BMY: A Comprehensive Look at Immuno-Oncology’s Next-Generation Approaches, and Why BMY is Best Positioned

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SEE END OF THIS REPORT FOR IMPORTANT DISCLOSURES

Richard Evans / Scott Hinds / Ryan Baum

203.901.1631 /.1632 / .1627

revans@ / shinds@ / rbaum@ssrllc.com

@SSRHealth

February 23, 2017

BMY: A Comprehensive Look at Immuno-Oncology’s Next-Generation Approaches, and Why BMY is Best Positioned

  • The anti-tumor immune response unfolds in a series of steps, all of which are subject to a host of checks and balances. Tumor survival in the face of immune system attack has much to do with exploiting quite a few of these checks and balances, only two of which (CTLA4 and PD-1/PD-L1) are addressed by approved products (BMYs’ Yervoy for CTLA4; BMY’s Opdivo, MRK’s Keytruda for PD-1; Roche’s Tecentriq for PD-L1)
  • There are at least 13 ‘next-generation’ immuno-oncology approaches in active clinical development of at least phase 2. In all likelihood, future immuno-oncology regimens will be combinations of currently approved and next-generation agents, raising the question of which companies are best positioned – by evaluating their currently approved agents in combination with next-generation agents, and/or by actively developing next-generation agents of their own. BMY is best positioned on both counts
  • BMY’s approved products (Opdivo, Yervoy) are being evaluated in combination with 9 of the 13 active next-generation mechanisms, as compared to 7 for MRK’s Keytruda, and 4 for Roche’s Tecentriq. Three times as many patients are receiving BMY’s Opdivo and/or Yervoy in combination with next-generation agents than are receiving MRK’s Keytruda in combination with next-generation agents; nearly five times as many patients are receiving BMY’s Opdivo and/or Yervoy in combination with next-generation agents as are receiving Roche’s Tecentriq in combination with next-generation agents
  • BMY has more of its own next-generation agents (7) in active development spanning more next-generation mechanisms (6) than any other company. MRK is sixth with 3 of its own next-generation agents across 2 mechanisms; Roche is seventh with 2 of its own next-generation agents across 2 mechanisms
  • Since losing first-line NSCLC to MRK in August of 2016, BMY’s change in valuation implies a zero value for Opdivo and Yervoy. This can only be true if BMY’s agents are less effective than competitors, if NSCLC accounts for nearly all the potential demand for immuno-oncology agents; and/or if BMY is hopelessly off the pace in developing its products for the remaining indications. As we’ve shown in our last note none of these conditions are true; and as we show in the present note BMY also is better positioned than its peers in the race to define the next-generation of immuno-oncology combinations
  1. Objective / Scope / Method / Major Findings

We recently showed[1] that the change in BMY’s market value since August of 2016 implies a zero value for the company’s checkpoint inhibitors (CIs) Opdivo and Yervoy. This can only be true if: Opdivo (and Yervoy) are ineffective as compared to alternatives, non-small cell lung cancer (NSCLC) represents the majority of potential demand for checkpoint inhibitors, and/or BMY has fallen off the pace in clinical trials for indications other than NSCLC. All of these potential explanations can be ruled out: across all prior trials / indications Opdivo’s efficacy has been on par with Keytruda’s, NSCLC accounts for roughly 23% of the mortality caused by tumors addressable by CIs; and, BMY’s clinical program has the best combination of scope (# of indications addressed) and timing (likely stage of approval v. peers) as compared to all other companies with active checkpoint programs

Because tumor immune responses are complex and subject to a multitude of checks and balances, there are a significant number of next-generation checkpoint targets being actively pursued; this raises the strategic question of whether any of the approved CIs are being more or less frequently evaluated in combination with potential next-generation agents. The objective of this note is to answer that question, and to describe the combinations in active development

We reviewed clinicaltrials.gov, Bloomberg, academic literature, and corporate publications for any non-vaccine immune checkpoint agonist / antagonist, or immune system modulator, that exploits a mechanism for which no agent is yet approved, and which is in active development for any type of tumor. We then identified all active molecules[2] for any given mechanism, and all instances in which any of these molecules are being evaluated in combination with an approved CI in an industry-sponsored trial. 13 unapproved mechanisms meet these criteria (and had advanced at least as far as phase 2 development)[3], all but one of which are being tested in combination with one of the approved CIs (Yervoy (CTLA4), Keytruda (PD-1), Opdivo (PD-1), Tecentriq (PD-L1)). Exhibit 1 summarizes these 13 mechanisms according to the number of unique compounds targeting each mechanism (y-axis), the year in which a compound targeting this mechanism could be approved[4] (x-axis), and the number of trials being conducted with compounds targeting that mechanism (bubble size)

