Category Archives: biologics

THE NEXT GREAT DRUG HUNT: Integrins, TGF-beta and Drug Development in Oncology and Fibrosis

April 5, 2020biologics, immunotherapy, integrins, monoclonal antibodies, oncology, TGF beta, tumor microenvironmentPaul Rennert

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PART 1: Integrin αvβ8

Advances in our understanding of the regulation and function of TGF-β is driving novel drug development for the treatment of diverse diseases. This is a field I’ve followed for a long time and of course in the development of cell therapeutics we (www.aletabio.com) always have an eye on immunosuppressive pathways – indeed, the immunotherapy and cell therapy fields cross-fertilize often and productively (see http://www.sugarconebiotech.com/?m=202002).

Several new papers in this space have caught my eye and I’m keen to share some key findings. This will be a multi-part post and today I want to talk about an integrin.

Long time readers will appreciate the importance of alpha v-integrin-mediated regulation of TGF-β release from the latent complex (http://www.sugarconebiotech.com/?p=1073). The model that first emerged around 2010 was elegant: various signaling pathways triggered GPCRs that could activate an integrin beta strand (paired with an alpha v integrin) and coordinate the release of TGF-β from the cell surface. Soluble TGF-β, free from restraint, could diffuse across nearby cells and trigger TGF-β-receptor activation. Three integrins have been linked to the regulation of TGF-β release: αvβ6, αvβ8 and αvβ3. The mechanism for releasing TGF-β from the latent complex on the cell surface requires a conformation change in the integrin structure. From this insight emerged diverse drug development efforts targeting specific integrins, targeting the ligands for specific GPCRs and so on. Notable examples include the anti-αvβ6 antibody STX-100 (Biogen), the autotaxin inhibitor GLPG1690 (Galapagos), small molecule inhibitors designed to block integrin conformational change, and isoform-specific anti-TGF-β biologics, among many others. The mechanism of action of these drugs includes reduction of free, active TGF-β and therefore reduced TGF-β-receptor signaling. STX-100 was withdrawn from clinical development due to toxicity – more on this another time. GLPG1690 is now in a Phase III trial (in IPF) having shown anti-fibrotic activity in earlier clinical trials – this drug has had an interesting life, originally partnered by Galapagos with Johnson & Johnson, later returned, and now part of the mega-partnership with Gilead. I’ve previously discussed these and many other drugs in development in the context of fibrosis pathogenesis (http://www.sugarconebiotech.com/?p=1073). We’ll look at novel TGF-β-directed antagonists and their role in immune-oncology in part 2, as part of a long-running thread (http://www.sugarconebiotech.com/?m=201811).

So back to integrins. The dogma that emerged based on work from disparate labs was that an activated integrin was required to release TGF-β from the latent (inactive) complex on cell surfaces, allowing for precise regulation of TGF-β activity. More specifically, this model refers to the release of two of the three isoforms of TGF-β – isoforms 1 and 3. Isoform 2 regulation is different and relies on physical force acting directly on cells to trigger release. Of note, isoform 2 antagonism contributes to the toxicity associated with pan-TGF-β blockade but does not appear to contribute significantly to disease pathology either in fibrosis or in oncology. Therefore, specifically antagonizing TGF-β-1/3 without antagonizing TGF-β-2 is ideal – and the model we’ve just outlined allows for this specificity by targeting specific integrins.

The model that alpha v integrins mediated release of free, active TGF-β has held firm for nearly a decade. Now however there is a fascinating update to this model that involves the αvβ8 integrin. Work from the labs of Yifan Cheng and Steve Nishimura at UCSF has revealed a novel mechanism of TGF-β regulation that has interesting implications for drug development (https://doi.org/10.1016/j.cell.2019.12.030). Uniquely, integrin αvβ8 lacks critical intracellular binding domains that allow an integrin to anchor to actin fibers within the cell. As a result, binding to αvβ8 does not cause the release of TGF-β from the latent complex on the cell surface but rather presents an active form of TGF-β on that cell surface, without release from the latent complex. Importantly the complex formed between αvβ8 and TGF-β is conformationally stable and relies (in their experimental system) on trans-interaction between one cell expressing αvβ8 and a second cell expressing TGF-β as displayed on a latent protein complex (here, containing the GARP protein), and expressing the TGF-β receptors. In this system TGF-β remains anchored to the GARP-complex, but the conformational rotation caused by αvβ8 binding allows anchored TGF-βto interact with TGF-β-RII, thereby recruiting TGF-β-RI and inducing signaling.

The focus on GARP (aka LRRC32) relates to this groups long-standing interest with T-regulatory cells, which uniquely express GARP. Biotech investors will recall the Abbvie/Argenx deal on this target, which is in clinical development (https://clinicaltrials.gov/ct2/show/NCT03821935). A related protein called LRRC33 has been discovered on myeloid lineage cells.

More important, in my view, is that αvβ8 is expressed widely on tumor cells and has been variably reported to correlate with metastases (depending on the indication). This suggests that one means that tumor cells have of inducing TGF-β activation on interacting cells (eg. lymphocytes, myeloid cells and perhaps stromal cells) is via αvβ8 activity. The dependent hypothesis would be that such activation is immunosuppressive for those tumor-interacting cells. This is consistent with the known effects of TGF-β on immune cells in particular, but also stromal cells like fibroblasts. As an aside I like this model as one way of accounting for the appearance of T-regulatory cells and myeloid lineage suppressor cells in the tumor microenvironment as result of, rather than the cause of, immunosuppression, that is, these cells may be epi-phenomena of broad TGF-β-mediated immunosuppression. This may in turn explain why targeting such cells as T-regs and MDSCs has been largely unsuccessful to date as a therapeutic strategy for cancer.

There are some other implications. As the authors point put, the integrin/TGF-β complex is stable, and the binding domain that mediates the interaction is buried with the protein complex. It is unclear whether anti-TGF-β antagonists that target the canonical integrin binding cleft would be able to access this site within the complex. It’s possible that some of these drugs (whether antibodies or small molecules) can’t work in this setting. On the other hand, antibodies to αvβ8 clearly prevent the complex from forming and should block TGF-β-mediated immunosuppressive signaling in settings where αvβ8 expression is dominant. An anti-αvβ8 antibody strategy is being pursued by Venn Therapeutics (disclosure: I sit on Venn’s SAB). Further, the structural features identified in the paper include well-defined pockets that might be suitable for small molecule drugs. Indeed, one of the structural features in the b8 protein, consisting of hydrophobic residues, appears to account for the differential binding of various integrins (β6, β1, β2, β4, β7) to TGF-β, a remarkable finding. Analyses of the differences between the structure of β8 and other β integrins has been extensive across laboratories (see https://www.nature.com/articles/s41467-019-13248-5 for another important paper). Small molecule drug discovery is well underway in this field (see for example Pliant Therapeutics and Morphic Therapeutics) and one might imagine that these novel results found an interested audience in many bio-pharma labs.

Next: what has Scholar Rock been up to, and what can we learn from their work?

Stay tuned.

Updates from #CowenHealthCare 2020 – CAR T and it’s competitors

March 3, 2020Aleta Biotherapeutics, ALL, AML, B cell lymphoma, B cell lymphomas, biologics, BITE bi-specific, cancer, CAR T, CAR T cells, Chimeric Antigen Receptor, chimeric antigen receptors, CNS pathologies, immunotherapy, leukemia, lymphoblastic leukemia, lymphoma, Lymphomas, Leukemias, Myelomas, myelofibrosisAML, CAR T cells, cell therapy, leukemia, lymphoma, myelomaPaul Rennert

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If you work in cell therapy you have follow all kinds of therapeutic developments in indications of interest which for us at Aleta Biotherapeutics (www.aletabio.com) includes specific solid tumor indications, and several hematologic malignancies.

Over the last few days we’ve gotten interesting updates regarding diverse hematologic malignancies, including news about therapeutics for front line (newly treated) or relapsed or refractory (r/r) Non-Hodgkin Lymphoma (NHL), multiple myeloma (MM) and acute myeloid leukemia (AML) patients and the myelodysplastic syndromes (MDS). Note here that the reference to different lines of therapy – front line or early line vs r/r, because the treatment paradigms change as patients fail earlier lines of therapy, ie. as they become refractory to or relapse from their current therapy. This can become a long and arduous battle for patients who repeatedly fail treatment. Unfortunately, this is often the case in r/r MM, r/r AML and MDS and in some subtypes of r/r NHL.

On Monday (2 March 2020) I attended the “Cell Therapy & Myeloma” panel at the 40^th Annual Cowen Heath Care Conference. This panel covered much more than the title implies, and I really liked the format which is built on the back of questions posed to the audience, to an (unnamed) group of specialists in the field who were polled in advance, and to the seated key opinion leaders (KOLs), in this case Dr Deepu Madduri (Mt Sinai) and Dr Jacob Soumerai (MGH).

They covered a lot of ground.

The first series of questions sought to pin down trends in r/r Follicular lymphoma (FL) a subtype of NHL that can become difficult to treat if patients fail successive lines of treatment. The Leukemia Lymphoma Society has a primer here –https://lymphoma.org/aboutlymphoma/nhl/fl/relapsedfl/. There has been brisk drug development in r/r NHL including FL. Novel drug classes include CAR-CD19 T cells, bispecific T cell engagers, small molecule drugs (targeting PI3K, Bcl2, BTK, EZH2) and new antibodies. The Cowen panel worked through a series of questions regarding this landscape and there were several key takeaways.

One was the clear preference, by the anonymously polled specialists and by the seated panelists, for CAR-CD19 therapy as the most exciting new drug for r/r FL. The driver here is the durability of response (DOR) in really late line patients and the sense that both overall response rate (ORR) and DOR will only improve as these cell therapeutics move to earlier lines of therapy. It was striking that several classes of bispecific antibodies (the CD3 x CD20 and CD3 x CD19 bispecifics) elicited strong enthusiasm from the audience (mostly analysts and investors) but only muted enthusiasm from the KOLs. This lack of enthusiasm had 2 distinct bases: 1) limited data to date, and 2) “I can give a bispecific after I give a CAR T, but not the other way around”, which was a very interesting thought (and given despite of the few case reports of CD3 x CD20 bispecific therapy working in several relapsed CAR-T patients). I think that in later line patients these clinicians want to keep their options open as long as possible.

