Category Archives: ADC

antibody drug conjugates

Novel Immunotherapeutic Approaches to the Treatment of Cancer: Drug Development and Clinical Application

Our new immunotherapy book has been published by Springer:

http://www.springer.com/us/book/9783319298252

I want to take a moment to acknowledge the stunning group of authors who made the book a success. I’d also like to promote our fund raising effort in memory of Holbrook Kohrt, to whom the volume is dedicated – 5% of net sales will be donated by me, on behalf of all of our authors, the the Cancer Research Institute in New York. So please consider buying the book or just the chapters you want (they can be purchased individually through the link given above.

Now, the authors:

from Arlene Sharpe and her lab (Harvard Medical School, Boston):

Enhancing the Efficacy of Checkpoint Blockade Through Combination Therapies

from Taylor Schreiber (Pelican Therapeutics, Heat Biologics):

Parallel Costimulation of Effector and Regulatory T Cells by OX40, GITR, TNFRSF25, CD27, and CD137: Implications for Cancer Immunotherapy

from Russell Pachynski (Washington University St Louis) and Holbrook Kohrt (Stanford University Medical Center)

NK Cell Responses in Immunotherapy: Novel Targets and Applications

from Larry Kane and Greg Delgoffe (University of Pittsburgh School of Medicine):

Reversing T Cell Dysfunction for Tumor Immunotherapy

from Josh Brody and Linda Hammerich (Icahn School of Medicine, Mt Sinai, NYC)

Immunomodulation Within a Single Tumor Site to Induce Systemic Antitumor Immunity: In Situ Vaccination for Cancer

From Sheila Ranganath and AnhCo (Cokey) Nguyen (Enumeral Inc, Cambridge MA)

Novel Targets and Their Assessment for Cancer Treatment

From Thomas (TJ) Cradick, CRISPR Therapeutics, Cambridge MA):

Cellular Therapies: Gene Editing and Next-Gen CAR T Cells

From Chris Thanos (Halozyme Inc, San Diego) and myself:

The New Frontier of Antibody Drug Conjugates: Targets, Biology, Chemistry, Payload

and a second topic covered by Chris Thanos (Halozyme):

Targeting the Physicochemical, Cellular, and Immunosuppressive Properties of the Tumor Microenvironment by Depletion of Hyaluronan to Treat Cancer

and finally, my solo chapter (and representing Aleta Biotherapeutics, Natick MA and SugarCone Biotech, Holliston MA):

Novel Immunomodulatory Pathways in the Immunoglobulin Superfamily

Please spread the word that all sales benefit cancer research and more specifically, cancer clinical trial development and execution through the Cancer research Institute, and as I said, consider buying the book, or the chapters you want to read.

cheers-

Paul

Yelling Yellen and The Least Licensable Unit (LLU)

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

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

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

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

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

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

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

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

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

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

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

cheers all, and stay tuned

Some ideas from Macrogenics: B7-H3, DARTs, ADCs and more

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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.

AML Therapeutics Part 3: Immunotherapy

Ryan Teague and Justine Kline recently put together a nice review of immune evasion in acute myeloid leukemia (AML). The open access paper is available online (http://www.ncbi.nlm.nih.gov/pubmed/24353898). These authors have particular interest in tumor escape from immune surveillance by two interesting mechanisms. The first is termed T cell exhaustion, and refers to a non-responsive state induced in CD8+ (cytotoxic) T cells. The second is immune suppression, mediated by TGFbeta and regulatory T cells (Tregs). Other means used by tumor cells to avoid the immune system include deactivation by co-opting signals that directly shut down immune responses, such as PD-1 and other signaling mechanisms.

Why the interest in immunotherapy for such an aggressive cancer? There are a number of good reasons. First I think it is fair to state that targeted therapeutics (small molecule drugs) and antibodies (mAbs, ADCs, bispecifics) have yet to achieve a breakthrough in AML. The best of these drugs, even in combination, are only modestly effective. The second reason, implicitly recognized by the T cell engaging bispecific antibodies (BiTEs, DARTs) and by the still nascent CAR-T cell engineering technology, is that there is evidence to suggest that AML can be controlled by an effective immune response. This evidence comes from the leukemia transplantation field. As Teague and Kline state:

“Treatment with modern chemotherapy regimens often induces complete remission, but a majority of patients will ultimately relapse … it has been recognized that allogeneic stem cell transplantation can be curative for some patients with AML … derived from the so-called graft-versus-leukemia effect thought to result … Unfortunately, only a minority of patients with AML are candidates for this procedure.”

