Category Archives: Astra Zenenca

The Tumor Microenvironment “Big Tent” series continues (part 4)

 

The Tumor Microenvironment (TME) series to date is assembled here http://www.sugarconebiotech.com/?s=big+tent containing parts 1-3

I’m happy to point you to the most recent content, posted on Slideshare: http://www.slideshare.net/PaulDRennert/im-vacs-2015-rennert-v2

In this deck I review the challenges of the TME particularly with reference to Pancreatic and Ovarian cancers. A few targets are shown below.

Feedback most welcome.

Screen Shot 2015-08-27 at 7.20.21 AM

 

Brodalumab for Psoriasis – what a mess

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.

IL-17 and friends

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:

broda 1

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:

broda 2

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):

CiteLine

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:

snapshot

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.

Celgene and friends…

The ever-nimble company Celgene (NASDAQ: CELG) was back in the news last week, signing a sweetheart deal with AstraZeneca (NYSE: AZN) that brings access to a Phase III immune checkpoint therapeutic.

The deal between Celgene and Astra Zeneca is remarkable for balancing the relative strengths and weaknesses of each company. For AZN the deal enhances the competitive reach of the anti-PD-L1 mAb MEDI4736, now backed by a rich war chest and the potential for combination therapy with Celgene’s myeloma and hematologic malignancy portfolio. Notably, these diseases have remained relatively indifferent to monotherapy with immune checkpoint therapeutics, with a few exceptions. Refractory multiple myeloma, an indication that Celgene dominates, is particularly resistant to monotherapy with immune checkpoint therapeutics and the bet is that efficacy will be seen when MEDI4736 is paired with Celgene’s approved drugs lenalidomide and pomalidomide, among others. The deal may also ultimately bring access to first line solid tumor patients in the form of a MEDI4736 combination with Celgene’s Abraxane, a synergy that has been overlooked I think.

For Celgene this is an overdue move into the immunotherapy space and reflects their willingness to spend their way into contention and expand market dominance from multiple myeloma into other hematological malignancies, a counter of sorts to Abbvie’s buyout of Pharmacyclics and it’s B cell cancer blockbuster Imbruvica. Celgene has already made forays into the immuno-oncology space with it’s in-licensing of Inhibrx’ anti-CD47 antibody and the deal with VentiRx and Array Biopharma to develop VTX-2337, a TLR8 agonist but these are much earlier stage assets. It is reasonable to predict that Celgene will also move quickly to acquire additional assets in the immune checkpoint space.

I’d expect to see both AZN and Celgene aggressively pursue additional deals. AZN did exactly that with Juno Therapeutics (combining CAR T and anti-PD-L1 therapies) and Innate Pharma in separate deals two weeks ago. It is interesting to speculate that there is additional synergy between the Innate Pharma programs and the Celgene programs that could be explored later on.

More importantly I think, and looking ahead, both AZN and Celgene are building multiplatform immuno-oncology companies, with cellular therapeutics (CAR-T and TCR), antibody therapies, targeted therapeutics, and immune checkpoint therapeutics – a broad reach across the evolving oncology clinical landscape, similar to the position Novartis has built for itself. Both AZN and Celgene floated that their deal could grow into a larger collaboration, if so, this means that similar deals in this space will have to become bigger and broader just to keep up. Merck and Pfizer’s recently announced collaboration is a good example of a deal not quite juicy enough to be transformative in the way the AZN/Celgene hookup may be for both of these companies. Novartis recently stated that they are looking for acquisitions in the 2-5 billion dollar range – this gives us a sense of scale required. We are entering a phase of “go big or go home” and the winners will dominate oncology clinical care.

The twisted tale of neoantigens and anti-tumor immune responses

Two papers out this week add to a pile of data addressing the role of neoantigens in tumor therapy. While these papers address tumor neoantigen “load” in the context of immune checkpoint therapy the results have implications for TIL therapeutics, TCR therapeutics and onco-vaccine development.

A really dramatic paper from diverse groups at the University of Pennsylvania and their collaborators, just published in Nature (link-1), explores the complex interplay of radiation therapy and anti-CTLA4 antibody therapy (ipilimumab, from BMS) in patients with stage IV metastatic melanoma (relapsed or previously untreated). In this Phase 1/2 clinical trial (NCT01497808) patients with multiple melanoma metastases received various doses of radiation therapy delivered to a single metastasis, termed the “index lesion”. They then received 4 doses of ipilimumab (3 mg/kg, i.v., once every 3 weeks) and non-irradiated lesions were evaluated within 2 months of the last dose.

Although the sample size reported is small (n=22) some interesting lessons emerged from the study. The response rate was low, and the progression free survival (PFS: 3.8 months) and overall survival (OS: 10.7 months) data bear this out. It appears that just shy of 40% of patients were still alive at ~30 months (see Figure 1c in the paper). It is too early to tell if there will be a “long-tail” effect going forward. In the original ipilimumab study a very small percentage of patients lived for a very long time, “pulling” the PFS and OS curves to the right. Regardless, most patients in this study did not respond and the questions posed in this paper are directed to the mechanisms of resistance.

The mouse B16-F10 melanoma model was used to model resistance. Mice with tumors were locally irradiated then treated with an anti-mouse-CTLA4 antibody, to mimic the clinical trial. Only 17% of the treated mice responded. Two predictors of response/non-response were elucidated: 1) the ratio of effector T cells (Teff) to regulatory T cells (Treg) and 2) a gene signature in the tumor cells that is dominated by the expression of PD-L1 and IFNgamma regulated genes. In short, if the melanoma cells are expressing PD-L1 and the tumor infiltrating lymphocyte (TIL) population is dominated by Tregs (which are PD-1+), then the radiation + anti-CTLA4 therapy failed.

