with driving interest. Similarly, emerging details from the BIOCIO conference indicate that Agenus (NASDAQ: AGEN), a somewhat obscure company, acquired novel LAG-3, TIM-3, OX40 and GITR antibodies as well as novel CTLA4 and PD-1 antibodies in its’ 4-Antibody acquisition. It would seem that this company, nominally a cancer vaccine company, is taking a huge leap forward by acquiring assets that could be combined with cancer vaccines. Barron’s labeled this a “genius move”, and I agree. This should make Agenus itself an attractive acquisition candidate. The Smith On Stocks Blog has much more on this (http://bit.ly/1ljmEzx).

 So I think it make sense to take on these targets one by one, do a quick update on the therapeutic rationale, and see who is leading the pack. Later we’ll fold this into a landscape analysis to try to understand where the large companies are heading.

We can start with a few targets that are represented by drugs in clinical development. Bristol-Myers Squib (NYSE: BMY), already loaded with anti-CTLA4 and anti-PD-1 programs, is moving their LAG-3 antibody ahead in both monotherapy and combination therapy trials. LAG-3 (lymphocyte activation gene, CD223) is a negative regulator of cell activation. It is expressed on various activated lymphoid cells, including T cells and NK cells that mediate tumor cell killing. The mechanism of action is the binding of LAG-3 to the MHC Class II complex expressed on antigen-presenting cells (B cells, monocytes, macrophages, dendritic cells, and other cell types). The high affinity binding event blocks cell proliferation and effector functions. LAG-3 is also an important mediator of the immune suppressive function of regulatory T cells. Of tremendous interest is the finding that LAG-3 is synergistic with other down-regulatory pathways, specifically PD-1 and TIM-3. As we will see this is driving much of the work on the design of combination therapy testing.

BMS-986016 is an anti-LAG-3 antibody from BMY currently in phase 1 testing in solid tumors and in B cell lymphomas. A very interesting study is NCT01968109: Safety Study of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors. This is a Phase 1 dose escalation study of BMS-986016 alone or in combination of one of two defined doses of nivolumab (anti-PD-1). The primary endpoint is safety (AEs, SAEs, fatalities, lab abnormalities). There is also a cardiovascular risk assessment (QTc interval) among the secondary endpoints. Otherwise the secondary endpoints cover PK and exposure, immunogenicity, and RECIST defined tumor responses.

The point is that this is an instructive example of rational combination immunotherapy being investigated at Phase 1.

Other LAG-3 antibodies of potential use in oncology include Immutep’s IMP701, an antagonist antibody. IMP701 ought not to be confused with their depleting anti-LAG-3 antibody IMP731 (partnered with GSK for treatment of autoimmune disease) nor with their activating LAG-3-Fc fusion protein IMP321 (and how this thing works I have no idea). We have already mentioned that CoStim and 4-Antibody had LAG-3 programs and IP, but these would be preclinical. Somewhat better known for its’ anti-CD70 mAb (see below), arGEN-X also lists TIM-3, LAG-3 and VISTA antibodies in its’ preclinical portfolio. No doubt there are other early stage programs, they just are not readily visible yet. I wager that we will see many more of these popping up in the poster aisles at AACR and ASCO this year.

Two proteins related to PD-L1, B7-H3 and B7-H4, are also T cell inhibitory ligands. Both proteins are expressed on tumor cells and expression of B7-H3 or B7-H4 correlates with poor outcome for some tumor types. Both B7-H3 and B7-H4 are normally expressed on myeloid lineage cells including monocytes and dendritic cells. Preclinical tumor model data have supported efficacy with blocking antibodies to these ligands in vivo. The mechanism of action of these ligands is not well understood, as the receptors are not known, or at least cannot be confirmed across different laboratories

The Macrogenics (NASDAQ: MGNX) antibody to B7-H3 has reached clinical development. The phase 1 study in patients with advanced carcinoma, melanoma, or glioblastoma that overexpresses B7-H3. The antibody, MGA271, is licensed to Servier; Macrogenics recently received a milestone payment indicating that the expansion part of the Phase 1 trial had been initiated. Five Prime recently disclosed novel antibodies to B7-H3 and B7-H4 along with TIM-3 and VISTA, as mentioned previously.

With TIM-3 we have a landscape that is a bit earlier than LAG-3 – the excitement about this pathway is driven by the preclinical tumor model data and the translational medicine data. Like LAG-3, TIM-3 has been identified as co-expressed with PD-1, in particular on tumor infiltrating lymphocytes. Genetic data (knockout, transgenic, etc) clearly indicate that TIM-3 is an important immunoregulatory pathway. This is true as well of CTLA4, PD-1 and LAG-3 – the number of “brakes” on the system is remarkable and hints at how dangerous the immune system can be when it is unregulated, as it is in autoimmune, inflammatory, allergic and similar diseases. One of the interesting observations about TIM-3 is that it is ectopically expressed by some tumors and also by dendritic cells associated with tumors, i.e. within the tumor microenvironment. Therefore by blocking TIM-3 in the tumor setting, multiple responses may contribute to efficacy. A confounding issue in the TIM-3 field is the identification of the relevant ligand for TIM-3, with a number of ligands having been proposed (galectin-9, phosphatidylserine (PS), HMGB1). The binding motif for PS is well defined, while binding to the other proposed ligands is less well understood. In particular, TIM-3 and galectin-9 activities seem distinct, at least as far as we can understand from the published genetic data.

The proteins mentioned so far (CTLA4, CD28, CD80, CD86, PD-1, PD-L1, PD-L2, B7-H3, B7-H4, LAG-3, TIM-3, VISTA and TIGIT) are all members of the immunoglobulin (Ig) superfamily of proteins. Two additional protein families of critical importance in regulating immune responses are the TNF and TNF receptor families. Again the leader in this field, clinically at least, is BMY. The antibody BMS-663513 (urelumab) is an agonist anti-4-1BB antibody that functions by stimulating T cell activation. 4-1BB (CD137) is best known for contributing a signaling moiety to the CAR-T constructs (a discussion for another day). BMS-663513 is now in phase 1/2 testing in lymphoma patients. The antibody had previously completed a phase 2 study in melanoma, but that program was put on clinical hold following dose dependent liver toxicity. The new studies utilize lower doses, as a very low dose appears to be efficacious. An important differentiating feature of anti-4-1BB is the apparent ability to eradicate established tumors, at least in some patients. With this is mind it is encouraging to look forward to combination treatment studies. Pfizer also has an anti-4-1BB antibody in development, PF-05082566. This antibody is in a very interesting phase 1 clinical trial in solid tumors and B cell lymphomas, the latter patients being treated with and without rituximab co-therapy.

4-1BB biology is well understood, and agonist stimulation of this receptor induces CD8+ T cell activation, interferon gamma secretion, secretion of cytolytic compounds and recruitment of helper T cells. Of interest, 4-1BB is only expressed on T cells that have been activated through the T cell receptor and CD28, and so is specifically expressed on those T cells that would potentially have anti-tumor activity.

