highlights from ash & sabcs · treatment regimens in any new indications that might be...

Novartis Investor Call

Highlights from ASH & SABCS

December 11, 2017

Novartis AG

Investor Relations

Disclaimer

This presentation contains forward-looking statements, including "forward-looking statements" within the meaning of the United States Private Securities Litigation Reform Act of

1995. Forward-looking statements can generally be identified by words such as "potential," " expected," "will," "planned," or similar terms, or by express or implied discussions

regarding potential marketing approvals, new indications or labeling for Kymriah and Kisqali, or regarding potential future revenues from these products. You should not place undue

reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and

unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially

from those set forth in the forward-looking statements. There can be no guarantee that either Kymriah or Kisqali will be submitted or approved for any additional indications or labeling

in any market, or at any particular time. Nor can there be any guarantee that either Kymriah or Kisqali will be commercially successful in the future, or that efforts to achieve

commercial success for these products in any new indications would not have a negative impact on the product’s sales in existing indications. In particular, our expectations regarding

these products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing

clinical data, as well as the planned clinical trials of these products, and the length of time such planned clinical trials may take; regulatory actions or delays or government regulation

generally; the particular prescribing preferences of physicians and patients, including uncertainties as to whether physicians and patients would adopt Kymriah or Kisqali into their

treatment regimens in any new indications that might be approved; global trends toward health care cost containment, including government, payor and general public pricing and

reimbursement pressures, and potential conflicts between the appropriate pricing of these products in the indications for which the products are currently sold, and potential

appropriate pricing of the product in any new indications that might be approved; general economic and industry conditions, including the effects of the persistently weak economic

and financial environment in many countries; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US

Securities and Exchange Commission. Novartis is providing the information in this presentation as of this date and does not undertake any obligation to update any forward-looking

statements contained in this presentation as a result of new information, future events or otherwise.

Novartis Investor Call l Highlights from ASH and SABCS l December 11, 20171

Strong presence and key highlights from ASH and San

Antonio Breast Cancer Symposium (SABCS)


• Kisqali® MONALEESA-7: 1L ribociclib vs placebo with goserelin+ tamoxifen or a non-steroidal aromatase inhibitor in pre-menopausal women with HR+, HER2– advanced breast cancer

• Kisqali® MONALEESA-2: Subsequent treatment + Treatment-free interval analyses

• LSZ102: Phase I/Ib study of the SERD LSZ102 alone or in combination with ribociclib in ER+ breast cancer

ASH

SABCS

• Kymriah™ JULIET: primary analysis (6-month data)

• CART-BCMA: infusion for refractory multiple melanoma

• SEG101 SUSTAIN: study secondary analysis in subgroups of patients by hydroxyurea use, Hb genotype or number of prior SCPC

173

Abstracts presented (including 34 oral presentations)

38

Abstracts presented (including 3 oral presentations)

American Society of Hematology Annual Meeting (ASH) –

Kymriah™ HighlightsDavid Lebwohl

San Antonio Breast Cancer Symposium (SABCS) –

Kisqali® HighlightsSamit Hirawat

Q&A

Agenda

Novartis gains real world experience in CAR-T with KymriahTM

;

the first CAR-T cell therapy approved anywhere in the world


Kymriah™ is the first CAR-T cell therapy approved by FDA

21 sites fully operational, 33 sites REMS certified

Target 22 day manufacturing time has been achieved in commercial setting

Cryopreservation provides more flexibility for patients and physicians

Commercial patients have been treated and access has been managed

efficiently through various programs

CAR-T Type Cancer indication Phase 1

Phase 2/

pivotal Phase 3 Submitted Approved

CD19 CAR-T Pediatric & young adult r/r ALL1 EU US

CD19 CAR-T r/r DLBCL2 US/EU

CD19 CAR-T DLBCL in 1st relapse2 Starting 2018

CD19 CAR-T r/r FL3 Starting 2018

CD19 CAR-T r/r DLBCL2 in combination

with pembrolizumabStarting 2018

CD19 CAR-T CLL4 Starting 2018

CAR-T-BCMA r/r Multiple Myeloma Starting 2018

CAR-T-EGFRvIII Recurrent GBM5 Started

CAR-T-Meso Advanced ovarian cancer,

MesotheliomaStarted

Novartis has one of the most comprehensive CAR-T

development programs across multiple large indications

1. ALL – acute lymphoblastic leukemia 2. DLBCL – diffuse large B-cell lymphoma 3. FL - follicular lymphoma 4. CLL – chronic lymphocytic leukemia 5. GBM – glioblastoma multiforme