To better understand how companies with approved CI’s are positioned with respect to potential combinations with next-generation agents, for each approved CI we identified the number of next-generation mechanisms being studied in combination with that CI (y-axis, Exhibit 2), the number of patients in which that CI is being studied in combination with next-gen agents (bubble size), and the average order of likely approval for a given CI/next-generation combination that same indication (x-axis). BMY’s approved CI’s are being evaluated in combination with 9 (8 for Opdivo, 6 for Yervoy) next-generation mechanisms, as compared to 7 for MRK, and 4 for Roche. MRK’s Keytruda has a slight timing of entry advantage relative to BMY’s Opdivo and/or Yervoy; this is entirely attributable to earlier potential entries in combination with two next-generation mechanisms: IDO1 and CD137

To give a sense of how companies with unapproved CI’s are positioned in the next-generation race, Exhibit 3 summarizes the number of next-generation mechanisms, number of next-generation mechanism / approved mechanism combinations, and latest stage of development by mechanism. BMY has 7 next-generation products in active development across 6 mechanisms, more than any other firm

  1. Like a war, but with rules and referees: a simplified sketch of anti-tumor immune responses, and where checkpoints fit in

The anti-tumor immune response is like a war, but with very specific rules, and very attentive referees. Mammalian immune responses fall into two broad groups: innate, and adaptive. The innate immune response is one in which the immune system reacts to cells identified as foreign simply by their lack of correct receptors[5] identifying the cells as ‘self’ (i.e. the target cell is killed for an error of omission). The adaptive response is one in which the immune system targets unique identifying features of ‘non-self’ cells (i.e. the target cell is killed for an error of commission)

Vastly oversimplifying, as part of the innate response to a cell identified as non-self, macrophages and dendritic cells (DCs)[6] (aka antigen-presenting cells or ‘APCs’) will phagocytize (‘eat’) the target cell, then migrate to a lymph node and display features of the phagocytized non-self cell to, among other things, T-cells. T-cells which have surface receptors (T-cell receptors, or ‘TCRs’) that match surface features of the non-self cell will bind to the non-self antigen displayed by the antigen-presenting cell (APC). For those T-cells to become activated, at least one additional receptor (CD28) on the T-cell surface must also be bound

Once activated, T-cells display CTLA4[7] as a surface receptor. CTLA4 competes with CD28 for the proteins[8] (aka ‘ligands’) that bind to CD28; in fact, CTLA4 binds these proteins more tightly than CD28. Because of this, as the number of activated T-cells increases, the CTLA4 on their surfaces has the effect of absorbing proteins that might otherwise bind CD28, thus limiting further T-cell activation. CTLA4 inhibitors such as BMY’s Yervoy and AZN’s tremelimumab prevent the CTLA4 expressed on the surface of activated T-cells from binding these proteins, leaving these proteins free to bind CD28 on the surface of ‘nascent’ T-cells, enabling these cells’ activation. CTLA4 is a natural ‘checkpoint’ that serves to limit the number of T-cells activated; blocking CTLA4 allows more T-cells to become activated

Once activated T-cells migrate to affected tissues and bind to target cells – such as tumor cells – the activated T-cells remain subject to a number of potential ‘stop’ and ‘go’ signals. The most actively developed of these is PD-1[9], which is a ‘stop’ signal. PD-1 is expressed on the surface of activated T-cells, and when bound by its ligands PD-L1[10] and/or PD-L2[11] (which are sometimes present on the surfaces of target cells) effectively prevents the activated T-cell from destroying the target cell. Blocking PD-1 prevents PD-L1 +/- PD-L2 expressing target cells from effecting this stop signal, leaving the T-cells free to destroy the target cell

The approved immune checkpoint inhibitors (CI’s) all work against either CTLA4 (Yervoy/BMY), PD-1 (Opdivo/BMY, Keytruda/MRK), or PD-L1 (Tecentriq/Roche)