Those who are familiar with allogeneic SCT will further recognize that this is a risky procedure that can outright fail. So, are there safer or more direct ways to harness an anti-tumor immune response?

Novel therapeutics developed to stimulate anti-tumor immunity include the CTLA4 antagonist mAb, ipilimumab (Vervoytm; Bristol Myers Squibb (BMS)), approved for use in refractory or non-resectable melanoma. BMS is also developing the anti-PD1 mAb nivolumab, and combination trials with ipilimumab are underway. Other anti-PD1 and anti-PDL1 antibodies in advanced development for a variety of tumor types include MK-3475, submitted last month for FDA approval for the treatment of advanced melanoma, MPDL3280A (Roche), MEDI4736 (Astra Zeneca), and others. These are critically important therapeutics in hematological cancer and solid tumors. The potential breadth of applications is illustrated by the announcement last week the Merck will seek collaborative partnerships to develop MK-3475 in combination therapies. Merck will partner with Pfizer to investigate combination therapy in a phase 2 renal cell carcinoma (RCC) trial with the VEGFR inhibitor axitinib (Inlytatm). Merck will also partner with Pfizer for a phase 1 trial(s) using MK-3475 with the agonist anti-41BB antibody PF-2566, in multiple cancers. Readers will note that 41BB signaling is a critical component of the CAR-T T cell engineering technology. The collaboration with Incyte is also a dual-immunotherapy approach, as MK-3475 will be combined with INCB24360, an IDO inhibitor, in a phase 1 non-small cell lung cancer (NSCLC) trial. IDO is secreted by tumor cells, is a mediator of T regulatory T cell activity, and in AML is associated with poor prognosis. With Amgen, MK-3475 will be used in combination with the oncolytic viral therapeutic T-VEC, which induces tumor cell death and stimulates anti-tumor immunity.

The point of all this is to illustrate that for difficult cancers – melanoma, RCC, NSCLC – its not going to be easy, and combinations of novel therapeutics will have to be utilized. AML is a very difficult cancer. With this in mind we can look at the state of immunotherapy drug development in AML.

The Teague and Klein review goes into considerable detail on this subject, so we’ll just hit a few highlights and then see if we can update the storyline. A point the review makes that I didn’t fully appreciate is that AML tumor cells (and many others) can downregulate MHC Class I and II, making the tumor cells difficult for the immune system to recognize in the context of allogeneic SCT. This fundamental type of immune evasion may be difficult to circumvent. Other mechanisms of immune evasion used by AML include expression of PD-1L on the tumor cells, which effectively shuts down tumor infiltrating T cells that express PD-1, the PD-L1 receptor and mediator of a potent signaling response that downregulates T cell activity. AML tumor cells also express B7 family proteins B7-1 and B7-2,that bind to CTLA4, another downregulatory receptor. Clinical trials enrolling AML patients for treatment with therapeutics such as ipilimumab, nivolumab etc are described in the review. Its sufficient to point out that the effort to use these therapeutics for AML is in its very earliest stages.

A few recent observations point to other immune evasion strategies that night be productively targeted in AML.

Several preclinical studies have identified co-expression of TIM-3 and PD-1 as markers of CD8+ T cell “exhaustion”, and have likewise identified PD-L1 and galectin-9 (a putative TIM-3 ligand) on AML patient cells. TIM-3 is yet another receptor on T cells that mediates downregulation of T cell activity. Other markers of AML cells from patients were recently described (https://ash.confex.com/ash/2013/webprogram/Paper56968.html).

Relevant proteins included B7-2 (CD86), B7-H3 (CD276) and PD-L1. Patients with very high expression of both B7-2 and PD-L1 had worse overall and relapse free survival. HVEM, a receptor for several critical immune proteins including LIGHT, CD160, and BTLA, was expressed on a subtype of AML with relatively good prognosis. The author’s conclude ” that the profile of immune checkpoint molecules … correlates with molecular disease characteristics in AML and may even possess prognostic information, especially for relapse … (and) as therapeutic targets with respect to boosting anti-leukemic immune responses.”