CD27 expression is also induced upon T cell activation, and the critical role of this receptor in immune responses is shown by patients who lack function CD27, as these patients are grossly immunosuppressed. The role of CD27 is subtly different from 4-1BB in that this receptor seems critical to activated T cell survival. Celldex (NASDAQ: CLDX) has developed an agonist anti-CD27 antibody, CDX-1127. In pre-clinical models, CDX-1127 had anti-tumor effects due to enhanced T cell activation. In addition various cancers, particularly B and T cell lymphomas, can express CD27 at high levels and the antibody may be able to such tumor cells directly and activate immune cell killing. Early data is promising, with no obvious toxicities.

The ligand for CD27 is CD70. Paradoxically (and stretching the limits of our understanding of these systems) CD70 is expressed at very high levels on a variety of tumor types, including solid tumors and hematopoietic cancers. Therefore, antibodies targeting CD70 to effect tumor cell killing have been developed. The most advanced of these are antibody drug conjugates, e.g. SGN-75 (SGEN) and MDX-1203 (BMY); there are other coming e.g. from Ambrx. In January. arGEN-X started a Phase 1b expansion study with ARGX-110, a novel cytotoxic anti-CD70 antibody. There are undoubtedly other antibodies in development.

A critical pathway found on cells that interact with T cells (dendritic cells, macrophages, B cells) is the CD40 pathway. Although early work is in the monotherapy setting, it is reasonable to speculate that agonists to CD40 would complement other approaches, such as cancer vaccines and modulators of T cell responses. Dacetuzumab, developed by Seattle Genetics (SGEN) was discontinued in phase 2b. The reason was unclear but appeared to involve both toxicity and futility analysis. Toxicities included cytokine release syndrome (common) and thrombosis (< 5% of patients), some liver toxicity and cytopenias. Most of these toxicities could be controlled with prophylactic agents. CP-870,893 (Pfizer) has completed Phase 1 clinical trials in melanoma, pancreatic cancer and other solid tumors. The current development in the US of CP-870,893 seems limited to trials being sponsored by U Penn’s Abramson Cancer Center. Of note, one of these trials is in combination with the anti-CTLA4 mAb, tremelimumab. The antagonist anti-CD40 antibody lucatumumab (NVS) competed a phase 1 trial in refractory follicular lymphoma in May of 2012. Here the hypothesis was that the bound antibody would activate cytotoxic killing of CD40+ tumor cells. This Phase 1 trial was in combination with chemotherapy (bendamustine).

At this point I would characterize the development of CD40 modulators in oncology as stalled, and awaiting a better understanding of the best antibody activity (and associated isotype) to use, the appropriate dose, and the most relevant tumor types.

Two final pathways to mention in this section are the OX40 and GITR pathways, the subject of headlines when Agenus bought out 4-Antibody. Several clinical stage therapeutics have been developed for these targets.

OX-40 (CD134) is another T cell survival pathway, activated downstream of CD28, and essential for the induction of anti-apoptotic proteins that keep activated T cells alive and functional. It may also be required for the establishment of the memory T cell pool. Stimulation of OX40 by the OX40-L or by agonist anti-OX40 antibodies enhances T cell responses.

AZN/Medimmune has developed a murine anti-OX40 agonist antibody designed to stimulate the immune system and block tumor suppression of the immune response. AZN’s OX40 collaborations are complex. AZN/Medimmune has partnered with AgonOx, a tech transfer spinoff from the Providence Cancer Center in Portland, OR. There are several clinical trials of anti-OX40 therapy underway at the Providence Cancer Center. AZN/Medimmune has also partnered with the Cancer Research Institute and Ludwig Institute for Cancer Research specifically to undertake clinical trials evaluating immunotherapy combinations including the MedImmune antibodies to OX40, and PD-L1 (MED14736), together with other agents within the CRI/Ludwig portfolio and the Cancer Vaccine Collaborative network of clinical immunologists and oncologists. There was one clinical trial co-sponsored by AgonOx and the Ludwig Institute, to study anti-OX40 in combination with ipilimumab. However, this trial has been suspended. According to AZN/Medimmune, the partnership trials are designed to complement their in-house clinical development effort.

GlaxoSmithKline (NYSE: GSK) gained rights to an OX40 antibody preclinical program from the MD Anderson Cancer Center’s Institute for Applied Cancer Sciences, as part of a deal focused on immune checkpoint antibodies that can trigger immune responses against cancer.

GITR was the other target grabbing headlines in light of the Agenus/4-Antibody deal. GITR is yet another cell surface receptor that is involved in amplifying T cell responses. It’s mechanism of action is distinct, in that GITR inhibits the suppressive activity of T-regulatory cells, thereby releasing effector T cells from active suppression. Secondarily GITR signaling is a pro-survival pathway for activated T cells.

GITR, Inc., is a biotech company spun out when Tolerx went under. The company is developing TRX518, an anti-GITR agonist antibody designed to enhance the immune response to cancer cells. A Phase 1 clinical trial in melanoma and solid tumors is currently recruiting after being released from clinical hold.

A few thoughts about these newer pathways. One is that some of them are very potent indeed (4-1BB, CD27) and we will have to watch carefully for toxicity issues. A second is that we can begin to outline rational combinations based on the biology of the pathways. For example, the CTLA4 and PD-1 antagonists may pair well with treatments that induce tumor cell death, thereby releasing novel tumor antigens that the newly stimulated immune system can then recognized. Some of the downstream T cell or antigen-presenting cell activators (CD40, OX40 as examples) may be better suited for use with cancer vaccine therapies.

There are two more classes of immune checkpoint modulators to consider. One consists of the IDO inhibitors. The second consists of the innate immune response modulators (TLRs, KIR, NKG2A). There are very exciting companies working in these areas, and these will be the subject of the next update.

as always please leave a comment or email me at rennertp@sugarconebiotech.com and follow @PDRennert

stay tuned.

Collaboration with The University of Iowa Produces a Novel Ebola Therapeutic Patent

A patent from SugarCone Biotech founder Paul D Rennert and collaborators from the University of Iowa has published. Entitled “ANTI-TIM-1 ANTIBODIES AND USES THEREOF” the patent describes the use of specific anti-TIM-1 antibodies to prevent infection by the Ebola and Marburg filoviruses. This seminal finding will lead to the development of prophylactic treatments for the prevention of Ebola and Marburg virus infection in “hot zone ” settings. The antibodies were developed at Biogen Idec.

Immunotherapy: Companies Chasing Immune Checkpoint Therapeutics

Excitement continues to build in the Immunotherapeutic drug development space following a recent flurry of deals. In the most recent, we saw Novartis acquire Costim Pharma(http://www.fiercebiotech.com/story/novartis-beefs-its-cancer-immunotherapy-pipeline-biotech-buyout/2014-02-17).

The deal making begs the question as to what, and who, is next. The immunotherapeutic space is very large and diverse so it’s important to focus. Lets start by defining the space broadly, using the following categories:

1) Immune checkpoint modulators. These are therapeutics specifically designed to alter the way the immune system interacts with a tumor. This field is exemplified by the anti-CTLA4 antibody ipilimumab (Vervoytm), from Bristol Myers Squibb and the anti-PD-1 antibody MK-3475, from Merck.