Among the other classes of therapeutics, Epizyme’s EZH2 inhibitor tazemetostat received significant support based on the ability to select EZH2-mutated patients, and on good DOR and on good tolerability, the latter thought to be better than the PI3Kdelta class inhibitors, BTK inhibitors or BCl2 inhibition. The consensus was that tazemetostat could see up to 20% market penetration in third line FL after the expected launch in June 2020.

Among the PI3Kdelta inhibitors, Bayer’s copanlisib was singled out as best-in-class with little differentiation among the others (from Gilead, Verastem, MEI, Incyte, or TG Therapeutics). Finally, in this setting of r/r FL, both venetoclax (a Bcl2-inhibitor) and polatuzumab vedotin (a CD79b antibody-drug conjugate), were relegated to minor use by the specialists and panelists.

The uptake of CAR-CD19 therapies has been brisk, and the panelists highlighted quicker payor approvals and the accelerating pace of referrals to cell therapy centers. The consensus is for 30% increase in patient number treated in 2020 (so roughly 1350 patients in the US, vs 1050 treated last year).

The discussion stayed on CAR-CD19 therapeutics to touch on some of the newer trials and entrants. Kite/Gilead is running a Phase III trial of axi-cel (axicabtagene ciloleucel, brand name Yescarta) in second line DLBCL patients vs a standard of care regimen of high dose chemotherapy followed by an autologous stem cell transplant. Data are anticipated in the second half of 2020. The Cowen moderators passed the question: will this trial show a progression free survival (PSF) benefit? Mind you, this is a low bar since overall survival – the shining triumph of cell therapy – is not part of the question. The audience (again, mainly investors and analysts) was overwhelming positive, giving about 70% odds of a positive impact on PFS. Here the panelists agreed, citing the fact that this trial was enrolling high-risk patients and therefore the comparator arm of the trial (chemo + ASCT) should do very poorly. Success with this trial would move axi-cel up a line of therapy (from 3^rd or later to 2^nd or later) and bolster the health care value argument that patients may avoid ASCT altogether. We are apparently already seeing this effect, as a talk at #TCMT20 highlighted the steep decline in transplants being done in DLBCL.

Sticking with axi-cel, this CAR-CD19 cell therapy was highlighted as the one most likely to be the market leader by 2023, based on the (currently) much shorter manufacturing and turnaround time as compared to tisa-cel (tisagenlecleucel from Novartis, brand name Kymriah). The panelists agreed with the specialist poll, despite the fact that they also felt that tisa-cel may be better tolerated by patients overall. Further, the panelists did note that the difference in manufacturing turnaround was likely to diminish as Novartis improves its product workflow. So we’ll have to wait and see.

Competition may also play a role. The long-awaited Juno > Celgene > BristolMyers Squibb CAR-CD19 liso-cel (lisocabtagene maraleucel) should see its first approval soon, and several allogeneic and non-T cell based programs are advancing. Cowen’s moderators highlighted a number of these for discussion. Allogene CAR-CD19, called ALLO-501 is currently in a Phase 1 trial enrolling r/r diffuse large B cell lymphoma (DLBCL) and r/r FL patients, with initial data expected later this year. The moderators put forward the question: what percent of (responding) patients have to show a durable response for this to be an exciting option to the autologous CAR-CD19 products. It’s a complex question since the current approved CAR-CD19s show about a 50% durable response rate within the responders, where a goodly proportion of the patients that do not have a durable response are relapsing after a response, sometimes with CD19-negative lymphoma or leukemia (ie. the cancer has undergone natural selection and loses target antigen expression). The polled specialists and the panelists wanted to see a pretty high durable response rate, 35-40% (specialists) up to 50% (the panelists). If the field were to see responses as good as axi-cel, tisa-cel and liso-cel, this would be “a huge advance”, according to Dr Soumerai of MGH.

Of note, Allogene itself was a bit more cautious at their public company presentation later in the day. Dr David Chang, Allogene’s CEO, provided some guidance and set expectations. He noted that the company would report early data form the ALLO-501 program at #ASCO20 and/or #EHA20 but stressed the readouts of safety and degree of lymphodepletion from up to 3 dose cohorts, and with several different doses of their lymphodepletion agent ALLO-647, and anti-CD52 antibody. In the ALLO-501 trial this is given along with the lymphodepeleting chemotherapy combination of cyclophosphamide and fludarabine (Cy-Flu). Among the other allogeneic and off-the-shelf CAR-CD19 programs several were highlighted either by the audience (Fate Therapeutics induced CAR-NKs) or the panelists (the Takeda/MD Anderson NK program). Other programs from Atara, CRISPR, and Precision all would have to show some or more data in order to get the specialists or the panelists to take notice.

Notably, there was consensus among the audience, polled specialists and panelists that CD3 x CD20 bispecifics would be less efficacious than CAR T cells, regardless of the specific therapeutics (eg. from Roche or Regeneron or Genmab). Further, Dr Madduri expressed concern at the need to keep dosing patients both because of inconvenience and possible safety over time. Her view is that patients prefer a single dose CAR.

Finally in the r/r DLBCL space, both polled specialists and the panelists saw minimal roles for the anti-CD79b-drug conjugate polatuzumab vedotin (brand name Polivy, from Roche) or the anti-CD19-ADCC competent antibody tafasitamab (from Morphosys, which now has a 30 August PDUFA date with FDA). Both of these biologics need to be given in combination with other therapeutics and there did not appear to be a benefit over standard combinations. More specifically, polatuzumab vedotin is given with rituximab and bendamustine and was considered “tolerable” but perhaps best used in a bridge to transplantation setting or a bridge to CAR-CD19 cell therapy. Tafasitamab was recently written up by Jabob Plieth here: https://www.evaluate.com/vantage/articles/analysis/why-2020-spotlight-will-fall-tafasitamab.

Turning to r/r MM there were a series of questions about lines of therapy and which were preferred. For newly diagnosed patients and for second-line patients the clearly favored standard of care was an ‘ImID’ (immunomodulatory agent, eg. revlimid) plus the anti-CD38 antibody daratumumab (brand name Darzalex, from Johnson & Johnson’s Janssen division) plus dexamethasone (aka triple therapy) with perhaps a proteasome inhibitor added (thus, a quad). The use of daratumumab in early line therapy will continue to grow as it is payor-approved for early-line use.

For later line therapy, the moderators first brought up selinexor (brand name Xpovio, from Karyopharm Therapeutics), a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE), which was granted accelerated approval last year for use in in combination with dexamethasone for adult r/r MM patients who received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two ImIDs, and an anti-CD38 monoclonal antibody. There was a consensus view that this drug will see flat to diminishing use due to poor tolerability. Dr Madduri noted that she gives this drug once week rather than twice a day (as labeled) in an effort to improve patient tolerance and only used it as a bridge to clinical trial enrollment (ie. on something else, for example, CAR-BCMA cellular therapy. Curiously there were no questions about isatuximab-irfc (brand name Sarclisa, from Sanofi-Aventis), newly approved in combination with pomalidomide and dexamethasone for adult patients with r/r/ MM and at least two prior therapies (see this SITC writeup: https://www.sitcancer.org/aboutsitc/press-releases/2020/isatuximab-irfc).

As for CAR T cells for multiple myeloma, the panelists were hesitant to pick a winner between the two advanced CAR-BCMA programs: bb2121 (Bluebird) and JNJ-4528 (from J&J, formally called LCAR-B38M) until J&J updated PFS data. At their public company presentation Nick Leschly, Bluebird’s CEO, noted that they will file the BLA for bb2121 (now called idecabtagene vicleucel or ide-cel) in the first half of this year, and would release longer-term follow-up data from the ide-cel clinical trials KarMMa and CRB-401 in the second half of the year. The BLA will be filed despite the “slow-down” from FDA necessitated by the agency’s request for additional lentivirus production characterization information from their chosen cell suspension manufacturing method (no details given). What the FDA has asked for apparently is both different from and more than the EU agency (EMA) wanted.

On the allogeneic CAR T cell front, Dr Chang at Allogene noted that they would have early data on ALLO-715 (their version of a CAR-BCMA therapy) at #ASH20. Here he noted they are considering dropping the Cy-Flu lymphodepletion and just using their anti-CD52 antibody to lymphodeplete, we’ll see (this doesn’t strike me as realistic).

In general both the polled specialists and the panelists were more enthusiastic about CAR-BCMA therapy than several other modalities, including belantamab mafodotin (from GSK), an antibody-drug conjugate, composed of an anti-BCMA monoclonal antibody bound to auristatin F. This drug was thought to be not quite good enough given the unmet need, there remain concerns about the ocular toxicity (the bane of ADC technology) and keen disappointment that the response rate dropped below 30% ORR in daratumumab-refractory patients. Clearly this therapeutic will see some use in late line therapy, and further clinical development has yielded results in earlier line as reported on 2 March (see https://www.evaluate.com/vantage/articles/news/trial-results/karyopharm-comes-boston-springtime). A similar wait-and-see approach is being taken by these specialists and panelists to the CD3 x BCMA bispecifics, which are currently viewed as best for community hospital settings without CAR T cell capacity or for patients who cannot wait for the cell therapy production.

One theme in r/r MM is the concern that patients are still not being cured, even with cell therapies. The gradual relapse from CAR-BCMA treatment that one sees in all the clinical studies has been linked either to CAR T persistence being limited or to diminished BCMA antigen expression on the cancer cells. Of course, these two things may be related. One desire expressed by Dr Madduri was for a CAR-BCMA therapy with better persistence properties.

Two short notes while we’re here. Gilead stated at their public company presentation during Cowen Health Care that the value driver for the Forty Seven acquisition was the MDS data (https://xconomy.com/san-francisco/2020/03/02/gilead-boosts-cancer-drug-pipeline-with-4-9b-deal-for-forty-seven/). And hematologic drug heavyweight venetoclax (the Bcl-2 inhibitor from Abbvie) scored a miss in an AML confirmatory trial (https//pharmaphorum.com/news/abbvie-roches-venclexta-fails-in-confirmatory-aml-trial/). In summary, a busy couple of days.

