Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

By Joseph Juan, Dimitre Simeonov, Katherine Woronowicz, Henok Eyob, Ph.D., Armen Mekhjian, and Evan Markegard

Overview of Cancer Immunotherapy

The buzz may be all about cancer immunotherapy this year, but this area of research has roots in experiments over 120 years old. A doctor named William Coley was the first to guide the power of the immune system to target his patients' inoperable tumors. He injected his patients' tumors with streptococcus bacteria in order to trigger a fierce immune response and subsequent regression of the targeted tumor.

Thanks to the fact that we no longer inject tumors with bacteria, interest in the field of immunotherapy is booming. Citigroup analyst Andrew Baum estimates that by 2023, immunotherapy will grow to a $35 billion industry and that immunotherapy will be the foundation of 60% of cancer patients' treatments.

Scientists have identified a number of immunological checkpoint inhibitors. These are mechanisms that the body uses to quell inappropriate immune cell activity in for example, Cytotoxic T-Lymphocytes (T-Cells) and/or Natural Killer (NASDAQ:NK) cells. Unwarranted T-Cell activity leads to the body attacking its own cells as in autoimmune diseases. Therefore, mechanisms have evolved to prevent self recognition and what has become apparent in recent years is cancer cells use these mechanisms to their advantage, by expressing these "I'm on your side!" signals.

The hottest checkpoint inhibitors in the biotech world are antibodies that bind to extracellular components of these signaling pathways, such as the ligand or its receptor, and disrupt receptor-ligand binding. Repressing an inhibitory response leads to heightened T-Cell activity and cancer killing potential. The most advanced checkpoint inhibitors target CTLA-4 (Cytotoxic T-Lymphocyte Antigen-4) which binds CD-80 (B7-1) and CD-86 (B7-2), as well as PD-1 (Programmed Cell Death-1), and its ligand PD-L1.

Bristol-Myers Squibb (NYSE:BMY) is leading the immune checkpoint inhibitor space with the acquisition of Medarex in July 2009 for $2.4B. Bristol-Myers Squibb obtained ipilimumab/Yervoy (anti-CTLA4) and nivolumab (anti-PD1). CTLA-4 blockade stimulates T-Cells by blocking inhibitory signals on antigen presenting cells during T-Cell activation. Ipilimumab was approved in 2011 for melanoma and had sales of $960M in 2013, with peak sales estimated to be $1-2B. Ipilimumab is also in clinical trials for many other cancer indications, 182 trials show up on clinicaltrials.gov,

PD-1 and PD-L1 also a hot targets. PD-1 is expressed on immune cells, and its ligand, PD-L1, is expressed on non-immune cells. When a T-cell bumps into another cell, it receives information about the identity of that cell. If the cell express PD-L1, then the T-cell will spare that cell from an immune response. Cancerous cells often overexpress PD-L1 on their surface in extremely high quantities, essentially making them invisible to T-Cells. Disrupting PD-1 and PD-L1 interaction enhances the immune systems ability to recognize and destroy cancer cells. A common analogy for this checkpoint inhibitor is to compare this signaling event to a brake pedal on the immune system. If PD-1 never binds PD-L1, then cancer cells are no longer able to jam the immune system's brakes and are eliminated.

Bristol-Myers Squibb is rapidly advancing development of their anti-PD1 antibody nivolumab. Nivolumab is in a race against Merck's (NYSE:MRK) lambrolizumab to win FDA approval as the first anti-PD1 cancer immunotherapy. Last year, in a long-term follow up of a completed phase I study, nivolumab elicited long-term immune responses in non-small cell lung cancer (NSCLC) patients as well as increased survival time. Nivolumab is currently enrolling in phase III trials for indications in lung cancer, renal cell carcinoma, melanoma, and other cancers with 36 trials on clinicaltrials.gov.

In recent months, there have been some noteworthy collaborations and acquisitions in the cancer immunotherapy space:

Bristol-Myers Squibb and Five Prime Therapeutics (NASDAQ:FPRX) Collaboration in March 2014

Bristol-Myers Squibb and Five Prime Therapeutics recently forged a $350 million collaboration in which Five Prime will use their screening technology to identify drug targets for Bristol-Myers Squibb in two immune checkpoint pathways. Specific details of the nature of the screen or the pathways being investigated were not disclosed.