2) Tumor depleting antibodies. These are antibodies with inherent or engineered cell-killing (cytotoxic) activity. The first generation of cytotoxic antibodies is best illustrated by the anti-CD20 antibody rituximab (Rituxantm) from Roche. Engineered antibodies have increased cytotoxic activity (ofatumumab from GlaxoSmithKline being an important example). Other formats include bispecific antibodies that recognize 2 different tumor proteins (antigens) simultaneously. All of these antibodies act by recruiting the immune system to kill cells that they have bound. The antibodies do this by activating cell killing NK and CD8+ T cells and by activating the complement cascade.

3) Bispecific antibodies and fusion proteins that recruit T cells, NK cells or dendritic cells and bind tumor antigen, simultaneously. These molecules function similarly to tumor depleting antibodies, but have the added activity of specifically engaging relevant immune cell types.

4) Modified T cells. Made famous by the CAR-T (CAR-19) technology developed by Carl June at U Penn, this technology uses genetic engineering to take a patients T cells and repurpose them for high impact tumor cell recognition and killing.

5) Cancer vaccines. Exemplified by Provengetm from Dendrion, these are techniques designed to induce an immune response to the tumor by immunizing with tumor antigens along with immune stimulants. There are ex vivo approaches (like Provenge) and in vivo approaches.

Note that we have left out the antibody-drug conjugates (ADC) and radiolabeled antibodies since they theoretically do not require the immune system to attack the tumors. In this class the cytotoxic drug or radioactive payload is brought to the tumor by the antibody.

Today we will only discuss novel and next generation therapeutics in the first class: immune checkpoint modulators.

The field has been dominated by discussion of the clinical stage drugs being developed to target the CTLA4 and PD-1 pathways. Blocking CTLA4 shuts down this T cell inhibitory pathway by preventing interaction of CTLA4 with it’s ligands, called CD80 and CD86, which are expressed on B cells, dendritic cells, macrophages and related cell types. This then allows these ligands to productively interact with the stimulatory receptor CD28, also expressed on T cells, thereby promoting T cell activation. In the case of the PD-1 pathway, blocking PD-1 or its ligand (PD-1L) prevents another inhibitory pathway on T cells, although in this case the ligand is often found overexpressed on tumor cells, that is, this is an active pathway for immune evasion.

Just for review, these are the key late stage clinical therapeutics:

drug

target

phase

company

 
     ipilimumab      CTLA4      approved      Bristol Myers Squibb
     nivolumab      PD-1      3      Bristol Myers Squibb
     MK-3475      PD-1      3      Merck
     MPDL3280A      PD-L1      3 (not yet recruiting)      Roche/Genentech

These are all monoclonal antibodies (mAbs). The approval and phase 3 designations refer to advanced metastatic melanoma however all of these drugs are in multiple clinical trials for many tumor types. Of equal interest are the ipilimumab/nivolumab co-therapy trials also underway.

So these are very advanced drugs. Earlier clinical trials with agents targeting the CTLA4 and PD-1 pathways are shown here:

drug

target

phase

company

       
     tremelimumab    CTLA4   1 and 2, in various solid     tumors      Astra Zeneca          (AZN)/Medimmune
     MEDI4736    PD-L1   1 and 1/2 in various solid   tumors      AZN/Medimmune
     pidilizumab    PD-1   2: hematological cancers,   solid tumors      CureTech Ltd
     BMS-9365569    PD-L1   1: multiple cancers      Bristol Myers Squibb
     AMP-224    PD-1   1: advanced cancers      Amplimmune/AZN
     AMP-514    PD-1   1: advanced cancers      Amplimmune/AZN

Again these earlier stage drugs are all mAbs, except AMP-224, a Fc-PD-L2 fusion protein that serves as a soluble inhibitor of PD-1. Pidilizumab had been partnered with Teva, but was returned last year. According to Nature Reviews Drug Discovery (NRDD), CureTech is seeking a partner for this drug to advance its’ development (http://www.nature.com/nrd/journal/v12/n7/full/nrd4066.html). The NRDD report is free to read and download.

There are other immune checkpoint modulators in the clinic, and we’ll get to those in a bit. What has been really shocking is how aggressive large pharma and biotech have been in acquiring very early stage assets in the immune checkpoint area. The CoStim acquisition by Novartis is an excellent example. CoStim had no clinical assets, and probably not even any IND-enabled assets, and yet was scooped up. Why? And importantly, who is next?

“Why” is a pretty interesting question, and translates into “What did they own?” The answer in the case of CoStim was that they owned patents on novel antibody inhibitors of PD-1 and PD-L1/PD-L2. Possibly of greater importance, they owned intellectual property (IP) portfolios covering new checkpoint pathways, notably the LAG-3 pathway and the TIM-3 pathway. We have no clinical data yet on either of these pathways, but preclinical tumor models, and the expression profile of these pathways, suggests very strongly that they will be critical for the prosecution of specific tumor types. Therein lies the value of buying early into the science. Bruce Booth writing on the role of Atlas Venture in the CoStim deal, has a great take on this on the LifeSci VC blog (http://lifescivc.com/2014/02/immuno-oncology-startup-costim-pharmaceuticals-acquired-by-novartis/).

So are there other CoStim Pharmas just waiting to be scooped up? The question is critical for biopharma portfolio gurus trying to peer into the future, and for stock investors wondering who to bet on. That second category, stock investors, will be looking for public companies or venture owned companies about to go public. The recent surge in biotech IPOs has helped bring plenty of candidates into public view.

Lets have a look around, but as an organizing principal, we’ll let the biology of tumor immune evasion and response lead the way.

We briefly mentioned the ligands for CTLA4 (CD80 and CD86) and for PD-1 (PD-L1 and PD-L2). These proteins are all related by protein sequence, and are members of the B7 protein family. The receptors for these ligands are also related and can be considered members of the CD28 protein family. Lets start with these, and line them up:

Screen Shot 2014-02-23 at 4.27.58 PM

This image is from Drew Pardoll’s excellent review in Nature Reviews Cancer. This paper is free to read and download, and can be found here:                       http://www.nature.com/nrc/journal/v12/n4/full/nrc3239.html. At the top you see the PD-1 and CTLA4 pathways and corresponding ligands – note here that an activating receptor for PD-L1 and PD-L2 is proposed, although none has been found yet. At the bottom we see some newer members of the B7 family, B7RP-1 (ICOS-L), B7-H3 and B7-H4. There are both stimulatory and inhibitory pathways proposed. Not surprisingly, there have been a number of development deals across this spectrum of targets.

Novartis. We’ve already mentioned the CoStim/Novartis deal, which purportedly includes PD-1 and PD-L1/2 assets and IP.

