Corporate Presentation
October 2018
Statements in this presentation that are not descriptions of historical facts are forward‐looking statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation
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Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance, achievements or events and
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Disclaimer
1
Lead candidate CAEL-101 is a first-in-class anti-amyloid antibody for treating AL Amyloidosis
AL Amyloidosis is a rare systemic disorder with a large orphan population (~30-45k combined patients in US/EU)
No FDA-approved therapies for the treatment of AL Amyloidosis
Pre-clinical data shows high selectivity and binding affinity to multiple AL light-chain subtypes
Phase 1a/1b data demonstrated rapid improvement in both functional (12 weeks) and biomarker measures (3 weeks)
Advanced preparations are underway to test CAEL-101 in a broad Phase 2 program; potential for accelerated approval in high mortality population
Caelum Biosciences is a biopharmaceutical company focused on treatments for rare hematologic diseases
2
CAEL-101 is a rationally designed antibody that has shown rapid improvement in both functional and biomarker endpoints in a Phase 1a/b clinical study
Key leadership
3
Michael SpectorPresident and Chief Executive Officer, Caelum
25 years experience in the pharmaceutical industry
Multiple prior roles at GlaxoSmithKline across commercial, GM and R&D
Previous roles at Johnson & Johnson, Laurel Pharmaceuticals and North Creek Pharmaceuticals
B.S. in biology from University of Pittsburgh and M.B.A. from Rider University
Dr. Suzanne LentzschChair of Scientific Advisory Board, Caelum
Professor of Medicine and Director of the Multiple Myeloma and Amyloidosis Program at the College of Physicians and Surgeons of Columbia University and at New York Presbyterian Hospital
Lead clinical investigator of CAEL1-101 P1a/1b trial through November 2017
Fellowship and Residency at Humboldt University (Germany)
Paul BrookeChairman, Caelum
40+ years experience in biotech and pharma
Previously Head of Global Healthcare Research and Strategy at Morgan Stanley, and Founder and former Managing Partner of VenBio
Serves on the board of directors of Incyte and several privately held companies
BA from Columbia College and MA from Columbia University
David Barrett CPADirector, Caelum
Strategic Advisor at Assembly Biosciences, previously served as COO, CFO, and CAO
BS in Accounting and Economics and MS in Accounting from Florida University
Dr. Lindsay RosenwaldChairman, President and CEO, Fortress Biotech
Chairman, President and CEO of Fortress Biotech
Founded Cougar Biotechnology, Chelsea Therapeutics, Cypress Bio, Keryx and Indevus, co-founded Ziopharm and TG Therapeutics, and former director of BioCryst
− 13 FDA approvals from companies founded B.S. in finance from Pennsylvania State University and M.D. from Temple University School of
Medicine
Three Main Types of Systemic Amyloidosis: CAEL-101 Is Targeted to Primary (AL) Subtype Systemic amyloidosis are a group of protein-misfolding diseases with different individual disease pathologies
Rationally designed drugs must be targeted toward the specific precursor protein
Source: Blancas-Mejia, Luis M., and Marina Ramirez-Alvarado. “Systemic Amyloidoses.” Annual Review of Biochemistry, vol. 82, no. 1, 2013, pp. 745–774.Note: GSK is developing an Anti-Sap antibody for the treatment of AA Amyloidosis; the program is early with limited cardiac data.
AL amyloidosis AA amyloidosis Hereditary amyloidosis (ATTR)
Prevalence ~30k - 45k(1)(2) ~10k – 15k(1)(3) ~50k(4)(5)
Precursor protein Immunoglobulin light chains Serum amyloid A protein Transthyretin
Point of misfolding Plasma cells (bone marrow) Liver cells Liver cells
Cause Acquired mutation and overproduction Overproduction secondary to chronic infections / inflammation (e.g. RA, IBD)
Hereditary mutation of TTR
Organs commonly affected Heart, kidney, liver Kidney, liver, spleen Nerves, heart, kidney
Developed to specifically bind to the AL light chain
Identified from an amino-terminal peptide fragment from human kappa light chain
CAEL-101 is a chimeric fibril reactive mAb that binds to both kappa and lambda light chains
NEOD001 was derived from Serum amyloid A protein and developed
to bind to C-terminal region
(1) Estimated patient populations in the US and Europe.(2) www.ncbi.nlm.nih.gov/pmc/articles/PMC4635176/
(3) Bellus Health Press Release, June 20, 2016.(4) Estimated worldwide patient population.
