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See our COPD post here. This is a tough disease with some big smart companies developing novel therapeutics.
KITE Pharma’s CAR-T technology. http://www.sugarconebiotech.com/?p=552
MSKCC/Juno’s CAR-T technology. http://www.sugarconebiotech.com/?p=544
CD19 targeting by Bi-specific antibodies and by Novartis’ CTL019. http://www.sugarconebiotech.com/?p=540
AACR packages – last chance! http://www.sugarconebiotech.com/?p=536
Macrogenics: Bi-specific antibodies and ADCs; immunotherapy. http://www.sugarconebiotech.com/?p=531
Immune Checkpoints: Innate immunity and IDO-targeting therapeutics. http://www.sugarconebiotech.com/?p=524
Immune Checkpoints: TIM-3, LAG-3, OX-40, 4-1BB and the rest of the new generation. http://www.sugarconebiotech.com/?p=522
Immune Checkpoints: PD-1, PD-L1, CTLA4 and the race to get into immunotherapy. http://www.sugarconebiotech.com/?p=515
Why we need transformative therapies for oncology. http://www.sugarconebiotech.com/?p=483
Immunotherapy of acute myeloid leukemia, AML. http://www.sugarconebiotech.com/?p=47
Acute myeloid leukemia. An evolving therapeutic landscape for AML. http://www.sugarconebiotech.com/?p=469
Treatment trends in acute myeloid leukemia, AML. http://www.sugarconebiotech.com/?p=464
Multiple sclerosis: Why Alemtuzumab flunked. http://www.sugarconebiotech.com/?p=89
High fiber and Tregs. Really? http://www.sugarconebiotech.com/?p=90
The human gut microbiome: lets be careful in there! http://www.sugarconebiotech.com/?p=6
ABT-199 in combination therapies for B cell lymphoma. http://www.sugarconebiotech.com/?p=7
Ibrutinib and idelalisib: looking for partners in the treatment of B cell lymphomas. http://www.sugarconebiotech.com/?p=8
Combination therapies for B cell lymphoma. http://www.sugarconebiotech.com/?p=9
Multiple sclerosis: Where are we headed in 2014? http://www.sugarconebiotech.com/?p=10
Lupus and Lupus nephritis: Where are we headed in 2014? http://www.sugarconebiotech.com/?p=11
Rheumatoid arthritis: Where are we headed in 2014 http://www.sugarconebiotech.com/?p=12
Fibrosis pathogenesis. It’s all about the cells! http://www.sugarconebiotech.com/?p=13
Cool Science: fibrosis pathways and targeted drug development. http://www.sugarconebiotech.com/?p=14
ASH2013: ABT-199. http://www.sugarconebiotech.com/?p=15
ASH2013: links to our posts on myelofibrosis, biologic therapies, targeted small molecule therapeutics, ADC technology, etc etc. http://www.sugarconebiotech.com/?p=16
Sorry for the slight delay getting this out. I was trying to account for each patient as even 1 or 2 misplaced will impact the response numbers in these small trials. Took a while.
Our last post focused on the CAR technology coming out of the MSKCC and affiliated institutions, being brought together under the Juno company umbrella. Juno was funded by ARCH Venture Partners and the Alaska Permanent Fund, through a partnership managed by Crestline Investors, along with Bezos Expeditions, and Venrock. We noted in closing that CAR T cell technologies were performing very well in acute lymphocytic leukemia (ALL), but not as well in the Non-Hodgkin Lymphomas (NHL). In early data sets response rates were not trending very high.
Recently I came across Kite Pharma’s JPM update on their version of CAR therapy. Kite is financed by Pontifax Ltd., Alta Partners, Commercial Street Capital, and individual investors, in partnership with the National Cancer Institute (NCI) Surgery Branch under a Cooperative Research and Development Agreement (CRADA). This reflects that the technology is coming out of NCI labs.
I was struck again by the duration and response rates reported and the indications they were pursuing. It seems that there is one extra patient in the JPM slide deck, so I went back to the ASH talk to get the right numbers. So lets review. Kite calls its lead CAR construct a very straightforward name: anti-CD19 CAR. Like 19-28z CAR from Juno/MSKCC, this CAR is built with a anti-CD19 scFv, followed by CD28 and CD3 signaling components. Quite unlike the 19-28z effort however, the lead here is NHL indications, specifically as seen here:
A few folks kindly emailed to point out that I had not mentioned the Memorial Sloan Kettering Cancer Center (MSKCC) in my previous post. The sin of omission. Apologies, but I’ve been trying to digest the press release that the MSKCC put out on February 19th. The presser served two purposes I think, one valid (here’s some data) and one just pure PR grandstanding. Plus, the release didn’t link to the actual study. That was published in Science Translational Medicine the same day as I found out after some text searching, only to run into a paywall.
So, here is the referenced paper:
Davila ML et al. 2014 Efficacy and Toxicity Management of 1928z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia. Sci Transl Med. Feb 19;6(224):224ra25. doi: 10.1126/scitranslmed.3008226.