Kymriah™ uses the 4-1BB costimulatory domain, enhancing

expansion and persistence of the cancer fighting cells

• Antigen binding domain

—Recognizes CD19 on B cells

• 4-1BB costimulatory domain

—Augments antitumor activity

—Enhances proliferation and persistence

of CAR T cells

• CD3-zeta signaling domain

— Initiates T-cell activation

—Mediates antitumor activity

VL

VH

Antigen binding

(anti-CD19) domain

CD8-alpha hinge

and transmembrane

4-1BB costimulatory

domain

CD3-zeta signaling

domain

T cell

VL: Light Chain Variable Domain

VH: Heavy Chain Variable Domain

6 Novartis Investor Call l Highlights from ASH and SABCS l December 11, 2017 Kymriah™ was developed in collaboration with the University of Pennsylvania

High unmet need: patients with relapsed or refractory

DLBCL have a poor prognosis

• Low rate of response to salvage therapy (CR, 8%; PR, 18%)1

• Short survival (median OS 4 months)2

• Potentially eligible patients for CAR-T therapies based on incidence3 2nd line ~29,000 / ≥3rd line ~16,000

Figure adapted from Friedberg, J American Soc Hem Education Book, 2011; 1: 498-505.

1. Crump M, et al. Blood. 2017;130(16):1800-1808.

2. Van den Neste E, et al. BMT. 2016;51:51-57.

3. Incidence: Based on 2017 incidence rate in US, EU-14, Israel, Japan and Canada -Surveillance, Epidemiology, and End Results Program (SEER);

Decision Resources; Novartis analysis Relapsed/Refractory %: Internal Novartis discussions.

~50 Transplant eligible

~25 Respond to

chemotherapy and proceed to transplant

~10Cured

~90No available SOC

chemotherapy options

~25 Transplant ineligible

(NR to chemoRx)

~50 Transplant

ineligible (age, co-morbidity)

~15 Relapse after

transplant100

r/r DLBCL

7 Novartis Investor Call l Highlights from ASH and SABCS l December 11, 2017

JULIET is first global CAR-T trial in DLBCL using

cryopreserved apheresis and centralized manufacturing

• 27 sites in 10 countries across North America, Europe, Australia, and Asia

• Cryopreservation of a patient’s harvested cells, gives flexibility to initiate therapy with Kymriah

based on the individual patient’s condition

8

*

Manufacturing site

*

*Novartis Investor Call l Highlights from ASH and SABCS l December 11, 2017

JULIET only pivotal trial in lymphoma allowing patients to receive

bridging chemo and manufacturing facilitated by cryopreservation

• Single-arm, multicenter, global phase 2 trial of tisagenlecleucel in adult patients with r/r DLBCL (NCT02445248)

9

Bridging Chemotherapy

Enrollment

Screening

Apheresis and

Cryopreservation

Tisagenlecleucel

Manufacturing

Lymphodepletiona

Tisagenlecleucel

Infusionb

Safety and Efficacy

Follow-Up

Imaging at months

1, 3, 6, 9, 12...

a To be completed 2 to 14 days prior to tisagenlecleucel infusion.b Infusion conducted in- or out-patient at investigator discretion.


Primary JULIET endpoint was met with 53% best ORR and at

6 months from infusion strong 37% ORR and 30% CR

* P < .0001 (95% CI, 42-64%). Null hypothesis of ORR ≤ 20%.