As many readers know, Aleta Biotherapeutics builds cellular therapeutics with exemplary persistence and fitness properties. We have two cell therapy programs heading for the clinic now. One will treat r/r AML patients both in the pediatric and adult patient populations. Our solid tumor program is designed to treat patients relapsing from breast or lung cancer with brain metastases. We also have a biologics program specifically created to ‘rescue’ CAR-CD19 T cells in patients relapsing from therapy. You can find out more at www.aletabio.com or email me at paul.rennert@aletabio.com or just call me at 1-508-282-6370 and of course follow me on Twitter @PDRennert and @BioAleta.

That’s it for now. Stay tuned.

The Tumor Ecosystem: some thoughts stirred up at the NY International Immunotherapy meeting

October 7, 2015biologics, CAR T cells, CRISPR, Enumeral, immunotherapy, monoclonal antibodies, tumor microenvironment, UncategorizedPaul Rennert

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Ecosystems in tumor immunity

The buzzword ‘ecosystem’ has popped like a spring dandelion, and it is now used everywhere in biotech. I’m as guilty as anyone of rapid adoption: the term does capture essential elements of modern biomedical science. Complex and interlaced, with key control nodes at work at all levels – scientific, financial, clinical, commercial – and also dynamic, constantly driving adaptation, and, we hope, innovation. Scientifically the ecosystem connections are easily spotted. CRISPR technology appears in cellular therapies including TCRs and CAR-Ts as we simultaneously learn that the mechanisms of immune checkpoint suppression deployed by tumor cells can derail genetically engineered CAR T cells as readily as normal T cells. Further, those genetically engineered CAR T cells and TCRs owe their existence in large measure to our newly developed ability to sequence tumors at the individual level, with great sensitivity, to identify novel targets. The whole enterprise in turn requires ever faster, cheaper, smaller and more reliable equipment (RNA spin columns and PCR cyclers and cloning kits and desktop sequencers and on and on) and software to handle the data. Enterprises like these in turn drive discovery and innovation.

Within the tumor is another ecosystem – the tumor microenvironment or TME. While TME is a fine term it does blur the notion that this microenvironment is in nearly all cases part of a larger environment and not a walled-off terrarium (perhaps primary pancreatic cancer is an exception, within its fibrous fortress). The tumor ecosystem is a more encompassing term, allowing for the ebb and flow of vastly different elements: waves of immune cells attempting attack, dead zones of necrotic tissue being remodeled, tendrils of newly forming blood vessels, a fog of lactate, a drizzle of adenosine, energy, builders, destroyers, progenitors, phagocytes, parasites, predators. When viewed this way we might wonder how any single drug could treat a tumor, since it is not a singular thing that we attack with a drug, but an ever-changing world we are seeking to destroy.

So it’s hard to do.

Our understanding of the tumor as a complex entity was first informed by pathology, then microscopy, then histology and immunohistochemistry, myriad other techniques and of course genetics, the latter leading to the identification of tumor oncogenes, tumor epigenetics, tumor mutations (referred to above) etc, etc. This ecosystem – that of the cell and it’s mutational hardware and software (genome and exome, or genotype and phenotype) we can hardly claim to understand at all, not matter how many arrows we might draw on a figure for a paper or a review. A few recent examples: we think that tumor cells adapt to immune infiltration in part by engaging CTLA4 expressed on T cells, and when that fails they secrete IDO1, or express PD-L1 on their cell surface, or the tumor cells direct tumor associated cells to do the work for them – maybe monocytes, or macrophages, perhaps fibroblasts, perhaps the endothelium, i.e. the ecosystem. As we know from studying patterns of response to PD-1 and PD-L1 therapeutics, it is hardly so simple, as patients who don’t express the therapeutic target will respond to therapy and patients who express the therapeutic target sometimes, in fact often, will not respond. Which just says we don’t know what we don’t know, but we’ll learn, the hard way, in clinical trials.

The abundance of therapeutic targets and our lack of knowledge is best displayed, with some irony, when we try to show what we do know, as in this figure from our recent paper on immune therapeutic targets:

from http://www.nature.com/nrd/journal/v14/n8/full/nrd4591.html

The picture is static, and fails to represent or visualize complexity (spatial, temporal, random, quantum), and we therefore cannot formulate meaningful hypotheses from the representation. Without meaningful hypotheses we just have observations. With observations we can only flail away hopefully, and be happy when we are right 15 or 20% of the time, as is the case with most PD-1 and PD-L1-directed immune therapeutics in most tumor indications, at least as monotherapies. Why focus so on the PD-1 pathway? Because at least for now, it is the singular benchmark immune therapeutic, stunning really in inducing anti-tumor immunity in subsets of cancer patients.

The success of the “PD-1” franchise has created another ecosystem, clinical and commercial. The key approved drugs, and the 3 or 4 moving quickly toward approval, are held by some of the world’s largest drug companies (BMS, Merck, Astra Zeneca, Sanofi, Pfizer, Roche). Playing in that sandbox has proven very lucrative for some small companies, and very difficult for many others. There is competition for resources, for patients, for assets and ideas. This has created new niches in the commercial ecosystem, as companies try to differentiate from each other and carve out their own turf – Eli Lilly for example has focused on TME targets, distinguishing itself from other oncology pharmaceutical companies in choice of targets, followed closely of course by smaller contenders – Jounce, with a T cell program directed at ICOS but perhaps more buzz around their macrophage targeting programs, and Surface, whose targets are kept subterranean for now. Tesaro and others are betting on anti-PD-1 antibodies paired rationally with antibodies to second targets in bispecific format. Enumeral is focused on building rationale for specific combinations of immune therapeutics in specific indications, perhaps even for the right subset of patients within that indication. And so on.

It’s complicated.

Lets imagine you are right now pondering an interesting idea, have a small stake, and want to engage this landscape of shifting ecosystems. What might you do?

Lets start with a novel target. You’ve read some papers, woven together some interesting ideas, formulated some useful hypotheses. The protein has been around, maybe there are patents, but not in the immune oncology space, so you think you might have some freedom to operate. Good, best of both worlds. You dig around, find you can buy your target as purified protein, or find a cell line that expresses the target. Now what? Maybe you would hire an Adimab or Morphosys or X-Body to perform an antibody screen. Different companies, varied technologies, but all directed at antibody discovery. My favorite of this group was X-Body, who had an extraordinary platform to screen human antibody sequences and produce antibodies with really stunning activity and diversity. Juno bought them in early 2015, seeking the antibody platform and a TCR screening platform built with the same technology. I hadn’t seen anything quite so powerful until recently, with the introduction of a novel screening technology from Vaccinex. This platform is about as diverse as the X-Body platform (i.e. ~10⁸ Vh sequences and up to 10⁶ Vl sequences; that’s a lot of possible Vh-Vl pairs). What sets them apart is that the entire selection process happens as full length IgG in mammalian cells rather than surrogates like bacteria or yeast. The net result is a reduction in risk associated with manufacturing. They’ve used it to power their own clinical programs and have selection deals with some big names including Five Prime Therapeutics. Remarkably (I think) you can access their platform to screen targets for your own, i.e. external, use. Their website explains the platform further (http://www.vaccinex.com/activmab/) but here is one nice sample of their work on FZD4 (a nice target by the way):

So now via Vaccinex or someone else you’ve acquired a panel of antibodies that you are ready to test for immune modulatory activity in models that are relevant to immune oncology. You can build out a lab (expensive, time-consuming), find a collaborator with a lab, or find a skilled CRO. The immune checkpoint space was until recently devoid of really focused CRO activity, that is, having diverse modelling capability and careful benchmarking. However, Aquila BioMedical in Scotland, UK placed a solid bet on developing these capabilities around a year ago, and that effort is yielding a terrific suite of assays in both mouse and human cell systems, with multiple readouts, solid benchmarking (e.g. to nivolumab) and careful controls. I like this very much, rich in functional data in a way that a binding assay simply can’t reproduce. Aquila BioMedical seeks to become a driving force in this area, and I like their chances very much: see http://www.aquila-bm.com/research-development/immuno-oncology/ for more information on assays like this IFNgamma secretion assay:

Those are clean and robust data.

Now you come to the point of translation to actual use, that is, targeting an indication. How does one proceed? We can probe the TCGA and other databanks for clues, stare at the IHC data online (not recommended), try to cobble together enough samples to do our own analyses (highly recommended but difficult). The goal is to make some educated guesses about two distinct features of the tumor ecosystem: First, is your target expressed on a relevant cell within the ecosystem (tumor, TME, vasculature, draining lymph nodes, etc) in a specific indication or indications, and second, is that ecosystem likely to respond in a clinically meaningful way to manipulation of your target with your antibody?

That second question is a troubling one. What we are really asking is that we deconstruct the ecosystem and look for clues as to how the therapeutic might impact that ecosystem. What are we looking for during deconstruction? Several things, and they are assessed using diverse techniques, adding to the challenge. First, a highly mutated tumor is more likely to respond to immune therapy, and there are several aspects to these phenomena. One is to understand the underlying genomic changes underpinning the oncogenetics of the tumor: what is driving its ability to outcompete the natural surroundings – in our ecosystem analogy perhaps the tumor can be considered starting out life as an invasive species. Genomic sequencing can accurately identify the mutations that support the tumor, but also a potentially vast array of “passenger” mutations that accumulate when tumors turn off the usual mutation repair machinery. Various algorithms exists that can predict which mutated proteins may be immunogenic, that is, capable of stimulating an anti-tumor immune response. Another method designed to determine if an immune response has in fact be stimulated (and has stalled) is to sequence the mRNA expressed in the tumor: exome sequencing. This will reveal, among other things, what the TCR usage is within the tumor, and that in turn will inform you if there is a very narrow anti-tumor response and a broad one, based on the breadth of TCR clonality. That sounds complex, but really isn’t – suffice to say that a broader TCR response in suggestive of immune potential, leashed T cells awaiting clear orders to attack.