The data from MSKCC investigators (the PIs are Renier Brentjens, Isabelle Rivière, and Michel Sadelain) is very impressive. In a small phase 1 study of patients with relapsed of refractory Acute Lymphoblastic Leukemia (r/r ALL), patient T cells were transduced with the CAR construct 19-28z CAR and reinjected into the patient. As seen with CTL019 (previous post), this is an effective strategy for producing a lasting T cell response to the CD19-positive leukemia. In the 16 patient trial, 88% of patients responded and just under half went on the receive allogenic HSCT, the standard of care for ALL. So thats great. Just to add some details, a complete response (CR) was reported for 14/16 patients. Two of these patients were already minimal residual disease (MRD)-negative when enrolled. The MSKCC study defines MRD- patients as CRm. The CRm is given as 75% so I’m guessing here that the 2 patients already MRD- at enrollment were not re-counted. Of these 75%, one third were further defined as CRi (CR with incomplete cellular recovery) meaning that they were cytopenic for one or more cell types. Other than this reference to toxicity, the paper generally focuses on cytokine release syndrome (CRS), noting that CRS can be accurately tracked using the routine clinical laboratory marker CRP. More importantly the investigators use a cytokine panel and CRP to define a severe CRS (sCRS) group of patients and a non-severe (nCRS) group of patients. Please note here that if you take the time to burrow through the supplemental tables you will find that both sCRS and nCRS patients had grade 3 and 4 adverse events including hypotension, febrile neutropenia, hyponatremia and altered mental state (CNS toxicity). sCRS patients (7/16 = 44%) further presented with fatigue, atrial fibrillation, sinus tachycardia, electrolyte imbalance, hypoxia and respiratory failure. It’s an important distinction, as the sCRS patients remained hospitalized, including ICU care, for an average of 57 days, versus 15 days for the nCRS group. Both groups are incurring very high health care costs post-treatment.
19-28z CAR differs from CTL019 in several interesting ways. The extracellular domain is a CD19-specific scFv. This is genetically linked to transmembrane and cytoplasmic domains from the costimulatory protein CD28, linked in turn to the CD3 epsilon signaling motif. CTL019 is similar overall, but uses 4-1BB domains instead of CD28 domains. One important consequence of the use of CD28 versus 4-1BB as the costimulatory effector domain is the persistence of the expanded T cell population after injection into the patient. For the 19-28z CAR T cells described in the present paper, the average duration was 3 months. The authors suggest that this is shorter than the duration seen with CTL019 treatment, and that this may be beneficial. That remains to be seen, as we really need duration of disease remission data to understand the benefit/risk of maintaining the T cells that control the leukemia. A final note on this: the MSKCC investigators go to some lengths to sketch out a clinical development plan that can be applied to various centers (not just theirs). This is a very important and useful development, which we would hope make these cellular therapies more widely available.
On the basis of this early data presented here and the phase 2 data coming from the U Penn group (see the prior post), its safe to say that we are watching the development of a new standard of care for ALL patients.
Back to the presser for a moment. The rest of the press release was amusing in a ballsy kind of way. There was the breathless prose and the very pointed “we were the first” claims that science journal editors (but not PR directors) generally avoid. As we all know, none of this science developed in a vacuum and the claim of precedence will be sorted out by patent courts as necessary. For the record I really have nothing against their PR campaign, it just makes me squirm a little. I happily support the MSKCC every year by donating through their Cycle for Survival Program (thanks to the strong legs of longtime friends John and Susan Canavari). Also I really look forward to watching this technology develop, along with technology from the Fred Hutchinson Cancer Center and the Seattle Children’s Research Institute, under the umbrella of Juno Therapeutics, which was formed in Seattle in December specifically to advance this and related therapies.
It’s pretty clear that this technology is very important and very very exciting.
Now, why don’t these cell based therapies work as well in other indications, like Non-Hodgkin lymphomas?
stay tuned.
We talked last time about the potential of Macrogenic’s DART bi-specific technology and we focused primarily on the T cell engaging bi-specifics, such as DART006, a CD3 x CD123 therapeutic. Lets just quickly state the hypothesis:
Bi-specific modalities will allow the targeting of the patients T-cell driven immune system to a precise (tumor-expressed) antigen.
Other outcomes are possible. For example, the drugs might not work at all, or they might not be as specific as designed, or they act in ways we have not anticipated. In the context of the Macrogenics platform, we actually don’t know yet, as DART006 is very early in clinical development. BiTEs (Bi-specific T cell Engagers), Micromet’s version of a bi-specific technology, have been around a while and are further advanced. Acute Lymphocytic Leukemia (ALL) patients are now being recruited into Phase 3 clinical trials for blinatumomab, the anti-CD3 x anti-CD19 BiTE, with study completion due in July 2017. Micromet was acquired for 1.2BB dollars in January 2012 by Amgen. At the time Amgen R&D head Roger Perlmutter pointed to the Phase 2 clinical trial results in ALL as driving Amgen’s interest in the technology. Indeed, blinatumomab has produced some remarkable data in ALL. Historically, chemotherapy treated ALL patients had a complete response rate (CR) of about 38% and a median overall survival (OS) of 5 months. Rituximab (anti-CD20) didn’t perform much better than chemo. In the blinatumomab Phase 2 trial of adult relapsed/refractory (r/r) ALL, patients received a continuous IV infusion of blinatumomab for 28 days followed by 14-days off drug. Patients who responded could re-up for 3 more cycles of treatment or proceed to allogeneic stem cell transplantation (HCST). There was a very high rate CR of ~70% and the apparent absence of minimal residual disease (MRD) in many patients. Blinatumomab also impacted overall survival (OS) in ALL, as reported at the American Society of Hematology conference (ASH) in 2012 (Abstract #670). The CR was still 69% with most patients being MRD negative. The OS for responders was 14.1 months while the OS for non-responders was 6.6 months (so median OS = 9.8 months). Thirteen of the 36 patients enrolled were able to receive allogeneic HSCT.
The most common adverse events (AEs) were fever, headaches, tremors, and fatigue. Some patients experienced severe AEs (SAEs) such as cytokine release syndrome (CRS) and central nervous system events, including seizures and encephalopathy. One patient stopped treatment due to fungal infection leading to death. So, there is tox to consider.