Response Rate

Best Overall

Response Rate

(N = 81)

Response

at 3 Months

(N = 81)

Response

at 6 Months

(n = 46)

ORR (CR + PR)1 53%* 38% 37%

CR1 40% 32% 30%

PR1 14% 6% 7%

1. ORR, overall response rate; CR, complete response; PR, partial response.


• In r/r DLBCL, the goal is long-term durable responses

• JULIET demonstrated strong durability, with a 30% 6 month CR rate

• In the JULIET trial, the median duration of response has not been reached

Responses seen in JULIET were durable – estimated

relapse-free rate at 6 months is 74%

• Median DOR and OS not

reached

• Majority of patients achieving

CR at month 3 have remained

in CR

• No patients proceeded to

transplant while in response

• Pilot study demonstrated

sustained remissions at a follow

up of 28.6 months among

patients who responded at six

months1

CR, complete response; DOR, duration of response; OS, overall response.

Efficacy analysis set = All patients who received a tisagenlecleucel infusion at least 3 months prior to data-cut date.

Patients still at risk

Pro

bab

ilty

of

Re

lap

se F

ree

(%)

Time From Onset of Response (months)

100

80

60

40

20

0

2 3 4 5 7 8 9 10 11 1210 6

01225913161825 936n = 43


Schuster S., et al. CAR-T cells (CTL019) in Refractory B-cell Lymphomas. N Engl J Med. December 10, 2017. doi: 10.1056/NEJMoa1708566. [Epub ahead of print].

JULIET population was heavily pre-treated patients

• Bridging

chemotherapy: 89 of

99 patients

• Lymphodepleting

chemotherapy: 92 of

99 patients

12

Patients (N = 99)

Age (years), median (range) 56 (22-76)

≥ 65 years 23%

ECOG performance status 0/1 55% / 45%

Double/triple hits in CMYC/BCL2/BCL6 genes (%) 15%a

Cell of origin

Germinal center B-cell type 52%

Non germinal center B-cell type 42%

Number of prior lines of antineoplastic therapy

2/3/4-6 44% / 31% / 19%

Refractory/relapsed to last therapy 52% / 48%

Prior auto-SCT 47%

a CMYC+BCL2, n = 4; CMYC+BCL2+BCL6, n = 8; CMYC+BCL6, n = 3.b Determined by the Choi algorithm.

auto-SCT, autologous stem cell transplant; ECOG, Eastern Cooperative Oncology Group; NOS, not otherwise specified.


No differences in

response rates by

• prior lines of therapy

• cell of origin

• high risk genetics


Responses were consistent regardless of prior lines of

therapy, cell of origin or high risk genetics

Adverse events were generally reversible and effectively

managed

14

Patients (N = 99)

AESI1All grade

%

Grade 3

%

Grade 4

%

Neurological

events21 8 4

Cytokine release

syndrome58 15 8

• 12% of patients with grade 3/4

neurotoxicity, 23% with grade 3/4

CRS

• No deaths attributed to Kymriah,

CRS or neurological events, and no

events of cerebral edema were

reported

• 26 (26%) patients were infused as

outpatients

• 20/26 (77%) patients remained

outpatient for ≥ 3 days after infusion

1. Adverse Events of Special Interest occurring within 8 weeks of tisagenlecleucel infusion.

Using Penn grading scale, which is

more stringent than other commonly

used CRS grading scales


Key takeaways for Kymriah™


Novartis has a comprehensive CAR-T development program exploring additional indications in multiple myeloma, follicular lymphoma, CLL and solid tumors2

KymriahTM in pediatric ALL provides real world experience as we prepare our DLBCL launch, large scale production for DLBCL ready for 2018 and DLBCL submitted to FDA and EMA in Q4 2017

1

JULIET median duration of response and OS not reached, 30% of patients in

complete response, estimated relapse-free rate at 6 months is 74%4

KymriahTM uses the 4-1BB costimulatory domain, which enhances expansion and

persistence of the cancer fighting cells3

Adverse events were generally reversible and effectively managed (no deaths attributed to KymriahTM, CRS, or neurological events). Additionally, KymriahTM was successfully administered in the outpatient setting