(5) Alnylam Corporate Presentation,February 2018.
4
ProthenaNEOD001
Repurposed and studied as a treatment for AL Amyloidosis
DiscontinuedPatisiran Inotersen
Tafamidis AG10
GLS and NT-proBNP(fixed time point and
response) are standard endpoints
Caelum has shown rapid improvement at fixed time points in both GLS and NT-
proBNP
Prothena failed to demonstrate best response in NT-proBNP in
phase 2b/3 trials
Rare systemic disease characterized by misfolding of pre-amyloid light chain proteins produced by plasma cells
Misfolded proteins are toxic and aggregate as fibrils
Fibrils deposit in and around tissues causing damage and affecting function
Symptoms of AL Amyloidosis frequently mimic other diseases (e.g. CHF, respiratory distress, proteinuria), often leading to misdiagnosis
AL Amyloidosis: many patients have severe organ damage at diagnosis…
5
~30k -45k
~4.5k
Plasma cells are produced in the bone
marrowBone
Plasma cells produce proteins. Abnormal plasma
cells produce misfoldedproteins called pre-amyloid
light chain proteins which are toxic to cardiomyocytes
Misfolded proteins collect
together
Collections of misfolded proteins
create amyloid fibrils
Amyloid fibrils deposit in tissues
Heart and kidney impacted in 60-75%
of patients
CAEL-101 may neutralize
CAEL-101 potentially dissolves and removes
Plasma cell production Mechanism of Amyloid formation in tissues
U.S. and EuropePopulation
Newly-diagnosed patients in the U.S. per year
Plasma cell therapies
Potentially understated given AL Amyloidosis often mis-diagnosed
Image of uptake of CAEL-101 in the
myocardium
…And die before getting benefit from current standard of care
6
No FDA-approved therapies for AL Amyloidosis
An effective treatment would:
a) reduce plasma light chain production; and,
b) eliminate existing light chains and amyloid fibrils infiltrating organs
Current standard-of-care inhibits plasma cells through either cytotoxic or anti-CD38 therapy
Patients exhibit variable hematological responses, ~10-11 month median time to organ response, and high morbidity and mortality
• Anti-CD38s
• Traditional chemotherapy agents
• Proteasome inhibitors and immunomodulators
• Stem cell therapy and organ transplants (primarily for earlier stage patients)
Current treatments
(1) NT-proBNP > 8,500 ng/L.(2) Stage 4 patients based on the Mayo Clinic’s staging system.
Median time to response for CAEL-101 vs. current standard-of-care…
One-year mortality rate of approximately 50% in patients with cardiac disease;5 months mean overall survival for most severe patients(2)
Standard of care CAEL-101
NT-proBNP 10.4 months 3 weeks
GLS No change seen over 12 months Improvement seen after 12 weeks
CAEL-101 is first-in-class anti-AL amyloid mAb
7
CAEL-101
Amyloid type Specific for AL misfolded light chain protein
In-vitro binding Strong in-vitro binding with high specificity to a neo epitope that forms on kappa and lambda misfolded proteins, but is not present on the native light chains
Animal imaging Clear co-location of CAEL-101 with human amyloid (both kappa and lambda sub-types) in murine models
Human amyloid dissolution in mice
7 different human amyloid samples; all were fully cleared rapidly
Human imaging In vivo binding in human imaging studies, including the heart
Cardiac response(1)
(Biomarker and functional data)
Phase 1a/1b (n=27)
Biomarker:67% response with single dose or 4 weekly doses3 week median time to response
Functional:90% of cardiac patients responded (statistically significant improvement)
Clinical efficacy in kappa and lambda subtypes
(1) Biomarker response measured by >30% and >300 pg/ml decrease in baseline NT-proBNP, functional response measured by change in left ventricular function in an echocardiogram analysis.