A smaller study directed to salvaging patients with MRD despite prior treatments showed even more dramatic results: 16/21 patients became MRD negative and the probability for relapse-free survival was 78% at a median follow-up of 405 days. This is a remarkable result. An SAE led to one drug discontinuation.
Last year at ASH (Abstract #1811) we saw early results from an open label phase 2 study in r/r Non-Hodgkin’s Lymphoma (NHL), specifically, Diffuse Large B cell Lymphoma (DLBCL). Blinatumomab was administered by continuous IV for 8 weeks. Patients received either stepwise blinatumomab dosing of 9, 28, and 112 μg/d during weeks 1, 2, and thereafter, or received 112 μg/d throughout. All patients received prophylactic dexamethasone. So you can see some dose modifications here designed to reduce SAEs. After a 4-weeks off drug, patients who had responded could receive a 4-week consolidation cycle. 11 patients had been enrolled, 7 patients were evaluable for response. These patients had failed >2 prior therapies, including some patients who had relapsed after HSCT. The overall response rate (ORR) was 57% (14% CR plus 43% partial response (PR); 30% had progressive disease (all from the stepwise dose regimen). Note this is a very small sample size so every patient has a large impact on the response numbers. Ten of 11 patients had at least one grade ≥3 AE with 2 patients having grade 4 AEs (one patient with neutropenia and leucopenia; one with respiratory insufficiency). There were no drug related fatalities. Ten of 11 patients had central nervous system (CNS) AEs, mostly tremor, speech disorder and disorientation: in 5 patients these CNS toxicities were grade 3. The overall benefit/risk assessment suggested stepwise dosing (9, 28, 112 μg/d) to be the recommended dose.
Well first of all let’s point out here that blinatumomab has orphan drug status for ALL and NHL. That’s just to remind ourselves that these are pretty rare diseases with high unmet need. For ALL in particular this seems a good risk/benefit scenario. Within the diseases that make up NHL, DLBCL is not the most treatable (nor the least), and we note also that there is no attempt in the open-label phase 2 to characterize DLBCL into its subclasses – these have different oncogenic drivers and different outcomes for patients. Blinatumomab has also been in Phase in in other NHL classes, including Mantle Cell Lymphoma and Follicular lymphoma. Response rates were generally below current standard of care. Similarly, we can go back to look at rituximab, ofatumumab, and even ibrutinib, idelalisib and ABT-199 in NHL and likely find better treatment paradigms for r/rDLBCL than this, although maybe not as a monotherapy (see those earlier posts here: http://www.sugarconebiotech.com/?p=16).
Given the modality (CD3 x CD19 bi-specific) maybe the most interesting comparison is with Novartis’ CAR-T CD19 technology CTL019. CTL019 is the product of genetic engineering technology developed by Carl June’s group at U Penn, and is currently advancing in close to 20 clinical trials. The most advanced is a Phase 2 trial in r/r ALL, with a primary outcome completion due in July of 2015. As a quick reminder, CARs combine a single chain variable fragment (scFv) of an antibody (e.g. anti-CD19) with intracellular signaling domains from CD3 and 4-1BB into a single genetically engineered chimeric protein. The CD19-specific version of this technology is termed CTL019. Patient’s T cells are lentivirally transduced with a CAR, expanded ex vivo then infused back into the patient. Infusion of these cells results in 100 to 100,000x in vivo T cell proliferation, anti-tumor activity, and prolonged persistence in patients carrying CD19+ B cell tumors. Results from a pilot study in pediatric and adult r/r ALL were presented at ASH in 2013 (Abstract #67). Most patients received lymphocyte-depleting chemotherapy just a few days prior to infusion. This helps de-bulk the malignancy. In this small trial, 82% achieved a CR, 18% did not respond. Of the patients achieving CR, 20% subsequently relapsed. The rest of the patients are being followed and there has been no update. Responding patients all developed CRS, and about 30% of patients were treated with the IL6-receptor antagonist tocilizumab plus corticosteroids to control CRS symptoms.
We have a little more data on CTL019 from NHL studies, specifically r/r CLL. In December 2013, Phase 2 data were presented at ASH (Abstract #873). Patients with r/r CLL received lymphocyte depleting chemotherapy and then one of several doses of transduced T cells (this is a dose study in that regard, although, cutting to the chase, no dose response was seen, so lets skip over that). Median follow-up for analysis was 3 months at which time the ORR = 40% (20% CR plus 20% PR, with clearance of CLL from the blood and bone marrow and at least a 50% reduction in lymphadenopathy. The toxicity profile was similar to that described above, dominated by treatable CRS. In a small Phase 1 study (Abstract #168), adult patients with r/r NHL including patients with chemotherapy-refractory primary mediastinal B cell lymphoma and DLBCL were enrolled. They received chemo to reduce disease burden and then an infusion of CTL019. 12 of 13 evaluable patients responded (ORR = 93%), the CR = 54% and PR = 38%. These are outstanding responses.