5

American Society of Hematology Annual Meeting (ASH) –

Kymriah™ HighlightsDavid Lebwohl

San Antonio Breast Cancer Symposium (SABCS) –

Kisqali® HighlightsSamit Hirawat

Q&A

Agenda

Breast cancer in pre-menopausal remains a challenge

• In 2017, of all invasive breast cancers, estimated 19% will be diagnosed in

women aged ≤49 years1

• The last randomized trial focusing solely on pre-menopausal women with

ABC was published in 20002

• Advanced breast cancer in young women is a more aggressive disease,

with higher likelihood of dying of cancer than older women3

• Current standard of care treatment is oral endocrine therapy with ovarian

suppression for pre- and peri-menopausal women with advanced breast

cancer, however, resistance develops

• There remains an unmet medical need to provide effective therapy

1. Desantis CE, et al. CA Cancer J Clin 2017;ePub ahead of print

2. Klijn JGM, et al. J Natl Cancer Inst 2000;92:903–911

3. Anders CK, et al. Semin Oncol 2009;36:237–249 .


• Early separation of PFS curves and PFS from M-2;

Hazard Ratio 0.568 (95% CI: 0.457-0.704);

p<0.0001

• Tumor shrinkage starts as early as 8 weeks and

ORR in measurable disease

• Manageable safety profile with periodic blood tests

and ECG monitoring

• FDA approved on March 13, 2017: “KISQALI is a

kinase inhibitor indicated in combination with an

aromatase inhibitor as initial endocrine-based

therapy for the treatment of postmenopausal women

with hormone receptor (HR)-positive, human

epidermal growth factor receptor 2 (HER2)-negative

advanced or metastatic breast cancer.”

• EU approved August 20, 2017

Kisqali®

has shown superior efficacy in combination with

aromatase inhibitor in postmenopausal HR+/Her2- aBC


MONALEESA-7 study investigated efficacy & safety of

Kisqali®

in pre-menopausal women with HR+/HER- aBC


• Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter

• Primary analysis planned after ~329 PFS events

– 95% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%, corresponding to an increase in

median PFS to 13.4 months (median PFS of 9 months for the placebo arm1,2), and a sample size of 660 patients

– Interim analysis removed due to rapid patient recruitment

‡PFS by blinded independent review committee conducted to support the primary endpoint.

1. Klijn JG, et al. J Clin Oncol 2001;19:343–353; 2. Mourisden H, et al. J Clin Oncol 2001;19:2596–2606.

Stratified by:

• Presence/absence of liver/lung

metastases

• Prior chemotherapy for advanced

disease

• Endocrine therapy partner (tamoxifen

vs NSAI)

Primary endpoint

• PFS (locally assessed

per RECIST v1.1)‡

Secondary endpoints

• Overall survival (key)

• Overall response rate

• Clinical benefit rate

• Safety

• Patient-reported

outcomes

• Pre-/peri-menopausal

women with HR+, HER2–

ABC

• No prior endocrine therapy for

advanced disease

• ≤1 line of chemotherapy for

advanced disease

• N=672

Randomization (1:1)

Ribociclib(600 mg/day; 3-weeks-on/1-

week-off)

+ tamoxifen/NSAI +

goserelin*

n=335

Placebo+ tamoxifen/NSAI +

goserelin*

n=337

MONALEESA-7 enrollment criteria were aligned with the

patient population seen in clinical setting

• Pre- or peri-menopausal women

• ≥1 measurable lesion (RECIST 1.1) or

≥1 predominantly lytic bone lesion

• ECOG performance status ≤1

• ≤1 line of chemotherapy for ABC

• Prior (neo)adjuvant therapy was

allowed

AI, aromatase inhibitor; QTcF, Fridericia’s corrected QT interval.

Perimenopausal defined as neither pre-menopausal nor post-menopausal.

Goserelin included in all combinations.

