After AACR 2012 in a piece we called “A Science Geek’s Thoughts on the 2012 AACR Annual Scientific Meeting”, we wrote about three larger-picture, emerging themes that we felt worth discussing: epigenetics, tumor cell metabolism, and cancer stem cell biology (science that leads to the exploitation of the stem cell for novel drug targets for therapeutic interdiction, not stem cells themselves as therapies). While these themes certainly repeated themselves in 2013, epigenetics and cancer stem cell research have matured, while tumor cell metabolism seems to still be searching for its killer app (although we continue to hear that Agios is very close to putting a molecule into the clinic after having recently published data on two inhibitors of IDH1 and IDH2 in the April 4 edition of Science). We also would add another concept that has caught our eye in the past, and that is the promise of harnessing the body’s immune system to fight cancer and produce long-lasting benefit. While this concept is hardly new as Bristol-Myers’ (BMY, NC) Yervoy (ipilimumab,) has been approved since May of 2011; however, Yervoy has not been, per se, a biotech pure-play. Further, the drug’s tolerability issues will likely limit its uptake and duration of use. This year, Bristol’s nivolumab has reset the bar for long-term benefit along with tolerability, even though its first-in-human study was published in the Journal of Clinical Oncology in 2010; likewise, nivolumab was the subject of two articles in the New England Journal of Medicine in 2012. We believe that future hindsight will mark the AACR 2013 plenary session as a harbinger for future ASCO plenary sessions. Inspiring talks were offered by Katie Couric regarding her crusade against colorectal cancer and role in creating Stand Up to Cancer (SU2C) as well as Siddhartha Mukherjee of Columbia University and author of The Emperor of All Maladies (a must-read, in our view). On a personal note, the AACR program organizers are to be commended for putting together a plenary agenda that was decidedly a non-snoozer.
Immunotherapy: When the Body Cures the Body
The common theme amongst the various presentations at the AACR plenary (as well as others throughout the conference) concerned complete eradication of tumors and/or durable remission of effect. Perhaps most emblematic of this was the talk given by Suzanne Topalian of The Kimmel Cancer Center at Johns Hopkins University. Dr. Topalian, the lead author of the 2012 NEJM article, discussed the biology of the PD-1/PD-L1 axis and the differences between it and the CTLA-4 axis, the target of Yervoy. Nivolumab blocks the binding of both PD-L1 and PD-L2 to the PD-1 receptor. She then discussed findings of both the JCO and NEJM articles, which examined the use of nivolumab in non-small cell lung cancer (NSCLC), melanoma, kidney, colon or prostate cancer. What most impressed us, and immediately caused us to crystallize the impact on patients of Dr. Topalian’s data, was the slide she showed on the durability of response of three patients who has ceased treatment with nivolumab. Dr. Topalian provided vignettes of three patients-one with colorectal cancer (CRC), one with renal (kidney) cancer (RCC), and one with melanoma-showing that patients can remain in complete or partial response 4-5 years into their therapy. The patient with CRC remains in complete response just short of four years into follow up after stopping treatment shy of one year. The RCC patient received therapy for approximately six months had a partial response (PR) as best response shortly thereafter, then went on to produce a complete response (CR) at roughly 3.5 years, and at nearly 4.5 years remains in CR. Finally, Dr. Topalian’s example of the melanoma patient was a bit more complicated. The patient achieved a PR just shy of two years on therapy, was diagnosed with a new metastasis just over three years after diagnosis, was retreated to a PR at year four, and was still in PR at roughly 4.5 years. Dr. Topalian also showed a slide that she showed at ESMO 2012. The key data point on this slide is a bullet that indicated 28 of 54 responses lasted more than one year in patients who had more than one year of follow-up. Grade 3-4 adverse events were a very reasonable 15%, and treatment-related mortality was only 1%. Perhaps most exciting was the slide shown by Dr. Topalian that described a patient with squamous non-small cell lung cancer, a tumor type that is widely thought to be non-immunogenic. This particular patient responded to anti-PD-1 antibody therapy after an immediately previous treatment with epigenetic therapy of 5-azacitidine (Vidaza, CELG, MO) and entinostat (Syndax, private, NC), an inhibitor of HDAC 6. Dr. Topalian indicated that this patient has recently completed two years of anti-PD-1 therapy. Moreover, Dr. Topalian indicated that there are five more patients like the one in the example she cited who have achieved durable responses after prior treatment with epigenetic therapy. While the number of patients is small, the 100% response rate in this population is impressive. We eagerly await the presentation of these data at an upcoming scientific conference. In terms of biomarkers and other correlates of response, Dr. Topalian showed a number of slides that spoke to the level of PD-L1 in the tissue as the most highly predictive of response in patients. In her findings, 13/31 patients with detectable levels (>5% of tumor cells) of PD-L1 achieved a PR or CR, whereas 0/18 patients with undetectable levels of PD-L1 did so. This has intuitive appeal to us, as it likely means that those patients without detectable PD-L1 have some other immune mediator of their disease. She also showed that patients whose disease had evidence of tumor infiltrating lymphocytes (TILs) experience improvements in overall survival. Dr. Topalian closed with suggestions as to how best to improve the therapeutic profile of these remarkable antibodies. These involved the blockade of lymphocyte activation gene 3, or LAG-3, and the blockade of interleukin-10 (IL-10), a cytokine known to tamp down the immune response to cancer cells, among other functions. We look forward to future developments with not only anti-PD-1 and PDL-1 therapy, as well as others that will enhance their effects.
