# Presentation: 335296

## Immune Control Inc.

- Immune Control Inc.

- National Institutes of Health; 2 April 2008Stephen Roth, Chief Executive OfficerEric Sandquist, Chief Business Officer

## Team

**Stephen Roth, Pres. & CEO (2003) **
- 	   Neose: CEO, CSO, scientific founder
- 	   U. of Penn: chair & professor of biology
**David Zopf, M.D., CSO (2008)**
-          Neose: CSO
**Eric J. Sandquist, CBO (2007)**
- 	   Merck: VP, Managing Director
**Peter Lutes, Dir., Operations (2003)**

- Management

- Clinical Advisors

**Douglas S. McNair, M.D., Ph.D. **
- 	Clinical Affairs Consultant (2001)
- 	   ABIOMED: VP, Clinical Affairs.
- 	   Cerner Group: VP; General Manager
**Bruce A. Silver, M.D., FACP**
- 	Medical Monitor (2005)
- 	   Clinical Development Consultant.
- 	   PRA International: VP; Medical Director.

- Key Personnel

**Clayton A. Buck, Ph.D., Dir., R&D (2005)**
**	****   **Wistar Institute. Acting Dir. & CEO.

- Board of Directors

**Stephen Roth**
**Patrick Gage, Ph.D.**
**Brian Halak, Ph.D., Domain Associates**
**Hyman Kahn, M.D. **
**Peter Sears, J.D., Quaker BioVentures**
**Zev S. Scherl, NewSpring Capital**

## Immune Control overview

- 5-HTR antagonism
- selectively induces apoptosis in activated T and B cells

- Repurpose existing
- 5-HTR antagonists
*(phase 1/2 in multiple myeloma; *
*phase 1 in psoriasis)*

- Create NCEs by modifying
- known drugs to reduce CNS effects
*(animal POC in RA and asthma)*

_**Central Scientific Hypothesis**_

_**Two-pronged Business Strategy**_

## Hypothesis: the role of serotonin in lymphocyte proliferation 

**Hypothesis: the role of serotonin in lymphocyte proliferation **

**Antigen Receptor**

**Quiescent**
**lymphocyte**

**5-HTR**
** ****transcript**

- Y

- Y

- Y

- Y

- Y

**Antigen**

- Y

**Activated lymphocyte**

- 

- 

**5-HT required for lymphocyte mitosis**

- Y

- Y

- Y

**Proliferation**

**5-HT antagonists block lymphocyte mitosis **

- 

- 

- Y

- Y

- Y

- 

- 

- 

**Serotonin**

**Serotonin Antagonist**

- 

## Recent publications support the serotonin hypothesis

-  O’Connell *et al*. Blood, 2006. 107(3):1010-1017. A novel form of immune signalling revealed by transmission of the inflammatory mediator serotonin between dendritic cells and T cells.
- Yin *et al*. J. Neuroimmunol., 2006. 181(1-2):68-81. 5-HT(1B) receptors play a prominent role in the proliferation of T-lymphocytes. (funded by Immune Control Inc.)
-  Walterscheid *et al*. Proc Nat Acad Sci, US, 2006. 103(46): 17420-17425. Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor.
-  Leon-Ponte *et al*. Blood, 109: 3139-3146; 2007. Serotonin provides an accessory signal to enhance T cell activation by signalling through the 5-HT7 receptor.
-  Ocio et al. Blood, 2006. ASH abstract. Serotonin receptor antagonists (ICI-735 & ICI-685) have an in vitro and in vivo anti-myeloma effect that is mainly mediated by caspase dependent apoptosis.
-  Akiyoshi *et al*. Experimental Transplantation, 2006. 82(8): 1051-1059. Induction of indefinite survival of fully mismatched cardiac allografts and generation of cells by sarpogrelate hydrochloride.

## Business Strategy #1Repurpose Existing 5-HTR antagonists

- Business Strategy #1Repurpose Existing 5-HTR antagonists

## Repurposing strategy

- Select indications where CNS effects (e.g., somnolence) can be either tolerated or avoided
-  Myeloma – tolerated due to severity of disease
-  Psoriasis – avoided via localized delivery
- Screened nearly all approved 5-HTR antagonists against  myeloma cell lines
- Selected fluphenazine (effective, safe, partitions avidly into marrow)
-  If data and commercial profile warrant, continue development as later stage lead program

## 5-HTR antagonists kill myeloma cells; killing is reversed only by serotonin

## Activated, human, peripheral T lymphocytes are also killed by 5-HTR antagonists

## In vitro experiments reveal a therapeutic window

## Fluphenazine partitions avidly into bone marrow

## Phase 1/2a dose escalation study – intravenous fluphenazine HCl in patients with multiple myeloma

-  Sequential, dose-escalating cohorts of 3-to-6 patients
-  Refractory/relapsed and measurable myeloma after at least two prior standard therapies

- Completed

- Current

## Efficacy data – cohorts 1 and 2

- * No subsequent central lab data due to plasmapheresis.