Merck Collaborates with Pfizer (NYSE:PFE), Incyte (NASDAQ:INCY), and Amgen (NASDAQ:AMGN) in February 2014

Merck established collaborations with three companies to explore potential combination therapies with its PD-1 targeting antibody, MK-3475, in separate phase I/II clinical trials. Merck's agreement with Pfizer will test efficacy of their anti-PD-1 antibody with PF-2566, Pfizers monoclonal antibody against 4-1BB. 4-1BB is expressed in activated T-Lymphocytes and stimulates proliferation, survival, and cytokine production, thereby enhancing tumor cell killing. Merck's agreement with Incyte involves IDO inhibitor, INCB24360, which boosts activity of numerous types of immune cells including T-Cells, dendritic cells, and natural killer cells. Merck's agreement with Amgen will test the efficacy of a combination anti-PD-1 and talimogene laherparepvec, which is injected into tumor cells causing massive lytic cell death releasing tumor antigens into the system and triggering an immune response at the tumor site.

Novartis Acquired CoStim in February 2014

This year, Novartis AG acquired CoStim Pharmaceuticals, a Boston based immunotherapy biotech, for an undisclosed amount. This acquisition underscores the hope that big pharma has placed on cancer immunotherapies. CoStim's pipeline contained candidates that target costimulatory immunity checkpoints with the goal of enhancing the immune response to cancer.

The cancer immunotherapy space is very exciting and offers new treatments for cancer patients. This article will focus on Innate Pharma (IPH.PA) (OTCPK:OTCPK:IPHYF) which is located in Marseille, France, and has 84 employees. Innate is valued at $441M and is a cancer immunotherapy company with a unique approach of activating the innate immune system and has partnered their lead compound with Bristol-Myers Squibb. Innate trades on the Paris exchange under the ticker IPH.PA, but can be bought in the secondary OTC market under the ticker IPHYF. Below is a summary of the cancer immunotherapy space.

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R&D Update April 10, 2014

Unique Approach

A role for Natural Killer (NK) cells in the immunosurveillence and destruction of cancer cells was first uncovered nearly four decades ago with the discovery that NK cells could kill tumor cells. Further experiments revealed a role for NK cells in preventing tumor initiation, growth, and progression, as mice lacking NK cells or with defects in NK cell activity developed aggressive tumors more frequently, and the tumors were more likely to metastasize. The strongest evidence in humans for a role of NK cells in tumor elimination comes from studies demonstrating an increase in survival and reduced relapse in leukemia patients receiving alloreactive NK cells during allogeneic hematopoietic stem cell transplantation. A number of experiments over the years have also revealed insights into how NK cells selectively kill tumor cells while sparing normal cells: NK cells use receptors on their surface to sense an intricate balance of activating and inhibiting signals to distinguish tumor cells from normal cells. NK cells recognize tumor cells because they downregulate inhibitory signals (typically found on every normal cell) and upregulate activating signals (rarely expressed in normal cells) on their membranes. However, tumor cells often evolve to evade NK cells typically through the upregulation and downregulation of these same inhibitory and activating signals, respectively. Innate Pharma aims to use this mechanistic understanding of NK cell/tumor cell interactions to unmask tumor cells from NK cell evasion and tip the balance toward NK-mediated tumor cell killing.

Lead Compound Lirilumab/IPH2102 (anti-KIR2DL1,2,3)

The unique approach Innate Pharma takes to increase NK-mediated tumor cell killing is through the use of antibodies that block inhibitory sensing receptors on the surface of NK cells (anti-KIR antibodies lirilumab/IPH2102, and anti-NKG2A antibody, IPH2201). The attractiveness of this approach is in its potential for efficacy in a broad range of cancers; while current therapies in cancers such as lymphoma and leukemia have shown success in the use of NK cell-dependent mechanisms of tumor cell killing, such mechanisms are not limited to blood cancers, and theoretically can be extended to solid tumors as well. While efforts to enhance NK cell numbers and activity through NK cell infusion, adoptive transfer, and stem cell transplantation techniques are also in various stages of development, the disadvantages are numerous including potential host rejection of these cells, and exhaustion due to the need to culture and expand these cells in vitro. This makes the antibody-based approach by Innate Pharma not only a superior option over these other techniques, but may also serve as a complementary therapy to augment the efficacy of these alternative approaches.