So let’s take a step back. It is a bit hard to compare these regimens head-to-head as they are in different stages of clinical development, the trails are generally small, and in the case of NHL, we have limited data on different types of lymphomas. At the same time we have to consider the larger landscape of therapies available, and ask ourselves how patients will best be served. In the case of the T cell engaging bispecific antibody landscape, it is very clear that robust anti-tumor responses are generated with very low concentrations of antibody. It seems to me very likely that there will be malignancies or subsets of malignancies where this technology will be very useful, including ALL, as we just saw. It will be important to either improve the antibody construction or alter the dose regimen sufficiently to reduce the toxicities associated with the BiTE therapeutic and competing modalities, including the DARTs. Now, people will claim that the tox is not so bad, and that it is only efficacy that matters, and that’s fine, but in the face of competition from CTL019 and other therapeutics, maybe this becomes a differentiating issue. This might also be different for the pediatric population (a critically important population in ALL) versus the adult population. When we look at the CAR T cell transduction technologies we need longer follow-up on the phase 2 studies but certainly anecdotal evidence from smaller trials suggests that some patients will experience long-lasting remissions. If this observational information holds up in the larger clinical trials than the technology will cement itself a place in ALL therapy, and perhaps in other diseases as well. We don’t know yet whether the BiTE therapeutic blinatumomab or the CAR therapeutic CTL019 will have a top-tier profile in NHL. This may change as more data become available, as some of the small studies are very encouraging. One of the interesting twists to the CAR technology is the question of how to make it widely available. In host-institutions (The U Penn system, MD Anderson, NCI) this is a centralized procedure, and in medical institutions world-wide, core patient cell facilities are commonplace. However it is rumored that Novartis at least wants to maintain the core facility model, as they picked up the Dendreon facility in Morris Plains New Jersey (at a bargain price) specifically to support CAR technology, and plan to duplicate those capabilities in Basel and in Singapore. Perhaps yesterday’s pickup of Israel’s Gamida Cell also plays into this centralized cell handling model. None of these complexities will bother the bi-specific therapeutics as these are injectable – that said, I’m not sure anyone will choose walking around with an IV pump for two months if they can avoid it.
So while these therapies and those like them are very potent, we will have to see how patients and providers ultimately use them.
Now, we’ve unfairly used blinatumomab and CTL019 to illustrate what are both pretty large areas of therapeutic development. We’ll come back to talk about the other players in the bispecific antibody and CAR spaces very soon.
stay tuned.
If you watched the news during ASCO and ASH last year you know how quickly our drug discovery landscape changes. You need boots on the ground for these meetings or you will miss critical intel. You can rely on Twitter or paywalled summaries, or you can get info specifically tailored for you.
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Macrogenics is a very interesting company whose next 2 or 3 years will surely determine its’ future. And it’s probably about time, as the company has 14 years under its belt. The company is public and trades on NASDAQ as MGNX.
We’ve watched many companies approach a critical time horizon, when possible futures begin appearing. Some companies become great, others wither away, but it is no longer possible to tread water. Macrogenics knows this well, and they are aggressively working to carve a successful path forward. CEO Scott Koenig and CFO James Karrels rang me up the other day, spending about an hour giving me a look under the hood. Our discussion was part history lesson, part update and all very interesting. What follows is just my personal opinion about what we discussed. I’ve tried to place my thoughts in the larger context of the antibody and immunotherapy landscape in the treatment of cancer.
The Macrogenics’ story includes an enhanced Fc technology for cytotoxic antibodies, a bi-specific antibody technology known as DART (see below), a series of partnerships with pharmaceutical companies, and some new initiatives. I’m not going to discuss the past type 1 diabetes effort and the teplizumab antibody as that story is well known.
Lets start with a very interesting program that has been built around the HER2 enhanced Fc antibody, margetuximab. Results from the Phase 1 trial were presented at ASCO last year, and there were early signs of therapeutic activity. The early data showed activity at doses ranging from 1-6 mg/kg qw and 10 mg/kg q3w. This is in the dose range already used for Herceptintm (trastuzumab; 4mg/kg qw or 8mg/kg q3w) and Kadcylatm (trastuzumab emtansine; 3.6 mg/kg q3w). Macrogenics’ hopes that margetuximab can eliminate cancer cells expressing lower levels of Her2 than tumors addressable by trastuzumab (which targets Her2 high expressing cancer cells). Program success hinges on this hypothesis.
Macrogenics is aggressively moving this antibody into Phase 2 and 3 programs including breast, bladder and gastroesophageal cancers with relatively low expression of Her2. The planned phase 3 trial of margetuximab plus chemotherapy in gastroesophageal cancer should start by the end of this year. A phase 2a trial in metastatic breast cancer should wrap up in the second half of this year, and we should see data in 2015. This is important because in the absence of compelling clinical data it will remain difficult for this program to drive further valuation. This is because the Her2 space is very crowded, and it may be hard to establish differentiation and gain leverage. The broad attack against diverse cancer types therefore makes sense. So while I like this program it is going to require compelling phase 2 data to really generate buzz.
The other day I wrote about immune-checkpoint programs (http://www.sugarconebiotech.com/?p=522) and in this area Macrogenics has nicely positioned its Fc-enhanced anti-B7-H3 antibody MGA-271. This first-in-class program is optioned to Servier, and has advanced to Phase 1 in solid tumors. The company was lucky to pick up this antibody target when it acquired Raven. It is one of a number of B7 family proteins with ill-defined biology. Importantly, Macrogenics focused on the expression pattern of this protein, that is, they treated it as a cell surface target and not as a biology target. This turned out to be a smart move, as this protein is highly and preferentially expressed on a wide variety of tumor cells, and Macrogenics is going after this antigen with a cytotoxic antibody. This type of immune targeting antibody is well positioned for combination with other therapies that “unleash” immune cell responses, particularly the NK cell and macrophage release strategies. We talked about a few of these last week (http://www.sugarconebiotech.com/?p=524). This program looks very interesting and has nothing but upside assuming we do not see a toxicity signal as the clinical trials move forward.