**Cohort 1**

**Cohort 2**

- *

- *

**Serum Paraprotein**

**Cohorts 1 and 2**

**0**

**2**

**4**

**6**

**8**

**Screen**

**Pre-Treatment**

**Post-Cycle 1**

**Post-Cycle 2**

**Post-Cycle 3**

**Post-Cycle 4**

**Post-Cycle 5**

**Post-Cycle 6**

**Post-Cycle 7**

**Serum Paraprotein (mg/dL)**

- A-B (05-01)

- J-M (05-02)

- D-M (05-03)

- H-F (05-04)

- A-H (04-01)

- JDM (05-05)

**Cohort 1**

**Cohort 2**

**Serum M Protein**

**Cohorts 1 and 2**

**0**

**2**

**4**

**6**

**8**

**Screen**

**Pre-Treatment**

**Post-Cycle 1**

**Post-Cycle 2**

**Post-Cycle 3**

**Post-Cycle 4**

**Post-Cycle 5**

**Post-Cycle 6**

**Post-Cycle 7**

**Serum M Protein (mg/dL)**

- *

- *

## Efficacy data – cohorts 3-5

**Serum M Protein**

**Cohorts 3 through 5**

**0**

**2**

**4**

**6**

**8**

**Screen**

**Pre-Treatment**

**Post-Cycle 1**

**Post-Cycle 2**

**Post-Cycle 3**

**Post-Cycle 4**

**Post-Cycle 5**

**Post-Cycle 6**

**Post-Cycle 7**

**Serum M Protein (mg/dL)**

**Cohort 3**

**Cohort 4**

**Cohort 5**

- *

- * No subsequent central lab data due to plasmapheresis.

## 1 Unit RBC TX

## Safety data – very few signs of toxicity through dose level 5

-  Generally well tolerated in 18 patients treated with one to eight cycles of therapy
-  One dose limiting toxicity (DLT) – jaw clenching that responded immediately to medication
-  Four grade 1 extrapyramidal AEs
-  Eight patients with SAEs – not related to study drug

## PK data – fluphenazine accumulates in bone marrow

-  Rat bone marrow/serum ratio 2 hours post dose (3.2 mg/kg) was 126:1

- 0

- 0.1

- 0.2

- 0.3

- 0.4

- 0.5

- 0.6

- 0.7

- 0.8

- 0.9

- Fluphenazine (uM)

- JDM cohort 2

- (72 hrs > dose)

- VCV cohort 4

- (25 hours > dose)

- ASK cohort 4

- (5 hrs > dose)

- J-R cohort 5

- (8.3 hrs > dose)

- SAP cohort 5

- (2.5 hrs > dose)

- WBS cohort 5

- (5.4 hrs > dose)

- Phase 1 serum and marrow PK

- Serum

- Bone Marrow

## Business Strategy #2Create NCEs by modifying known drugs to reduce CNS effects

- Business Strategy #2Create NCEs by modifying known drugs to reduce CNS effects

## NCE strategy, R&D process, and results 

- NCE strategy, R&D process, and results

- _Strategy_
- Modify 5-HTR antagonists to reduce CNS effects, and to create novel, orally available compounds.

- _Results_
-  Over 90 compounds synthesized
-  Over 20 with superior efficacy
-  Animal POC in RA and asthma

- _R&D process_
- 1. Synthesize 5-HTR antagonist analogues
- 2. Effect on dividing cells in vitro
- 3. Effect on LPS-induced    inflammation in vivo
- 4. Select indications
- 5. Test in appropriate animal models

## Immune Control employs a two-stage screening process

- _Stage 1:  effect on dividing cells in vitro_

**Effect on RPMI-8226 cells**

## Immune Control employs a two-stage screening process

- _Stage 2:  effect on LPS-induced inflammation in vivo_

## Immune Control selected target indications based on scientific and commercial criteria

## Rat model for effect of drugs on collagen-induced arthritis

**Animals: Female Lewis rats (CR) 125-200g, accl 4-8 D**
**Dosing:**
**Type 2 collagen 2mg/mL in 0.01N HAc mixed 1:1 w/ FIA**
**injected id 0.1 mL at each of three sites on back**

**      ****SD 1                6      9      10    11     12    13   14   15   16 **

**Collagen           baseline  **_**randomize**_**  **_**dose  ip**_**   **_**weigh and measure joints**_
_**Immunization **_**   **_**measure**_

**Rat model for effect of drugs on collagen-induced arthritis**

**Year of the rat**

**Rosloniec EF *****et al Curr. ProtI. Immunol *****1996 15.5.1 – 15.5.24**

## Effects  of new derivatives in rat collagen-induced arthritis model

**Effects  of new derivatives in rat collagen-induced arthritis model**

## New, orally-available compound in mouse arthritis model

## New compounds perform extremely well in a mouse system

- _Acute asthma model_

## ICI-735 performs well in a mouse model of asthma

## Next steps with NCEs

** **Additional testing of ICI-847 in rat arthritis model
-  Further testing of ICI 735 in chronic, mouse asthma model at three
-     different dose levels
-  Pending efficacy and non-GLP tox data,
-  ICI 735 and ICI 847 will be manufactured according to cGMP standards, and
-  Development of an IND-appropriate package (CMC, ADME, tox, PK and PD, and stability data) will begin