An example of such an approach is provided by Innate Pharma, which is developing an anti-KIR antibody, lirilumab. KIR negatively regulates NK cell anti-tumor activity. A phase 1 trial in AML is continuing                             (https://ash.confex.com/ash/2013/webprogram/Paper59174.html). Preclinical data support the use of this mAb in combination with the cytotoxic anti-CD20 mAb rituximab in lymphoma. One might envision a similar approach using a cytotoxic mAb targeting AML such as the anti-CD33 mAbs discussed in part 2. Another possibility are the anti-CD38 mAbs. Second generation CD38 mAbs with improved cytotoxic activity are under intensive development for multiple myeloma by Sanofi (mAb SAR650984), Jannsen (daratumumab aka HuMax CD38) and MorphoSys (mAb MOR03087).

Another example is CoStim Pharma, bought today by Novartis. In their portfolio are novel immunotherapeutic mAbs, including TIM-3 antagonist mAbs. Novartis is moving quickly here to beef up its immunotherapeutic pipeline, which it can now develop in parallel with the U Penn CAR-T technology. Another local, private immunotherapy company is Jounce Therapeutics.

As we have also seen in parts 1 and 2, drug development for AML lags significantly behind other leukemias, lymphomas, myelomas, and the like. However, targeted therapeutics such as the tyrosine kinase inhibitor sorafenib, HDAC inhibitors vorinostat and panobinostat, and proteosome inhibitors bortezomib and carfilzomib hold some promise. The FLT3 and c-Kit targeting agents seem less likely to provide meaningful long-term benefit, although we’ll see what the combo trials brings. While it is too early to assess the CAR-T technology, the bispecific modalities, or immunotherapies in AML, the cytotoxic mAbs and ADCs should have a prominent role in controlling this aggressive disease.

We asked in Part 1 who the winners would be in 5 years. Looking over the landscape of therapeutics its pretty clear that winning will require collaboration among companies. With that said those companies with the biggest concentration of effort in AML include Merck, Onyx, Novartis, Amgen and perhaps Seattle Genetics. Given their past successes we can be hopeful that several of these companies will succeed in establishing breakthrough treatments for AML. In the end, patients should benefit the most from all of this activity. Perhaps stockholders will also benefit. With this in mind we note that Onyx probably has the most to gain (or lose) in this indication.

 stay tuned.

Anticipating new therapeutics and forecasting treatment trends for acute myeloid leukemia – Part 2

Here is a quick recap of Part 1: we looked at some of the targeted small molecule drugs being developed for AML. That class of therapeutics can be binned into logical groups, as follows:

1) pan-signaling pathway inhibitors like sorafenib, sunitinib, even ponatinib

2) drugs that hit c-Kit (and various other receptor tyrosine kinases) like dasatinib and imatinib

3) drugs that target FLT3 (and usually hit other kinases) like quizartinib, midostaurin, lasartinib, and PLX3397

4) proteosome inhibitors like bortezomib and carfilzomib

5) epigenetic modulators like vorinostat, panobinostat, 5-azacitidine, decitabine and entinostat

6) miscellaneous. We discussed several of these in Part 1, and there are many more. One more of interest is AG-221 (Agios; AGIO) that targets the mutated IDH2 gene. IDH1 can also undergo mutation in AML. Such drugs are a nice idea, unlikely to work as monotherapy (just my view), but perhaps useful in combo. AG-221 is currently in early stage clinical development.

In the small molecule drug development landscape there is logic that is readily understandable, and the combinations of drugs being tried make good sense. In contrast the biologics side of AML drug development is pretty haphazard. On the other hand true breakthroughs leading to transformative changes in clinical practice very likely will be found here.

So lets move on to Part 2: Biologics, including cytotoxic monoclonal antibodies, ADCs, bi-specific antibodies, cell based therapy and few odds and ends.