Apart from the very cool science that was on display during Dr. Topalian’s talk, we were struck by the thought of the effect on patients as the knowledge of the durable effect of PD-1 blockade make its way across patient blogs and discussion groups. What patient would not want to be cancer-free for three, four, five years or more? Anti-PD-1 therapy could make this possible. Even if the duration of response diminishes over time, as it inevitably will, we believe the pull of durable response could eventually make drugs in the class the largest selling oncology drugs extant. The robust effect, broad applicability, and acceptable tolerability could result in sales of the drugs that would put sales of Avastin (~$6 billion) to shame. Were Vidaza, Dacogen, or SGI-110 to hitch their respective wagons to the PD-1 bandwagon, it would likely be an unmitigated (and currently unanticipated) boon to the top line for these drugs. We take a deeper dive into the science later in this report.
Engaging Scientists in a Discussion about Stem Cells with Slick Graphics
The JMP Securities Award for the Sexiest Scientific Graphics goes to Hans (a/k/a “Very”) Clevers of the Hubrecht Institute in Utrecht, The Netherlands. Dr. Clevers talk was peppered with some of the slickest scientific animations and graphics we have ever seen this side of the SciFi Channel. If every science teacher in America had access to graphics like this we would end the crisis in science education virtually overnight. Sadly, we speculate that Dr. Clevers presentation must have been hideously expensive and that he is the fortunate recipient of gobs of grant money. Having said that, Dr. Clevers scientific findings were as informative as his graphics were elegant. His work focuses on Lgr5 cells in the intestinal crypt, where stem cells demonstrate significant proliferation; a gut stem cell can transform itself into an enterocyte or goblet cell in the space of roughly five days then die within days, a huge turnover rate compared to other cells in the body. Most of Dr. Clevers’ talk concerned his work on the creation of a gut model he and his research team derived from Lgr5 cells, which they can use in vitro and in vivo; however, we were encouraged by his further validation of some of our favorite cancer stem cell targets, including wnt, frizzled, LRP, Lgr and Rspo. All of these components comprise a sophisticated signaling complex on the exterior of the cells of the colon. In colorectal cancer, the wnt signaling pathway is locked in the “on” position, while Rspo binding to Lgr activates Lgr and, in turn, Lgr then binds to LRP and amplifies wnt-mediated signaling. The Lgr5 cells can be readily located as they are in contact with so-call Paneth cells, which also are found in the intestinal crypt, and appear to nurture the Lgr5 cells. In Dr. Clevers’ words, every cell that touches a Paneth cell is a stem cell, and Paneth cells secrete gobs of wnt3 as part of their support role to the Lgr5 cell. Dr. Clevers also showed that inhibition of the protein porcupine, can block the secretion of wnt. Novartis (NVS, NC) is developing a small molecule inhibitor of porcupine, referred to as LGK974. In addition, privately-held OncoMed Pharmaceuticals is developing OMP-54F28, an antagonist of the wnt signaling pathway.