More complex is the nature of those orders, and counter-orders. Various methods are being developed to measure the “quality” of the immune response that confronts the tumor. Are key costimulatory molecules present on T cells that would allow stimulation? Are the T cells instead coated with immunosuppressive receptors? Are the tumor cells masked with inhibitory proteins, are they secreting immunosuppressive factors, have they hidden themselves from immune view by downregulating the proteins that T cells “see” (i.e. the MHC complex). What are the cells within the TME doing? Are they monocytes, macrophages, fibroblasts? Where are the T cells? Within the tumor, or shunted off to the side, at the margin between the tumor and normal tissue? Are NK cells present? And on and on it goes. It seems impossible to answer all these diverse questions.

You might try IHC, as mentioned, or targeted PCR for select genes, and Flow Cytometry to look at the distribution of proteins on various cells, or try deep sequencing. All of this is achievable with equipment, labs and people, or by assembling various collaborators, but all in all, quite a challenge. Very recently an interesting company called MedGenome came to my attention, offering a diverse range of services, starting with neo-epitope prioritization and immune response analyses. These offerings, plus some routine IHC, should give most researchers a comprehensive look into tumor ecosystems, informing indication selection, mechanism of action studies and patient profiling. They explain the technology at http://medgenome.com/oncomd/. This is a schematic they sent me showing their neoepitope prioritization scheme that enriches for peptides that trigger anti-tumor immunity, e.g. in a vaccine setting or perhaps in a cellular therapeutic format.

It’s a good start on democratizing a suite of assays typically available only to specialty academic labs and well-funded biotechs and pharma companies.

So now you’ve gotten your antibodies (Vaccinex), performed critical in vitro (and soon, in vivo) assays (Aquila Biomedical), and analyzed the tumor immune ecosystem for indication mapping (Medgenome).

You’ll have spent some money but moved quickly and confidently forward with your preclinical development program. Your seed stake is diminished though, and it’s time to raise real money. Now what? … now you face the financial/clinical/commercial ecosystem.

stay tuned.

Brodalumab for Psoriasis – what a mess

May 25, 2015Amgen, Astra Zenenca, biologics, IBD, IL-17, IL-23, immunology, inflammation, autoimmunity, fibrosis, inflammatory bowel disease, Johnson & Johnson, lupus, monoclonal antibodies, Novartis, psoriasis, Rheumatoid arthritis, SLEPaul Rennert

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Let’s agree that the headline “Suicide Stunner” – penned by John Carroll for FierceBiotech – can never auger anything but very bad news, and never more so then when it is used to describe clinical trial results. Released on the Friday before the long US holiday weekend, bookended to the announcement of positive news on it’s PSCK9 program, Amgen stated that it was walking away from an expensive co-development program with AstraZeneca, basically washing it’s hands of the anti-IL-17 receptor (IL-17R) antibody brodalumab because of suicidal tendencies and actual suicides that occurred in the Phase 3 psoriasis trials. Brodalumab is under development for the treatment of plaque psoriasis, psoriatic arthritis and axial spondyloarthritis. Amgen stated that they believed that the approval label for brodalumab would contain warning language regarding suicide risk, and this would limit the success of the drug. By using such language while pulling the plug Amgen has essentially put AstraZeneca in the position of having to prove to the FDA that there is no suicide risk.

Holy crap.

Note here that we are not talking about a psychiatric drug, where the risk of suicide might be the consequence of trying to re-align an aberrant central nervous system. Instead we are talking about a drug that targets autoimmune disorders by blocking the action of T cells. This is not a biology linked to psychiatric health, at least not as we understand it today (more on this later).

Backing up: in April 2012, AstraZeneca and Amgen announced a collaboration to jointly develop and commercialize five clinical-stage monoclonal antibodies from Amgen’s inflammation portfolio: AMG 139, AMG 157, AMG 181, AMG 557 and brodalumab (aka AMG 827). The drivers for the collaboration were Amgen’s biologics expertise, the strong respiratory, inflammation and asthma development expertise of MedImmune (AstraZeneca’s biologics division), AstraZeneca’s global commercial reach in respiratory and gastrointestinal diseases, and the shared resources of two experienced R&D organizations

Under the terms of the agreement, AstraZeneca paid Amgen a $50MM upfront payment and the companies shared development costs. The breakout was as follows: AstraZeneca was responsible for approximately 65 percent of costs for the 2012-2014 period, and the companies now split costs equally. Amgen was to book sales globally and retain a low single-digit royalty for brodalumab. Amgen retained a mid single-digit royalty for the rest of the portfolio with remaining profits to be shared equally between the partners.

It gets even more complicated. Amgen was to lead the development and commercialization of brodalumab (and AMG 557, see below). Amgen was to assume promotion responsibility for brodalumab in dermatology indications in North America, and in rheumatology in North America and Europe. AstraZeneca was to assume promotion responsibility in respiratory and dermatology indications ex-North America. AstraZeneca remains responsible for leading the development and commercialization of AMG 139, AMG 157 and AMG 181. We’ll touch on these other antibodies at the very end.

Back to brodalumab. On balance, Amgen was on the hook for the development and commercialization costs, direct, indirect and ongoing, for dermatology indications in the US and also rheumatology, which in this case refers to psoriatic arthritis and axial spondyloarthritis. On the other hand, AstraZeneca was on the hook for commercialization in respiratory indications worldwide, and dermatology ex-US. This is interesting because brodalumab failed in its’ respiratory indication, moderate to severe asthma, and failed late, in a Phase 2b patient subset trial. So, on balance, much of the overall development cost seems to have shifted back onto Amgen over time (this is not to say that the companies would not have changed terms mid-term, they may have).

Two weeks ago I chaired a session on “Biologics for Autoimmune Disease” at the PEGS conference on Boston. In my opening remarks I used psoriasis as an example of an indication in which we were making clear and important progress, including with IL-17-directed therapeutics. Indeed, psoriasis is now a “crowded” indication commercially, with antibodies and receptor fusion proteins targeting the TNFs, IL-6, IL-12, IL-17, and IL-23 pathways all showing at least some activity. Notably, IL-17 and IL-23 targeting drugs appear to offer the greatest benefit in clearing psoriatic plaques. These pathways intersect in myriad ways, not all of which are well understood. This cartoon shows the effector cytokines and the receptors are expressed by diverse cell types, including dendritic cells, macrophages, T cells, and keratinocytes in the dermis.

In simplistic terms, IL-6 triggers IL-12 and IL-23, and IL-23 triggers IL-17. As mentioned, the IL-17 and IL-23 targeting agents have great efficacy in psoriasis. Amgen and AstraZeneca were preparing an NDA (new drug application) for FDA submission based on results from three large Phase 3 studies. Here are the listed Phase 3 programs for brodalumab:

I suppose those Phase 3 studies in psoriatic arthritis will now be tabled or transferred to AstraZeneca. For the sake of completeness here are the earlier studies:

Certainly the clinical program was a robust one. So, what went wrong? Amgen R&D head Sean Harper summed up Amgen’s thinking about the suicide issue in the press release: “During our preparation process for regulatory submissions, we came to believe that labeling requirements likely would limit the appropriate patient population for brodalumab.”

The news aggregator and commentary website UpdatesPlus had this to add, questioning whether this result was “bad luck, bad target or victim of brodalumab’s efficacy: Despite high efficacy in Phase 3 studies, whispers of suicidality associated with brodalumab started to emerge at AAD. At the time Amgen suggested this was related to disease however the company refused to comment on total rates and whether events were seen across arms … The question is whether Amgen is being hyper-cautious or whether the risk of suicidality is especially concerning. Questions also emerge around the cause of risk – is this a spurious cluster of events unrelated to brodalumab; is suicidality perhaps related to relapse from the excellent efficacy associated with brodalumab after withdrawal (remember most patients exhibited at least PASI 90 on treatment but durability was very poor upon withdrawal); or perhaps suicidality is related to blocking the IL-17RA (note that suicidality has not to our knowledge been reported for the IL-17A ligand mAb Cosentyx) … One final point is whether regulators will now reevaluate suicide risk of IL-17 related molecules as a class – much greater clarity of brodalumab data is required to make a judgement.” That’s quite a nice summary from UpdatesPlus.

FierceBiotech’s report added “AstraZeneca would face some stiff competition if it decides to move forward solo on the drug. Novartis is already well in front with its IL-17 program for secukinumab, approved in January as Cosentyx. Eli Lilly has also been racking up positive late-stage studies for its IL-17-blocking ixekizumab, trailed by Merck’s MK-3222 and Johnson & Johnson’s IL-23 inhibitor guselkumab.”

Still, brodalumab demonstrated remarkable efficacy in psoriasis – Amgen and AstraZeneca went so for as to include a PASI100 score in one of their trials, meaning 100% clearance of psoriatic plaques, and the drug would have shown well against the best of breed, which today is likely Novartis’ anti-IL-17 antibody secukinumab. It is crowded space however, with antagonists targeting multiple nodes in the IL-17/IL-23 axis, alongside the biologics mentioned earlier.

Here is the current landscape from CiteLine (including brodalumab):

All in all, a tough crowd, and one that Amgen likely felt it could not face with a compromised label.

Let’s go back to the question posed above: bad luck, bad target or victim of superior efficacy? “Bad luck” suggests a statistical fluke in the data, potentially caused by the generally higher rates of suicidal tendencies observed in the moderate to severe psoriasis patient population. “Victim of superior efficacy” is in a sense a related issue, since the suggestion is that the loss of responsiveness to the drug, or a relapse, triggers a suicidal response as plaques return. Neither of these statements is really formulated as a hypothesis, and it doesn’t matter, as we don’t have the actual trial data yet with which to perform hypothesis testing.

“Bad target” is the most worrisome suggestion, and this can be formulated as a hypothesis, formally, the null hypothesis is that targeting the IL-17 receptor does not cause suicidal tendencies. Unfortunately, we still can’t test the hypothesis, and it seems likely that having the actual data won’t really help, that is, the study is probably not powered to reject that particular null hypothesis. So, what do we know? A few things, as it turns out.