Macrogenics is smartly building out this space. Scott and Jim explained that some of the money recently raised in their stock offering is going to support best-in-class antibody process and manufacturing, and that this will include antibody-drug-conjugates (ADCs), which are toxin payloaded antibodies. Importantly, DARTs directed to appropriate targets will internalize – a prequisite for good ADC-mediated cell death. I asked them if they had chosen a partner for the ADC work (like Seattle Genetics or Immunogen) and they hedged just a bit, saying that different linker-payload combinations might be employed for different antibodies and targets. That’s certainly a reasonable approach, if heavy on the downstream process and formulation steps, so we’ll see what they decide.
An important part of the Macrogenics portfolio is certainly the DART technology. DART is an acronym of Dual Affinity ReTargeting (or Redirected T-cell), depending on the compound. So, there are a couple of different plays here. One is a T cell engagement technology. The furthest developed technology in this class is Micromet/Amgen’s Bi-specific T-cell Engager (BiTE). The CD3 x CD19 BiTE, blinatumamab, recruits T-cells through CD3 and directs them to kill CD19 positive cancer cells. Blinatumamab is reportedly active at concentrations of 100pg/ml or less and certainly in some leukemia settings induces very impressive and durable therapeutic responses, although the side effect profile includes CNS toxicity, including encephalopathy. We will talk much more about the BiTE technology in the next post.
I asked Scott and Jim about the encephalopathy toxicity, specifically whether this is a class effect due to T cell activation. Scott pointed to the way Micromet BiTEs are constructed, and the “floppiness” of the two arms, suggesting that this could have a different impact on a responding T cell than the covalently “locked” DART construct. A second point is that this could be a toxicity that is only seen with the CD19 x CD3 bi-specific and not other bi-specifics. Scott mentioned that similar toxicity has been seen in the setting of CAR-T CD19-directed therapy (CAR19). Honestly, we can’t really judge at this point and will have to await clinical results before we actually know the efficacy/toxicity profiles of various T cell recruitment and activation technologies will compare.
Preclinically, Macrogenics has done a nice job of differentiating itself from BiTEs. In an in vitro study comparing CD19 x CD3 bi-specific formats using the DART technology and the BiTE technology the DART compound was active at much lower concentrations, including against patient derived chronic lymphocytic leukemia cells (http://bloodjournal.hematologylibrary.org/content/117/17/4403.full). This may not matter so much just yet, as Macrogenics has chosen different bi-specific pairings, and for the moment will not compete directly with the CD3 x CD19 modalities, whether blinatumamab or CAR19.
Macrogenics DART technology has been validated in the partnership space. Boehringer Ingelheim (BI), Servier, Pfizer, and Gilead have all bought into the DART story with partnership deals. BI signed for up to 10 targets across diverse therapeutic areas and modalities and recently choose a DART compound to advance into preclinical development. Pfizer also signed a DART technology deal in 2010 for two cancer targets. Most recently, Gilead acquired rights to four pre-clinical DART programs for cancer indications. Gilead will fully fund research activities for all four programs and will receive global rights to three of the programs. Servier has rights to three DART programs and recently exercised an option to develop the MGD006 DART molecule in development for hematologic malignancies. This antibody is bispecific for CD123 (expressed on leukemias and lymphomas) and CD3 (expressed on T cells). Pre-clinical studies showed that the compound killed CD123-expressing leukemia cells at very low concentrations. A Phase 1 study in relapsed and refractory acute myeloid leukemia will start in the second quarter of 2014. This is the first study of a DART in the clinic.
So while this falls short of actual clinical success, the fact that diverse companies have lined up here is promising. Additional deals should be expected. Macrogenics also mentioned that they have an NK cell retargeting platform as well (one that would compete with the BiKE platform) and it will be interesting to see if deals are made on this technology as well.
Lets take a closer look at the DART targets.
The T cell engagement targets are CD123 (for MGD006) a target on acute myeloid leukemia (AML) cells, and gpA33 (for MGD007) a target on colorectal cancer cells. CD123 expression on AML is a target for ADCS, Bi-specific technologies, and CAR-T technology (CART123). So, this is an important target to understand.
CD123, a subunit of the IL-3 receptor, is over-expressed on AML tumor cells (and other hematopoietic tumor types). It is also expressed on normal hematopoietic stem cells, at a somewhat lower level. Recently, cancer stem cells (CSC) have been highlighted as sources of resistance to therapy. These are stem-like tumor cells that are very resistant to chemotherapy or irradiation, and are hypothesized to be a component of relapse in various tumor types. AML CSC are CD123 positive. Ideally then, therapeutics targeting CD123 will deplete AML tumor cells, deplete AML CSCs and hopefully not deplete normal cells. Because of the uniqueness of the CSC hypothesis, agents targeting CD123 and other CSC markers have gotten a lot of attention.
Lets start with CART123. Just a quick reminder, with CAR-T we are talking about the transduction of patient T cells with a modified TCR, a CD3 subunit and the 4-1BB signaling domain. Very nice preclinical data were presented at ASH last year by the group at The Children’s Hospital of Philadelphia (https://ash.confex.com/ash/2013/webprogram/Paper60937.html) using technology that has been licensed to Novartis. However, there has been no further news on this target. Very recently, a second CAR-T/CD123 program was described by investigators in Italy and the UK (http://www.nature.com/leu/journal/vaop/ncurrent/abs/leu201462a.html). The preclinical data were compelling, and there did not seem to be an effect on normal cells. We’ll have much more on CAR-T technologies in a separate post.