Session on Epigenetics Packs the House
The Sunday morning plenary session on epigenetics, hosted by Robert Copeland, PhD, Chief Scientific Officer of privately-held Epizyme, played to a packed house. While there were multiple sessions held during the five days of AACR on epigenetics, none was as forward-looking nor as absolutely packed as this one (an estimate of the number of attendees to the session exceeded 10,000). Peter Laird of the USC Epigenome Center in Los Angeles led the speaker’s roster and provided a fascinating discussion of how the epigenetic signature of cancer cells is vastly different than that of normal cells in terms of both the number of genes silenced as well as turned on (or “de-silenced”). Dr. Laird showed that there is massive (“focal”) hypermethylation at CpG islands (the start sites for gene transcription) across a wide variety of tumor types. These regions of hypermethylation are in areas of gene expression that would normally be associated with genes that would either prevent the outbreak of cancer or provide signals to the cancer cell that would normally tell cancer cells to die. What was particularly fascinating about Dr. Laird’s talk was not only did he provide us with optimism towards finding additional validated drug targets in these hypomethylated regions, but also tied mutations in kinase signaling pathways (such as BRAF) to changes in the epigenome. Fearless prediction: more of these integrative, or “systems biology” studies, will continue to be done (indeed, must be done) as we advance our assault against cancer. In our opinion, not only will mutations or changes in the regulation of the epigenome be tied to mutations or up-regulation of cellular growth pathways and vice versa, but simultaneous changes in aspects like cellular metabolism, immune evasion, and stem cell-like properties will be tied together in a more holistic picture going forward. During the same talk, James “Jay” Bradner from the Dana-Farber Cancer Center gave an outstanding talk (though similar to the one we had seen at ASH 2012) about his work on the probe molecule, JQ-1, and its role in the regulation of the MYC gene, one of the most commonly over-expressed genes in all of cancer (behind only p53). JQ-1 (and presumably chemical matter from privately-held Constellation Pharmaceuticals) blocks a key regulator of MYC activation, bromodomain 4 (brd4), a key regulator of MYC gene transcription. Dr. Bradner’s slides showed the pattern of benefit that is now becoming familiar to those of us groupies of epigenetics-that of a flat-line pattern of tumor growth (better yet, death). Dr. Bradner showed some amazing CT scans of a patient with KRAS-mutated lung cancer who experienced a near-total regression of a massive tumor. Dr. Copeland finished the session with a comprehensive discussion of the two targets of focus for Epizyme, DOT1L, mutated in mixed-lineage leukemia (MLL), and EZH2, a very hot gene target that has generated a lot of interest due to its dysregulation in a variety of tumor types (NHL, breast, prostate, colon, gastric and bladder, among others) and which has drawn the attention of a number of large pharmaceutical and biotechnology companies. Again, the shape of Dr. Copeland’s Kaplan Meier curves was virtually identical to those of the other speakers-flat-to-downward sloping, rather than right-shifted as has been seen with so many other interventional therapies in oncology. We will be producing a fuller report on the epigenetics space in the near-term.
Early Signs that Epigenetics Holds the Keys to Immunotherapy & Vice Versa
In addition to the separate plenary sessions on immunotherapy and epigenetics, we noted several poster presentations that hinted strongly at the ability to boost anti-tumor immune responses through the epigenetic reprogramming, primarily through the use of hypothmethylating agents. Some of these presentations were in prior notes by us relation to Astex (ASTX, MO) in which tumor specific antigen expression, namely of NY-ESO1 and MAGE-A, in peripheral blood mononuclear cells (PBMCs) was found to increase in response to global gene demethylation in AML/MDS patients treated with SGI-110. In a separate poster, Dacogen induced demethylation in AML cell lines correlated with increased NY-ESO1 and MAGE-A protein expression, further supporting the likelihood that T cell activation plays a role in the mediation of tumor responses by hypomethylating agents (HMAs). Future experiments from Griffiths et al. will measure if tumor antigen specific CD4+/CD8+ T cell responses are in fact elicited by HMA therapy. Meanwhile, a forthcoming prospective study will test the hypothesis in vivo, assessing the combined effect of Dacogen plus the NY-ESO1 vaccine CDX-1401 (CLDX, NC) in patients with AML/MDS. One has to take the good with the bad when it comes to HMA induced gene expression, however. This was evidenced in part in a poster presented by Edward Kadel et al of Genentech (Roche, NC) showing that differential expression of PD-L1 mRNA in NSCLC cell lines was regulated by the level of the promoter by DNA methylation. Induction of PD-L1 expression was most responsive to treatment with Dacogen in cell lines where baseline methylation was high and gene expression low. One initial interpretation of these data might be that DNA demethylation and immune checkpoint activation are antagonistic and that without PD-1/PD-L1 blockade, HMA activity is actually undermined by immnosuppressive mechanisms. Such was the conclusion reached by Garcia-Manero et al in a poster presented at last ASH last December in which the expression of PD-1, PD-L1, PD-L2 and CTLA4 were all induced in the PBMCs of AML/MDS patients treated with low dose Dacogen, or Vidaza in combination with Revlimid (CELG) or vorinostat. On the other hand, it is possible that the induction of PD-L1 expression though HMA exposure acts as primer or homing mechanism for activated T cells. Recall in relation to the plenary talk by Dr. Topalian that tumors responding to nivolumab exhibited relatively higher levels of PD-L1 expression compared with non-responders. Taken together, we believe that future clinical studies of epigenetic therapy used combination with PD-1/PD-L1 antibodies (given perhaps in sequence) will indeed show these regimens to be synergistic in their activities.
In our view, AACR is an exceptional meeting in that it provides the scientific and business community with an opportunity to view the up-and-coming drugs and drug targets of the future. To use a sports analogy, it is akin to being able to see all the college football or basketball teams and their players over the course of just a few days. While there is a lot of information for investors to digest, it also provides incredible opportunities to select the stars of the future, without the distraction of running to numerous sessions to see clinical data. The latter purpose is best served by ASCO, coming in June. However, there is a certain pride (and profit) to be had when one can say “I saw that drug when it was still in Phase II trials” like a promising rookie. We hope the character of the AACR conference never changes.
by Mike King, Managing Director and Senior Biotechnology Analyst, JMP Securities
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