An antibody that illustrates that haphazard nature of AML drug development is gentuzumab, a monoclonal antibody (mAb) directed to CD33, a protein expressed at high levels on AML cells. The mAb was coupled to a calicheamicin derivitive and developed as gentuzumab ozogamicin (GO). GO is therefore an antibody-drug conjugate (ADC). This drug was originally approved as Mylotargtm (Wyeth, now Pfizer; PFE) for the treatment of AML more than a decade ago based on a phase 2 trial data showing a CR + CRp rate of 30%. However the drug showed less benefit than expected in phase 3, plus unanticipated hepatic toxicity, and was pulled off market. GO continues to see use in clinical trials and off-label and has been shown to add to the effectiveness of chemo in AML patients carrying specific cytogenetic markers. A meta-analysis of large phase 3 trials was reported in the Annals of Oncology 2 weeks ago                           (http://annonc.oxfordjournals.org/content/25/2/455.abstract). Data from nearly 3600 patients (half treated, half controls) from five randomized phase 3 trials were analyzed. Compared with induction chemotherapy alone, adding GO significantly prolonged OS (HR 0.93, P = 0.05) and relapse free survival (HR 0.87, P = 0.003), decreased rates of resistance (OR 0.71, P = 0.01) and relapse (OR 0.75, P = 0.002), but oddly had no effect on CR rate, suggesting that complete response status was disconnected from longer term outcomes (this is actually very common). Subgroup analysis identified cytogenetic status as an important variable for response to GO. On the downside, the risks of grade 3–4 nausea/vomiting, diarrhea and liver aspartate transaminase (AST) elevation were increased in the GO arm.

Additional analysis is due this spring, and will likely be available at AACR or ASCO.

GO provided clear clinical POC that targeting CD33 could be an effective strategy for AML, and Seattle Genetics (SGEN) had also developed a naked antibody called SGN-33 (lintuzumab) that failed in phase 2b, demonstrating no efficacy benefit compared to chemo alone. Seattle Genetics has therefore developed a second-generation anti-CD33 targeting mAb, as an ADC. The mAb is coupled to pyrrolobenzodiazepine (BPD) a DNA minor groove-binding molecule that effectively stops tumor cell division and induces cell death. The resulting ADC is called SGN-CD33A. A phase 1 trial in AML just got underway (NCT01902329).

A very different mechanism for targeting CD33 is being developed by Amgen (AMGN) using technology acquired when they bought Micromet. Micromet developed a bi-specific antibody technology termed BiTE. BiTE antibodies fuse two single-chain mAbs, one that binds CD3 on T cells and a second that binds tumor cell antigens. The idea is to redirect T cells to selectively lyse tumor cells. AMG330 is a BiTE antibody with CD33 antigen recognition. This therapeutic is still in preclinical development.

A different bispecific modality is BiKE, in which an NK cell targeting mAb (anti-CD16) is coupled to anti-CD33. The idea is to trigger NK cells to degranulate thereby killing the tumor cells. Nice idea, probably a long shot, in preclinical development.

Yet another approach to targeting CD33 has been developed in the context of CAR-T technology. CAR-T technology is based on introducing a tumor-targeting construct to the patients own T cells ex vivo. A lentiviral vector expressing a chimeric antigen receptor with specificity for AML antigen CD33 is coupled with CD137 (4-1BB) and CD3-zeta signaling domains. A low dose of modified T cells are then re-infused into the patient. This technology is dubbed CART-33. The cells rapid proliferate and are activated in the presence of antigen (ie. the tumor cells), inducing a robust and long-lived anti-tumor response. A phase 1/2 trial has begun in Beijing (NCT01864902). We can expect additional trials to be added. This therapeutic approach has worked well in advanced lymphomas (with CD19 as the antigen). The technology, licensed by Novartis, is one to watch very closely.

Finally, radioactively labeled anti-CD33 mAbs have been developed, including conjugates of anti-CD33 mAb M195 to 131-I and 213-Bi. The latter conjugate was run in a Phase 1 trial but the clinical trial literature here is sparse. Other radiolabeled mAbs used for AML treatment include a 131-I-conjugated anti-CD33 mAb BC8 and a Y90-conjugated anti-CD45 mAb. Both are undergoing clinical testing at the Fred Hutchinson Cancer Center, apparently with very promising results. In general, radiolabeled mAbs that emit β-particles, such as I131-anti-CD33, Y90-anti-CD33, and I131-anti-CD45, deliver high doses of radiation to the bone marrow and are used as pre-conditioning prior to SCT. Re188-anti-CD66c also falls in this catagory. Short-ranged α-particle emitters like Bi213 Bi-anti-CD33, are used to treat low-volume or residual disease.

