This deck describes the role of proteasome inhibitors in the treatment of multiple myeloma

1. 1
Relapsed and
Refractory Multiple Myeloma:
Unmet Need

2. Multiple Myeloma
2
 Multiple myeloma (MM) is a clonal plasma cell
disorder that accounts for 1.5% of all cancers1,2
 It is the second-most common hematological2
malignancy
 Incidence in the US is estimated at 24,000 people
annually2
 11,000 deaths expected in 2014
1. Moreau P and Touzeau C. Am Soc Clin Oncol Educ Book. 2015;35:e504-11. doi: 10.14694/EdBook_AM.2015.35.e504.
2. Sugumar D et al. Pharmgenomics Pers Med. 2015; 8:23–33.

3. History of Multiple Myeloma Treatment
Adapted from: Durie BGM. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation.
2011/2012 edition.
1960s
1970s
1980s
1990s
2003
2006-­‐
2007
VBMCP: Vincristine, carmustine, melphalan, cyclophosphamide, prednisone.
BMCP: Carmustine, melphalan, cyclophosphamide, prednisone.
VAD: Vincristine, doxorubicin, dexamethasone.
2012
Ongoing clinical investigations with
novel agents and combinations
3

4. Clinical Use of Approved Drugs in MM
4
Drug Front Line Relapsed Relapsed
and
Refractory
Alkylating agents
Melphalan
Cyclophosphamide
✔ ✓ ✓
Anthracyclines
Liposomal doxorubicin
✔
Nitrosoureas
Carmustine
IMiDs
Thalidomide
Lenalidomide
✓
✔ ✔ ✔
Proteasome inhibitor
Bortezomib
✔ ✔ ✔
Adapted from: Durie BGM. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation.
2011/2012 edition.

5. The Proteasome: Key to Protein Regulation
5
 Timed degradation/
recycling of proteins is
essential for viability
 Proteins conjugated to
multiple units of the
polypeptide ubiquitin are
degraded by the
proteasome
 Cancer cells are more
dependent upon the
proteasome due to their
genetic instability and
rapid proliferation
 Accumulation of
ubiquitinated proteins and/or
mis-folded can proteins lead
to apoptosis
Teicher BA and Tomaszewski JE. Biochem Pharmacol. 2015: doi: 10.1016/j.bcp.2015.04.008.

6. Proteasome Inhibitor: Bortezomib
6
SUMMIT Study Design:
 Single arm, Phase 2
 N=202 patients; 193
analyzed for efficacy
 Relapsed myeloma,
refractory to last prior
therapy
 Primary endpoint:
Response Rate
 Statistical design: lower
limit of 90% CI > 10%
defined activity
Patient
Characteristics
N=202
Median prior regimens,
n
6
Stem cell transplant 64%
Bortezomib 0%
IMiD
Lenalidomide
Thalidomide
83%
0%
83%
Corticosteroids >99%
Alkylating agent
Cyclophosphamide
Melphalan
92%
-
-
Anthracycline 81%
Richardson PG et al. N Engl J Med. 2003;348(26):2609-17.

7. Bortezomib: Efficacy
7
Efficacy N = 193
ORR (≥ PR) 27%
CBR (≥ MR) 35%
Duration of response, median 15 months
Overall survival, median 16 months
Richardson PG et al. N Engl J Med. 2003;348(26):2609-17.
ORR=overall response rate, CBR=clinical benefit response, DOR=duration of response
• The SUMMIT trial supported the accelerated approval of Bortezomib
• Clinical activity confirmed in the subsequent Phase 3 APEX trial

8. Current Therapies Have Serious Side Effects
8
Drug Class Limiting Toxicities
Alkylating agents Myelosuppression
Anthracyclines Cardiotoxicity, myelosuppression
Nitrosoureas Pulmonary disease,
myelosuppression
Corticosteroids Hypertension, hyperglycemia, mood
disorders
IMiDs Thromboembolic events,
myelosuppression,
peripheral neuropathy
Bortezomib Neuropathy, GI disorders,
myelosuppression
Adapted from: Durie BGM. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation.
2011/2012 edition.

9. Limitations of Current Treatment Approaches
9
 Response rate decreases with increasing lines of
therapy
 Retrospective cohort study by IMWG* (2007-10)
 383 patients in 1st relapse identified
 ORR following each subsequent relapse
Relapse Line of
Therapy
Patients
Treated
Response
Rate %
1st 2nd 383 58
2nd 3rd 207 45
3rd 4th 86 30
4th 5th 27 15
*Adapted from Durie B et al, J Clin Oncol 30, 2012 (suppl); Abstract 8095.

10. Unmet Need in MM Treatment
10
Frontline
Relapsed
Treatment
Relapsed Refractory
or Intolerant
Expected
survival (months)
20-50 14-16 6-10
Sensitivity to
therapy
Sensitive Less Sensitive/
Resistant
Resistant
Treatment
limitations/
comorbidities
Peripheral
neuropathy
(~15% at
diagnosis)
>80% incidence of
Peripheral
neuropathy;
Compromised
marrow reserve;
Cytopenia
Intolerant to or
ineligible for
available
therapy
Elderly population are at risk for heart, lung, renal,
liver dysfunction and diabetes2
1. Adapted from: Durie BGM. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation.
2011/2012 edition. 2. Jagannath S. Clin Lymphoma Myeloma. 2008;8 (Suppl 4):S149-S156.