To further subset TIL into active Teff versus non-responsive “exhausted” Teff, the authors used an expression profile of PD-1+/Eomes+ to identify exhausted Teff and PD-1+/Eomes+/Ki67+/GzmB+ for active Teff. Importantly, exhausted Teff could be reanimated upon treatment with PD-1 pathway antagonists: anti-PD-1 antibody or anti-PD-L1 antibody. This reanimation led to an improved CD8+ Teff/Treg ratio and led to tumor control in the majority of the mice (up to 80%) when the treatment consisted of irradiation plus anti-CTLA4 plus anti-PD-L1. Of note, radiation plus anti-PD-L1 did not achieve this effect; the triple therapy was required (see Figure 2d).

The striking conclusion is that upregulation of PD-L1 on tumor cells can subvert the effect of anti-CTLA4 antibody therapy, and this therefore qualifies as a mechanism of resistance.

What about the role of irradiation? In both the patients and the mouse model irradiation was local, not systemic. Further, this local irradiation was required to achieve complete responses in the mouse model. What is going on here? Irradiation was linked to a modest increase in TIL infiltration of melanoma tumors in the mouse model, but sequencing of the T cell receptors (TCR) revealed that there was an increase in the diversity of TCRs, meaning that more antigens were being recognized and responded to by TIL after irradiation. In this context then, anti-CTLA4 reduced the Treg population, anti-PD-L1 allowed CD8+ TIL expansion, and irradiation set the antigenic landscape for response.

Returning to the patients armed with this information from the mouse study, the authors find that low PD-L1 expression on the melanoma cells correlates with productive response to irradiation plus ipilimumab therapy, while PD-L1 high expressing tumors were associated with persistent T cell exhaustion. In addition, monitoring the state of the CD8+ T cell population (PD-1+/Eomes+ versus PD-1+/Eomes+/Ki67+/GzmB+) suggested that these phenotypes might be useful as peripheral blood biomarkers. The patient numbers are very small for this analysis however, which awaits further validation.

The conclusion: irradiation combined with ipilimumab plus anti-PD-L1 antibody therapy should be a productive therapeutic combination in PD-L1+ stage IV melanoma. Similar strategies may be beneficial in other solid tumor types. This is interesting news for companies developing anti-PD-L1 antibodies, including BMS-936559 (also from BMS), MPDL3280A (Roche/Genentech), MEDI4736 (AZN) and MSB0010718C (Merck Serono).

A second paper (link) bring our focus back to PD-1, in the context of non-small cell lung cancer (NSCLC). Using the anti-PD-1 antibody pembrolizumab (from Merck) a group from the Memorial Sloan-Kettering Cancer Center sought to determine correlates of response of NSCLC patients to anti-PD-1 therapy. Their findings again hone in on neoantigen load, as the best predictors of response were the non-synonymous mutational burden of tumors, including neoantigen burden and mutations in DNA repair pathways. What all this means is that mutations that change the amino acid sequence (thus, are non-synonymous) can produce neoantigens that can be recognized by CD8+ T cells; mutations in the DNA repair pathways increase the rate that such mutations go uncorrected by a cell.

The authors sequenced the exomes (expressed exons – these encode proteins) from tumors versus normal tissue, as a measure of non-synonymous mutational burden that could produce neoantigens. Patients were subsetted based on response: those with durable clinical benefit (DCB) and those with no durable benefit (NDB). High mutational burden was correlated with clinical efficacy: DCB patients averaged 302 such mutations, while NDB patients averaged 148; ORR, PFS and OS also tracked with mutational burden. In a validation cohorts the number of non-synonymous mutations was 244 (DCB) versus 125 (NDB).

Examination of the pattern of exome mutations across both cohorts was studied in an attempt to discern a pattern of response to pembrolizumab treatment. The mutational landscape was first refined using an algorithm that predicts neoepitopes that can be expressed in the context of each patients specific class I HLA repertoire – these are the molecules that bring antigens to cell surfaces and present them to T cells for recognition (I’m simplifying this process but that is the gist of it). The algorithm identified more potential neoepitopes in the DCB patient tumors than in the NDB cohort, more impressively, a dominant T cell epitope was identified in an individual patient using a high-throughput HLA multimer screen. At the start of therapy this T cell clone represented 0.005% of peripheral blood T cells, after therapy the population had risen 8-fold, to 0.04% of peripheral blood T cells. Note that most of this clone of T cell would be found in the tumor, not in circulation, so that 8-fold increase is impressive. The T cells were defined as activated CD8+ Teff cells by expression markers: CD45RA-/CCR7-/LAG3-. As in the first paper we discussed, it is useful that these markers of systemic response to immunotherapy treatment are being developed.

There is an interesting biology at work here. It is often noted that high mutational burden is associated with better outcome, for example to chemotherapy in ovarian cancer, and irrespective of therapy across different tumor types (link-2). This suggests that tumor neoepitopes are stimulating an ongoing immune response that is stifled by active immunosuppression, yet is still beneficial. Once unleashed by immune checkpoint blockade, the immune system can rapidly expand it’s efforts.

We recently reviewed the importance of neoantigens in anti-tumor therapy (link-3) although the focus then was on cellular therapeutics rather than on immune checkpoint modifiers such as anti-CTLA4 and anti-PD-1 or PD-L1 antibodies. We can mow add that our ability to track neoantigens and the immune response to neoantigens is opening new avenues for investigating immuno-oncology therapeutics and their efficacy.

Side Effect Profiles of Immune Checkpoint Therapeutics – Parts 2 and 3

Part 2 – The Border Wars.

One of the fascinating aspects of the toxicity of immune checkpoint therapeutics is that it is a lot of is triggered at the border between self and non-self, where non-self is everything that the immune system must encounter and sort through continuously. The sorting serves to identify pathogens and ignore non-pathogens among the myriad components of the microfauna and flora that inhabit these borders. The “sampling” of these ecosystems is continuous and highly reactive – one glass of unpurified water taken on foreign soil will teach you this lesson pretty quickly. When the immune system is unrestrained by blockade of CTLA4 and/or PD-1 it is not surprising that we see the breakdown of immune tolerance in these border zones.