• Any prior endocrine therapy for ABC

• Inflammatory breast cancer

• Active cardiac disease or history of

cardiac dysfunction, including QTcF

>450 msec

• CNS metastases

• Symptomatic visceral disease

Key Exclusion Criteria Key Inclusion Criteria



More than 50% of the patients had visceral

metastatic disease with ~30% Asian patients

Characteristic*Ribociclib + tamoxifen/NSAI

n=335

Placebo + tamoxifen/NSAI

n=337

Median age, years (range) 43 (25–58) 45 (29–58)

Race

Caucasian 187 (55.8) 201 (59.6)

Asian 99 (29.6) 99 (29.4)

Other‡ 29 (8.7) 19 (5.6)

Unknown 20 (6.0) 18 (5.3)

ECOG performance status§

0 245 (73.1) 255 (75.7)

1 87 (26.0) 78 (23.1)

Missing 3 (0.9) 3 (0.9)

Metastatic sites

Visceral disease 193 (57.6) 188 (55.8)

Bone-only disease 81 (24.2) 78 (23.1)

De novo metastatic disease 136 (40.6) 134 (39.8)

Non-de novo metastatic disease 199 (59.4) 203 (60.2)

Disease-free interval

≤12 months 23 (6.9) 13 (3.9)

>12 months 176 (52.5) 190 (56.4)

Prior (neo)adjuvant endocrine therapy 127 (37.9) 141 (41.8)

Prior chemotherapy

For advanced disease 47 (14.0) 47 (13.9)

(Neo)adjuvant only 138 (41.2) 138 (40.9)

None 150 (44.8) 152 (45.1)

Goserelin included in all combinations.*All values are n (%), unless stated otherwise; ‡other includes Black, Native American, and other; §1 patient in the placebo arm had an ECOG performance status of 2.


Kisqali®

in combination with oral endocrine

treatment leads to ~10 month improvement in PFS

Pro

ba

bil

ity o

f

pro

gre

ss

ion

-fre

e s

urv

iva

l (%

)

Time (months)No. at riskRibociclib +

tamoxifen/NSAI

335 301 284 264 245 235 219 178 136 90 54 40 20 3 1 0

Placebo +

tamoxifen/NSAI

337 273 248 230 207 183 165 124 94 62 31 24 13 3 1 0

PFS (Investigator assessment)

Ribociclib +tamoxifen/NSAI

n=335


n=337

Number of events, n (%)

131 (39.1) 187 (55.5)

Median PFS, months (95% CI)

23.8(19.2–NR)

13.0(11.0–16.4)

Hazard ratio (95% CI)

0.553 (0.441–0.694)

One-sided p value 0.0000000983

1086420

100

80

60

40

20

0

30282624222018161412

10

30

50

70

90


In MONALEESA-7 study superior efficacy was seen across

all subgroups predefined and analyzed

Combination of Kisqali®

& AI or tamoxifen also led

to responses in a higher proportion of patients

14.5% more responders in ribociclib arm for pts with measurable disease

Patients with measurable disease at baseline

Confirmed Best Overall ResponseRibociclib 600 mg

(N=335)Placebo(N=337)

Complete response 3.0% 2.5%

Partial response 48.0% 33.8%

Stable disease 39.4% 43.6%

Non-CR/Non-PD NA NA

Overall Response Rate 50.9% 36.4%

P-value 0.000317

ORR (95% CI) per BIRC assessment: 45.9% (37.4%, 54.3%) vs. 28.4% (20.7%, 36.0%)



Safety profile of Kisqali®

was similar to the observations in

MONALEESA-2 trial

• Neutropenia (76% all grade and 61% grade 3/4) was the most common

adverse event

• Common (>20%) non-hematological AEs included hot flash, nausea,

arthralgia, fatigue, headache and diarrhea

• QT prolongation (>480 msec) was observed in 23 patients in the ribociclib

arm. However, only 1 patient discontinued treatment due to this event

—6 patients had dose reduction due to QT increase; others managed with dose

interruption

—No associates with clinical sequela of sudden death, TdP, or arrhythmia


In MONALEESA-7 study treatment with the combination led

to improvement in pain sores and delayed time to QoL

deterioration

• There was a sustained improvement

in time to deterioration of at least

10% for the global health status/QoL

scale in the ribociclib arm vs the

placebo arm

• A clinically meaningful (>5 points)

improvement from baseline in pain

score was observed as early as

Cycle 3 in the ribociclib arm and was

sustained

Ribociclib +tamoxifen/NSAI

n=335


n=337

Number of events, n

102 114

Median, months (95% CI)

NR(22.2–NR)