Another company that is using bispecific technology to target AML to activated T cells is Macrogenics (MGNX). They have developed an anti-CD3/anti-CD123 DART mAb MGD006, partnered with Servier. This Dual Affinity Re-Targeting (DART) construct is built from 2 different polypeptides, each comprising the VH of one antibody in tandem with the VL of the other antibody, creating a heterodimer that is stabilized by disulfide binding. This construct binds to both CD123 and to CD3 in the human T-cell receptor complex. A phase 1 trial should begin this year.

CD123 is the IL-3 receptor, expressed on myeloid lineage cells and elsewhere, highly expressed on AML cells. It also is expressed on leukemic stem cells, leading to the hypothesis that targeting CD123 might prevent relapses by eliminating residual tumor progenitor cells from the bone marrow niche. Recent data suggest that mutations in the signaling chain of CD123 may contribute to oncogenesis in some lymphomas and leukemias, including AML. Early POC was provided by the mAb 7G3, which showed potent in vitro and in vivo killing of human AML cells. This mAb did not undergo further development, although it appears occasionally in the radio-immunotherapy literature, e.g. as In-111-NLS-7G3 where NLS is a 13-peptide linker.

An anti-CD123 mAb already in Phase 1 is CSL362, a novel monoclonal antibody therapy. This antibody has been engineered antibody to efficiently recruit NK via the Fc portion of the antibody, so this is a classic antibody-mediated cytotoxicity approach. The mAb is being developed by CSL LLC and is partnered with Janssen.

 Stemline Therapeutics (STML) is developing SL-401, which is comprised of the IL-3 protein conjugated to a truncated diphtheria toxin, a potent inhibitor of protein synthesis. This construct reportedly has anti-tumor potency against tumor cell lines and primary tumor cells in the femtomolar (10-15 M) range. SL-401 is in Phase 2a in AML. That trial should report out preliminary data this year.

Of great interest is the CAR-T technology as applied to CD123 (CART-123). The technology is the same as discussed above for CART-33, and is in preclinical development. Again this is technology developed at U Penn and licensed to Novartis. We won’t get into the competitive landscape of modified T cell technologies, nor the intellectual property wars, a subject perhaps for another time.

A few other biologics to keep an eye on:

- Trebananib (AMG386) is a peptibody targeting the Angiopoietin 1/2 proteins. These are ligands for Tie2, a receptor on endothelial cells that promotes tumor angiogenesis. Peptibodies are petides fused to the Fc domain of an antibody. The peptide provides the parget recognition. A phase 1 reported at ASH that the therapeutic was safe and showed preliminary signs of efficacy in adult AML (Abstract #2710).

- Igenica is a private company that just received Series D funding of 14MM USD to advance IGN523 into the clinic. The funding round was led by Third Rock Ventures. IGN523 is an anti-CD98 antibody that targets both the tumor cells and tumor stem cells. CD98 is the neutral amina acid transported expressed on dividing lymphocytes, and it has been argued that IGN523 functions not only by inducing antibody-mediated cytotoxicity (by NK cells and CD8+ T cells) but also by blocking activity of the receptor.

- CXCR4 has emerged as an attractive target in AML, beyond the standard application of CXCR4 to mobilize stems cells. More recent work has focused on using CXCR4 antagonists like plerixafor (a small molecule) for chemo-sensitization (see ASH 2013 abstract #2680). More direct targeting is being pursued by Bristol Myers Squibb (BMS), with the antibody BMS-936564 (ASH abstract #3882), currently in phase 1 for AML (NCT01120457). Other CXCR4 agents are in development.

- other antigens have been recently identified.

If we look broadly at the biologics being developed for AML a few things jump out. First, there are no home runs, as we have seen in other lymhomas such as Non-Hodgkin’s lymphoma, where the anti-CD20 mAb rituximab showed dramatic response rates early in clinical development. Second, it’s still early for nearly all of these agents, with the exception of the GO ADC. Third, and this is a very common theme, combination therapies will be required to control this brutal disease. We saw in the review of small molecule therapeutics that companies and the NCI are co-sponsoring trials in order to move clinical practice forward, and we should expect similar collaboration as the biologics move ahead (indeed we already see this with the GO combo trial).