First is that a link between the immune system and the nervous system is well established, although much of the focus has been on the role of neuronal enervation on immune responses. But clinically at least, the picture is muddier than that. High dose IL-2 can cause neurotoxicity, even hallucinations, according to Dr. Kathleen Mahoney, an oncologist at Beth Israel Deaconess and the Dana Farber. But what is really interesting is what else happens: “Some IL-2 treated patients can have odd dreams, really crazy dreams, and they last for weeks after treatment, long past the time when IL-2 would still be present in the body”, Dr. Mahoney said. Interferon alpha therapy is associated with pathological (severe) fatigue and also depressive symptoms that develop after 4–8 weeks of treatment. Of note, preventive treatment with anti-depressants, in particular serotonin reuptake inhibition attenuates IFN-alpha-associated symptoms of depression, anxiety, and neurotoxicity. Some researchers have suggested (controversially) that anti-TNF antibodies can control depression. Such anecdotal clinical observations suggest that we really do not yet understand the immune system connection to CNS activity.

On the other hand, antagonism of cytokine activity, and particularly of the cytokines IL-6, IL-17 and IL-23, has not been associated with neurological symptoms. For example the anti-IL-6 receptor antibody tocilizumab has shown a positive impact in rheumatoid arthritis patients quality of life scoring, which includes fatigue, anxiety, depression and a number of other factors. More to the point, the anti-IL-17 antibody secukinumab, that targets the IL-17 ligand (rather than the receptor), has not shown a link to suicide.

Clearly more data are needed, and it would not be surprising if the FDA began a drug class review if the data in the brodalumab trials warrant. They could cast quite a wide net given the complexity of this pathway, which overlaps with IL-6, IL-12 and IL-23. This casts a pall over the dermatology and particularly the rheumatology landscape, which is really waiting for novel therapeutics to move them successfully into new and important indications such as lupus and Type-1 Diabetes. The IL-17/IL-23 axis was to be that next great hope, and with luck we will still see these drugs moving out of their core indications of psoriasis and inflammatory bowel disease into new indications.

One last thing.

Those other antibodies – where are they now? A quick scorecard:

It is readily seen that none of these are beyond early Phase 2, so it’s fair to say that the rest of the Amgen/AstraZeneca partnership has a long way to go. I, for one, wish the ongoing collaboration the very best of luck, particularly in the lupus indications, where we can really use some good news.

stay tuned.

Snow Day Reading: The New Multiple Myeloma Therapeutics

February 14, 2015$CELG, biologics, Celgene, daratumumab, Genmab, Johnson & Johnson, Lymphomas, Leukemias, Myelomas, monoclonal antibodies, myeloma, Onyx, SanofiPaul Rennert

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There was a comment floating around Twitter that “Biotech was boring this week” and that’s true, it has been a slow news week. Sanofi took the ax to about 100 Genzyme site staffers, Bayer and J&J announced R&D reorganizations, another CAR T cell deal got done (China) and IPOs and follow-on financings were announced: business as usual.

In the background though, slow but steady therapeutic advances are being made that will impact long-term company values. The development of antibody-based therapeutics in multiple myeloma (MM) is one nice example. Among the hematologic malignancies MM is a major disease. The incidence in the US is ~30K yearly and the prevalence is ~85K. A quick glance at that math reveals a disease with pretty short-term survival, less than 5 years according a report produced by the Leukemia & Lymphoma Society in 2014.

The age of onset for MM is 70 years old in the US, and this is important because it limits some treatment options for many patients who are physically frail. Such patients may not be candidates for high-dose chemotherapy and stem cell transplantation (SCT) and even patients who are given this first line regimen will eventually relapse. Those patients are served by second line therapeutics, described below.

The huge advance is this field has been the development of non-chemotherapeutic drugs. The IMiDs such as lenalidomide and pomalidomide (Revlimid^tm and Pomalyst^tm, both from Celgene), are used with the proteasome inhibitors such as bortezomib (Velcade^tm from Takeda) or carfilzomib (Kyprolis^tm, from Onyx) along with steroids (dexamethasone, prednisone) in various combinations. “Triplets” are the preferred therapeutic, as exemplified by the combination of lenalidomide, bortezomib and dexamethasone.

At the ASH conference in December a large retrospective outcomes study of newly diagnosed MM patients was presented (link 1). Here is some of the data from that study:

Cohort % Probability of 3 yr Survival

All ages (N = 1444)	63
< 65	70
65 to < 75	65
≥ 75	47
SCT
Yes	77
No	54
Triplet therapy
Yes	69
No	55
IMWG risk
High	59
Standard	66
Low	76
del(17p)
Present	53
Absent	63

So a few things here to note: age of onset is a negative factor for survival, in part due to the inability to get the majority of elderly patients to autologous stem cell transplantation (ASCT). In addition to age of diagnosis, the International Myeloma Working Group

(IMWG) risk score is a composite of factors that determine outcome, and finally the presence of a chromosome deletion (called del(17p)) is known to be associated with significantly shortened survival.

In this study they demonstrated further that the use of triplet therapy vs. non-triplet therapy was associated with significantly prolonged OS regardless of IMWG risk but no improvement was noted for triplet vs. non-triplet therapy in patients with del(17p). Two things are clear from this study – one, we have patient subsets that remains underserved (the elderly and those patients carrying del(17p), and two, triplet therapy is keeping 70% of patients alive for at least three years.

What about patients that fail triplet therapy and who relapse and or are refractory to further treatment (rrMM)? They fare very poorly indeed, as shown here:

newly diagnosed treatment failures

There are a variety of novel therapeutics moving forward in rrMM, including novel proteosome inhibitors, HDAC inhibitors, nuclear export protein inhibitors and any others. One class of therapeutic gaining significant attention are the antibodies directed to the MM cells. These include the antibodies to CD38 and other MM-selective cell surface proteins.

The lead therapeutic among the anti-CD38 antibodies is daratumumab from Genmab in collaboration with Janssen. The deal included a US$55 million upfront payment, an $80 million equity stake in Genmab, and milestone payments adding up to $1.1 billion or more.Daratumumab is a huMAX CD38 mAb which kills CD38+ tumor cells via CDC and ADCC activity and antibody-dependent cellular phagocytosis (ADCP) by macrophages. Additional activity may be due to apoptosis upon secondary cross-linking and modulation of CD38 enzymatic function (see ASH 2014 abstract # 3474). Daratumumab received the FDA’s breakthrough therapy designation in May 2013 for treatment of rrMM (for patients failing 2 lines of therapy).

When combined with lenalidomide and dexamethasone (len/dex), daratumumab produced an overall response rate (ORR) of 75% in the phase I dose ranging clinical trial. The trial was designed to accommodate an expansion cohort dosed at the MTD (maximum tolerated dose) of 16mg/kg. In the expansion cohort the ORR was ~ 92%.

In a phase Ib study daratumumab was combined with various regimens:

These efficacy numbers are startlingly good. What will be really impressive is the associated duraton of response (DOR) and overall survival (OS) data once the trial is mature. In early February preliminary results from another Phase II study were announced. The study, called MMY2002, is listed as NCT01985126 on clinical trials.gov (link 2). This two-part study enrolled 124 rrMS patients who had received at least three prior lines of therapy, including both a proteasome inhibitor and an IMiD, or were double refractory to therapy with a proteasome inhibitor plus an IMiD. The primary objectives of the study were to define the optimal dose and dosing schedule, to determine the efficacy of two treatment regimens of daratumumab as measured by ORR, and to further characterize the safety of daratumumab as a single agent. Two doses of daratumumab were compared in part 1, at 8 mg/kg and 16 mg/kg. The expansion cohort (part 2) received the higher dose based on interim safety analysis of the initial dose comparison.

The ORR was 29.2% in the 16 mg/kg dosing group with a DOR of 7.4 months. We can expect additional data to be presented at a medical conference this year, perhaps ASCO or ESMO, and ASH or EHA. These data will support the breakthrough therapy designation for daratumumab in rrMM and may lead to a 2015 approval in this patient population, i.e. based on the phase II results.

Additional daratumumab trials include 5 phase III trials in MM, including a series of studies in newly diagnosed MM, therefore, as front-line therapy, and a phase II trial ((LYM2001) in hematological malignancies. The study will evaluate daratumumab monotherapy in three different types of NHL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). The study is expected to start enrolling patients in 2015.

Sanofi Oncology is developing SAR650984 (SAR), is a human IgG1 antibody that targets CD38. TCD11863 (NCT01749969) is a phase Ib trial evaluating the combination of SAR with len/dex in rrMM: patients averaged six prior therapies. These prior therapies included the second line therapeutics lenalidomide (94%), pomalidomide (29%), bortezomib (94%), and carfilzomib (48%). Eighty four percent of patients were relapsed and refractory to a least one second line therapeutic. In the dose ranging phase, the highest SAR dose of 10mg/kg was well tolerated.

After a median 9 month follow up, the ORR was 58%, with a clinical benefit rate of 65%, including a 6% stringent complete response rate. In patients receiving the 10 mg/kg dose, the ORR was 63%. The median progression free survival (PFS) was 6.2 months for all evaluated patients but was not yet reached in patients who received fewer than three prior therapeutic regimens before entering the study.

Looking just at the 84% of who were relapsed and refractory to least one second line therapeutic, the ORR was 50%.

An interesting study presented at ASH in December suggested that Immunogenetic factors contributing to NK cell function influenced clinical activity in pts treated with SAR/LEN/Dex. Specifically, the presence of a high-affinity KIR3DL1, HLA-B Bw4-80Ile genotype was associated with high ORR and prolonged PFS. This suggests that the NK cell competency of the patient influences the ability of NK cells to become activated in the presence of tumor cells coated with SAR antibodies. This fascinating study (ASH 2014, Abstract # 2126) should stimulate investigation of mechanisms of NK cell activation that could be used in combination with SAR, assuming the presence of len/dex does not complicate the picture. There are additional clinical studies of SAR, listed here: link 3. These include a phase I/II study in hematologic malignancies.

In addition to daratumumab and SAR650984, Celgene and MorphoSys are collaborating on the development of the CD38 antibody MOR03087 (aka MOR202). This antibody is currently being investigated as monotherapy and in combination with len/dexamethasone or bor/dex in a phase I/II rrMM study (NCT01421186). The Morphosys licensing deal with Celgene included a $92M upfront, $60M equity investment and downstream milestones. Takeda is developing the anti-CD38 antibodies Ab79 and Ab19, currently in preclinical studies (link 4). Xencor has a CD3/CD38 bispecific program. The small private biotech Molecular Templates has an anti-CD38 antibody-drug conjugate program. There are likely other programs out there.