R&D Update April 10, 2014

Due to historical data demonstrating a role for NK cells in eliminating cancers of the blood, the first obvious indications in which anti-KIR antibodies are most likely to find success are leukemias and lymphomas. Of these cancers, the prognosis of patients with acute myeloid leukemia (AML) is remarkably poor, with a 5-year survival rate of only 5-15% in older patients. Currently, the standard of care for these patients is chemotherapy, which often requires stem cell transplantation as a post-remission therapy. This underlies the need for more efficient drugs with better safety profiles in the treatment of this disease.

With these factors in mind, a Phase I trial with IPH2101 was performed in patients with acute myeloid leukemia (AML). Four French centers enrolled a total of 23 patients into a classical, modified Fibonacci Phase I designed dose-escalation study. Results from this trial were very positive. KIR-occupancy by IPH2101 occurred in a dose-dependent fashion and full KIR saturation was attained at all dosing regimens, with duration of occupancy also occurring in a dose-dependent fashion. One concern with therapies enhancing NK cell activity is the potential to trigger autoimmune diseases as an adverse side effect. Promisingly, IPH2101 was very well tolerated in all patients, with adverse events being of the mild and transient variety and MTD not being reached. Biological measures both in vitro and within patients demonstrated an ability of IPH2101 to enhance NK cell cytotoxicity and activity. Most importantly, the clinical effects of IPH2101 were largely positive. Despite being a Phase I study, overall survival was significantly increased in patients receiving the highest doses of IPH2101 compared to those receiving the lowest doses (29.7 months (high dose) vs. 11.8 months (low dose); log rank p = 0.034). Trends toward improved median progression free survival and relapse free survival were observed and are impressive, but were not significant, likely due to the small trial size. This demonstration of biological and clinical efficacy alongside a favorable toxicity profile bodes well for the use of IPH2101 both as a monotherapy and in combination with conventional therapies.

 

1 and 3 mg/kg IPH2101

< 0.3mg/kg IPH2101

P-Value

N

6

16

N/A

OS (months)

29.7

11.8

0.034

PFS (months)

12.6

2.3

0.076

RFS (months)

21.1

9.5

0.079

Indeed, as a monotherapy, a Phase II trial with lirilumab in AML is already underway (the same monoclonal antibody as IPH2101 with improved manufacturing process). This trial sponsored by Innate Pharma will enroll 150 patients with AML in complete remission to test the efficacy of single agent lirilumab in a maintenance setting at two different doses (0.1 mg/kg every 3 months and 1 mg/kg every 4 weeks) versus placebo (saline every 4 weeks). One risk factor is that if this Phase II trial shows positive outcomes, they will likely need to put lirilumab up against the standard of care or move to front line therapy, which may skew the ability to recapitulate Phase II success in a Phase III trial. On March 12, 2014 Innate Pharma announced that the Data and Safety Monitoring Board (DSMB) completed its second assessment of this trial and recommended continuation of the trial suggesting lirilumab continues to exhibit favorable toxicity profiles in this expanded group of patients. The primary efficacy endpoint will be leukemia-free survival, and secondary endpoints will be safety and overall survival. The final data from this trial is expected in the second half of 2015.

In identifying treatment options in which lirilumab can be combined to induce a synergistic reaction, one class of therapies that immediately makes sense are those that induce tumor cell killing via antibody-dependent cell-mediated cytoxicity (OTC:ADCC). ADCC is the process through which cytotoxic effector cells (specifically, NK cells) destroy an antibody-coated cell. NK cells are able to recognize the Fc portion of antibodies through the CD16 receptor, which then activates NK cell cytotoxic activity. To date, a successful first in class therapy that can enhance ADCC has not yet been identified in late stage clinical trials. As mentioned previously, NK cell activity is dependent on an intricate balance between inhibitory and activating signals. Therefore the potential mechanism of synergy between lirilumab and antibody-dependent therapies is apparent: lirilumab blocks the inhibitory signals while other therapies such as rituximab/Rituxan (anti-CD20) or trastuzumab/Herceptin (anti-HER2) simultaneously enhance NK cell cytotoxicity. With promising Phase I data exhibiting the safety and clinical efficacy of lirilumab as a monotherapy, and its ability to augment NK cell activity, there is a strong rationale behind why lirilumab should be successful in accomplishing this feat.