Because the immune response unfolds in stages (e.g. recognition of non-self cells by APC’s, activation of T-cells (and other cells) by APC’s, and direct action by T-cells (and other cells) against target cells), and because each stage is subject to a host of possible checks and balances, CI regimens are almost certain to expand to include next-generation agents affecting targets other than just CTLA4 and PD-1

  1. Review of next-generation mechanisms in active development

We identified 13 unapproved immuno-oncology mechanisms in phase 2 or later human testing (Exhibit 4). A little more than two-thirds of trials involving these next-generation mechanisms are being conducted in combination with another CI, typically one of the four approved agents

IDO1 (17 active trials; 10 in combination with another CI – 9 of which are in combination with an approved CI)

Unlike most immuno-oncology targets IDO1[12] is an intracellular enzyme as opposed to a cell surface receptor. IDO1 is the rate limiting enzymatic step in the degradation of the essential amino acid tryptophan in antigen-presenting cells (APCs); as such over-expression of IDO1 leads to tryptophan depletion in these cells, which has the downstream effects of suppressing the formation and activation of the specific type of T-cells (CD8+ ‘effectors’) that target non-self cells such as cancer, and allowing the greater formation and activity of the T-cell types (T-regulatory or ‘T-reg’) which moderate the CD8+ effector T-cells’ anti-tumor effects. All five active IDO1 inhibitors that we have identified are small molecules with the potential for oral administration

The most advanced IDO1 study is a phase 3 trial in which INCY’s IDO1 inhibitor epacadostat is being evaluated in combination with MRK’s Keytruda for melanoma. MRK and INCY announced in October of 2015 their intention to take the epacadostat/Keytruda combination into phase 3 for melanoma, as well as their agreement, for a period of two years, not to launch pivotal studies in melanoma with other IDO1 inhibitors or PD-1/PD-L1 inhibitors. In January of this year the companies announced their intention to move the combination into phase 3 for non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and squamous cell cancer of the head and neck (SCCHN), with all trials expected to begin in 2017. It is not immediately clear whether MRK and INCY have agreed to exclusive terms on these tumors, along the lines of their agreement in melanoma

If MRK and INCY are exclusive on these indications, this leaves BMY with only ovarian cancer, non-Hodgkins lymphoma (NHL), tumors of the brain / CNS, colorectal cancer (CRC) and Hodgkins lymphoma as indications in which an epacadostat/Opdivo combination is actively being studied, and can still be fully developed. In aggregate, these 5 indications account for about 18 percent of CI addressable mortality. BMY’s Opdivo and Yervoy also are being evaluated in combination with NewLink Genetics’ (NLNK) indoximod in phase 2, as is MRK’s Keytruda. BMY also has its own IDO1 inhibitor (BMS-986205), which is being evaluated in combination with Opdivo in phase 2

NLNK is evaluating a separate IDO1 inhibitor, NLG-919, in a single phase 1 combination study with Roche’s Tecentriq in patients with various solid tumors; and, NLG-919 recently completed a phase 1 trial as monotherapy in patients with solid tumors. The only other IDO1 in early testing is PFE’s PF-06840003, which is conducting a single phase 1 trial as monotherapy in patients with malignant glioma

Exhibit 5 summarizes the potential approval year[13] for an approved CI (columns) with any inhibitor of IDO1, by indication (rows)

LAG3 (16 active trials; 15 in combination with another CI – 12 of which are in combination with an approved CI)

LAG3[14] is a T-cell surface receptor present on activated T-regulatory (‘T-reg’) cells; binding of LAG3 directly amplifies the immune response moderating effects of T-reg cells, and indirectly inhibits the activity of the CD8+ effector T-cells responsible for attacking and killing tumor cells. Simultaneous inhibition of both LAG3 and PD-1 has been shown to have a synergistic effect on tumor killing in animal models[15]

Of the approved CI / LAG3 combination trials, the Opvido/LAG3 and Yervoy/LAG3 trials are the most advanced (7 of the 10 trials have reached phase 2), and all of these trials are using BMY’s own LAG3 inhibitor BMS-986016. Opdivo and Yervoy are being evaluated in combination with BMS-986016 in NSCLC in phase 2; Opdivo is being evaluated in combination with BMS-986016 in renal / kidney, gastroesophageal, and leukemia / lymphoma in phase 2, and in brain / CNS and sarcoma in phase 1. Keytruda is being studied in a single phase 1 trial in combination with MRK’s own LAG3 inhibitor MK-4280, in patients with various advanced solid tumors; and, in combination with Prima Biomed’s (PBMD) IMP321 in patients with unresectable or metastatic melanoma. NVS’ LAG525 and REGN’s REGN3767 are the only other LAG3’s in human testing, though neither is in combination with an approved CI. LAG525 is in phase 1/2 evaluation both as a single agent and in combination with NVS’ (unapproved) PD-1 inhibitor PDR001, in patients with various advanced solid tumors. Similarly, REGN3767 is being evaluated in a phase 1 trial both as a single agent and in combination with REGN’s (unapproved) PD-1 inhibitor REGN2810, in patients with advanced malignancies, including lymphoma (Exhibit 6)