Merck. Merck took the biopharma world by surprise a few weeks ago by announcing a suite of partnerships for MK-3475 anti-PD-1 mAb. The stance is bold and aggressive and shows that Merck recognizes the importance of anticipating combination therapy clinical practice and developing MK-3475 accordingly. The company is capitalizing on the momentum behind MK-3475 that has accelerated with FDA breakthrough therapy designation (for advanced melanoma) in April of last year and an aggressive rolling submission drug application, which should be completed by mid-year.

Merck plans to run clinical studies of MK-3475 in combination with axitinib, Pfizer’s small molecule kinase inhibitor for renal cell carcinoma. This deal is similar to the one that Merck did with GlaxoSmithKline (GSK) in December 2013, to pair MK-3475 with GSK’s kinase inhibitor, pazopanib, also in advanced renal cell carcinoma.

In a combination immunotherapy effort, MK-3475 will be paired with PF-05082566, Pfizer’s agonist mAb to the 4-1BB receptor. We’ll discuss 4-1-BB and related pathways later, as this is an interesting area. The combo therapy will be tested in multiple cancer types. In a similar effort, Merck will partner with Incyte to pair MK-3475 with INCB24360, an indoleamine 2, 3-dioxygenase (IDO) inhibitor, in patients with advanced or metastatic cancers. IDO inhibitors are a very hot subject, which we will tackle below. Finally, in collaboration with Amgen, Merck will combine MK-3475 treatment with Amgen’s investigational oncolytic immunotherapy talimogene laherparepvec, in patients with previously untreated advanced melanoma.

Merck also signed on with Ablynx in a very interesting deal to develop nanobody therapeutics to immune checkpoint targets. Nanobodies are derived from camelid (camels, llamas, etc) antibodies and have some nice intrinsic properties (small size, good pharmacodynamics). Of interest, the Merck deal specifies bi- and tri-specific nanobodies targeting different proteins.

Servier. In another very recent deal (February 13, 2014), French pharmaceutical firm Pierre Fabre licensed a peptide therapeutic directed to PD-1 from Biotech company Aurigene. This new therapeutic is IND-enabled, but clinical development has not begun. Servier also acquired rights to Macrogenic’s anti-B7-H3 mAb MGA271 in December 2011. B7-H3 is overexpressed by a variety of solid tumors (prostate, pancreatic, melanoma, renal cell, ovarian, colorectal, gastric, bladder, and NSCLC). It has been hypothesized that B7-H3 expression by tunors is a mechanism of immune evasion, however, since the receptor in unknown this remains a hypothesis. So, although an anti-B7-H3 antibody may have biological impact on the tumor, Macrogenics is taking no chances, and has engineered MGA271 for optimized interaction with cytotoxic immune cells, including NK cells, macrophages and CD8+ T cells. MGA271 is currently in phase 1, in patients with B7-H3+, refractory neoplasms.

Astra Zeneca. In October of 2013, AZN/Medimmune announced that it had acquired Amplimmune, a privately held company developing immune checkpoint modulators for oncology. This preclinical company’s assets included AMP-224, the Fc-PD-L2 fusion protein mentioned earlier, and AMP-514, an anti-PD1 mAb. In December of 2013, Amplimmune registered its first clinical trial for AMP-514, a phase 1 in patients with advanced solid tumors. As discussed in a column by FierceBiotech’s John Carroll “the widely acknowledged area for differentiation will be combinations … mAbs (anti-CTLA4 tremelimumab, anti-PD1 AMP514,  OX40 agonist MEDI6469) and … targeted therapies … AZN is gearing up for combination trials with Iressa & tremelimumab … AZN’s purchase of Amplimmune gained it access to other … targets … likely including another attractive checkpoint antibody to B7-H4″. You can see the article here:                     http://www.fiercebiotech.com/story/can-astrazeneca-catch-leaders-cancer-immunotherapy/2013-10-03

Amplimmune’s discovery portfolio covers many B7 family members and their patent portfolio includes both agonist and antagonist assets and IP. Within the database-visible patents there are claims to fusion proteins and antibodies targeting PD-1, PD-L1/2. B7-H3, B7-H4, “B7-H5″, ICOS and ICOS-L.

Bayer Healthcare. Late to the party is Bayer, who to date has not made a big play in immune modulatory drugs. The company took a step forward perhaps in a deal with Compugen (NASDAQ: CGEN), paying 10MM USD upfront in a collaboration/licensing agreement. The goal is to develop novel antibody based immune checkpoint regulators discovered by Compugen. While the company is secretive as to the specific targets, one may be TIGIT, a relatively new member immune regulatory protein with some very exciting preclinical biology.

Early stage assets like Compugen’s are hard to judge without the benefit of full due diligence. We can list some of the asset players however, and some are pretty easy to score just based on the prior reputation of the company:

-  Earlier this month Five Prime Therapeutics went on record as having novel ligands for B7-H3 and B7-H4 (http://www.biotech-now.org/business-and-investments/2014/02/bio-ceo-five-prime-therapeutics-company-snapshot#) among other targets. Five Prime has an antibody discovery and development deal with Adimab. As far as I can tell, none of these are visible in the patent databases to date. Five Prime recently went public (NASDAQ: FPRX).

-  Kadmon LLC, backed by the former head of Imclone, lists anti-PD-1 and anti-PD-L1 mAbs on its pipeline chart. However this company seems focused on other areas.

-  Locally, Third Rock funded Jounce Therapeutics is developing antibodies and proteins to undisclosed immune checkpoint targets. Jounce and Adimab have announced a collaboration to drive the antibody technology. It will of great interest to see if Jounce will take the IPO route over the next few years, or instead will be acquired while still private.

-  VISTA is another relatively new immune regulator being developed by privately held ImmuNext, in partnership with Johnson & Johnson.

-  In January of this year Johnson & Johnson’s Janssen unit agreed with BiocerOX Products to develop a new mAb to an immune checkpoint protein. The target was not released but is rumored to be PD-1.

-  By the way, J&J/Janssen really does seem to be taking a multi-pronged approach to get into this space. In late January J&J Innovation partnered with MD Anderson Cancer Center, as part of its “Moon Shots” oncology effort. The joint program will evaluate new combination therapies and identifying useful biomarkers for eight critical cancers. MD Anderson has a very similar agreement with Pfizer.

-  AnaptysBio, Inc has publicized a portfolio that includes an anti-PD-1 antibody, ANB011, and novel antibodies against other immune checkpoint receptors, including TIM-3 and LAG-3.

I’m going to assume that there are other CTLA4, PD-1, PD-L1 and PD-L2 assets out there in the hands of companies large and small. We’ll track the progress of these as they pop up, whether in the poster hall at AACR, or in press releases! Also, we will discuss companies targeting TIM-3 and LAG-3, along with 4-1BB, OX40, GITR, IDO, and various other interesting targets, next post.

 stay tuned.

Oncology Treatments in Perspective: Why We Need Innovation and Transformation

Today was exciting. A great little company got bought out (see today’s news release) and we all got very pumped up about Immunotherapy for cancer treatment. If you saw our AML series (below) you’ll know why new therapies are desperately needed.