11. Unmet Medical Need in Relapsed and Refractory MM
11
 No standard of care and few options
 Trials of repeat single agent/combination novel
agents
 Transient and diminishing responses
 Short progression-free survival and overall survival
 Urgent need for additional novel agents
 Clinically meaningful responses
 Durability of response
 Associated clinical benefit
 Carfilzomib represents a promising next
generation proteasome inhibitor in this clinical
setting
Teicher BA and Tomaszewski JE. Biochem Pharmacol. 2015: doi: 10.1016/j.bcp.2015.04.008.

12. Carfilzomib (KYPROLIS™): A Novel Proteasome
Inhibitor
 Carfilzomib induces
irreversible proteasome
inhibition lasting ≥48
hours
 In 2012, carfilzomib was
approved for the treatment
of patients with multiple
myeloma
 Who have received at least
two prior therapies including
bortezomib and an
immunomodulatory agent
 And have demonstrated
disease progression on or
within 60 days of completion
of the last therapy
KYPROLIS [prescribing Information]. South San Francisco, CA: Onyx Pharmaceuticals Inc; 2013.
• Potent and prolonged inhibition
• Irreversible and highly specific
Carfilzomib is a modified tetrapeptidyl
epoxide proteosome inhibitor
12

13. Carfilzomib Does Not Induce Neurodegeneration
13
 Bortezomib induces significant neurite degeneration in vitro
 No neurodegeneration seen with carfilzomib
 Does not inhibit serine protease critical to neuronal cell
survival
 Consistent with results from chronic dosing studies in
animals
Arastu-Kapur S et al. Clin Cancer Res. 2011;17(9):2734-2743.

14. Key Inclusion
Criteria
• Received ≥ 2prior
therapies including
Bortezomib and
thalidomide and/or
lenalidomide
• ≤25% response to
the most recent
therapy or had
disease progression
during or within 60
days of the most
recent therapy
Primary
Endpointb
• Overall Response
Rate (ORR)
Secondary
Endpoint
• Duration of
Response (DOR)
• Safety
• All cycles=28 days
• 6 doses per cycle
• Administered on
consecutive days each
week for 3 weeks followed
by 12-day rest period
Cycle 2-12a
27 mg/m2
aUntil disease progression,
unacceptable toxicity, or for
a maximum of 12 cycles
Cycle 1
KYPROLIS
20 mg/m2
bAssessed by an Independent
Review Committee using
International Myeloma Working
Group criteria. ORR = stringent
complete response (sCR) +
complete response (CR) + very
good partial response (VGPR) +
partial response (PR).
Siegel DS et al. Blood. 2012;120(14):2817-25.
Pivotal Phase 2 Study (003A1) of Single-agent
Carfilzomib in Relapsed Multiple Myeloma
14

15. Pivotal Phase 2 Study (003A1): Efficacy
0.4%
N=1
4.9%
N=13
17.7%
N=47
0
5
10
15
20
CR VGPR PR
PercentageofPatients(%)
• ORR=22.9% (95% CI: 18.0, 28.5)
• DOR=7.8 months (95% CI: 5.6, 9.2)
ORR=22.9% (N=61)
 Patients with high unmet
medical need
 Actively progressing, multiply
relapsed, and refractory
myeloma
 Objective, durable, and
clinically meaningful benefit
 ORR by IRC and investigator
highly concordant
 CBR 35.7%, median DOCBR
of 8.3 months
 Consistent benefit in clinically
important subgroups
 Benefit replicated in
supportive Phase 2 myeloma
trials
15
Siegel DS et al. Blood. 2012;120(14):2817-25.

16. Pivotal Phase 2 Study (003A1): Safety
 Patients with comorbidities
can be safely treated with
carfilzomib
 Low discontinuation rate
 Serious cardiac event and
mortality rates comparable
to literature
 Carfilzomib can be used for
long-term treatment, even
in patients with peripheral
neuropathy
 No cumulative toxicity
Deaths due to all causes (7%)
Serious Adverse Reactions (ARs)
(45%)
• Pneumonia (10%)
• Acute renal failure (4%)
• Pyrexia (3%)
• Congestive heart failure (3%)
ARs leading to discontinuation (15%)
• Congestive heart failure (2%)
• Cardiac arrest, dyspnea, increased blood
creatinine, and acute renal failure (1%
each)
16
Siegel DS et al. Blood. 2012;120(14):2817-25.

17. Challenges for Relapsed and Refractory Patients with
Multiple Myeloma
17
 Reuse of agents but with lower ORR and shorter
duration
 Combination regimens needed to achieve efficacy
but are poorly tolerated
 Supportive, palliative care and hospice