CAEL-101 is a rationally designed antibody that has shown rapid improvement in both functional and biomarker endpoints in a Phase 1a/b clinical study
Phase 1a/b, open-label dose escalation study completed in 2017
8
Patient criteria
Op
en
la
be
l d
ose
esc
ala
tio
n
Single IV infusion @
week 1
Weekly IV infusion for4 weeks @weeks 1 - 4
Primary endpoint
Secondary endpoints
Select exploratory
endpoints
Phase 1an=8
Phase 1bn=19
Patients with relapsed or refractory AL Amyloidosis
− Refractory AL Amyloidosis patients had no prior organ response; or
− Relapsed AL Amyloidosis patients had a prior organ response from chemotherapy
Establish maximum tolerated dose (up to 500mg/m2) of CAEL-101
Cardiac response (NT-proBNP)
Renal response (24-hour Proteinuria)
Pharmacokinetic profile (single dose vs. multiple weekly doses)
GLS
Phase 1a and 1b data presented at ASH in 2016 and 2017
Encouraging Early Functional Data9 out of 10 cardiac patients improved against baseline
9
Left ventricular data: All Phase 1b Cardiac Patients (N=10)
Mean
Improvement
Mean absolute improvement of 1.69 points in GLS scores (range of -10 to -20 points) in Phase 1b cardiac patients after 12 weeks
• Increasingly recognized as a more effective technique than conventional ejection fraction in detecting subtle changes in left ventricular (LV) function(1)
• Considered to be a sensitive measure of pre-treatment cardiac functional impairment in AL (cardiac) amyloidosis and a predictor of survival over and above cardiac biomarkers(2)
• Evidence suggests cardiac AL amyloidosis patients treated with chemotherapy showed no change in GLS from baseline to 1 year(3)
(1) Krishnasamy et. Al. 2015, “Left Ventricular Global Longitudinal Strain (GLS) Is a Superior Predictor of All-Cause and Cardiovascular Mortality When Compared to Ejection Fraction in Advanced Chronic Kidney Disease.”(2) Salinaro et. Al. 2016, “Longitudinal systolic strain, cardiac function improvement, and survival following treatment of light-chain (AL) cardiac amyloidosis.”(3) Salinaro et. Al. 2016, “Longitudinal systolic strain, cardiac function improvement, and survival following treatment of light-chain (AL) cardiac amyloidosis.”
No change in GLS was seen from baseline to 1 year both in patients that were recorded as achieving a hematologic complete response and those that did not achieve a complete response.(4) Buss et Al. 2012, “Longitudinal Left Ventricular Function for Prediction of Survival in Systemic Light-Chain Amyloidosis: Incremental Value Compared With Clinical and Biochemical Markers.”
Reduced LV longitudinal function was shown to serve as an independent predictor of survival in AL amyloidosis(4)
Importance of GLS
Positive Initial Biomarker Data
10
Biomarker data: Evaluable Phase 1b Cardiac Patients (N=8)
(1,000)
(800)
(600)
(400)
(200)
0
Mean of 8 patients
Treatment period Post treatment period
0.02010.0978
0.0525
0.3647
0.0031
0.2732
Mean 35.6% improvement in NTproBNP levels in 8 evaluable cardiac
patients after 4 weeks
LS
Me
an
(SE
) ch
an
ge
s fr
om
ba
seli
ne
in
NT
pro
BN
P
Data shows positive improvement during the treatment period followed by reversal post treatment period
Functional (global longitudinal strain) Biomarker (NT-proBNP)(1)
Absolute change in GLS score from baseline to 12 weeks after baseline Change from baseline to last dose (week 4) (pg/mL)
11
(1.23)
(1.94)
(3.07)
(2.05)
(2.21)
(3.81)
(0.43)
(1.23)
1.12
(1.99)
(1.69)
(5.00) (4.00) (3.00) (2.00) (1.00) 0.00 1.00 2.00
1
2
3
4
5
6
7
8
9
10
Mean
(1,182)
(348)
(171)
(1,148)
(316)
(415)
(445)
(1,105)
(641)
(1350) (850) (350) 150
Patient 10
Patient 9
Patient 8
Patient 7
Patient 6
Patient 5
Patient 4
Patient 3
Patient 2
Patient 10
Mean
NA(2)
Mean
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Patient 8
Patient 9
Patient 10
Patient 7
(1) Mean baseline NTpro-BNP was 1,797.(2) Patient 9 and 10 were not evaluable for biomarker response as baseline NT-proBNP was less than 650 pg/mL.
Data measures taken at pre-determined time points which is considered more robust than best response data
Phase 1b cardiac patients: GLS and NT-proBNP data measured at fixed time points with consistent directional trend
NA(2)
(35.6%)
(29.0%)
(49.8%)
(30.1%)
(28.2%)
(18.5%)
(45.0%)
(41.3%)
(42.7%)
∆ from baseline
Dose(mg / m2)
100
5
10
500
250
250
500
500
500
250
Case Study 1: Organ response occurs independent of depth of response to chemotherapy
12
Patient with cardiac lambda AL Amyloidosis
Six prior treatments with no organ response
Best prior hematologic response was PR – partial response
Following the initial dose of CAEL-101, the patient’s NT-proBNP level decreased for three consecutive periods
A clinically meaningful organ response was observed after only three weeks but the patient continued to have an insufficient hematologic response
Source: 2017 ASH Presentation from Dr. Suzanne Lentzsch.