Last year at ASCO was very exciting, as immunotherapy was showing great promise across tumor types, but especially in melanoma. The buzz was amazing. But there was also a funny undercurrent.

The ads placed in the daily news bulletin from the American Society of Clinical Oncology (ASCO) meeting last year in Chicago were striking. They came in two distinct formats. One set, aimed squarely at MDs, came loaded with technical information, focused on progression free survival (PFS) and overall survival (OS) data. Lets keep in mind that for advanced solid tumors, such numbers can be small: a few months, maybe a year. Indeed much of the buzz at that meeting came from immunotherapy clinical trial results. It became clear that a small number of patients in immunotherapy clinical trials were living long enough to create a long “tail” on the mortality graphs. Ribas et al. (http://clincancerres.aacrjournals.org/content/18/2/336.long) illustrated the concept in 2012:

 Screen Shot 2014-02-16 at 2.28.39 PM

Targeted therapies (small molecule drugs, chemo, radiation) are illustrated, schematically, on the right. The is a futility inherent in that graph. Immunotherapeutics are illustrated on the left. Again, this is not real data, just a thought cartoon.

The long tail phenomena suggests that Immunotherapy is an example of drug development that has the potential to be transformative, to utterly alter cancer patient care. CAR-T technology may be another. Real examples of successful transformative therapies include the TNF antagonists in the treatment of RA. The use of beta interferons (and many other drugs) to treat MS, and CD20 antibodies to treat B cell lymphomas are other good examples. Getting there in advanced solid tumor treatment will take some time. And 10% of patients living a long time can also move the OS number a bit, even though most patients are not benefitting. Regardless, this is a big step, as it suggests that one could work to increase the “height” of that tail, to 20, 30, 40% and so on. That’s a great goal.

We’re not there yet for most solid tumors. This brings us to the second ad style that featured prominently in the pages of the ASCO daily bulletin. These ads were still loaded with technical information, in the small print, but were presented in an emotional manner. These ads were aimed at patients, or perhaps at the way oncologists think about their patients. In these ads well-groomed 60ish looking couples sat smiling at sunsets or grazing lovingly at each other. “Its not just another Sunday, it’s another Sunday!” said one. It might as well have been a Cialis ad.

 There is nothing wrong with this, except perhaps demographically, as the ads featured mostly white models, but even then I think this reflects the demographics of oncologists more than patients. But it should make us think a little bit about the ephemeral nature of most of the progress being made – a few more months as a new drug works, only to be undermined by the next set of treatment resistant mutations. Many new drugs are not transformative, they are incremental. We should also remember that when talk about the promise of combination therapies we often forget that many of the combination agents are very hard to take, especially for older patients. For many patients, another Sunday is another day of struggle against brutal disease and harsh treatments. Obviously, we want to do better.

On a positive note, I remind myself that when I look at new clinical trial data I am almost always seeing data on patients who are out of options, having failed standard of care. There is a lot of argument about clinical trial design in these settings. One good question is whether the FDA should allow investigational drugs to be given to cancer patients earlier – this sounds great until something doesn’t work or makes things worse. As a result it takes time for newly developed drugs to move from third line to second line to front line therapy.

We spend a lot of time tracking clinical trial information and data for signs of “actionable” data. Actionable may mean that a biopharma client advances or kills a program or an investment client executes a trade. Both of these examples reflect the reality that drug development creates a very difficult competitive landscape, requiring years of investment and endless effort. At the end of the day, if all goes right, the patient, the investor, and the drug development industry all win. That’s why we’ll be back at ASCO, AACR and ASH. It’s also why we track other difficult diseases, like lupus, fibrosis, diabetes and COPD, to name a few. And of course it’s why we start new companies. We want to find those drugs that will make the patient’s next Sunday pretty much like every other Sunday – transformative therapies. Drugs that are transformative in such diseases will be few, and special. We want to be there when they debut.

 stay tuned.

SugarCone Client CoStim Pharma bought by Novartis

In 2012 and early 2013 we were engaged by CoStim Pharmaceuticals founder Robert Millman and CSO Walter Blattner to help work through a large portfolio of potential immunotherapeutic targets. We vetted each, reviewed the competitive landscape, and drew up preclinical development plans for the lead programs. The company obtained funding from MPM Capital and Atlas Ventures. Today, CoStim was purchased in its entirety by Novartis.

We are proud of the significant role we played in getting CoStim off the ground, and offer the CoStim team and their investors our congratulations for a job well done. Great ideas, great science, great execution.

AML Therapeutics Part 3: Immunotherapy

Ryan Teague and Justine Kline recently put together a nice review of immune evasion in acute myeloid leukemia (AML). The open access paper is available online (http://www.ncbi.nlm.nih.gov/pubmed/24353898). These authors have particular interest in tumor escape from immune surveillance by two interesting mechanisms. The first is termed T cell exhaustion, and refers to a non-responsive state induced in CD8+ (cytotoxic) T cells. The second is immune suppression, mediated by TGFbeta and regulatory T cells (Tregs). Other means used by tumor cells to avoid the immune system include deactivation by co-opting signals that directly shut down immune responses, such as PD-1 and other signaling mechanisms.

Why the interest in immunotherapy for such an aggressive cancer? There are a number of good reasons. First I think it is fair to state that targeted therapeutics (small molecule drugs) and antibodies (mAbs, ADCs, bispecifics) have yet to achieve a breakthrough in AML. The best of these drugs, even in combination, are only modestly effective. The second reason, implicitly recognized by the T cell engaging bispecific antibodies (BiTEs, DARTs) and by the still nascent CAR-T cell engineering technology, is that there is evidence to suggest that AML can be controlled by an effective immune response. This evidence comes from the leukemia transplantation field. As Teague and Kline state:

“Treatment with modern chemotherapy regimens often induces complete remission, but a majority of patients will ultimately relapse … it has been recognized that allogeneic stem cell transplantation can be curative for some patients with AML … derived from the so-called graft-versus-leukemia effect thought to result … Unfortunately, only a minority of patients with AML are candidates for this procedure.”

Those who are familiar with allogeneic SCT will further recognize that this is a risky procedure that can outright fail. So, are there safer or more direct ways to harness an anti-tumor immune response?

Novel therapeutics developed to stimulate anti-tumor immunity include the CTLA4 antagonist mAb, ipilimumab (Vervoytm; Bristol Myers Squibb (BMS)), approved for use in refractory or non-resectable melanoma. BMS is also developing the anti-PD1 mAb nivolumab, and combination trials with ipilimumab are underway. Other anti-PD1 and anti-PDL1 antibodies in advanced development for a variety of tumor types include MK-3475, submitted last month for FDA approval for the treatment of advanced melanoma, MPDL3280A (Roche), MEDI4736 (Astra Zeneca), and others. These are critically important therapeutics in hematological cancer and solid tumors. The potential breadth of applications is illustrated by the announcement last week the Merck will seek collaborative partnerships to develop MK-3475 in combination therapies. Merck will partner with Pfizer to investigate combination therapy in a phase 2 renal cell carcinoma (RCC) trial with the VEGFR inhibitor axitinib (Inlytatm). Merck will also partner with Pfizer for a phase 1 trial(s) using MK-3475 with the agonist anti-41BB antibody PF-2566, in multiple cancers. Readers will note that 41BB signaling is a critical component of the CAR-T T cell engineering technology. The collaboration with Incyte is also a dual-immunotherapy approach, as MK-3475 will be combined with INCB24360, an IDO inhibitor, in a phase 1 non-small cell lung cancer (NSCLC) trial. IDO is secreted by tumor cells, is a mediator of T regulatory T cell activity, and in AML is associated with poor prognosis. With Amgen, MK-3475 will be used in combination with the oncolytic viral therapeutic T-VEC, which induces tumor cell death and stimulates anti-tumor immunity.