Tomorrow we’ll talk about the role of immune-checkpoint therapeutics in AML, a field with great promise.

LINKS TO THE #ASH13 ABSTRACT PREVIEW CHAPTERS @ SUGAR CONE BIO

ASH13 previews

Part 8.   ABT-199
Part 7.   CAR-T tech                        

Part 6b. new targets for Myelofibrosis           

Part 6a. Jak inhibitors in Myelofibrosis                       

Part 5.   Biologics for Non-Hodgkin Lymphomas              

Part 4.   New & noteworthy: CLL etc             

Part 3.   Btk and PI3K inhibitors for CLL      

Part 2.   Ibrutinib                              

Part 1.   Idelalisib

pre-ASH post on ADC technology:  here                         

ImmunoGen’s ADC Platform and Toxicity – Not So Simple After All

November 11th, 2013
Last week ImmunoGen’s candidate Antibody-Drug Complex (ADC) IMGN901 (aka lorvotuzumab mertansine)blew up in a Small Cell Lung Cancer (SCLC) phase 2 clinical trial. ADCs are designed to bind to proteins expressed at a high level on tumor cells. Upon binding these antibodies are internalized and release their payload, a cytotoxic drug. The idea is to load the tumor cells with a lethal poison while sparing normal cells.
The problem with IMGN901 seems a simple one. The antibody recognizes and binds to its target (called CD56) expressed on tumor cells including SCLC, Multiple Myeloma (MM), and Merkel Cell Carcinoma. In the SCLC trial the ADC was given either alone or with standard-of-care chemotherapy, which is the combination of etoposide and carboplatin (E/C).
It can be inferred from the press release that the ADC treatment, either alone or in combination therapy (ADC plus E/C) did not work: tumor cells were not killed off to a degree that resulted in measureable clinical benefit. Further, “an imbalance in the rate of infection and infection-related deaths was noted between the arms” and it was “recommended that all patients discontinue IMGN901 treatment. Infection-related death is a recognized risk in SCLC trials, including trials with E/C. Among the 198 patients receiving IMGN901 as a single agent in early trials, there was one incidence of infection-related death; it was deemed possibly drug related”. The quotes here are from the Business Wire version of the press release.
The tumor protein targeted by ’901, CD56, is also expressed on immune cells called NK cells. NK cells are essential for immune responses to infection, and it is possible that they were diminished enough by ’901 treatment to allow infections to occur at a rate higher than normal. CD56 expression on human NK cells is bright by flow cytometric analysis, generally giving a 2-log shift in staining intensity with standard reagents. This suggests somewhere between 10,000 and 50,000 copies of CD56 on each NK cell. This is similar to the expression of CD56 on multiple myeloma cells. We do not have comparative data for SCLC but immunohistochemical staining on these solid tumors shows extremely dark CD56 reactivity, implying robust expression. On balance it is plausible that there was enough expression of CD56 on human NK cells to cause their depletion, and this might have been associated with a higher infection rate. However, proving this is the case is currently not possible.
The combination of lack of efficacy and high rate of infections led the company to suspend the clinical trial.
Of note, a high infection rate was not noted in the ’901 MM phase 1 trial. This is from the presentation given at ASH in 2012, as summarized by The Myeloma Beacon web site: “Of the 39 patients evaluated for response, 57 percent of the participants responded to the combination therapy, including 3 percent who achieved a stringent complete response, 28 percent a very good partial response, and 26 percent a partial response. The most common side effects of all grades (both moderate and severe) included peripheral neuropathy (56 percent), fatigue (42 percent), low white blood cell counts (32 percent), and low platelet counts (32 percent).” In this trial the combination therapeutics used were Revlimid (lenalidomide) and dexamethasone, and the side effect profile is consistent with the use of those agents.