OX40 (15 active trials; 10 in combination with another CI – 4 of which are in combination with an approved CI)

OX40 is a cell surface receptor found on, among other types of cells, activated T-helper (aka CD4+) and T-effector (CD8+) cells. In contrast to CTLA4, which has early effects on T-cell activation and initial proliferation, OX40 influences later stages of T-cell proliferation and prolongs T-cell survival[16]. OX40 also diminishes the immune-response moderating effects of T-reg cells[17]

Of the 10 active CI / OX40 trials only 4 involve any of the approved CI’s. BMY’s Opdivo and Yervoy are being evaluated in combination[18] with BMY’s own OX40 agent BMS-986178 in phase 2, in patients with various advanced solid tumors. MRK’s Keytruda is being evaluated in combination with GSK’s GSK-3174998 in a single phase 1 study in patients with various advanced solid tumors. Finally Roche’s Tecentriq is being evaluated in combination with their own anti-OX40 RG7888, with or without Avastin, in a single phase 1 study in patients with advanced solid tumors

PFE is evaluating its OX40 PF-04518600 in combination with PFE’s 4-1BB agonist utomilumab (PF-05082566), and in combination with PFE / Merck Serono’s PD-1 avelumab. AZN has 3 OX40 candidates in clinical trials, the most advanced of which (MEDI6469) is being evaluated alone or in combination with either AZN’s PD-1 durvalumab or its CTLA4 tremelimumab in phase 2, in patients with colorectal cancer (CRC), breast cancer, B-cell lymphomas, head and neck cancer, and prostate cancer (Exhibit 7)

4-1BB (aka CD 137; 11 active trials; 7 in combination with another CI – 3 of which are in combination with an approved CI)

4-1BB is a surface receptor present on multiple cell types, including CD4+ helper and CD8+ effector T-cells. Binding 4-1BB on activated T-cells promotes expansion (like OX40) of both types of activated T-cells, with CD8+ cells being expanded preferentially. Among other effects, binding of 4-1BB promotes longer-term survival of activated T-cells (also like OX40), and leads to an increase in IFNγ[19] production by CD8+ T-cells; in this context IFNγ has the effect of adding further momentum to the immune response

There are two agonists of 4-1BB in clinical development (with at least one more, BMS-554271, identified in preclinical studies), the most active of which is PFE’s utomilumab (7 currently active trials, the most advanced of which is phase 3), followed by BMY’s urelumab (7 total trials, 5 of which are currently active including one phase 2). PFE’s utomilumab is being evaluated in phase 3 in combination with PFE/Merck Serono’s PD-L1 avelumab in regimens also containing either Rituxan or Vidaza in patients with large B-cell lymphoma. BMY’s utolimumab is being evaluated in phase 2 in combination with Opdivo in patients with various advanced solid tumors or non-Hodgkin’s lymphoma, and in patients with urothelial cell carcinoma of the bladder (Exhibit 8)

TLR9 (9 active trials; 5 in combination with another CI, all of which are approved)

Among their many roles, toll-like receptors (TLRs) enable antigen-presenting cells’ (APCs, e.g. macrophages and dendritic cells (DCs)) recognition of target cell features that signal a target cell is foreign, or diseased. And, binding of TLR9 on CD4+ helper T-cells prolongs these cells’ survival, and increases overall numbers of both CD4+ helper and CD8+ effector T-cells