In regards to the ability of lirilumab to enhance ADCC, recent preclinical results with rituxamab demonstrate enhanced anti-lymphoma activity of NK cells when lirilumab is combined with rituximab versus rituximab on its own, with significant improvements in disease outcomes and animal survival in the combination treatment. This preclinical work suggests that Innate Pharma and Bristol Myers-Squibb will likely initiate Phase I studies of rituximab in combination with lirilumab in lymphoma patients in the near future, the results will have major implications for the use of lirilumab. Many other antibody-based cancer therapies, including trastuzumab, function in a similar manner and bind to protein targets specific to tumor cells to induce ADCC. If favorable outcomes are achieved in these trials, this would expand the commercial potential of lirilumab to many other indications in which ADCC plays a role in tumor cell killing.

Along these lines, in regards to the combination of lirilumab with other standards of care, clinical trials are underway exploring the efficacy of lirilumab in combination with lenalidomide/Revlimid in patients with multiple myeloma. However, though the direction Innate Pharma has taken in regards to its clinical trials with lirilumab is a reflection of its predicted and likely efficacy in multiple hematopoietic cancers, the true value for lirilumab lies in the treatment of solid tumors. As mentioned previously, due to the role of NK cells in innate immunity, the mechanisms of action and therefore success of NK cells as an avenue for cancer therapy is not limited to hematological malignancies. Preclinical data suggests key roles for NK cells in other types of cancer including melanoma, ovarian, and breast cancer.

Seeing the value in lirilumab very early, Bristol-Myers Squibb licensed it in July 2011. In the agreement, Bristol-Myers Squibb obtained exclusive worldwide rights to develop, manufacture and commercialize lirilumab and related compounds, although Innate Pharma is responsible for finishing the Phase 2 AML trial. Bristol-Myers Squibb paid Innate Pharma $35M upfront, $430M in milestones, and Innate Pharma is eligible for double digit royalties worldwide. The partnership provides Innate Pharma with much needed capital, and greatly increases the developmental and commercial capabilities of lirilumab. Innate Pharma retains royalties and will be able to advance other programs in their pipeline, while their lead compound is advanced by big pharma and combined with leading checkpoint inhibitors from Bristol-Myers Squibb. In our view, this is a very attractive partnership for Innate Pharma.

Bristol-Myers Squibb initiated two large Phase I studies with lirilumab in combination with ipilimumab (125 patients) and nivolumab (150 patients) for the treatment of advanced (metastatic and/or unresectable) solid tumors including non-small cell lung cancer (NSCLC), castrate resistant prostate cancer (CRPC), and melanoma. As previously described, ipilimumab and nivolumab are two of the leading drugs in immunotherapy. Ipilumumab was approved by the U.S. Food and Drug Administration for the treatment of metastatic melanoma and has demonstrated success in this indication. For example, in a Phase III trial with previously treated melanoma patients, those receiving ipilimumab with and without vaccine demonstrated a clear survival benefit versus those receiving vaccine alone. Similar success has been seen with nivolumab: Data reported at the American Society of Clinical Oncology (OTC:ASCO) back in June 2013 reported that some previously treated melanoma patients demonstrate a durable and persistent remission out to two years after initiation of a Phase I study.