Further along are competing anti-CD123 antibodies. Xencor developed two anti-CD123 antibodies that were then licensed to CSL limited. The first, CSL360, failed to show signs of clinical activity in a Phase 1 AML trial. The second, CSL362, had excellent cytotoxic activity in preclinical models and a Phase 1 trial in AML is recruiting. In December of 2013, CSL Limited licensed this program to Janssen/Johnson&Johnson. So, this program now has some real muscle behind it. An interesting note on the trial, it is being run in patients currently in remission. If I think this through I think this means the therapeutic hypothesis is two-fold. One, to drive the leukemia to MRD status (minimal residual disease = below the limit of detection); two, to eliminate CD123+ CSCs.
Stemline (NASDAQ: STML) has brought an anti-CD123-ADC antibody into the clinic. They had several presentations at ASH last year, including a phase 1 trial in Blastic Plasmacytoid Dendritic Cell Neoplasm, a rare cancer with high expression of CD123. They showed 5/5 patients responded, with 4/5 having a complete response (https://ash.confex.com/ash/2013/webprogram/Paper64672.html). This will be an interesting therapeutic to watch.
Macrogenics presented preclinical data on MGD006 at ASH (https://ash.confex.com/ash/2013/webprogram/Paper55959.html). As mentioned above the phase 1 study in AML will start later this year. A second CD123 x CD3 bispecific is being developed by the Cancer Research Institute at Scott & White Healthcare in Texas (they already have an IL-3 fusion protein). There is also a tri-specific targeting CD33, CD123 and CD16 (to activate NK cells). This has made it to the clinic (http://www.translational-medicine.com/content/11/1/289).
Gpa33 is an antigen that is highly overexpressed on colon cancer. This antigen was targeted a few years ago using a humanized anti-gpa33 monoclonal antibody. However the humanization effort did not work well and the therapeutic was highly immunogenic. As far as I can tell Macrogenics is alone in this space.
An earlier stage bi-specific technology at Macrogenics targets multiple antigens. Their CD32 x CD79 bispecific cross links these receptors on B cells and stops cell activation.
As discussed above much of the effort ongoing at Macrogenics is directed to their many partnerships. We do not know the targets for most of these, but one can imagine the direction that Gilead might take, or perhaps Pfizer. The deal with Servier is very interesting in the context of the Servier CAR-T technology deal. As reported in mid-February Servier will collaborate with Paris-based Cellectis on UCART19, an engineered T cell with a chimeric antigen receptor targeting CD19, plus 5 other programs all in leukemia and lymphoma. The company plans to develop combination therapies with immunotherapeutic monoclonal antibodies, small molecules, etc.
What we are seeing then is the co-development of bi-specific modalities directed to the same targets as CAR-T modalities, sometimes by the same company. This latter point is critical and fascinating. Could DARTs and BiTES compete not only with ADCs but also the CAR-T technologies? I don’t know, but we may find out in just a few more years. And we do have to be patient – Macrogenics has no clinical news scheduled until 2015. One way the company could make a splash is if it were to do something big on the corporate side – a buyout, merger, acquisition. Certainly their promotional deck (link here: http://bit.ly/1qpPQWL) makes the point on the last slides that Macrogenics is flexible as it has plenty of capital.
I really like this company – their technology is gutsy and innovative and I wish them the best. Now it’s time for clinical execution: the data will guide us from there. In the meantime there are a few really interesting ways to think about the technology opportunity and the underlying equity value.
cheers, and stay tuned for some thoughts about BiTEs, BiKEs, CARTs and KITEs.
The Next Wave of Immune Checkpoint Modulator Targets
presented by Paul D. Rennert, Founder & Principal, SugarCone Biotech Consultants LLC
at the Conference:
Immunomodulatory Therapeutic Antibodies for Cancer
August 11-12, 2014 Boston MA, Long Wharf Marriott Hotel
Lets quickly set the stage. In part 1 we reviewed the CTLA4 and PD-1 pathways and therapeutics targeting these pathways. In part 2 we brought in a few more targets within the immunoglobulin superfamily: LAG-3, TIM-3, B7-H3, B7-H4, and very briefly TIGIT and VISTA. Then we reviewed therapeutics being developed to target proteins in the TNF receptor (OX40, CD40, 4-1BB, CD27, GITR) and ligand (CD70) superfamilies.
While some of these pathways play a role in the innate immune system, they are all more closely aligned with the adaptive immune system. The innate immune system is hard-wired, triggering a rapid immune response, while the adaptive immune system relies on the orchestrated interaction of antigen presenting cells (dendritic cells, macrophages, etc) with T cells and B cells, leading to a robust immune response and, importantly, immunologic memory, i.e. memory of “that which” induced the immune response in the first place. Memory underlies immunity, as in “I am immune to…”, and is the basis for vaccination. In the context of oncology, memory allows sustained immune response to cancer cells over time.
In most immune responses to pathogens, both the innate and adaptive arms of the immune system are critical for efficient and sustained protection. We are learning from work with innate immune checkpoint therapeutics that the same may hold true for anti-tumor immunity.
One of the critical cells in the innate immune response is the natural killer (NK) cell. The name tells their story, as these cells are primed to disgorge toxins onto pathogens and pathogen-infected cells or tissue. Recently, an adaptive immune role for NK cells has been described, a finding that only increases the importance of this cell type. The activity of NK cells is controlled to a great degree by the killer inhibitory receptors.
Killer inhibitory receptors come in 2 flavors: killer cell immunoglobulin-like receptors (KIRs) and C‑type lectin transmembrane receptors. There are many different proteins within these groups, with various functions. KIRs are normally kept quiescent through interaction with cell surface HLA proteins. Both HLA and KIR have variable genotypes, and not all are compatible. Further complicating the picture is the existence of multiple KIR family proteins. We are just beginning to understand the expression and regulation of these proteins in the context of tumor biology, and choosing which of the 20 or more receptors to target remains an open question. However, some progress has been made.