Elotizumab (ELO) from Bristol Myers Squibb targets a different MM antigen, SLAMF7 (aka CS-1). A presentation at ASH (abstract #2119) reported early results from a phase Ib study of ELO in combination with len/dex.ELO selectively kills SLAMF7-positive MM cells through both direct activation and engagement of NK cells. A multicenter, open-label, Phase Ib trial (NCT01393964) enrolled patients with newly diagnosed or rrMM and varying renal function. Renal function is a dose limiting feature of rrMM treatment and disease progression. ELO (10 mg/kg) plus len/dex was given in 28-day cycles until disease progression or unacceptable toxicity. 26 pts were treated, 8 with Normal Renal Function (NRF), 9 with Renal Insufficiency (RI), and 9 with End Stage Renal Disease (ESRD). 89% had received prior therapy (median 2 regimens). Prior bor, thalidomide, or len treatment occurred in 21 (81%), 11 (42%), and 9 (35%) patients, respectively. ORRs were 75% (NRF), 67% (SRI), and 56% (ESRD). Thirty-eight percent NRF, 56% of SRI, and 11% of ESRD patients had a very good partial response or better. Therefore ELO/len/dex was well tolerated and showed clinical responses in MM patients regardless of renal function.

These new therapeutics for MM will certainly complement the existing triple therapies, giving patients added hope and time. We certainly expect that one of the new combinations of antibodies and the second line “triple therapeutics” discussed above will have an even more dramatic impact on MM when given in the front-line setting.

In the meantime Janssen (J&J) and Genmab are poised to give Celgene some real competition in the MM space.

Focus on Breast Cancer Therapy – Literature Sampling – Oncology – October 13, 2014

October 14, 2014biologics, Breast cancer, oncology, Puma BiotechPaul Rennert

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This is a tumor class we don’t write about that often but it bears remembering that there remains significant unmet need in an indication often touted as an example of victory over cancer. For those patients encountering resistance to therapy, metastases or breast cancers subtypes with few new options (e.g. triple negative breast cancer, TNBC) victory can seem far away.

There was a flurry of interesting papers over the last few weeks that I think give a peek behind the curtain at progress and frustrations in the ongoing evolution of breast cancer care. This post assumes some baseline knowledge of breast cancer therapy and application to specific oncogenic signatures.

As many readers will know, HER2-directed therapy has transformed care for patients carrying elevated levels of the growth factor receptor HER2 aka EGFR2. About 20% of breast cancer patients are HER2+ or become HER2+ as a mechanism of resistance to other therapies). This is an aggressive breast cancer subtype that has yielded to HER-2 targeting agents such as the small molecule inhibitor lapatinib that blocks EGFR and EGFR2 signaling, trastuzumab, an antibody that specifically kills EGFR2 positive cells, and T-DM1, an antibody-drug conjugate (ADC) consisting of trastuzumab bound to a cytotoxic “payload”. Lapatinib (Tykerb^tm) is made by GlaxoSmithKline (GSK), trastuzumab by Roche/Genentech (Herceptin^tm) and T-DM1 (Kadcyla^tm) by Roche in collaboration with Immunogen. A second anti-EGFR2 antibody, pertuzumab (Perjetatm, Roche/Genentech) binds a different epitope than trastuzumab and is approved in combination with that antibody.

Although some patients experience long-term remission with HER2-directed therapeutics, relapse is a common problem. There are various mechanisms of relapse, and PI3K activation is a common one (first identified in 2009 by multiple groups). PI3K signals through AKT to mTOR to drive expression of numerous pro-growth and pro-survival genes, making this a known oncogenic pathway, indeed it is a known oncogenic pathway in breast cancer.

Recently Loibl et al. (http://jco.ascopubs.org/content/32/29/3212) reported that activating mutations in the PIK3CA gene that encodes for the PI3K alpha subunit were associated with poor response to initial HER2-directed therapy, that is, not in the relapse setting. This means we are seeing the impact of the activation of both the EGFR2 and PI3K pathways in these patients. Of the breast cancer patients examined, 21.4% harbored a PIK3CA mutation. Detection of a PIK3CA mutation was associated with a lower Complete Response (CR) rate in a cohort of nearly 300 EGFR–positive tumors. The CR rate was 11.3% with a PIK3CA mutation compared with 27.5% without the mutation. Worse yet, in patients with PIK3CA mutation, the CR rates were 16%, 24.3%, and 17.4% with lapatinib, trastuzumab, and the combination, respectively, compared to 18.2%, 33%, and 37.1%, respectively in patients not carrying the mutation. The difference in CR rates was significant (P = .017). Fortunately, multiple drugs targeting different parts of this pathway have been developed, and it is of course possible to combine these inhibitors with anti-HER2 therapies in patients with defined PIK3CA activating mutations. Indeed one such study of the mTOR inhibitor everolimus (Afinitor^tm, Novartis) in combination with trastuzumab showed an increase in progression-free survival, although there was considerable toxicity associated with the regimen (Andre et al. 2014). Many other trials with more selective inhibitors of the pathway are underway targeting PI3K rather than mTOR, and may give a better efficacy/toxicity profile. However most of these trials are in the relapse setting rather than the first-line setting, and results may not be as effective once relapse has occurred. One take home from the Loibl et al. is that HER2+ breast cancer patients should be screened for PIK3CA activating mutations so that combination therapy can be initiated earlier in the therapy cycle.

Saura et al. (link) reported early phase clinical results of a new pan-EGFR inhibitor for HER2+ breast cancer. Neratinib, developed by Pfizer and Puma Biotechnology, was tested in combination with chemotherapy. This study presents the results of the multinational, open-label, phase I/II trial in patients with HER2-positive metastatic breast cancer, and is most notable for defining the maximum tolerated dose (MTD) of 240 mg per day (with the chemotherapeutic capecitabine). The most common drug-related adverse event was diarrhea (in 88% of patients), severe enough to cause dose interruptions or dose reductions in some patients. In July of this year Puma announced interim results of a Phase III trail of neratinib versus placebo after adjuvant treatment with trastuzumab in women with early stage HER2-positive breast cancer. The ExteNET trial enrolled over 2,800 patients with early-stage HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab, and were then randomized to receive extended adjuvant treatment with either neratinib or placebo for a period of one year. The primary endpoint of the Phase III trial was disease free survival (DFS). Neratinib therapy resulted in a 33% improvement in DFS (versus placebo, p = 0.0046). There was also a 37% improvement in DFS including ductal carcinoma in situ versus placebo (this was the secondary endpoint).

Neratinib has had tolerability issues due to the grade 3 or higher diarrhea, and we will have to see if this is enough to limit its use outside the clinical trial setting. However, the drug’s efficacy is very promising, and the toxicity may be manageable. It is unclear where the companies will present the full results of this Phase III trial, although the upcoming San Antonio Breast Cancer Congress is one likely venue.

A quick look at Puma’s stock (NASDAQ: PBYI) over the last year shows the impact this data set had in July:

The stock jumped on large volume in July and has held steady even through the recent downturn. I think we can expect little movement until the full Phase 3 results are presented. While we are likely to see more detailed DFS data from the Phase 3 study, significant upside would be possible if an impact on overall survival (OS) was demonstrated – but that is a very high hurdle in this patient population.

Notably, ongoing clinical trials of neratinib include TNBC and lung cancer (NSCLC) (both in combination with chemotherapy) and renal cancer (RCC) in combination with cetuximab (anti-EGFR antibody, Erbitux^tm, from BristolMyersSquibb). Preliminary NSCLC data were presented at the ESMO conference last month. If the new indications are impacted positively by this therapy, we can expect further value in PBYI shares.

Lets turn to a late phase disappointment in metastatic breast cancer. An antibody to a different growth factor receptor, VEGFR2, failed to shown clinical benefit in the first-line setting when added to docetaxel chemotherapy. Mackey et al (link2) reported that ramucirumab (Cyramza^tm, Eli Lilly), a human antibody that binds VEGFR2 receptor-2 and blocks ligand-stimulated activation, had no impact in a Phase 3 trial of 1,144 patients with HER2–negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting. The primary end point was progression-free survival (PFS) and the secondary endpoint was OS. HER2-negative breast cancer is less aggressive than HER2-positive breast cancer and can be controlled with debulking and chemotherapy if it has not advanced to extensive lymph node involvement (TNBC is a further, and very aggressive, subset). Eli Lilly is also testing icrucumab, an anti-VEGFR1 in a similar setting.

Several studies have focused on the predictive value of tumor-infiltrating lymphocyte (TIL) status in breast cancer settings. Nabholtz et al (TIL-1 link) studies the therapeutic utility of panitumumab combined with anthracycline-taxane-based chemotherapy in patients with operable, stage II-III, TNBC. The CR rate for combination therapy was ~55% compared to ~47% with chemotherpy alone. Poor response to therapy was associated with high EGFR expression and low cytokeratin 8/18 expression. A positive response to therapy was correlated with a high density of CD8+ TILs, suggesting that interrupting growth factor receptor signaling allowed a productive immune response to the tumor to take place.

Loi et al. (TIL-2 link) reported that TIL status was a useful marker for both TNBC and HER2+ patients treated with trastuzumab. In TNBC, TIL numbers correlated with metastatic recurrance of disease. In HER2+ breast cancer, TIL numbers were associated with better response to trastuzumab therapy.

These two latter studies suggest that immunotherapy will play a significant role in the treatment of diverse breast cancers. Early attempts here include the CD3 x HER2 bispecific antibodies, ipilimumab treatment, nivolumab treatment and many others. That’s a story for another time.

stay tuned.

Yelling Yellen and The Least Licensable Unit (LLU)

July 16, 2014ADC, biologics, chimeric antigen receptors, immunotherapy, monoclonal antibodies, oncology, PD-1Paul Rennert

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In grad school we laughed about the LPU (Least Publishable Unit), those 2 or 3 crappy papers that should have been one better paper.

Today lets introduce the Least Licensable Unit, the LLU. Amidst all the angst and anger directed at the Fed chair yesterday it occurred to me that excessive valuation has a trickle-down effect. When anything is worth too much, almost nothing is still worth a little. That almost-nothing is an LLU. When we look at the current state of asset acquisition in the immuno-oncology (IO) space we see this clearly. Very early stage assets are being land-grabbed by very large companies, and a certain sly sense of glee has crept up the brainstems of savvy biotech entrepreneurs who are rightly looking at looking at IO assets as the rarest of gemstones. Even the mere hint of sparkle in an otherwise dirt sample has prospectors racing to the wilds of Waltham and the coffee shops of Cambridge looking for LLUs.