There are three major surfaces where toxicity has been an issue: the skin, the gut mucosa, and the airspaces of the lung. Ipilimumab treatment can cause pretty intense inflammation of the skin, generally dismissed in the clinical trial literature as “rash”. In a pooled analysis of nearly 1500 patients enrolled in various ipilimumab clinical trials, 45% developed dermatological AEs considered drug related, and 2.6% (so 39 people) developed severe symptoms rating a grade 3-4 (where grade 5 is lethal) (see Tarhani, A. Scientifica 2013, Article ID 857519). A fair amount of the milder skin AEs can be ascribed to an anti-melan-A response, as this antigen is abundant in melanoma, the setting for the clinical development trials. In the Phase 3 registrational trials dermatologic AEs were reported in more than 40% of patients in the ipilimumab arms, and there were very severe AEs that cannot be ascribed to an anti-melan-A (i.e melanocyte) immune response. This is from Tarhani’s review of patients in the ipilimumab + gp100 (vaccine) and ipilimumab monotherapy arms having dermatological irAEs,

“of these, 2.1% and 1.5%, respectively, were grade 3 or higher … Severe, life threatening, or fatal immune-mediated dermatitis (Stevens- Johnson syndrome, toxic epidermal necrolysis, … full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; grade 3–5) occurred in 13 of 511 (2.5%) patients treated with ipilimumab. One patient (0.2%) died as a result of toxic epidermal necrolysis, and one additional patient required hospitalization for severe dermatitis… .”

That’s some rash. We note in passing that dermatologic AEs were see in a phase 2 trial of ipilimumab plus chemotherapy in non-small cell lung cancer (NSCLC) and so this is certainly not limited to the melanoma setting. PD-1 pathway antagonists also cause skin inflammation in both the melanoma and other settings, similarly suggesting that what we are seeing here are immune responses to antigenic stimulation that is normally immunologically inert. Nivolumab-induced dermatologic toxicity can be severe, but is less common than seen with ipilimumab therapy.

The issue of skin toxicity is well known clinically, and there are established treatment protocols requiring cessation of therapy and treatment with anti-inflammatories, usually steroids (i.e the REMS protocols). The gastrointestinal (GI, “gut”) AEs are also common, can arise suddenly, be resistant to therapy (corticosteroids, and rarely, anti-TNF antibody), and are of significant concern. Returning to the pooled analysis of ~1500 ipilimumab patients we see roughly half of the patients developing GI symptoms (this includes diarrhea). If we focus on grade 3/4 SAEs we have 10-12% of patients with GI disorders that include colitis, enterocolitis, intestinal perforations etc that can proceed to lethal septic complications. Of note, inflammatory infiltrates in the intestines include abundant T cells and neutrophils, showing that acute ongoing inflammation is occurring. GI toxicity is less common and less severe in nivolumab-treated patients, and this is true also of Merck’s anti-PD-1 antibody pembrolizumab and the anti-PD-L1 antibody MPDL3280A from Roche. Colitis is generally not a big issue, for example, GI SAEs are seen in less than 1% of nivolumab-treated patients. We might conclude here that other pathways are maintaining tolerance in the gut mucosa when the PD-1 pathway is blocked.

A different picture emerges when we consider AEs in the lung. Pulmonary toxicity is rare in the context of ipilimumab monotherapy, with only scattered case reports in the literature (see Voskens et al for a review of rare ipilimumab-induced AEs: link). Anti-PD-1 pathway therapeutics, particularly nivolumab, are associated with pneumonitis, which is inflammation of the lung tissues. In the monotherapy setting, both nivolumab and pembrolizumab causes pneumonitis in 3-4% of patients – the condition is generally mild and treatable. Of note this AE rate is consistent across indications (e.g. melanoma, renal cell). The anti-PD-L1 antibodies (Roche’s MPDL3280A and Astra Zeneca’s MEDI4736) have not been associated with pneumonitis to date, perhaps reflecting a unique profile. The recent data from the anti-PD-L1 antibody MEDI4736 trial in NSCLC presented a tolerable profile. While response rate was low, significant numbers of patients remained on therapy with stable disease (ASCO 2014, Abstract #3002).

More worrisome is the pneumonitis rate and severity in combination therapy particularly in the NSCLC setting where diminished lung function is already a concern (smokers with lung cancer can’t breathe). When nivolumab was combined with platinum-based chemotherapy in NSCLC the SAE rate jumped to 45%, with notable findings of grade 3/4 pneumonitis (7%) and acute renal failure (5%) (ASCO 2014, Abstract #8113). Nivolumab plus erlotinib was not associated with pneumonitis (ASCO 2014, Abstract #8022) but response rates were low as well suggesting that these therapies were not particularly additive. The combination of nivolumab with ipilimumab was most worrisome, with grade 3/4 pneumonitis (6%) now seen along with grade 3/4 SAEs of skin (4%), GI (16%) and others (16%) (ASCO 2014, Abstract #8023). Most problematic is that 35% of patients discontinued, and between 3 to 5 patients died due to drug related SAEs including respiratory failure (caused by severe colitis), epidermal necrolysis (in a patient with multiple SAEs) and pulmonary hemorrhage (pneumonitis). As indicated above, the anti-PD-L1 antibody MEDI4736 may better suited for combination therapy. A combo trial in NSCLS with anti-CTLA4 mAb tremelimumab is enrolling, so we’ll wait and see.