TLR9 is one of the 10 TLR receptor types in humans; there are 5 TLR9 agonists in clinical development. Mologen AB’s MGN-1703 is the most advanced, with an ongoing phase 3 trial as monotherapy for colorectal cancer (CRC). MGN-1703 is also being evaluated in combination with BMY’s Yervoy in phase 1 in patients with various solid tumors. Idera Pharmaceuticals’ (IDRA) IMO-2125 is in phase 2 testing in combination with either BMY’s Yervoy or MRK’s Keytruda in patients with metastatic melanoma. Dynavax’ (DVAX) SD-101 is in phase 2 testing as monotherapy, and also in combination with MRK’s Keytruda; the Keytruda/SD-101 trials are being conducted in patients with metastatic melanoma, squamous cell carcinoma of the head and neck (SCCHN), and prostate cancer. Checkmate Pharmaceuticals’ CMP-001 is in phase 1 testing in combination with MRK’s Keytruda, in patients with melanoma (Exhibit 9)

KIR (8 active trials; 5 in combination with another CI – 4 of which are in combination with an approved CI)

Killer cell immunoglobulin-like receptors, or KIRs, are present on the surfaces of natural killer (NK) cells, and certain T-cells. Like ‘effector’ (aka CD8+) T-cells, NK cells directly attack virally infected and tumor cells; however unlike CD8+ effector T-cells (which are part of the ‘adaptive’ response), NK cells (part of the ‘innate’ response) don’t have to recognize the specific surface features of the target cell, they only have to recognize that the target cell is missing surface features that identify the cell as ‘self’. There are multiple variants of the KIR family of receptors, some of which activate NK cells, and some of which inhibit NK cells. Self-identifying surface receptors bind NK cells’ inhibitory KIR receptors, preventing NK cell attack. Because many tumors still express the correct ‘self’ receptors, NK cells can be taken out of the fight against such tumors

BMY’s lirilumab is the only KIR being evaluated in combination with an approved CI; 3 trials in combination with Opdivo, and 2 in combination with Yervoy (1 of which is still current). Lirilumab is also being evaluated in combination with BMY’s 4-1BB agent urelumab. Except for a single Opdivo/lirilumab phase 2 trial in patients with leukemia / lymphoma, all of the lirilumab / CI combination trials are in phase 1. Opdivo and Yervoy are both being evaluated in combination with lirilumab in Hodgkins lymphoma, non-Hodgkins lymphoma, and myeloma (Exhibit 10). Only one other KIR inhibitor is in active development; Innate Pharma (IPHYF)’s IPH4102 is in early testing as a single agent in a lone phase 1 trial

CD27 (6 active trials; 5 in combination with another CI – all 5 of which are approved)

CD27 is a co-stimulatory receptor found on the surfaces of activated T- and B-cells. CD27 typically is bound by its ligand CD70, with the amount of available CD70 being a rate limit on stimulation level. Celldex’ (CLDX) varlilumab is the only agent in development targeting the CD27 receptor. Varlilumab is a CD27 agonist which can stimulate activated T-cells, thus easing the CD70 rate-limit, and which may also serve as a targeted therapy for T-cell and B-cell lymphomas that over express CD27. Varlilumab is being evaluated in combination with BMY’s Yervoy, MRK’s Keytruda, BMY’s Opdivo, and Roche’s Tecentriq (Exhibit 11)

GITR (6 active trials; 4 in combination with another CI –3 of which are in combination with an approved CI)

GITR[20] is a cell surface receptor present in abundance on T-reg cells, and present also on activated CD8+ T-effector cells. Like OX40 and 4-1BB, agonists to GITR promote expansion and activity levels of activated CD8+ cells. However GITR agonists also suppress T-reg activity levels and/or the responsiveness of CD8+ T-effector cells to T-reg suppression. As such GITR agonists should tip the balance in favor of more aggressive / less restrained CD8+ T-cell effector responses

There are six GITR agonists in active clinical trials; two (MRK’s own agents MK-4166 and MK-1248) are being evaluated in combination with MRK’s PD-1 Keytruda, one (BMY’s own BMS-986156) is being evaluated in combination with BMY’s PD-1 Opdivo, and one (NVS’ own GWN-323) is being evaluated in combination with NVS’ (unapproved) PD-1 PDR001. Only two of the GITR agonists – INCY/AGEN’s INCAGN-1876 and BMY’s BMS-986516 / Opdivo combo – have reached phase 2. INCY/AGEN’s phase 2 trial of INCAGN-1876 is evaluating the agent as monotherapy in patients with advanced solid tumors (Exhibit 12)

CD94/NKG2A (4 active trials; none in combination with other CI’s)