The point of all this is to illustrate that for difficult cancers – melanoma, RCC, NSCLC – its not going to be easy, and combinations of novel therapeutics will have to be utilized. AML is a very difficult cancer. With this in mind we can look at the state of immunotherapy drug development in AML.

The Teague and Klein review goes into considerable detail on this subject, so we’ll just hit a few highlights and then see if we can update the storyline. A point the review makes that I didn’t fully appreciate is that AML tumor cells (and many others) can downregulate MHC Class I and II, making the tumor cells difficult for the immune system to recognize in the context of allogeneic SCT. This fundamental type of immune evasion may be difficult to circumvent. Other mechanisms of immune evasion used by AML include expression of PD-1L on the tumor cells, which effectively shuts down tumor infiltrating T cells that express PD-1, the PD-L1 receptor and mediator of a potent signaling response that downregulates T cell activity. AML tumor cells also express B7 family proteins B7-1 and B7-2,that bind to CTLA4, another downregulatory receptor. Clinical trials enrolling AML patients for treatment with therapeutics such as ipilimumab, nivolumab etc are described in the review. Its sufficient to point out that the effort to use these therapeutics for AML is in its very earliest stages.

A few recent observations point to other immune evasion strategies that night be productively targeted in AML.

Several preclinical studies have identified co-expression of TIM-3 and PD-1 as markers of CD8+ T cell “exhaustion”, and have likewise identified PD-L1 and galectin-9 (a putative TIM-3 ligand) on AML patient cells. TIM-3 is yet another receptor on T cells that mediates downregulation of T cell activity. Other markers of AML cells from patients were recently described (https://ash.confex.com/ash/2013/webprogram/Paper56968.html).

Relevant proteins included B7-2 (CD86), B7-H3 (CD276) and PD-L1. Patients with very high expression of both B7-2 and PD-L1 had worse overall and relapse free survival. HVEM, a receptor for several critical immune proteins including LIGHT, CD160, and BTLA, was expressed on a subtype of AML with relatively good prognosis. The author’s conclude ” that the profile of immune checkpoint molecules … correlates with molecular disease characteristics in AML and may even possess prognostic information, especially for relapse … (and) as therapeutic targets with respect to boosting anti-leukemic immune responses.”

An example of such an approach is provided by Innate Pharma, which is developing an anti-KIR antibody, lirilumab. KIR negatively regulates NK cell anti-tumor activity. A phase 1 trial in AML is continuing                             (https://ash.confex.com/ash/2013/webprogram/Paper59174.html). Preclinical data support the use of this mAb in combination with the cytotoxic anti-CD20 mAb rituximab in lymphoma. One might envision a similar approach using a cytotoxic mAb targeting AML such as the anti-CD33 mAbs discussed in part 2. Another possibility are the anti-CD38 mAbs. Second generation CD38 mAbs with improved cytotoxic activity are under intensive development for multiple myeloma by Sanofi (mAb SAR650984), Jannsen (daratumumab aka HuMax CD38) and MorphoSys (mAb MOR03087).

Another example is CoStim Pharma, bought today by Novartis. In their portfolio are novel immunotherapeutic mAbs, including TIM-3 antagonist mAbs. Novartis is moving quickly here to beef up its immunotherapeutic pipeline, which it can now develop in parallel with the U Penn CAR-T technology. Another local, private immunotherapy company is Jounce Therapeutics.

As we have also seen in parts 1 and 2, drug development for AML lags significantly behind other leukemias, lymphomas, myelomas, and the like. However, targeted therapeutics such as the tyrosine kinase inhibitor sorafenib, HDAC inhibitors vorinostat and panobinostat, and proteosome inhibitors bortezomib and carfilzomib hold some promise. The FLT3 and c-Kit targeting agents seem less likely to provide meaningful long-term benefit, although we’ll see what the combo trials brings. While it is too early to assess the CAR-T technology, the bispecific modalities, or immunotherapies in AML, the cytotoxic mAbs and ADCs should have a prominent role in controlling this aggressive disease.

We asked in Part 1 who the winners would be in 5 years. Looking over the landscape of therapeutics its pretty clear that winning will require collaboration among companies. With that said those companies with the biggest concentration of effort in AML include Merck, Onyx, Novartis, Amgen and perhaps Seattle Genetics. Given their past successes we can be hopeful that several of these companies will succeed in establishing breakthrough treatments for AML. In the end, patients should benefit the most from all of this activity. Perhaps stockholders will also benefit. With this in mind we note that Onyx probably has the most to gain (or lose) in this indication.

 stay tuned.

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

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

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

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

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

4) proteosome inhibitors like bortezomib and carfilzomib

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A few other biologics to keep an eye on:

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

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

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

- other antigens have been recently identified.

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

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

ANTICIPATING NEW THERAPEUTICS AND FORECASTING TREATMENT TRENDS FOR ACUTE MYELOID LEUKEMIA – PART 1

 by Paul D Rennert, February 11, 2014

In looking at Acute Myeloid Leukemia (AML) we see a cancer field right on the cusp of change in clinical practice. Standard of care chemotherapy regimens and stem cell transplantation protocols have proven to be of limited utility, especially in older patients. However, potentially big advances in care are being made, with exciting news coming out regularly. As we move toward the spring Medical Conference season, we felt an overview of this rapidly evolving area of oncology would be timely.

AML is a rapidly growing cancer of myeloid lineage cells that proliferate in the bone marrow and interfere with normal hematopoiesis. AML typically arises in the context of defined genetic mutations. For example, translocations of chromosome 16 disrupt RUNX1 gene activity and are one of the several underlying causes of Core Binding Factor AML. CBF-AML). Since RUNX1 regulates the transcription of many genes, the effect of its disruption is complex. CBF-AML patients are generally responsive to chemotherapy initially, although up to half of these patients will relapse over time due to additional genetic mutations.

Mutation of the FLT3 protein is the most common genetic abnormality in AML, found in about 30% of patients. This is a genetic characteristic associated with poor prognosis. The most common FLT3 mutation, FLT3-ILD, is caused by an tandem duplication within the coding region of the gene. The resulting protein drives hyper-signaling and oncogenic cell responses. Mutations that change the active site of the protein, causing unregulated phosphorylation, have also been described. Mutations in the receptor tyrosine kinase c-Kit are also associated with oncogenic signaling in AML. Both of these pathways cause mutiple downstream effector pathways to be activated. The JAK2 mutations, commonly see in myelofibrosis and other myeloproliferative disorders, are rare in AML but when characterized can potentially be treated with Jak2 inhibitors.