It’s fair at this point to take a step back and say “so what?” These are close to terminal patients with deadly cancers usually highly refractory to treatment, and we cannot expect a free ride. The unmet need is acute and urgent, and these therapeutics offer potential cures and increase in life expectancy – as shown very clearly in last weeks early termination of the Phase 3 trial of nivolumab versus dacarbazine due to the obvious overall survival advantage offered by nivolumab (see John Carroll’s story in Fierce Biotech here: link)

The problem is that the response rates we are seeing are generally low, the discontinuation rates high, and for anti-CTLA4 and anti-PD-1 therapeutics there is no clear consensus regarding the use of biomarkers to select patients most likely to respond. Therefore the actual percent penetrance of therapy in the patient cohorts becomes quite low. For those relatively few patients who respond well the outcomes can be sustained and robust. It is critical however to get these response rates up. The blockbuster combination of nivolumab plus ipilimumab in metastatic melanoma gives us a sense of what is possible, if the drugs are tolerable. It is also critical to understand how and why immune therapy can make subsequent therapy intolerable, as we’ve seen in case reports, or conversely, how and why prior therapies can cause such problems for patients going onto an immune therapeutic (see that Voskens review mentioned above). We’ve seen some the issues that can bedevil combinations in metastatic melanoma (with vemurafenib) and in renal cell carcinoma clinical trials (pazopanib) When we look at all of the combination clinical trials underway with these agents we have to wonder what surprises lay in store.

Part 3 – The Fifth Column.

The fifth column refers to enemies lurking within the boundaries of the state, in this case the human body. These are a mixed collection of AEs that can be difficult to understand. While we are used to see liver and kidney inflammation in the setting of cancer therapy, it remains a bit mysterious that immune checkpoint therapy can cause severe inflammatory responses in these organs, the most notable is probably the induction of hepatitis in patients treated with ipilimumab. Even weirder (for me anyway) are the endocrinopathies, headlined by pituitary inflammation, seen with both CTLA4 and PD-1 directed immunotherapies. Primary thyroid inflammation is also seen although less frequently. These are of course autoimmune targets in this setting, but the triggers are obscure, as is also almost always true in autoimmune disease. Somewhat remarkable is the emergence of a sometimes fatal but normally very rare condition known as autoimmune hypophysitis or lymphocytic hypophysitis, which is inflammation of the pituitary gland. Hypophysitis is a unique toxicity of immune checkpoint inhibitors, and has been been seen in patients treated with ipilimumab, tremelimumab, and nivolumab. Because the pituitary sits in the middle of the limbic hypothalamic-pituitary-adrenal axis effects on the thymus and adrenal gland are also noted, with adrenal insufficiency being a severe and life-threatening complication. It must be stressed that the frequency of this AE is stunningly high, reaching 17% in some trials, as the disease has been described only very rarely, with a good deal less than 1000 cases ever known prior to the introduction of immune checkpoint therapeutics.

So we won’t dwell on this, as clinicians now know what to watch for, and treatment paradigms have been developed. As mentioned earlier, treatment generally involves initiation of steroids to control to autoimmune response, and cessation of immune checkpoint therapy.

Let’s return to the consideration of combination therapy, which I think we all agree is essential if we are really to expand use of immune therapeutics in the treatment of these difficult cancers. Great hope has been placed in the combination of CTLA4 and PD-1 targeting agents with “safe” immune checkpoint modulators, notably the IDO-inhibitor from Incyte. We have very little information to date, but it is notable that the dose limiting toxicity in the first combination trial of ipilimumab and INCB024360 from Incyte (INCY) was liver damage as measured by ATL elevation. It may be that merely piling on ways of disrupting Treg activity will not help with the toxicity profile; in fact, one might make the prediction that this approach will make things worse in some settings.

We’ve remarked in passing on the apparently mild safety profile of the anti-PD-L1 inhibitors compared to the PD-1 inhibitors. This makes some sense, as the ligands are expressed by the target tumor cells, and this may be the main sink for the injected antibody, i.e. antibody may not be evenly bio-distributed but rather predominantly localized to the tumors. The concordance of anti-PD-L1 antibody activity with tumor PD-L1 expression is consistent with a direct and localized effect. The fact that there is less consistent concordance of anti-PD-1 antibody activity with PD-1 expression by tumor-infiltrating T cells suggests less specificity in the induced immune response, and this may be why we see autoimmune toxicity in the nivolumab setting. As CTLA-4 is exclusively T cell expressed, the same seems to hold true for anti-CTLA4 antibody therapy. So combining these may not be the most ideal way forward.

We will discuss alternative approaches next time, but first there is some new data on novel immune checkpoint therapies to consider. These are the TNF receptor superfamily proteins that we discussed last month (link): 4-1BB, CD27, OX40 and GITR. There is admittedly very little data to date. Pfizer’s (PFE) anti-4-1BB antibody PF-05082566 reached a safe dose in Phase 1 without undue toxicity signals (ASCO 2014, Abstract #3007). Pfizer disclosed combination trials with rituximab in Non-Hodgkin Lymphoma (NHL) and pembrolizumab (anti-PD-1). The BMY antibody urelumab was tolerated through its’ dose escalation cohorts, and ex vivo analysis showed activation of CD8+ T cells and NK cells (ASCO 2014, Abstract #3017). The Celldex anti-CD27 mAb also has demonstrated safe dose escalation, although to date without signs of clinical activity (ASCO 2014, Abstracts #3024 and #3027). Celldex (CLDX) claims planned studies in combination with nivolumab, ipilimumab, and the targeted therapeutics darafenib and trametinib.

As we discussed in an earlier post, 4-1BB, CD27, OX40 and GITR are evolutionarily closely related receptors. Biomarker studies such as the one performed in the urelumab trial will be essential in understanding how these immune stimulatory pathways will differentiate clinically and which will be safe in combination settings. We’ve reviewed the biology of this superfamily recently (see these posts) so won’t do so again until we get some more clinical data.

Next we will introduce some novel targets in the TNF receptor superfamily, revisit some apoptotic pathway “influencers”, and will swing back around to PD-1 and PD-L1 in some other solid tumor settings (not necessarily in that order).

stay tuned.