CD94/NKG2A is an inhibitory receptor found on NK cells and CD8+ effector T-cells. When bound by the ‘self’ identifying protein HLA-E[21] on potential target cells, CD94/NKG2A prevents destruction by NK and CD8+ T-effector cells. Because HLA-E can be over-expressed by some types of tumor cells, blocking CD94/NKG2A may expose these tumor cells to attack by NK cells and CD8+ T-effectors

There is a single antagonist of CD94/NKG2A in active development – Innate Pharma’s (IPHYF) monalizumab (IPH2201). Monalizumab is being evaluated as monotherapy in gynecologic cancers and in stem cell transplantation, and in combination with non-checkpoint inhibitors ibrutinib (Imbruvica) and cetuximab (Erbitux) in patients with chronic lymphocytic leukemia (CLL) and squamous cell carcinoma of the head and neck (SCCHN), respectively (Exhibit 13)

A2aR (3 active trials; all in combination with other CI’s, 1 in combination with an approved CI (Tecentriq))

Adenosine is a common molecule that plays multiple physiologic roles; of the more important in the context of oncology is that adenosine is found in high concentrations in tissues with active inflammatory processes, including the tumor microenvironment. Various cell types, including in particular T-cells, carry any of four adenosine cell surface receptors. Adenosine receptor 2a (A2aR) inhibits T-cell function when bound by adenosine; as such the tendency for adenosine to be present in high concentrations in areas of inflammation results in a natural inhibitory feedback loop on inflammation caused by various cells, including T-cells. Because adenosine is often present in high concentrations in the tumor microenvironment, blocking the A2aR receptors on T-cells has the potential to allow more complete T-cell responses to tumors

There are 3 active A2aR receptor antagonists in clinical development – AZN’s AZD-4653, NVS’ PBF-509, and Corvus Pharmaceuticals’ (CRVS) CPI-444 (another, Juno Therapeutics’ (JUNO) vipadenant, is in preclinical development). CPI-444 is being evaluated in combination with Roche’s PD-1 Tecentriq in a phase 1 trial in patients with advanced solid tumors. NVS’ PBF-509 is being evaluated in combination with NVS’ PD-1 PDR001 in a phase 1/2 trial in patients with advanced NSCLC. AZN’s AZD-4653 is being evaluated in a phase 1 trial in patients with NSCLC in combination with AZN’s PD-1 durvalumab (Exhibit 14)

CD122 (2 active trials; 1 in combination with another CI – which is approved (BMY’s Opdivo))

CD122 is a sub-unit of a larger IL-2 surface receptor present on CD4+ helper T-cells, CD8+ effector T-cells, and T-reg cells. Via this receptor these cells react to the presence of IL-2 by increasing their levels of activity. Enhanced CD4+ T-helper and CD8+ T-effector activity means an enhanced anti-tumor response; however simultaneous enhancement of T-reg activity counterbalances this response. Two steps forward, one-step back

There is a single agent targeting CD122 in clinical development – Nektar’s (NKTR) NKTR-214, which is an anti-CD122 agent that preferentially blocks IL-2 receptors on T-reg cells, tilting the IL-2 response further in favor of CD4+ T-helper / CD8+ T-effector cells. NKTR-214 is being evaluated in phase 1/2 in combination with BMY’s Opdivo in patients with advanced solid tumors (Exhibit 15)

ICOS (2 active trials; both in combination with another CI – 1 each in combination with MRK’s Keytruda and BMY’s Opdivo)

ICOS[22] is a cell surface receptor present on activated T-cells, and is expressed in abundance in patients having received anti-CTLA4 agents such as Yervoy or tremelimumab. ICOS agonists should result in preferential expansion of CD8+ effector T-cells relative to T-reg cells, thus tilting the immune response in favor of anti-tumor efficacy. Given the interaction between anti-CTLA4 treatment and ICOS expression, there may be an underlying rationale for combining anti-CTLA4 agents such as Yervoy and tremelimumab with ICOS agonists

There are 2 ICOS agonists in active development; GSK’s GSK-3359609 is being evaluated in combination with MRK’s Keytruda in phase 1, in patients with advanced solid tumors. Jounce Therapeutics’ (JNCE) JTX-2011 is being evaluated in combination with BMY’s Opdivo in patients with advanced solid tumors, also in phase 1 (Exhibit 16)

TIM3 (2 active trials; both in combination with another CI)

