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.

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