As both ipilimumab and nivolumab function through the modulation of T cell activity and persistence, the rationale behind combining ipilimumab and nivolumab with lirilumab comes from the complementary nature of these two drugs in mobilizing different aspects of the immune system against tumor cells to drive an even greater, and sustained anti-tumor response. For full activation NK cells need stimulating cytokines. Ipilimumab and nivolumab both increase cytokine production. Therefore, by removing an NK inhibitory signal with anti-KIR and stimulating the NK cells with cytokines produced by anti-CTLA4 and anti-PD1, NK anti-cancer activity could increase. Safety will be the primary measure from both these trials. For the lirilumab trial with ipilimumab, secondary efficacy measures include tumor assessment per immune-related Response Evaluation Criteria for Solid Tumors (irRECIST) v1.1 and Response Evaluation Criteria for Solid Tumors (RECIST) v1.1. For the lirilumab trial with nivoluman, secondary efficacy measures include Best overall response (BOR), objective response rate (ORR), duration of response (DOR), and Progression-Free Survival Rate (PFSR) using RECIST and irRECIST v1.1. Recently the lirilumab and nivolumab combination trial completed dose escalation, which is very important since combining two immune system activators could cause severe side effects. Innate Pharma also announced cohort expansion in non-small cell lung cancer, castrate resistant prostate cancer, and melanoma. Response rates from both trials are expected in the second half of 2015.

The complementary nature of lirilumab to existing standard of care (conventional chemotherapeutics, targeted therapies, immune checkpoint inhibitors, etc.) provides a potential for synergy in augmenting and sustaining tumor regression when combined with these therapies. Such promises suggest an even greater market potential than what has been suggested by past and ongoing clinical trials with lirilumab. Demonstration of clinical efficacy of lirilumab in combination with rituximab, lenalidomide, ipilimumab, or nivolumab should open the door for the continued expansion of lirilumab into multiple indications. On this note, because tumor cells possess multiple mechanisms which can lead to NK cell evasion, there remains a need to develop biomarkers to identify which indications and which subsets of patients within each indication will benefit from receiving lirilumab (as well as other NK-stimulating therapies such as IPH2201, which will be discussed below). Results from the upcoming Phase I and Phase II clinical trials with lirilumab should begin to answer these questions.

R&D Update April 10, 2014

Other Pipeline

IPH2201 (anti-NKG2A)

In addition to lirilumab, Innate Pharma has several compounds in clinical trials and in preclinical development. IPH2201 is a first-in-class antibody that targets NKG2A, an inhibitory receptor expressed predominantly on the surface of NK cells and cytotoxic T-Cells (CD8+), which also have cancer killing potential. Activation of NKG2A by the major histocompatibility complex class Ib protein, Human Leukocyte Antigen(HLA)-E, suppresses NK proliferation and cytotoxic activity. In adult tissue, surface expression of HLA-E is limited to endothelial and lymphoid cells and is thought to play an immune-regulatory role through NKG2A interactions. Interestingly, HLA-E was also found to be up-regulated in several tumor types and increased HLA-E expression was shown to correlate with a poor prognosis. These observations have led to the hypothesis that overexpression and secretion of HLA-E by tumors is a mechanism by which cancer cells evade immune surveillance. IPH2201 aims to subvert this mechanism by binding to and blocking NKG2A activity, thus removing cancer's HLA-E protective shield against NK cell mediated death. Innate Pharma recently showed HLA-E expression data for multiple cancer types: 81% colorectal, 71% ovarian, 67% oesophagus, 39% lung, 48% melanoma, 93% AML, 100% ALL, and 100% CLL. Innate Pharma plans to target high expressing tumor types with IPH2201 to increase the chances of efficacy. IPH2201 and lirilumab both help activate NK cells to see cancer cells, but appear unique to different subsets of NK cells, so there is potential for anti-cancer synergy.

img src="https://static.seekingalpha.com/uploads/2014/4/6339421_13987321052964_3_thumb.jpg"">>

R&D Update April 10, 2014

However, the literature suggests that HLA-E biology is much more complex. For example, a breast cancer study found that HLA-E expression predicted recurrence risk and OS only in patients with tumors that also had decreased expression of MHC class I molecules. Furthermore, some studies in colorectal carcinoma and cervical cancer have shown that overexpression of HLA-E can correlate with improved survival. Therefore, the role of HLA-E in cancer remains unclear and calls into question the broad application of the anti-tumor potential of IPH2201.