21.2(15.4–23.0)

Hazard ratio (95% CI)

0.699 (0.532–0.917)

Log-rank test p value

0.004

Ribociclib +

tamoxifen/NSAI

Placebo +

tamoxifen/NSAI

No. at risk

335 281 256 236 218 201

337 258 217 197 177 157

188

131 96

145 112

66

69

37

43

17

41

16

15

5

3

1

0

0

100

80

90

60

50

70

40

30

20

10

0

Eve

nt-

free

pro

bab

ility

(%)

Time to deterioration (months)

1086420 282624222018161412

Key takeaways for MONALEESA-7 study


Kisqali® is first and only CDK4/6 inhibitor to show superior median PFS compared to oral endocrine therapy as first-line treatment in a prospective, randomized Phase III trial dedicated to pre-menopausal women

2

MONALEESA-7 is the first Phase III trial of CDK4/6i specifically in pre-

menopausal women; high unmet need with estimated ~19% of invasive breast

cancer cases in the US in women under 50

1

Pending approval in this indication, the clinical benefit demonstrated in the MONALEESA-7 trial expected to support the use of Kisqali as a standard of care for pre-menopausal women with HR+/HER2- advanced breast cancer. Novartis intends to submit data in 1H 2018

3

MONALEESA-3 on track for filing in the US and EU in 20184

American Society of Hematology Annual Meeting (ASH) – Kymriah™ Highlights

San Antonio Breast Cancer Symposium (SABCS) – Kisqali® Highlights

Q&A

Agenda

Appendix

JULIET: Eligibility, Dose and Endpoints

30

Key eligibility criteria

—≥ 18 years of age

—Central confirmation of histology

—≥ 2 prior lines of therapy for DLBCL

—PD after or ineligible for auto-SCT

—No prior anti-CD19 therapy

—No active CNS involvement

Target dose

—Range of 1- 5 x 108 transduced cells

Endpoints and Analyses

– Primary endpoint:

Best overall response rate

(ORR: CR + PR)

– Secondary endpoints:

DOR, OS, safety

– Using “Lugano Classification”

based on central review by an

independent review committee1

– Null hypothesis of ORR ≤ 20%

1. Cheson BD, et al. J Clin Oncol. 2014;32(27):3059-3068; Auto/allo-SCT, autologous/allogeneic stem cell transplant; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma

Key Eligibility Criteria

Target Dose

Endpoints and Analyses



JULIET: Cytokine Release Syndrome

Patients (N = 99)

Time to onset, median (range), daysa,b 3 (1-9)

Duration, median (range), daysa 7 (2-30)

Admitted to intensive care unit 25%

Hypotension that required intervention 28%

High dose vasopressors 6%

Intubated 8%

Anti-cytokine therapy 16%

Tocilizumab 15%

Corticosteroids 11%

1. Porter DL, et al. Sci Transl Med. 2015;7(303):303ra139.

a Calculated based only on patients who had cytokine release syndrome (n = 57); excluding 1 patient who had onset on day 51.b CRS was graded using the Penn scale and managed by a protocol-specific algorithm.1


4.8 (1.8–NR); P=0.025 vs placebo

1.6 (0.6–6.7)

2.4 (1.3–7.8); P=0.012 vs placebo

SEG101 data: time to first SCPC event by prior SCPC event

history (ITT population)

Hazard ratio (95% CI): 0.53 (0.31, 0.90) Hazard ratio (95% CI): 0.47 (0.25, 0.89)

Data are median (interquartile range [IQR]) unless otherwise stated. NR, not reportable

1.0 (0.3–3.0)


2.4 (1.2–NR); P=0.038 vs placebo

1.2 (0.3–4.9)

5.7 (3.1–NR); P=0.004 vs placebo

2.9 (0.8–4.5)

SEG101 data: time to first SCPC event by concomitant HU

use (ITT population)

Hazard ratio (95% CI): 0.58 (0.35, 0.96) Hazard ratio (95% CI): 0.39 (0. 20, 0.76)

Data are median (IQR) unless otherwise stated

BCMA (TNFRSF17, CD269)


BCMA study design


BCMA data: Clinical activity


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