According to a recent market research analysis                           (http://www.transparencymarketresearch.com/acute-myeloid-leukemia-therapeutics-market.html) a total of 62,226 new cases of Acute Myeloid Leukemia (AML) were recorded in 2010, with 95,000 predicted new cases for 2015 and nearly 130,000 predicted new cases in 2020. Note that as of February 2014 approved agents for AML remain limited to chemotherapeutics (http://www.cancer.gov/cancertopics/druginfo/leukemia#dal2). Despite the lack of new targeted drugs, the AML therapeutics market was nearly 240 MM USD in 2011. At the current rate of growth the AML market could reach over 700 MM USD by 2018. These numbers are based on the analysis of future AML drugs growing at a 17% compound annual growth rate from through 2018.

Numbers like these are continuing to drive intensive research into effective, novel therapies for AML. It only helps that in many cases such therapeutics find use in other hematopoietic diseases such as Chronic Myeloid Leukemia (CML) and in the B cell lymphomas, including Hodgkin’s Lymphoma and the non-Hodgkin’s Lymphomas (NHL).

 There is obvious unmet medical need for effective therapies in AML since this is a disease characterized by quick relapse after therapy with grim survival statistics. In some older patients, survival is as little as 1-1.5 years despite first and second line treatment regimens.

What’s exciting from the drug development and biotech investment perspectives is that the AML treatment landscape is advancing simultaneously across therapeutic modalities. This rapidly changing landscape give us a chance to look at targeted small molecule drugs, monoclonal antibodies (naked, bi-specific, radiolabelled, immunotherapeutic, ADC), targeted T cells and other novel technologies.

 We can then ask ourselves: who will the winners be in 5 years?

 A) Targeted small molecule drugs.

Lets just be clear upfront that the goal of these targeted therapies is to get patients who have relapsed, or are refractory to chemotherapy, to a complete response (CR) with minimal residual disease (MRD) so they can qualify for an allogeneic stem cell transplant (SCT). That’s a lot of acronyms but what this is really saying is that for most patients the goal is a modest one – we are not asking for a durable remission, at least not yet.

 A variety of established drugs are being tested in AML. Also, the identification of oncogenic mutations in FLT3 and cKIT has driven interest in developing new tyrosine kinases inhibitors (TKIs) for AML.

 Sorafenib (NexavarTM; Bayer and Onyx) is a dual targeting drug that blocks RAF signaling (and therefore the MEK>ERK signaling) and also the growth factor receptor tyrosine kinases VEGFR and PDGFR. The NCI is running a large phase 3 trial enrolling new onset pediatric AML patients (NCT01371981) with sorafenib being given in combination with various chemo regimens.  Bayer and Onyx are running several earlier phase AML trials. An interesting phase 1 trial in patients 18 or older combines sorafenib with plerixafor and G-CSF (NCT00943943). The idea here is to have the CXCR4 blocker (plerixafor) and the growth factor (G-CSF) flush tumor cells, and also tumor stem cells, from the bone marrow and lymph nodes so that they are more sensitive to sorafenib treatment. This trial is co-sponsored by Genzyme/Sanofi, which owns plerixafor.

Another interesting trial is the Phase 1/2 study of the combination of sorafenib, with vorinostat, and bortezomib (NCT01534260). Here we have a proteasome inhibitor and an HDAC inhibitor added to growth factor and signaling inhibition provided by sorafenib. This potent combination is being used in patients with a poor genetic risk profile, including FLT3-ILD positive tumors. This study is co-sponsored by Bayer/Onyx, Millennium/Takeda and Merck Sharp & Dohme Corp.

Bristol Myers Squibb is running an interesting trial (NCT01620216) in which AML and acute lymphocytic leukemia (ALL) patient samples are analyzed for sensitivity to drug treatment ex vivo, after a period on drug in the trial, as follows:

“An in vitro kinase inhibitor assay will be used to determine the sensitivity of primary leukemic cells to four kinase inhibitors/drugs:

Drug: Sunitinib, 50 milligrams (mg) qd, with or without food, for 4 weeks

Drug: Dasatinib, 100 mg qd…possible escalation to 140 mg qd for 28 days

Drug: Nilotinib, 400 mg twice daily for 28 days

Drug: Sorafenib, 400 mg (2 tablets) orally twice daily without food for 28 days

Drug: Ponatinib, 45 mg dose once per day

Sunitinib (Sutenttm; Pfizer) makes sense as a pan-growth factor receptor inhibitor; dasatinib (Spryceltm; Bristol Myers Squibb) is a Src and c-Kit inhibitor and is a reasonable choice for AML; nilotinib (Tasignatm; Novartis) is a pretty specific Bcr-Abl kinase inhibitor and is probably only being used for the ALL population – and even there only 25% of ALL patients carry this translocation; sorafenib we discussed earlier; ponatinib (Iclusigtm; Ariad) has a grab bag reactivity profile, hitting the BCL-ABL kinase, FLT3, RET, c-KIT and the FGFR, PDGFR and VEGFR growth factor receptor kinases. This is a dangerous drug, with a very narrow FDA approval in CML, and I suspect enrollment in this little exploratory trial will be stopped if possible.

If I had to guess I would say that this rather odd trial design has several goals. One is to look for signs of efficacy, although a month is pretty short duration. One might also look for patterns of resistance to therapy, which would be very interesting. Since this is BMY, I’d be surprised if they weren’t also looking at cell surface markers for possible immunotherapy treatment – more on this subject later.

Results from a dasatinib trial in CBF-AML were recently presented at the American Society of Hematology (ASH) conference (Abstract #357). Dasatinib was added to induction and consolidation chemotherapy in newly diagnosed AML patients. Unlike the rrAML population, the CBF-AML population can experience sustained periods of remission prior to relapsing, especially in younger patients. Since some of the relapses are driven by gain of function mutations in c-Kit, dasatinib should prevent at least those clones from becoming established. Early results looked good but longer term data are needed to see if this regimen will remain effective.

Imatinib (Gleevectm; Novartis) another Bcr-Abl, c-Kit and PDGF-R inhibitor, has been tested in multiple AML trials, but the results have not led to approval for use in AML. An interesting trial of the cytotoxic/immunomodulatory agent lenolidomide (Revlimidtm; Celgene) plus chemotherapy is being run by the NCI (NCT01246622). Lenolidomide has been approved for the treatment of a different bone marrow resident cancer, multiple myeloma (MM).

Anyway there is a lot of similar clinical trial work being done – using approved drugs in this new indication and looking for efficacy. This is ultimately good both for patients and the drug development companies.

Lets move on to some newer drugs in the pipeline. The FLT3 inhibitors give us a sense of the difficulty here, with low response rates as monotherapies.