To date, IPH2201 has only been tested in rheumatoid arthritis (NYSE:RA) as part of a Phase I clinical trial run by Novo Nordisk (NYSE:NVO). While IPH2201 showed a good safety profile, Novo Nordisk decided not to continue development. In February of 2014, Innate Pharma acquired full development and commercialization rights to IPH2201 back from Novo Nordisk. However, Novo Nordisk is still eligible for milestone payments and single digit tiered royalties from Innate Pharma. Innate Pharma plans to prioritize IPH2201 for cancer immunotherapy and will initiate multiple clinical trials starting with cancer types that frequency have high expression of HLA-E. Specifically, data from the phase 1 dosing study, which includes antibody occupancy analysis, in rheumatoid arthritis is expected mid-2014. An interim analysis revealed the MTD was not reached, which supports the safety of IPH2201. Next Innate Pharma plans to initiate 5 phase 2 trials in blood and solid tumors (priority is head & neck, chronic lymphocytic leukemia, and ovarian cancer) as a single agent and in combinations during 2014, 2015, and 2016. Innate Pharma has done a tremendous amount of research in these cancer types which you can access from their R&D Day presentation.

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R&D Update April 10, 2014

IPH4102 (anti-KIR3DL2)

Innate Pharma is also developing a cytotoxic antibody, IPH4102, against KIR3DL2, an inhibitory receptor expressed on a small fraction of NK cells as well as some T-cells. KIR3DL2 is aberrantly expressed in the cutaneous T-cell lymphomas, transformed mycosis fungoides (NYSEARCA:TMF) and Sezary Syndrome (SS). Although several studies have reported overexpression of KIR3DL2 in SS peripheral blood mononuclear cells as well as CD4+ T cells, some studies have also found decreased expression of the receptor in these cell types. Again, this finding calls into question the molecular target Innate Pharma is going after. It also suggests that the company will have to pre-screen patients prior to drug treatment. This is concerning since the combined annual incidence for TMF and SS is estimated to be only 9.6 cases per 1 million person-years. Current treatments for advanced stage disease include HDAC inhibitors and chemotherapy, with several investigational drugs in clinical trials. Innate Pharma plans to submit an IND application in 2014 and intends to solely develop IPH4102. The preclinical work supporting IPH4102 was presented in a recent poster.

IPH33 (anti-TLR3)

IPH33 is an antibody that targets Toll-Like Receptor 3 (TLR3). TLR3 is an intracellular innate immune receptor and a major component of the inflammatory response. Upon activation, TLR3 signals as part of a positive feedback loop that stimulates inflammation via the production of type I interferons and inflammatory cytokines. Although TLR3 is primarily found on endosomal membranes within the cell, IPH33 can bind TLR3 as it is recycled through the membrane and internalize with the receptor to block intracellular activity. In mouse models of chronic obstructive pulmonary disease and colitis, Innate Pharma's TLR3 antibodies compare favorably to approved therapies. At this time no other companies have initiated clinical programs to inhibit TLR3 function. IPH33 is entering preclinical development and Innate Pharma is looking to partner the clinical development of this program.

IPH43 (anti-MICA)

IPH43 targets MICA, which is expressed on solid tumors such as breast, colorectal, and lung. MICA is a ligand of the NK activating receptor NKG2D. IPH43 is still in preclinical development. The preclinical work supporting IPH43 was presented in a recent poster.

Additional Targets

The company is also looking at additional targets to move into development for trials in oncology and inflammation. However, at this time these programs are still early on in their development. These programs include the use of antibody drug conjugates (NYSE:ADC), as presented in a recent poster.

NN8555 (previously IPH 2301) (anti-NKG2D)

NN8555 is a monoclonal antibody in Phase II for rheumatoid arthritis. NN8555 was part of a partnership with Novo Nordisk and his wholly owned by Novo Nordisk.

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R&D Update April 10, 2014

Financials and Valuation

As of March 31, 2014 Innate has ~$51M (€37M) in cash, of which $28M (€20.3M) was raised in November 2013 from a private placement with mostly US specialist investors, notably QVT Financial, Redmile Group, and OrbiMed. Management expects $17-$19M (€12-14M) cash spend per year from 2014-2017, although expenses could be higher as IPH2201 trials aggressively advance in 2015. This leaves enough cash for ~2 years, although milestone payments from Bristol-Myers Squibb could help offset expenses, including the potential for a payment after the lirilumab phase 2 AML data expected in the second half of 2015. More details can be found from the 2013 Annual Report.