PD-1 Pathway Inhibition: Moving Beyond Melanoma

As we watch the clinical development of PD-1 pathway inhibitors we are struck by the ability of this approach to produce clinical efficacy in diverse cancers. Here we will briefly run through the rest of the landscape, starting with non-small cell lung cancer (NSCLC), then touching on metastatic renal cell carcinoma (RCC), glioblastoma (GBM), bladder cancer (UB), ovarian carcinoma and others. In many cases we are beginning to see the use of combination therapy, a setting that generally requires a careful look at toxicity. We’ll also look at the contentious issue of biomarker development for PD-1 and PD-L1 antagonists. The data are broken down into easy to understand bits, otherwise the whole thing is overwhelming.

The Emerging Role of PD-1 Pathway Inhibition in Lung Cancer

In the context of the often brutally aggressive tumors classified as the Non-Small-Cell Lung Cancers (NSCLC) progress is difficult and even incremental improvement in care is cause for celebration. Even so it was difficult to gather a consensus view of the clinical data being generated by the PD-1 pathway antibodies in NSCLC. In the melanoma setting (parts 1 and 2) our enthusiasm for PD-1 pathway inhibitors is driven by really terrific responses in some patients. The goal there is to improve the response rates while controlling toxicity. The clinicians argue, certainly with merit, that the responses seen justify the occasionally difficult toxicity. After all, all of their available therapies are limited by toxicity concerns, not only chemotherapy but also the small molecule targeted therapeutics. In this context, PD-1 directed therapies are well positioned.

It is not yet clear how these issues will play out in NSCLC. On the positive side, a subset of patients respond remarkably well to PD-1 pathway inhibition, and we may develop an understanding of how identify such patients. However, the overall response rates remain low, and impact on PFS and OS is small (see part 1 for a list of abbreviations). Complicating our understanding of the benefit of this class of therapeutics in NSCLC are three observations. The first observation is that tumor responses in this disease setting can be anomalous and may not be appropriately captured by standard RECIST tumor response criteria. The second observation is that severe toxicity can truly derail patients, and may even sensitize some patients to chronic toxicity that prevents application of other types of therapies. The third observation is that some targeted therapeutics for molecularly defined subsets of NSCLC patients are an attractive option to PD-1 directed therapeutics, and we don’t know yet if these can be combined.

The amount of data presented at ASCO14 was huge, and won’t try to cover it all.

There was a pretty dramatic response to the clinical trial data describing the utility of PD-1 pathway inhibitors in NSCLC. Bristol-Myers Squibb’s (NASDAQ: BMY) stock price dropped more than 6% from the start of ASCO on May 30th through the following week, and this on top of a long slide that started in March. Merck & Co (NYSE: MRK) stock jumped more than 2.5% at the same time. What was going on here? Let’s look at the estimated market sizes for three critical indications:Screen Shot 2014-06-18 at 6.55.32 PM

It is clear from the table that NSCLC is the largest patient population by more than 10-fold. It is also the case that NSCLC lacks the range of treatment options available to advanced melanoma and RCC patients. From the investor perspective then, NSCLC is a very big deal. Lets start there, and see how the emerging PD-1 pathway therapeutic class did in this setting.

Nivolumab anti-PD-1 antibody was studied in a number of clinical settings (ASCO14 abstracts #8024 and #8113). As monotherapy, nivo was generally well tolerated, and very effective for some patients. The ORR = 22% – 36% and a subset of patients had a durable response. Combining nivo with dual-platinum based chemotherapy increased the response rate but dramatically increased the SAEs, and in this early data did not appear to impact 1 year survival rates significantly. This table sums up some of the available data.

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Some patients responded very well – these were typically patients that had a non-squamous cell phenotype and whose tumors expressed PD-L1 and were therefore actively shutting down T cell responses by binding PD-1 on T cells. This figure is from a poster presented by Scott Gettinger (ASCO14 Abstract #8024).

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Tumor size is given on the Y-axis and duration is shown across the X-Axis, so for some responding patients the outcome is very good. In an effort to boost the effectiveness of immunotherapy for NSCLC, BMY ran a combination trial of nivo + ipi, as they had done previously in melanoma. They enrolled chemo-naive NSCLC patients, stratified by cell type into squamous or non-squamous groups, then gave these patients an induction regimen of nivo + ipi for 84 days (4 x 21 day cycles). The doses were either 1 + 3 mpk IV Q3W or 3 + 1 mpk IV Q3W, referring to the dose or nivo + ipi, respectively. Then the patients went onto a nivo maintenance schedule. The combination worked rather well, seeming to wipe out the disparity between the two cell types and overcoming some of the resistance seen in PD-1 tumors. Here are some illustrations of the data from Scott Antonio’s poster (ASCO14 Abstract #8023):

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As you can see, a fair number of patients have a sustained decrease in tumor volume or a stable disease course (no change in tumor volume over time). That’s a very nice result. Now the bad news. This combination therapy was nasty, a toxic brew. Discontinuation rates averaged 35% across the treatment arms with AEs including pneumonitis, liver damage, colitis, autoimmune nephritis (kidney inflammation & fibrosis), pulmonary hemorrhage, endocrinopathy, neuropathy, etc. Six patients (12%) died. We note that only 3 fatalities were directly attributed to the study drugs, but no one felt comfortable with these results. BMY’s stock price promptly dropped. We won’t know if the reaction was justified until other dosing and combo regimens are tried, but investors found another home, and that was with the competing drugs from Merck and Astra Zeneca (NYSE: AZN).

Immediately striking were the results from an NSCLC trial with the  anti-PD-1 antibody  pembrolizumab as monotherapy. Patients were selected based on positive PD-L1 staining on > 1% of tumor cells and given 2 or 10 mpg pembro Q3W or 10 mpk Q2W (ASCO Abstract #8077). The response rate was 26% or more, and the SAE rate was low (4%) although 18% dropped out due to AEs of any grade. Responses were durable with more than half of responders still on treatment at the time of data lock. A couple of things to note: these were treatment-naive patients, so presenting early in disease course. Second this figure (from the presentation by Naiyer Rizvi, ASCO #8007) shows maximum responses (ie. best response) and would not capture rebounding tumor size.