Case study shows the antibody effect of CAEL-101 on the heart as well as its potential to neutralize the toxic pre-amyloid light chain protein
Skin biopsy showed amyloid caused by lambda light chain
Case Study 2: Co-location of Amyloid, CAEL-101, Neutrophils, and Macrophages
13
Phase 1a patient (lambda light chain) showed symptoms of rash and pruritus after a single dose of CAEL-101
Onset 4 days after infusion, duration of 11 days Subcutaneous fat with positive immunohistochemical staining
for CAEL-101
Neutrophils and macrophages co-located at the site of amyloid and CAEL-101
Patient developed less pronounced rash and pruritis when re-dosed with 100 mg/m2
in Phase 1b
Supports the hypothesis of antibody binding and amyloid dissolution
The same patient also had a sustained cardiac response measured as a reduction in NT-proBNP
(1) Baseline measurements were taken prior to first dosing on Day 1 for Phase 1a and Phase 1b.
Case Study 3: Organ response and reduction in liver size occurred independent of free light chain (FLC) response
14
Patient with liver kappa AL Amyloidosis
Organ response 8 months before FLC response
Source: 2017 ASH Presentation from Dr. Suzanne Lentzsch.
Case study shows enlarged liver returned to normal size in patient that had a hematologic response 8 months post organ response
US-Liver Pre-treatment
6/2/16: “The liver is enlarged with normal echogenicity. The liver measures 19.4 cm in length. Liver surface is smooth.”
US-Liver Post-treatment
8/2/16: “The liver is normal in size and echogenicity. The surface is smooth. Right lobe measures 17.3 cm in length at the midclavicular.”
Development of CAEL-101
Robust and Unique Development of CAEL-101
16
3. In vivo data (cont’d) 4. Clinical data
1. Design
Specifically designed to bind to light chain fibrils
2. In vitro data
Shows high binding specificity to light chains (both kappa and lambda)
3. In vivo data
Showed in-vivo binding in animal imaging studies(both kappa and lambda)
CAEL-101 is a first-in-class anti-amyloid antibody
CAEL-101 showed in-vivo binding in human imaging studies
Murine models showed CAEL-101’s amyloid clearance ability in 7 different human amyloid samples
(2 kappa samples, 5 lambda samples)
Mean absolute improvement of 1.69 points in GLS scores (range of 9 – 20 points)
Mean 35.6% improvement in NT-proBNP levels after 4 weeks
Mean
22.0%
9.5%
Kappa Lambda
11-1F4 specificity
(mean % ID / g)
0.3
Kd
Kd tested against K4
(nM)
CAEL-101 expedites the clearance of amyloid deposits in a human patient derived xenograft mouse model
17
Results from an in vivo mouse model showed that CAEL-101 dissolved human amyloid deposits taken from seven different patients
CAEL-101 cleared both kappa and lambda deposits
Day 14
Amyloid fibril suspensions sourced from human postmortem samples were injected into mice to form amyloid deposits
Mice received either CAEL-101 or no
treatment
Untreated mouse
CAEL-101 treated mouse
Day 1
Day 14
Source: Hrncic et al, Am J Path 2000.
CAEL-101 mediates complete clearance of human kappa and lambda amyloid deposits in mouse model
18
Day 0 2 4 6
Clearance
Day 0 2 4 6
AmyloidDeposit
Clearance
28
24
17
9
8
4
4
28
25
24
21
14
15
14
0 5 10 15 20 25 30
λ-05
λ-04
λ-03
λ-02
λ-01
k-02
k-01
Untreated Treated
Single Dose Multiple Doses
AmyloidDeposit
7
6
9
9
28
25
26
24
0 5 10 15 20 25 30
λ-05
λ-04
λ-03
λ-02
λ-01
k-02
k-01
Untreated Treated
Not Tested
Not Tested
Not Tested
Am
ylo
id S
ub
-Typ
e
Time to Clearance (Days)
Am
ylo
id S
ub
-Typ
e
Time to Clearance (Days)
Dissolved kappa deposits 10 days fasterthan the mouse on its own
Dissolved lambda deposits ~3 weeks fasterthan the mouse on its own