There are approximately 1,400 patients over 60 with AML in the UK, which is the population Innate Pharma is currently targeting with lirilumab. Lirilumab is used as a maintenance therapy after a complete response from chemotherapy, which occurs in 40-55% of patients. As a comparable, another antibody immunotherapy, ipilimumab, costs $120,00 for a complete course of therapy. The market opportunity for lirilumab as maintenance AML therapy is very low. Even with optimistic assumptions of 1,400 AML patients over 60 years old, 40% with a complete response, 20% peak penetration, $100,000 per year per patient, and peak sales in 2020, 3x sales, 50% chance of approval, 20% royalties, discounted 15% per year, we get a value of just over $1M. It is clear that lirilumab will not be a blockbuster drug in AML maintenance therapy, but will provide a path to approval and serve as proof of concept.

The real value of lirilumab comes from the combination therapies with ipilimumab and nivolumab in solid tumors including non-small cell lung cancer (NSCLC), castrate resistant prostate cancer (CRPC), and melanoma. Since these trials are still in phase 1, and we do not know which cancer indications will be successful, it is very difficult to assign value, but the potential is large. The other major value driver is IPH2201, but with multiple phase 2 trials starting in 2014, 2015, and 2016, we do not know which indications will be successful, making it also very difficult to assign value. But, the potential for Innate Pharma's cancer immunotherapy to be used as monotherapy, in combination with each other, and existing antibody therapies, across many cancer types, is very high and a story worth following.

Management/Board

Innate has a very knowledgeable and experienced executive board, supervisory board, and scientific committee. Herve Brailly, PhD, is the Chairman of the Executive Board and Chief Executive Officer, co-founder. Herve was previously in charge of marketing, business development, and R&D at Immunotech SA from 1986-1994, which was acquired by Beckman-Coulter. You can read more about Innate Pharma's experienced management team here.

Key Events:

2014-mid: IPH2201 phase 1 dosing and antibody occupancy analysis

2014 Q4: IPH4102 IND application in cutaneous T cell lymphoma

2014-end: IPH2201 initiate phase 2 in head & neck, single agent

2015: IPH2201 initiate phase 2 in four cancer types

2015-early: IPH4102 initiate phase I in cutaneous T cell lymphoma

2015 2H: Lirilumab phase 2 AML results

2015 Q3: Combination with nivolumab phase 1 solid tumors results

2015 Q3: Combination with ipilimumab phase 1 trial solid tumors (NSCLC, melanoma and prostate) results

Summary

Cancer immunotherapy has the potential to be the next frontier in effective cancer treatment. Innate Pharma is using a unique approach of targeting innate immune cell surface receptors (KIR, NKG2A, etc.) with antibodies. By inhibiting the "brakes" of the natural killer (NK) cells, cancer cells can be cleared from the body at a much higher rate. Plus, there is opportunity for anti-cancer synergies between Innate Pharma's immune checkpoint inhibitors and other approved or investigational antibody cancer therapies. For more details on Innate Pharma's pipeline, the R&D Update April 10, 2014, provides a wealth of information. It is very difficult to assign value to Innate Pharma since their pipeline is so immature and we do not know which cancer indications will be successful, but they have multiple "shots on goal" and enough cash to last approximately 2 years. While the targets are specific, the mechanism of action is generally applicable to all cancer types and have broad therapeutic potential.

Disclosure: I am long IPHYF. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: Evan Markegard is long IPHYF.

Source : https://seekingalpha.com/article/2176193-innate-pharma-and-the-role-of-the-innate-immune-system-in-cancer-immunotherapy

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Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Source:Seeking Alpha

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Source:Medical Xpress

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Source:Nature

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Source:Seeking Alpha

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Source:WBOC

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Source:mynewsdesk.com

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Source:Medical Xpress

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests

Source:Nature

Two Immune Checkpoint Inhibitors Efficiently Block Leukemia Development In Preclinical Tests