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As side note: the authors introduced an “immune response” criteria response rate because some patients would respond after having a new lesion appear (which would trigger the progressive disease (PD) score). Using these new criteria responses were even higher. We’ll see if these become more widely accepted.

AZN/Medimmune presented early expansion data on their anti-PD-L1 antibody, MEDI4736 (ASCO14 Abstract #3002 presented by Neil Segal) in advanced solid tumors. 84 patients with NSCLC were enrolled. The reported ORR was low but this was an accident of sampling as most patients had not gotten to their second screen yet and could not be scored as responders, per protocol. More impressively the vast majority of patients, across diverse tumor classes, remained on therapy.

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While it will be critical to see this data updated, the early read is very encouraging. Not waiting, AZN has initiated a pivotal trial in NSCLC and also a combo trial with their own anti-CTLA4 antibody, tremelimumab. We should be cautiously optimistic that the combination of anti-PD-L1 antibody with anti-CTLA4 antibody will have fewer tox issues than the anti-PD-1 combination, as mild tox appears to be a common feature of targeting the ligand rather than the receptor.

At this point of development, nivo has run into some problems in the combination setting, pembro looks promising, and MEDI4736 also looks promising. It will be very interesting to follow these story lines as they mature.

OK, RCC and other tumor types next, stay tuned.

PD-1 Pathway Inhibitors Reveal Unique Benefit/Risk Profiles Across Cancer Indications

Introduction

Anyone attending the immunotherapy sessions at ASCO earlier this month would have heard several distinct messages about PD-1 pathway inhibition in oncology. PD-1 appears to be a central control point for curtailing T cell responses in the peripheral tissues, similar to the role that CTLA4 plays in regulating initial T cell activation in secondary lymphoid organs such as the lymph nodes and spleen. Remarkable progress has been made in the 13 years since Gordon Freemen and colleagues first proposed in Nature Immunology that the PD-1 pathway was used by tumor cells as a shield against immune system attack (http://www.ncbi.nlm.nih.gov/pubmed/11224527).

It is clear that PD-1 pathway antagonists show tremendous promise in treating diverse cancers. Less clear is an understanding of why certain patients respond or don’t, what biomarkers might predict response, how to increase response rates, how to accurately measure response, and how to safely combine PD-1 pathway inhibition with other therapies.

Table 1 lists the PD-1 therapeutics in development (some of these therapeutics did not have updates at ASCO).

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As the table demonstrates, the PD-1 pathway inhibitors are being developed in diverse tumor types. As late Phase 2 data and Phase 3 data are coming out we can begin to see the real promise of these drugs in clinical responses measured in large numbers of patients. The amount of data presented at ASCO was a bit overwhelming so to simplify the landscape we can address each tumor type individually, when possible. Some terms we will use are given in the table below.

Table 2 defines the RECIST1.1 clinical response parameters and their abbreviations.

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To put these terms in perspective we can just consider that a meaningful clinical response is a measureable response to therapy (SD < PR < CR) that is durable and leads to an increase in PFS, which in turn allows a significant increase in OS. There are other terms used to describe clinical responses but these are the most common. We will start with some of the most recent data, and see where that takes us.

Part 1: Immune Checkpoint Combination Treatment of Melanoma 

The very first trials of PD-1 pathway inhibitors began with the investigation of nivolumab in metastatic melanoma. As such, there was an impressive amount of progress reported and we now have mature data on different therapeutics. To set the stage, we can consider the benefit shown by nivolumab monotherapy compared to standard of care treatment protocols, and also to ipilimumab (brand name Vervoy) an anti-CTLA4 antibody, also from Bristol-Myers Squibb (BMY). Ipilimumab is approved for the treatment of metastatic melanoma based on Phase 3 clinical trial data in metastatic melanoma patients that had failed prior therapy (a chemotherapy regimen). The trial compared ipilimumab to a tumor vaccine targeting the melanoma antigen gp100. Ipilimumab treatment improved median OS to 10 months versus 6 months with the vaccine treatment (which was no better than standard of care). The 1 year survival rate was 45%. ORR however was low, just about 10%. Also, adverse events (AEs) were a problem, and included autoimmune manifestations (colitis, pituitary inflammation) and some treatment-related deaths (2% of patients). In a separate study of treatment-naive metastatic melanoma patients, ipilimumab therapy was associated with an OS = 11.2 months and a 1 year survival rate of 47%, falling to 21% by year 3. Patients were given ipilimumab or placebo plus chemotherapy (dacarbazine), and then moved to ipilimumab or placebo alone if there was a response measured or if the initial therapy caused toxicity. One consequence of this scheme was that AEs went up dramatically, with 38% of patients experiencing an immune related, grade 3 or 4 severe AE (SAE). We dwell on the anti-CTLA4 antibody ipilimumab because it is the benchmark for other immunotherapies such as nivolumab.

Nivolumab therapy for advanced melanoma has produced impressive data, with median OS = nearly 17 months, and 1 and 2-year survival rates of 62% and 43%. ORR was 33%. AEs were significant if less severe than those seen with ipilimumab. Grade 3-4 treatment-related AEs were seen in 22% of nivolumab-treated patients. Immune-related adverse events (all grades) were seen in 54% of treated patients, and included skin, GI and endocrine disorders. However only 5% of patients experienced immune-related SAEs of grade 3 or 4 and there were no drug-related deaths. These data from Topalian, Sznol et al. from John Hopkins University School of Medicine were presented at ASCO last year and published earlier this year                       (http://jco.ascopubs.org/content/early/2014/03/03/JCO.2013.53.0105.full.pdf).