Innate Pharmaceuticals (OTC: IPHYF) is taking the first steps in exploring NK cell therapeutics. The company’s lead drug is lirilumab, a first-in-class anti-KIR antibody that specifically recognizes the KIR2DL1, -2, and -3 receptors, and prevents their inhibitory signaling. The antibody increases NK cell–mediated killing of HLA-C–expressing tumor cells. A phase II study of lirilumab in 150 patients with acute myeloid leukemia is in progress. Lirilumab has been licensed by Bristol-Myers Squibb. BMY is sponsoring Phase 1 trials of lirilumab in combination with ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1) in patients with solid tumors. These early lirilumab trials will start to read out over the next 2 years and the data will generate considerable interest.
Innate Pharma’s expertise in NK cell biology has produced several other programs. KIR3DL2 is another KIR family protein that is highly expressed in aggressive forms of cutaneous T cell lymphoma. Innate has developed an anti-KIR3DL2 antibody that has cytotoxic activity against cutaneous T cell lymphoma in vivo (mouse models) and ex vivo (primary patient cells). They gave an update at the T cell lymphoma forum in January: (http://www.innate-pharma.com/sites/default/files/tclforum2014_iph41_1.pdf). The company will file an IND this year. Innate Pharma also has several interesting earlier stage programs.
One of the reasons this is an exciting pathway is reflected in the combination therapy approaches mentioned, in which a boost in T cell activity is combined with a boost in NK cell activity. Other combinations worth considering include KIR inhibition with 4-1BB agonist activation. Ron Levy (Stanford) has described the transient expression of 4-1BB on NK cells that are exposed to tumor cells coated with antibody (e.g. lymphoma cells coated with rituximab or breast cancer cells coated with herceptin). This suggests that the presence of activating antibody induces 4-1BB expression on NK cells. If so, and if one could get the timing right, very potent combinations can be considered. One might also consider such mechanisms in the development of bispecific therapeutics. Obviously there are critical considerations here – one is toxicity (will the combination be safe) and second is timing, if the antibodies are administered separately.
Another critical cell in the innate immune response is the macrophage, that has an ancient and fundamental role in the clearance of dead, dying and infected cells from the body. Galectin-3 is an anti-apoptotic protein that is widely expressed, and may regulate apoptosis of tumor cells and tumor-associated macrophages. There are also reports that galectin-3 can regulate macrophage/T cell interaction, although the mechanism of action is unclear.
I honestly don’t know what to make of therapeutics targeting galectin-3 as this is a very promiscuous protein. That does not mean such therapeutics won’t be useful, it is just a point of risk assessment. Galectins bind to sugar moieties that are hanging off of proteins or bound to extracellular matrix (ECM). In this sense galectins are “sticky”, capable of binding distinct targets. There are about 15 different human galectins, and to add to the fun, some of these can oligomerize with each other.
Specificity is imposed by the preference of galectins for sugars having a terminal galactose. Further specificity is imposed by the preference of different galectins for different sugars adjacent to the terminal galactose in the oligosaccharide chain. Oligomerization allows galectins to support cell-cell and cell-matrix interactions, either of which can induce cell signaling. Galectins are most highly expressed in macrophages but are pretty ubiquitous. Galectins, including galectin-3, are proposed to play a role in diverse diseases, including asthma, fibrosis, cardiovascular disease, inflammatory disease and oncology. Well, that gives me pause, as a lot of biology is involved here. Already some big bets on galectin-3 have failed, such as BG Medicine’s cardiovascular disease program.
Galectin Therapeutics Inc (NASDAQ: GALT) has several galectin-targeting programs in development for liver fibrosis (notably, non-alcoholic steatohepatitis aka NASH) and oncology. GR-MD-02 and is a polysaccharide polymer that binds to galectin-3 and galectin-1, with higher affinity for galectin-3.
Mouse models have demonstrated that GR-MD-02 plus ipilimumab enhances T-cell function and anti-tumor responses greater than either agent alone. The data suggest a role of GR-MD02 in promoting the CD8+ T cell response to tumor antigens. GR-MD-02 is in Phase 1 testing to establish dose and tolerability. Providence Portland Medical Center has filed an IND to test GR-MD-02 plus ipilimumab in a Phase 1B study, enrolling patients with metastatic melanoma. Galecto Biotech has also developed galectin-3 inhibitors, these are preclinical stage programs.
The mechanism of action remains unclear. This remains the biggest issue with galectin-3 drug development – we really have no idea how it the system works. Galectin Therapeutics has built mechanism of action studies into the oncology clinical trials, which is a good step forward. To be clear, this is not to suggest that galectin-3 is not a good target, but if it is it will be nice to know more about the mechanism of action.
Phosphatidylserine (PS) can be classified as a pattern recognition target, making its expression a component of innate immunity regulation. This may or may not have anything to do with the mechanism of action of Peregrine Pharmaceuticals (NASDAQ: PPHM) anti-PS antibody bavituximab. Bavituximab is being tested in multiple solid tumor settings. It’s an oversimplification, but let’s define PS as an immunosuppressive molecule. PS is an inner membrane protein that is “flipped” to the cell membrane surface in cells undergoing apoptosis. PS is also a component of ECM, and is found on the surface of activated cells, such as activated T cells, although at much lower levels than on apoptotic cells. Tumor cells can express a lot of PS on their cell surface, and this is thought to provide protection from immune cells because the immune system will often ignore cells undergoing normal (i.e. programmed) cell death, which always occurs by apoptosis. Bavituximab may act to block PS and therefore allow an immune response to cancer cells.