Why is this? A few years ago (a very few) you would need to drag a program right up to the threshold of IND enablement in order to attract any attention at all. Your IP would have to be rock solid and be good for 30 years (with extensions, I know I know). Preclinical pharmacology? check. Repeat dose toxicology? check. Non-human primates? of course. A validated biomarker program? well underway!

What changed? Pretty simply, IO creates a paradigm shift in the way oncology (and many other diseases) are treated. Think rheumatoid arthritis, psoriasis and Crohn’s disease before anti-TNFs. Multiple sclerosis before beta-interferons. HCV before Vertex, Gilead and Abbvie. We are looking at a similar level of evolution in clinical practice across the whole of oncology – meaning massive disruption. With the stakes this high you have to get out, or go big. And so we see that big bets and lots of them are the order of the day. But now, a few years in, the hunt for quality is harder, and programs are taken early. The hunt for assets is so intense that the academic licensing groups at our top tier universities and medical centers are overwhelmed with inquiries. The beautiful thing here is that such leaps of faith (lets face it) are now less risky in part because technologies are rapidly differentiating. Are you in danger of stumbling into patents that block your CAR T designs? Bolt on a gene editing company and tinker so you can move into new ip. No room for your new PD-1 antibody? Blaze trail to a newly defined epitope and defend your little patch. With so many companies applying technology to assets, novel composition is easier to define. You might be able to fix an LLU, make it better, make it into a drug.

All such asset stampedes eventually run into a wall of diminishing returns as the front runners take off and the leftovers get trampled by too many competitors. That is starting to happen now in IO. Yes, it is. So what do we do now? I have a few ideas:

1) Sifting through LLUs take hard-core due diligence, so let us know if we can help

2) It is going to be harder to partner “me too” assets – programs need to differentiate or better yet track novel biology

3) In IO the T cell space is not played out yet, but we should be looking at NK cells and myeloid lineages for extra traction, and watch for the development of novel immune checkpoint pathways and better agonist antibodies (or both)

4) The CAR T space seems overwrought – I think this has to settle out over a few years – but despite this I also expect to see a big wave of new companies emerge from stealth in the next 0 – 18 months

5) Bispecific antibodies and ADCs will quietly advance to capture a dominant position in IO

6) Finally if you are looking for or have a beautiful asset, seek help in partnering – you’ll save time and wind up in a better partnership (sure, call me, this is what we do best)

cheers all, and stay tuned

ADC snapshots from #ASCO14

May 27, 2014#ASCO14, ADC, ALL, biologics, immunotherapy, Lymphomas, Leukemias, Myelomas, monoclonal antibodiesPaul Rennert

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We present a table outlining top tier results for antibody-drug conjugates (ADC). The tables will be updated as we come across additional abstracts and new data

Targeting TNFRs with agonist antibodies for cancer therapy: 4-1BB, GITR, CD27

May 22, 2014#ASCO14, 4-1BB, biologics, CD27, CLDX, GITR, immunotherapy, Merck, monoclonal antibodies, OX40, Pathways for Drug Development, Pfizer, TNF receptorsPaul Rennert

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One of the puzzles in thinking about the available costimulatory receptors on T cells (and NK cells) is the unsettling number of them. Sticking just to the TNF receptor superfamily (TNFRSF) we have OX40 (discussed earlier), 4-1BB, GITR, CD27, and also the TNF receptors themselves (1 and 2), the lymphotoxin beta-receptor, HVEM, and TNFRSF25. There may be some I’ve forgotten. As noted in part 1 OX40, GITR, 4-1BB and CD27 are evolutionary cousins, as are their cognate ligands. Why did the immune system evolve such a complexity of T cell costimulators?

The answer is not entirely clear although the expression patterns and kinetics of expression suggest some rationale for understanding the number of different receptors. Also, as it’s understood that all the TNF receptors signal via NF-kB, Jun and p38, we might see these receptors either compete (for signaling proteins) or cooperate. All of the available genetic and pharmacologic data suggest they cooperate or even synergize, thereby powering the T cell response when needed. Since T cell responses (and immune responses generally) are so dangerous when dysregulated, the multiplicity of on and off switches presumably allows for redundancy of control.

As we said previously, OX40 comes on slow and easy, starting about 12 hours after TCR stimulation, and riding along for up to 96 hours. This is in vitro, cell culture data … so lets recognize that in vivo, in response to the chaotic presentation of antigen, the population of T cells is likely to be turning over, proliferating … so it’s unlikely we will see a finely tuned kinetic response in the real world, as regards the population of responding cells. Nonetheless we can focus on a single T cell, just the one. And we’ve guessed it will be expressing OX40 say from day 2 to day 5 after activation. Lets ignore the fact that activated effector T cells are likely dividing more rapidly than every 5 days, and just ask the simple question – of the other TNFSF receptors, what else is expressed and when, and on what T cell and other cell types?

Cue 4-1BB.

4-1BB is also expressed following T cell activation, and is expressed on other cell types also. 4-1BB expression come up much more quickly after T cell activation, within a few hours, and wanes after several days. This receptor is critical to supporting activated T cell proliferation, differentiation and survival. Expression on T cells may be coincident with OX40, but the consequences of engaging the receptor with an agonist antibody are different. 4-1BB preferentially supports the proliferation and survival of CD8+ T cells, although at least in some settings the activity of CD4+ T cells is also stimulated through 4-1BB. Much of the anti-tumor activity of 4-1BB agonist antibodies in preclinical studies can be traced to stimulation of NK cells although this depends of the tumor type and model used. Less well understood is the role on 4-1BB on other cells types. This receptor is also found on DCs, macrophages, granulocytes, and Tregs. Expression has also been described on vascular endothelium and on some tumor cells. The role of 4-1BB is confusing, with various studies showing expansion of the Treg subset and others suggesting that 4-1BB dampens Treg responses, perhaps via direct effects on DCs. The 4-1BB gene-knockout mouse shows aspects of autoimmune disorders (at least in the mouse strains tested), suggesting a role for 4-1BB in maintaining immune homeostasis following activation. 4-1BB knockout mice have trouble handling tumor challenge, and at least some spontaneously develop B cell lymphomas as they age. It is all a bit complicated.

Regardless, there are two antibodies that can provide some early clinical data. Bristol-Myers Squibb (BMY) started development of the BMS-663513 antibody quite early, before the immunotherapy wave had really gotten started. BMS-663513 is a specific anti-4-1BB agonist antibody, isotype IgG4. The antibody ran into toxicity issues in a phase 2 trial of metastatic melanoma in 2011, leading to a halt of three trials with that antibody. As the toxicity was correlated with dose, BMY has restarted the clinical campaign with BMS-663513, now called urelumab to establish a safe and efficacious dose. A monotherapy trial is being run in patients with advanced/metastatic solid tumors or with relapsed/refractory Non-Hodgkin Lymphoma (NHL). A second trial in NHL is being run in combination with rituximab treatment. A third trial in advanced/metastatic colorectal and head and neck cancers is being run in combination with cetuximab (anti-EGFR). Pfizer’s (PFE) PF-05082566 is an agonist anti-4-1BB antibody (IgG2 isotype). One trial is listed at clinicaltrials.gov, a 3×3 dose escalation phase 1 trial run as monotherapy in patients with advanced cancers, and as combination therapy with rituximab in NHL.

At the June ASCO meeting there will be updates on both the BMY and PFE programs. BMY has a presentation focused on mechanism of action and biomarker analyses. Abstract #3017 outlines the goal of monitoring the immune status of 4 patients prior to and during the phase 1 study of urelumab (BMS-663513: clinical trial NCT01471210). The antibody was given every 3 weeks and the analysis presents results through 3 cycles. PBMCs were isolated from whole blood, and stimulated for 4 hours with PMA/ionomycin to activate lymphocytes. There was an increase in CD8 T cells up to 41% and NK cells up to 62%. CD4 T cells decreased by as much as 23% and regulatory CD4 T cells decreased by as much as 18% comparing the 3rd cycle to baseline. The results are consistent with a preferential impact on CD8+ T cells and NK cells. The level of the cytokines GM-CSF and IFNgamma were increased.

The PFE study (abstract #3007) describes very early data from clinical trial NCT01307267. Patients received PF-05082566 IV every 4 weeks (one cycle) with an 8 week period for assessment of dose-limiting toxicity (DLT) and radiographic analysis of tumor burden (RECIST 1.1). 27 patients were up to 0.3 mg/kg, the highest dose reported in the abstract. The majority of patients had either colorectal cancer (n=11) or Merkel cell carcinoma (n=6), the rest were a collection of solid tumor patients and 2 patients with B cell lymphoma. 25/27 patients completed the DLT assessment period (first cycle). No DLT was established but only 7 patients remain on therapy. All discontinuations from treatment were due to disease progression. A best overall response of stable disease was observed in 6 patients. No duration data is supplied.

These two early trials suggest that safe dose levels can be achieved, that a mechanism of action can be confirmed (urelumab: expansion of CD8+ T cells and NK cells), and that some clinical response can be observed (PF-05082566: stable disease). That’s a pretty good picture coming out of Phase 1. As preclinical data suggest that 4-1BB is most effective in various combination formats, it will be interesting to monitor advances in the rituximab and cetuximab co-therapy arms of these trials. Several potent combinations arising in the preclinical literature include 4-1BB with immune checkpoint inhibition (CTLA4 or the PD-1 pathway) and in combination with agonist OX40 antibody therapy.