So with that as our backdrop lets update the state of PD-1 pathway antagonism in melanoma. One of the obvious next steps in the development of immunotherapy is to combine treatments and we saw dramatic long-term data from the combination trial of ipilimumab plus nivolumab in advanced melanoma. Early trial results presented at ASCO last year introduced 4 cohorts of patients given different doses of nivolumab and ipilimumab in combination, with an ORR across all four cohorts of 40% and a 1 year survival rate of 82%. Median OS had not been reached. SAE rate across the 4 cohorts was 53%. This quickly gets complicated so let’s define the cohorts. Numbers are doses of nivolumab and ipilimumab, respectively, in mg/kg: Cohort 1 (0.3 + 3), Cohort 2 (1 + 3), Cohort 3 (3 + 1), Cohort 4 (3 + 3). No data were presented for Cohorts 6 and 7 so we’ll skip those. Cohort 8 is designed to mimic the dose schedule chosen for later clinical trials.

Note that after the induction phase, patients are moved onto maintenance therapy, as show below.

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The slide is taken from the trial update presented at ASCO by Dr Sznol (Abstract #LBA9003). The data updates drove home several critical points. First, at the optimal dose rates of 1 + 3 and 3 + 1 the ORR ranged from 43-53%. The author’s introduce a new classification of clinical response to capture the observation that many patients are experiencing benefit while not strictly meeting RECIST1.1 criteria, this is termed “Aggregate Clinical Activity Rate” and reaches 81-83% in Cohorts 3 and 4 (note that Cohort 4 (3 + 3) was the maximum tolerated dose due to SAEs and will no longer be used). Perhaps more meaningfully, the percent of patients whose tumor burden was reduced by > 80% at 36 weeks was 42% across the cohorts. This is a remarkable number suggesting sustained clinical benefit. Indeed, in those patients who responded, the median DOR in Cohorts 1-3 plus Cohort 8 has not been reached. In Cohorts 1-3, 18/22 patients are still responding and 7 of those had discontinued therapy due to AEs (more on this below).

Dose cohorts were analyzed for impact on 1 and 2 year survival. In Cohorts 2-3 the 1 year OS = 94% and the 2 year OS = 88%. Most stunning of all was this data showing a median OS in Cohorts 1-3 of 40 months. Median OS in Cohort 3 (1 + 3) has not yet been reached.

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These data are best-in-class for treating advanced melanoma, and place ipilimumab plus nivolumab at the forefront of therapeutic options for these patients. The one outstanding issue remains that of toxicity. 23% of patients had to discontinue therapy due to toxicity, and one patient died of complications resulting from treatment. While Dr Sznol repeatedly pointed out that the toxicities observed are controlled by standard interventions, the problem is that these standard interventions include cessation of therapy. We have already learned from the ipilizumab experience that responses to immune checkpoint inhibition can take time, and for those patients who have to stop treatment after 1 – 2 doses due to toxicity, time may not be kind. It will certainly be beneficial to reduce SAEs so that more patients can remain on therapy.

Tomorrow we’ll look at other PD-1 pathway therapeutics and combinations in melanoma before moving on to other tumor types.

Merck’s MK-3475 Deals: Assets, Risk and Innovation in Immunotherapy Pipelines

The recent news that Merck will aggressively partner the anti-PD-1 program MK-3475 with competitors Pfizer and Amgen, and biotech Incyte, was a welcome recognition that the immunotherapy landscape is too vast and complex for most companies to handle alone. Companies that will succeed in this space over the long haul will position themselves to “sample” many assets and technologies, particularly in combination settings. Why? First, because many combination therapies will fail or be too toxic to use, second, therapeutic modalities will evolve rapidly or be replaced, and third, personalized oncology practice will fragment patient populations.

Merck’s anti-PD-1 antibody MK-3475 is an example of the first generation of immune checkpoint inhibitors, for which we have clinical data. Other first generation therapeutics are ipilimumab (Vervoytm) approved for the treatment of metastatic melanoma, and nivolumab, an anti-PD-1 antibody moving toward regulatory submission this year, both from Bristol Myers Squibb. There are other anti-CTLA4 and anti-PD-1 pathway antibodies in clinical development, just a bit behind, including antibodies to PD-L1 from Roche (RG7446) and Astra Zeneca (MEDI-4736) and to CTLA4 from Pfizer (tremelimumab). It is fair to say that Merck has generated intense buzz around the MK-3475 program, driven by excellent clinical data and an aggressive approval strategy.

If we look over the details of the Merck collaborations we see a convergence of technologies around combination therapy. The Merck/Amgen collaboration centers on developing the oncolytic vaccine T-Vec in combination with MK-3475. The therapeutic hypothesis is relatively straightforward. The immune response to vaccines built using tumor antigens is blunted, in part, because of the immunosuppressive signals induced by PD-L1 expression on tumor cells. So blocking PD-L1/PD-1 mediated immunosuppression may allow a more robust immune response to anti-tumor vaccination strategies. I’ll note here that Amgen recently reported Phase 3 results from their T-Vec trial in metastatic melanoma, hitting the primary clinical endpoint of durable response but just missing the secondary endpoint of improving patient overall survival, which is an endpoint that the immune checkpoint inhibitors do hit. So Amgen has clear motivation here to combine T-Vec with immune checkpoint inhibitors. In addition to the collaboration with Merck, Amgen also has a collaboration with Bristol-Myers Squibb to clinical evaluate the combination of ipilimumab and T-Vec in metastatic melanoma.

The collaboration between Merck and Incyte is also focused on disabling immunosuppressive signaling, in this case as mediated by inhibition of indoleamine 2,3-dioxygenase (IDO), a pathway that regulates T cell responses by depleting tryptophan from the local tumor environment. IDO also appears to regulate T cell activity in lymph nodes draining the tumor site. IDO inhibitors promote T cell effector function while reducing the immunosuppressive activity of T regulatory cells. Incyte’s IDO inhibitor INCB24360 is in Phase 2 clinical trials in metastatic melanoma and in ovarian cancer. In this case then we are considering the potential of dual immune checkpoint inhibition, blocking PD-1 and IDO simultaneously. Incyte already has a Phase 1/2 trial in metastatic melanoma of INCB24360 in combination with ipilimumab and a Phase 1 trial in late stage melanoma in combination with a tumor vaccine.