On top of the increased infection observed in the ’901 SCLC trial, there is also the larger question of whether ImmunoGen’s ADCs are inherently unsafe. This hypothesis has been brought forward based on multiple reports of ocular toxicity associated with ImmunoGen’s drugs, thought to be related to the “linkers” used by ImmunoGen to attach its antibodies to the toxin. The linker is a biochemical construct – these are designed to be stable while in circulation, and then cleaved once the ADC is internalized by the target tumor cell. Much has been made of the hypothesis that some linkers are “leaky”, that is, they undergo some cleavage even while in circulation and that this leakiness contributes to toxicity. This is a very difficult hypothesis to evaluate, as ImmunoGen has used multiple different linkers for different ADCs. Also there is anecdotal reference to ocular toxicity seen with Seattle Genetics ADCs, which use a different linker and toxin combination.
Some insight can be gleaned from ImmunoGen’s recent patents in the area of linker development. US 2012/0282282 “relates to charged or pro-charged cross-linking moieties and conjugates of cell binding agents and drugs comprising the charged or pro-charged cross-linking moieties and method of using the same to reduce ocular toxicity associated with administration of antibody drug conjugates”. The benefit of charged groups in the linker appears to be to increase solubility, which implies that the ocular toxicity is a drug precipitation or drug aggregation effect seen at higher doses. Example 8 of the patent states that  “administration of the substituted charged sulfo-SPDB linker for the uncharged SPDB linker greatly decreases ocular toxicity in a rabbit model.” Example 9 of the patent further states that “MGN242 is an antibody drug conjugate for the treatment of CanAg-expressing tumors … Forty-five patients have been treated with IMGN242 at 8 different dose levels (18 to 297 mg/m2) in two clinical trials. Dose limiting toxicities (DLTs) included decreased visual acuity, corneal deposits and keratitis, which appeared to improve in patients where follow-up data is available. A two-phase pharmacokinetic profile was observed for IMGN242 in plasma from patients with low circulating CanAg levels (1000 U/mL) compared to patients with low levels (
So, at least in this case, a high level of circulating drug is associated with ocular toxicity.
Similarly, ImmunoGen reported ocular toxicity associated with IMGN853, an ADC targeting folate receptor alpha on diverse tumor types. Toxicity was managed by dose reduction (from 7mg/kg to 5mg/kg, as reported at ASCO this year – abstract #2573). Related to this observation is the finding that changing the dose schedule can reduce ocular toxicity, as reported for with SAR3419, an ADC targeting CD19 (Beck et al. 2012. mAbs 4: 637-647).
ImmunoGen appears to have suffered a perfect storm of negative publicity on the heels of the ’901 efficacy/toxicity results. The data relevant to a specific drug (’901) in a specific cancer (SCLC) have been extrapolated to reflect on the entire pipeline. As we’ve seen from even this brief look under the hood, it’s not that simple. The bigger issue of ocular toxicity may be addressable by adjusting dose and dosing schedule, although I’ll grant this is not an ideal situation. ImmunoGen is continuing the development of next generation linkers as discussed above. Finally, ImmunoGen is seeing continuing success with T-DM1/Kadcyla, an earlier generation ADC with its own issues and history, approved for treatment of Her2-positive breast cancer. However, StartUp, writing in 2011, disclosed that ImmunoGen’s upside from the Kadcyla deal with Genentech/Roche was very limited, with single digit royalties following the payment of ~50MM in milestones. At total worldwide current Kadcyla sales of ~200MM per annum this will not amount to much cash. I have no idea what ImmunoGen’s broader financial picture looks like, but investor’s were clearly spooked by last week’s news, driving the stock down over 20% on November 4th. It has regained about half of that ground since.
 
With at least 10 ADCs using 4 different linkers already in the clinic, trial results may inform ImmunoGen’s developmental strategy in a timely manner, and at the end of the day this technology may be refined to a point that it achieves broader application. In the meantime we should anticipate a bumpy ride, to be expected I think when innovation is the driver. ImmunoGen aside, Seattle Genetics, Roche, BMS, Takeda etc have programs running in this space, with 32 clinical programs listed by Credit Suisse in November 2012. A host of small companies (and investor’s dollars) are competing to add value, whether at the level of antibody technology, alternative scaffolds, novel linker technology or new ways to couple toxins in ADCs. Identifying the best chances for adding value is a discussion for another day.