Unmet need in multiple myeloma

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Relapsed and Refractory Multiple Myeloma:

Unmet Need

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.

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

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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

✔ ✔ ✔


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.

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

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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.

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

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


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.

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.

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.

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

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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.

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

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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 Perc

enta

ge o

f Pat

ient

s (%

)

•  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

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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)

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Challenges for Relapsed and Refractory Patients with Multiple Myeloma

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  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

Unmet need in multiple myeloma

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