Merck’s MK-3474 collaboration with Pfizer is very interesting. A phase 1/2 combination trila with axitinib a VEGFR-selective multi-kinase inhibitor (Inlytatm), will be run in renal cell carcinoma. Axitinib is approved as second line therapy in kidney cancer, but the drug has limited potential as a long term therapy and has struggled to distinguish itself from the older multi-kinase inhibitor sorafenib (Nexavartm, from Bayer/Onyx). It is very hard to guess what such a trial will yield, but such combinations of targeted therapies (kinase inhibition in this case) and immune-checkpoint modulators will have to be tried. A recent example, combining ipilimumab and the BRAF inhibitor vemurafenib (Zelboraftm, from Roche) in metastatic melanoma induced unacceptable liver toxicity and was stopped after only four patients had received the combination. Ipilimumab and nivolumab have very different toxicity profiles, and attempts at different combinations are certainly warranted.

The collaboration between Merck and Pfizer also includes development of the combination of MK-3475 with Pfizer’s PF-05082566, an agonist anti-4-1BB antibody. 4-1BB is a potent immune stimulatory pathway that acts by boosting T cell activity. Of interest, PF-05082566 is already in a Phase 1 solid tumor (as monotherapy) and B cell lymphoma (as dual therapy, with Roche’s anti-CD20 mAb rituximab). Finally, Merck and Pfizer have an second agreement to investigate the combination of MK-3475 with palbociclib, a CDK4/6 inhibitor that recently showed encouraging data in advanced breast cancer, although without yet demonstrating an impact on overall survival. These types of combinations are designed to give that precise boost in efficacy, allowing at least some patients the benefit of long term responses that impact disease progression and survival.

Merck’s internal immunotherapy pipeline is thin but as we noted the other day they are beginning to target other pathways, in part via the Agenus/4-Antibody platform deal.

I titled this post “Risks, Assets and Innovation in Immunotherapy Pipelines” because Merck’s efforts around MK-3475 illustrate some clear themes in this space. One, already mentioned, is that going into this space solo is something no company, except perhaps Bristol Myers Squibb (BMY), can contemplate. Even BMY reached outside the company recently to license an anti-KIR antibody from Innate Pharma and to partner with Five Prime Therapeutics on antibody discovery. Why is BMY in such a dominant position? They were innovative (CTLA4 biology) and they have multiple assets including antibodies to CTLA4, PD-1, LAG-3, KIR, 4-1BB and PD-L1, with more on the way. Note that I’m not saying that BMY’s anti-PD-1 antibody nivolumab is better or worse than Merck’s MK-3475, nor do I much care which gets approval first, a race that lots of folks are watching. No one horse will win this field, which brings us back to assets and pipelines.

Beyond BMY, companies like Merck are aggressively partnering because as the immunotherapy field was developing they were less innovative, took fewer risks, and therefore have fewer assets in this space. Companies like Pfizer and Novartis that spent the last decade chasing one oncogenic mutation after another down the rabbit hole found themselves very quickly on the outside looking in. They are now buying and partnering to build portfolios.

And that’s just fine; further, this should be a “pull” environment that motivates the biotech community to generate an abundance of assets. Small biotechs are classically trying to be innovative (to differentiate), take risks (to return dollars on investment) and therefore develop new assets. These are the fundamentals that should drive further expansion of the immunotherapy portfolio across the industry. So how is biotech doing in this new landscape? It is a mixed picture. There is a dearth of new first and second-generation immunotherapeutics, a space that I believe should be asset-rich. This is why Five Prime, 4-Antibody and Costim were all able to do healthy deals relatively early in their development – there is just not a lot of competition.

What happened? Why aren’t there half a dozen anti-PD-1 and anti-PD-L1 antibodies looking for partners, or a dozen agonist antibodies to 4-1BB, OX40, and GITR, and multiple inhibitors of TIM-3 and Lag3? I think this is a case of history repeating itself. After remicade and etanercept were approved, biotechs ran from the TNF inhibitor space, all believing, incorrectly, that they would never be able to compete. Seven TNF inhibitors later, this class still dominates the rheumatoid arthritis market. I wonder if small biotechs are reluctant to follow-on with additional antibodies to the first and second-generation immune checkpoint space because they think they are “too late” – in other words, the value proposition is too risky. If so, I believe they are wrong. The appetite is clearly there, with large biopharma and antibody engineering companies hungry for assets to pull into their pipelines.

Instead, many small biotechs are trying to stay well ahead on the innovation curve, chasing new targets. The problem, as always, is that no one wants to fund that work, because the risk is very high. So the answer is to try to balance innovation and risk in order to create assets that investors will fund. Its a tricky proposition, but essential to biotech’s ability to continue contributing to immunotherapy, and driving value creation. That said, there are some terrific innovative programs out there, in the hands of focused and smart small companies. In the meantime, there are more companies seeking validated assets than there are good programs developing these assets. SugarCone Biotech spends a lot of time building strategic programs for biotechs and a lot of time matching quality assets with partners and investors, so we see this first- hand.

Why else would we need more assets? Straight off, the existing immune checkpoint antibodies ipilimumab and nivolumab induce some terrific responses, but the response rates could be improved. Second, development of the existing combination therapy of ipilimumab and nivolumab has been tricky, with excellent efficacy but troubling toxicity. Note here that BMY can tinker with the dosage and dose schedule of each agent in such combination trials, because they own them both. Less asset-rich companies seeking to develop combination therapy strategies either have to partner their programs (Merck, as discussed here, but AbbVie might be another good example), or acquire everything they can afford (Novartis).

We’ll be watching closely.

stay tuned.

Immune checkpoint inhibitors – Part 2

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

stay tuned.