Lets get back to the Treg cells, whose function is to suppress immune responses, primarily those of CD4+ T cells. These express 4-1BB constitutively, although it’s not clear how or if they are responding to treatment with agonist anti-4-1BB antibodies. Let’s turn to a different pathway known to have a profound effect on Tregs, the Glucocorticoid-Induced TNFR Related gene (GITR). GITR was first identified as a regulatory T-cell marker and was shown to play a critical role in breaking T cell tolerance by direct suppression of Treg activity. The preclinical evaluation of GITR produced some very striking data, including in combination settings in which anti-GITR antibodies essentially synergized with other immune checkpoint therapeutics to eliminate established tumors. Such combinations have included PD-1 blockade and CTLA4 blockade. GITR agonism is also synergistic with chemotherapy in preclinical models. Clinical development of GITR antibodies has been slow. A program initiated at TolerX and reborn at GITR, Inc., is recruiting for a phase 1 trial in advanced melanoma and other solid tumors. The antibody is TRX518 (NCT01239134). Merck is advancing a phase 1 study with the anti-GITR antibody MK-4166, although this trial (NCT02132754) is not yet recruiting patients. Review articles have mentioned an ongoing clinical program at MSKCC – this is one of the three sites enrolling patients in the TRX518 trial.

To the extent that the driving mechanism of action (MOA) of GITR stimulation is shown to be downregulation of Treg activity, this pathway should be a good candidate for combination therapy with 4-1BB, OX40 or CD27 agonists (see below) as well as with the CTLA4 and PD-1 pathway antagonists. If the MOA in human cancer patients is different or more complex than proposed, different combinations may be more or less attractive.

One last receptor – CD27.

The costimulatory molecule CD27 is constitutively expressed on most effector T cells, memory B cells, and an NK cell subset. So its expression may also overlap with those of the other receptors. CD27 appears to be important for sustained T cell effector function and also the development of T cell memory. CD27 is a marker of memory T cells, conversely, it is low or absent on Tregs. More broadly, CD27 supports germinal center formation that drives B cell maturation and the differentiation of plasma cells that produce high affinity antibodies, and is also important in driving the cytolytic activity of some NK cells.

Although there is a large preclinical literature on CD27 and its ligand CD70, there are few antibodies in clinical development. There are several historical explanations for this I think. CD70 is expressed at high levels on certain tumor types, particularly renal cell carcinoma (RCC). Much effort has gone into the development of cell-depleting antibodies targeting CD70. This expression pattern also called into question the relevance of CD27 in controlling tumor growth, as the ligand would be expected to stimulate immune responses. We now know that RCC and other solid tumors expresses high levels of PD-L1, and likely disables immune responses via this pathway. Not surprisingly then, one of the ongoing clinical efforts is a combination trial of nivolumab, the anti-PD-1 antibody from BMY with CDX-1127, an anti-CD27 antibody from Celldex (CLDX) in a collaboration announced by the 2 companies last week. In the meantime we have 2 abstracts from CLDX at ASCO in June to look forward to. In a 3×3 phase 1 dose escalation study of B cell lymphoma patients the drug was well tolerated with weekly IV dosing, and there were signs of clinical response, including a durable complete response in one patient with advanced refractory disease (abstract #3024; clinical trial NCT01460134). In the same trial, solid tumor patients were treated in a dose escalation phase and then an expansion phase (RCC and melanoma). The drug was well tolerated, there were preliminary signs of clinical response, and measureable activation of the immune system (Abstract #3027). With the potential to support memory T cell differentiation, CD27 may provide an important additional signal to drive long term tumor control. We’ll have to wait and see.

So, we have 4 receptors with overlapping activities and we have multiple antibodies in various stages of development. There will be plenty to learn about these targets and their roles in the future of combination immunotherapy. One of the most promising paths forward is the analysis of immune checkpoint and costimulatory proteins on tumor infiltrating lymphocytes (TILs). It seems very likely that the makeup of the tumor cell defense against the immune system will diverge between tumor types, and perhaps between patients with the same tumor types, or even with the same patient tumor at different times, or in different metastatic locations. Profiling TILs, and perhaps sentinel lymph nodes, for the expression patterns of lymphocytes and antigen presenting cells is likely to help guide combination therapy.

We’ll come back to that. And we’ve not forgotten those NK cells either.

stay tuned.

A Conversation with Agenus Leadership

May 6, 2014biologics, immunotherapy, oncology, UncategorizedPaul Rennert

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Recently I had the opportunity to talk with Robert Stein, CSO and CMO, and Garo Armen, Chairman and CEO of Agenus Inc. (NASDAQ: AGEN). Agenus, formerly Antigenics, broke into the public eye earlier this year with their acquisition of 4-Antibody AG (4-Ab), a privately held European biotech. This week they announced a two-target deal with Merck, using the 4-Ab platform for the generation of novel antibodies to two undisclosed Merck checkpoint targets. These targets are in addition to the six internal checkpoint modulator programs, a quite positive development. This alone makes the company worth a look.

On the other hand a large Phase 3 trial of GSK’s MAGE-A3 vaccine in lung cancer failed, and this vaccine uses AGEN’s saponin-based adjuvant. That was certainly seen as a negative, although there are still 20 clinical programs using AGEN’s saponin-based adjuvant at GSK, Pfizer, and J&J, including GSK’s malaria vaccine that is heading toward Regulatory filing this year. While the company has its fans and detractors among stock analysts, our focus is on the science; so let’s see where that leads us. My conversation with AGEN leadership was wide-ranging but focused on the future of the company, particularly goals and near-term milestones.

I’ll start with the 4-Ab deal, which was touted in February for its transformational potential (adding checkpoint modulators to a vaccine company), and also financials, featuring a modest upfront with most of the value back-ended. The deal brought multiple immune checkpoint programs into AGEN- 6 programs in total. That’s quite a haul. Less well appreciated I think was the 4-Ab antibody platform, branded Retrocyte Display. The technology is interesting. According to the 4-Antibody website, Retrocyte (Retroviral B lymphocyte Display) is a “high throughput cellular antibody expression platform … to allow expression and screening of full-length immunoglobulin antibody libraries in mammalian B-lineage cells … Libraries of full length immunoglobulin heavy and light chains are encoded by separate retroviral expression vectors within B-lineage cells to yield efficiently and stably expressed fully human monoclonal antibodies on the surface of the B-lineage cells in the form of B-cell receptors. Retrocyte Display can be used to directly screen combinations of antibody heavy and light chain libraries for antigen-specific binders.”

This is the platform Merck sought to generate antibodies for two of their targets. Importantly the deal financially supports the R&D work that will be ongoing at AGEN to carry out their end of the collaboration. This is in addition to a potential $100 million in milestone payments and royalties on product sales. Considering that Merck brought proprietary checkpoint targets to the collaboration, participating in the upside is somewhat atypical. This deal makes a statement regarding how much Merck valued accessing the platform and of course it also sets the stage for future platform deals.

Back to those assets, Dr Armen stated quite clearly that the company will internally develop the first tier of antibodies acquired in the 4-Ab acquisition, with a stated goal of moving development candidates targeting CTLA4 and PD-1 and selected additional immune checkpoint modulator programs to IND filings with a target date of approximately 2 years. One of the uses of least some of the immune checkpoint modulators might be to “turbo-charge” the company’s long-standing tumor vaccine programs. These have certainly struggled to gain traction, as have nearly all vaccine plays in oncology, for reasons we now understand well – active immune suppression mediated by the highly adaptable tumor for its survival. Prophage is a personalized cancer vaccine based on patient-specific antigens isolated from each patient’s tumor, bound to heat shock proteins to drive the activation of anti-cancer T-lymphocytes. The company has been exploring the use of Prophage in patients with Glioblastoma Multiforme (GBM), influenced in part by the decision of the NCI to fund the ongoing Phase 2 trial. Over the years the company had conducted Phase 3 trials in melanoma, renal cell carcinoma, and earlier phase trials in multiple other cancers. AGEN is no longer advancing Prophage programs in these tumor types however they are participating in an investigator-sponsored clinical study of Prophage plus the checkpoint inhibitor Yervoy (the anti-CTLA-4 antibody ipilimumab from Bristol-Myers Squibb) in patients with advanced melanoma. Additional work could be done with their internal checkpoint modulator pipeline in the future. It is certainly true to say (although harder to predict) that positive results from the GBM trial would transform the company. I suspect that a failure here would lead the company to drop the platform.

It’s important not to confuse the Prophage tumor vaccine effort with the QS-21 Stimulon adjuvant programs. This is the adjuvant that GSK has licensed for use in much of their vaccine work. GSK’s MAGE-A3 vaccine failure is one of the few settings in which QS-21 was used as a tumor vaccine adjuvant. The company expects approvals for use in a malaria vaccine this year, with 20 advanced trials underway at GSK and J&J. GSK’s renewed emphasis on its prophylactic vaccine business might help AGEN even more going forward. AGEN receives a milestone payment when the first QS-21 containing vaccine is registered by GSK and also royalties on both prophylactic and therapeutic vaccines.

If AGEN seems difficult to get one’s arms around, it may be because of this three-platform business model. On the other hand, these three platforms address three critical components of immune modulation, with immunotherapy programs a few years away from the clinic, a very long-standing vaccine effort, and an adjuvant program that is not well appreciated outside the company. Valuing this collection of technologies has been difficult, and certainly progress in any or all three will be important catalysts going forward.

Dr Armen and Dr Stein are well aware of the fuzzy picture that the outside world, and investors in particular I suppose, have had of the company. The refocus on immune checkpoint modulators was very well received allowing AGEN to raise $56M from investors in February. AGEN has articulated specific goals to drive the company forward:

Execute on the 4-Ab programs internally and through partnerships. This includes IND filings for two or more programs within 2 years, developing appropriate strategic partnerships, and further advancing other checkpoint inhibitors that were acquired with 4-Ab, but have not been disclosed.
Leverage the value of the 4-Ab platform, as has just been done in the Merck deal
Reboot the Prophage program via combination use with immune checkpoint modulators as results warrant. One cautionary note – this will require additional translational research efforts that are just now getting underway.
Design personalized therapeutic interventions utilizing the vaccine platform and an understanding of the basis for immune suppression in individual patients. AGEN leadership envisions that this will be done by a combination of internal efforts and through strategic partnerships with centers of excellence in translation medicine.
Acquire a later stage asset in the immune-oncology space that would complement the evolving immunotherapy portfolio. That could be a good use of capital.

It’s a full dance card. We’ll keep an eye on AGEN as they execute on these critical goals, especially in the immunotherapy space.

Disclosure: I own no stock in AGEN and have no opinion as to the value of the stock or its’ future performance.