TIM3[23] is a receptor expressed on the cell surface of activated CD4+ T-helper and CD8+ T-effector cells. Binding of TIM3 by its ligand galectin-9 limits the duration and magnitude of target-specific immune responses mounted by these two cell types. Conversely blockade of the TIM3 receptor allows for more robust and longer-lasting target-specific T-cell responses

NVS is studying its TIM3 blocker MBG-453 in combination with its own PD-1 PRD001 in a phase 1/2 trial of patients with advanced solid tumors. Tesaro (TSRO) is evaluating its TIM3 blocker TSR-022 in a phase 1 trial of patients with advanced solid tumors; TSR-022 is being administered either alone, or in combination with an unspecified inhibitor of PD-1[24] (Exhibit 17)

  1. Review of indications targeted by next-generation mechanisms

Exhibit 18 summarizes the percentage of mortality attributable to any indication in which CI’s are being evaluated. Exhibits 19 through 40 on the following pages summarize next-generation mechanism development activity, by indication, and by combination. Each table summarizes the next-generation mechanisms in active development for a given indication (rows), as well as the CI’s (columns) being evaluated in combination with each next-generation agent. Dates indicate the year any next-generation / CI combination would likely be approved, on the assumption that time spent in development after completion of the current phase is on par with average values for time in any subsequent development phase. These estimated dates should not be considered reliable point estimates of approval timing for any given next-generation / CI combination, but should be considered reliable indicators of the potential sequence of approval for a next-generation / CI combination for a given indication. For example using Exhibit 19, LUNG-NSCLC as an example, the Keytruda/IDO1 combination (estimated date 2022) is ahead of the Opdivo/IDO1 combination (estimated date 2024). 2022 is not a reliable estimate of the specific date on which a Keytruda/IDO1 combination might be approved for NSCLC; however given Keytruda’s more advanced stage of development in an IDO1 combination relative to Opdivo, it is reasonable to expect a Keytruda/IDO1 combination to reach approval in NSCLC before an Opdivo/IDO1 combination. The summary row at the bottom of each table counts the number of next-generation mechanisms and next-generation / CI combinations in development for any given indication. Again using Exhibit 19 as an example, there are 8 next-generation mechanisms in active development for NSCLC; 3 of these are in combination with an approved BMY CI (1 is in combination with Yervoy, 3 are in combination with Opdivo), and 2 are in combination with Keytruda


 

  1. “BMY: Opdivo/Yervoy For Sale, Current Bid: $0. Seems a Bit Low”, SSR Health LLC, February 1, 2017
  2. Though we have made every effort to be comprehensive, and used a range of sources to cross-reference our lists of molecules, in a field that is evolving as rapidly, and in as many different directions as immuno-oncology it’s certainly possible that our filters missed something
  3. Throughout this note, whenever we refer to “next-generation” mechanisms we exclude those that are only in preclinical/phase 1 development
  4. We estimated potential year of approval by applying normal time in phase assumptions to targeted completion dates for any given compound. These estimates should not be viewed as precise estimates of the specific year in which a given mechanism might see its first approval, but should be viewed as a reasonable approximation of the sequence in which mechanisms are likely to see first approvals
  5. Major Histocompatibility Complex, or ‘MHC’ receptors
  6. Other innate cells include natural killer ‘NK’ cells, mast cells, eosinophils, basophils, and neutrophils
  7. Cytotoxic T-lymphocyte associated protein 4, aka CD152
  8. CD80 and CD86, aka B7.1 and B7.2
  9. Programmed cell death protein 1
  10. Programmed death ligand 1
  11. Programmed death ligand 2
  12. Indoleamine 2,3 dioxygenase 1
  13. See note 4
  14. Lymphocyte activation gene 3
  15. W. Seng-Ryong, et al, “Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T cell function to promote tumoral immune escape”, Cancer Res. 2012 February 15: 72(4): 917-927
  16. M Croft, et al “The significance of OX40 and OX40L to T cell biology and immune disease”, Immunol Rev. 2009 May: 229(1):173-191
  17. Ibid 11
  18. BMS-986178 + Opdivo v. BMS-986178 + Yervoy, v. BMS-986178
  19. Interferon gamma
  20. Glucocorticoid induced TNFR-related protein
  21. Histocompatability antigen, alpha chain E, aka Major histocompatibility complex (MHC) class 1 antigen E
  22. Inducible co-stimulator
  23. T-cell membrane protein 3
  24. TSRO has an anti-PD-1 in phase 1 testing (TSR-042)

 

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