Quizartinib (Ambit Biosciences; AMBI) remains stuck between phase 2 and 3 for relapsed/refractory (rr) AML. This drug is a FLT3 inhibitor with a somewhat tortured history, having been partnered for a time with Astellas, then returned, then running nicely in the clinic before running into disagreement with the FDA over approvable endpoints and safe dosage. In early December the company announced it would have to run a phase 3, likely with lower starting doses, in order to obtain FDA approval. Investors were hoping the company could file on its phase 2 trials. Notably, later in December Ambit showcased its’ quizartinib data from the FLT3-ILD rrAML trial, in which a 50% response rate (50% or greater reduction in leukemic blast cells) was reported with relatively low doses of drug. Unfortunately, it will be a while yet before more news becomes available about this drug.

In the meantime heavy hitter Novartis is already in phase 3 with its’ FLT3 and Protein Kinase C inhibitor midostaurin. The phase 3 in newly diagnosed patients is being run by the NCI (our tax dollars at work), along with The Alliance for Clinical Trials in Oncology and the Cancer and Leukemia Group (NCT00651261). A trial of midostaurin administered with or without bortezomib in adult rrAML patients is being run by Novartis and Millennium/Takeda (NCT01174888). Preliminary results were presented at ASH (abstract #3966). While response rates were impressive the toxicity was extreme, and this seemed to be due to the bortezomib dose, which was adjusted. Phase 2 trials in adult patients who carry c-KIt, FLT3-ILD, and various other mutation or cytogenetic markers are also underway (NCT01830361, NCT01846624). A phase 2b midostaurin  monotherapy study published several years ago showed modest improvement in AML patients with mutated FLT3; this study recognized the need for combination therapy to improve the clinical response (http://www.ncbi.nlm.nih.gov/pubmed/20733134).

Another FLT3 inhibitor, lestaurtinib, is the subject of 2 NCI sponsored trials in pediatric ALL/AML but drug development of this agent seems to have stalled when Teva bought Cephalon. Another FLT3 inhibitor is PLX3397 (Plexxikon) which has activity against  KIT, CSF1R and FLT3. This drug is in a phase 1/2 trial in adult rrAML (NCT01349049).

One of the major challenges for FLT3 inhibitors is breadth of action. These inhibitors work best on patients who have mutated FLT3 and are less effective in patients with normal FLT3. Also, secondary mutations have already been discovered in response to FLT3 inhibition. Specifically, in those patients who have mutations in the active site of the kinase, so-called gatekeeper mutations arise, conferring resistance to the drug.

A dominant theme in recent drug development for AML has been built on the observation that proteasome inhibitors can impact cancers of the bone marrow. Disruption of proteasome activity blocks a wide spectrum of cellular activities, and is particularly effective against rapidly dividing cells (like leukemic blasts) but also relatively quiescent tumor stem cells, that require specific proteasome-dependent signaling pathways (e.g. NK-kB). Bortezomib (Velcadetm, Millennium/Takeda) has shown activity in older patients when combined with chemotherapy. A phase 3 combination trial with sorafenib in newly diagnosed AML patients is underway, sponsored by the NCI (NCT01371981).

Carfilzomib (Onyx Pharmaceuticals) is in an early stage trial for AML, along with extensive trials in MM, B cell lymphomas, etc. The drug is furthest along in MM, now in phase 3 (NCT01568866). Early reports so far have suggested that this drug has an activity profile similar to bortezomib, but may have a better safety profile. This is an interesting drug (and company) to watch. They have a second generation oral version of carfilizomib, oprozomib, in phase 1 MM trials. Millennium/Takeda are developing ixazomib in MM and lymphomas. An AML trial is listed but not yet recruiting.

A third theme that we can follow in AML therapeutic drug development is the use of drugs that impact epigenetic gene regulation. Because AML is driven by genetic translocations, gene regulation at the level of chromatin structure is disrupted. There are two processes at work here that can be targeted. One is the aberrant methylation of CpG islands in gene promoter regions, which can be targeted by DNA methyltransferase inhibitors. The second is changes in the conformation of chromatin caused by dysregulated histone acetylation. This process can be therapeutically targeted using histone deacetylase [HDAC] inhibitors.

The HDAC inhibitor vorinostat (Zolinzatm, Merck) has been extensively studied in AML, and is currently in a phase 3 trial with chemotherapy for young patients with newly diagnosed disease (NCI; NCT01802333). Vorinostat monotherapy was generally ineffective, but combination with chemo agents proved much more potent. As detailed at ASH in December (Abstract #2684), newly diagnosed and rrAML patients were enrolled in a phase 2 expansion study. Of 75 patients, 57 patients achieved CR, and 7 achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 85 percent. Median overall survival was 82 weeks and median event free survival was 47 weeks. For patients with the high-risk Flt-3 ITD mutation the 10/11 achieved CR and 1/11 CRp. The ORR = 100% in these patients. Their median overall survival was 91 weeks and median event free survival was 66 weeks. About 25% of the total patients in CR received SCT.

Other combination trials include the sorafenib trial mentioned above, and a trial in combination with antibody therapy (gemtuzumab ozogamicin) for rrAML (NCI; NCT00895934). This trial reported early results at ASH (Abstract #3936). The response rates ere encouraging and about 20% of patients obtained durable remission. There were significant toxicity issues. This drug is very likely to play a critical role in the evolution of combination therapy for AML. We’ll discuss antibody therapies further in Part 2.

Other important HDAC inhibitors in development for AML is panobinostat (Novartis). What’s interesting about the development campaign with this drug is the pairing in multiple trials with 5-azacitidine, a DNA methytransferase inhibitor. In such settings two modes of epigenetic regulation are being targeted simultaneously. One of these studies published findings last month                                 (http://www.nature.com/bcj/journal/v4/n1/full/bcj201368a.html) and demonstrated good tolerability and reasonable response rates. Clearly, this combination should move forward in the context of chemotherapy or other drugs. Of note the DNA methyltransferase inhibitor decitabine (Dacogentm, MGI Pharma) is already approved for AML. There was also a presentation on the HDAC inhibitor entinostat (Syndax Inc) with 5-azacitidine in myeloid neoplasia (Abstract #2777), and there are several clinical trials listed for AML, however this drug is mainly being used in solid tumor trials.

Other interesting drugs in this area include alisertib, an Aurora A kinase inhibitor (Millennium/Takeda) being tested extensively in B and T cell lymphomas and in solid tumors. There are several AML trials including a phase 2 trial completed by MLMN (NCT00830518). Selinexor, (Karyopharm) a selective inhibitor of nuclear export, in in phase 1 trial for advanced AML. Abbvie’s Bcl2 inhibitor ABT-199 is also in an AML trial.

If we take a step back we can appreciate that in small molecule development Novartis, Merck and Onyx are placing big bets in this therapeutic area. We’ll sort out the best looking therapeutics as we dig in a little deeper.

In Part 2 we’ll take a look at the biologics landscape, and begin to draw the bigger picture.

Examples of Smaller Projects We Have Tackled

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