Somewhat amazingly, a Phase 2 trial of bavituximab in advanced NSCLC yielded positive results on PFS and more importantly, improved OS, from less than 6 months to 12 months. This was a second line study in patients who had failed chemotherapy. FDA granted fast track designation for bavituximab for second line NCSLC even though the drug had failed as a first-line therapy in Phase 2. In other words, there is some disconnect in the results. Peregrine is currently testing bavituximab in phase 3 trials of advanced NSCLC as second-line therapy.
Again what we have here is a drug with a poorly defined mechanism of action. This will not matter if the Phase 3 results are positive, but it will complicate rationale design of co-therapies. One wonders how this drug might be paired with another immunotherapeutic, or even with a targeted therapy like ramucirumab (anti-VEGFR2 from Eli Lilly), which just reported out positive Phase 3 data in a very similar patient population.
The SIRPalpha/CD47 system is another fundamental component of blocking innate immune responses, in this case by macrophages. There are a few companies trying to utilize antibodies to CD47 or to SIRPalpha (CD172a). Expression of CD47 on tumors provides a shutdown signal to macrophages via CD127a, that basically prevents phagocytosis. Of note, cancer stem cells also utilize CD47 to escape the attention of macrophages. The approach is effective in models of human tumors in mouse, and there is a report of synergy with rituximab in a non-hodgkin’s lymphoma model. Irving Weissman and colleagues at Stanford and Oxford Universities will initiate Phase 1 testing of an anti-CD47 antibody this year. Several very small biotechs have begun working on antibodies to CD47 and CD127a.
There are other targets in this class although most are even earlier in development. TGFbeta is a good example of a target around which there is a lot of early activity in oncology (among other things). There are also, scattered in the literature, hints as to the next wave of immune checkpoint targets emerging.
OK, on to IDO.
Indoleamine 2,3-dioxygenase (IDO1) is an IFN-inducible enzyme that catabolizes the essential amino acid tryptophan from the cellular microenvironment. IDO1 is induced by interferon gamma, and is therefore elevated in settings of innate or adaptive immune responses. Elevated tryptophan degradation stops T cell activation and induces T-cell apoptosis. Furthermore, generation of biologically active tryptophan metabolites are associated with the induction of immune tolerance. Therefore IDO expression in APCs or the tumor cells is a potential mechanism by which the immune tolerance to tumor antigens is induced.
Incyte Corporation (NASDAQ: INCY) has developed a clinical stage oral IDO1 inhibitor. INCB24360 is currently in Phase 1 and 2 for metastatic melanoma in combination with ipilimumab and as monotherapy for ovarian cancer. Incyte presented PK/PD and tolerability data from a phase 1 trial at ASCO in 2012, and monotherapy data in advanced disease was presented at ASCO in 2013. In general that data showed only modest efficacy, with some patients being able to maintain stable disease, and these were late-stage patients. Results from the ipilimumab combo trial should be available this year, probably at ASCO.
Earlier this month Incyte entered into a collaboration with Merck to evaluate INCB24360, in combination with Merck’s anti-PD-1 antibody MK-3475. The first trial is a Phase 1/2 study in advanced or metastatic cancers including melanoma and NSCLC. The trial is designed to set appropriate doses and then randomize to MK-3475 with or without INCB24360. NewLink Genetics (NASDAQ: NLNK) is also in phase 2 with indoximod, a tryptophan analogue inhibitor of IDO1. The mechanism of action of this drug is not well understood, as it does not appear to influence free tryptophan levels. NewLink presented Phase 1 data at ASCO last year, showing good tolerability and some early signals of clinical activity.
Several companies have preclinical inhibitors of IDO and related enzymes. Privately held iTeos Therapeutics has preclinical drug discovery programs on IDO1 and Tryptophan 2,3-dioxygenase (TDO2), a second key enzyme in tryptophan catabolism. ToleroTech is developing an siRNA approach to targeting IDO. Other programs are no doubt underway in pharma and biotech.
Recall that in Part 1 we identified five or six distinct areas of immunotherapeutic development, and immune checkpoint inhibition was only one of these. We’ve stretched the definition a little bit to allow coverage of some of the targets in this last bit, Part 3. We’ve also deliberately skipped over the Toll-Like Receptor (TLR) field as these agents may best be viewed in the context of tumor vaccines and adjuvants.
There are compelling questions to consider.
1- how the heck will “healthcare” fold all these therapeutics together in a way that makes the best sense for individual patients?
2- how are companies coping with the overload of targets and modalities? How do you build a credible pipeline?
3- what modality is best suited for which tumor types? plus we’ll need biomarkers to sort out responses to these new therapeutics and combinations- what are they?
4- can we identify gaps that can be filled by new targets, perhaps new companies?
5- can we find hidden drug development gems already out there waiting to be licensed or bought?
6- what are the pivotal data coming up that will move companies and their stock prices?
7- can we foresee changes in clinical practice that will support some therapeutic modalities, and doom others?
8- where are the transformative therapies that will change the clinical landscape
We have spent a lot of time working on this competitive landscape, and have arrived at some very interesting answers (and lots more questions).
If we can help you or your company work through some of these issues feel free to connect with us via the Contact page.
As always you may leave a comment or reach us at rennertp@sugarconebiotech.com. Please follow us @PDRennert.
What will we cover next? Honestly, I don’t know yet.
stay tuned.