IG- -Biologic Micellar Paclitaxel Formulation for the Treatment of Metastatic Breast Cancer

Kouros Motamed1*, Larn Hwang1, Chao Hsiao1, Chulho Park1, Vuong Trieu1

INTRODUCTION

IG-001 (Genexol-PM), utilizes biodegradable di-block copolymers composed of methoxy poly (ethylene glycol)-poly (lactide) to form micellar nanoparticles with paclitaxel containing a hydrophobic core and a hydrophilic shell and is being developed as the next generation nanoparticle paclitaxel. The evolution of paclitaxel therapy came about with Abraxane®, a solvent-free, nanoparticle albumin-bound (nab) formulation of paclitaxel that extended the maximum tolerated does (MTD) of Taxol by 48% (Fig. 1). Unlike Abraxane®, IG-001 is free of human albumin, benefits from a simple handling and preparation formulation, and has displayed a 15-30% increase in MTD over Abraxane®. Its target indications are solid tumors such as Breast, Lung, Ovarian, Bladder, Pancreatic and Melanoma.

We have recently shown that the dissolution profile of IG-001 is very similar to that of nab-paclitaxel/Abraxane® 1. Once injected into the circulation, both formulations quickly dissolve into paclitaxel complexed with endogenous circulating albumin, suggesting that both formulations deliver paclitaxel to the targeted tissue via albumin-mediated transport. Herein, we provide a summary report of our clinical studies in Metastatic Breast Cancer (MBC) that includes two Phase 2 studies, interim results for a Phase 3, as well as a Phase 4 post-marketing surveillance (PMS) study.

1IGDRASOL Inc. 11100 Warner Ave. Suite 266, Fountian Valley, CA 92708.

Contacting Author: Kouros Motamed; phone: 1-818-919-6107; fax: 1-714-445-0127; email:kmotamed@igdrasol.com

RESULTS

GPMBC-201: A Phase 2 safety and efficacy study of IG-001 in anthracycline-resistant metastatic Breast cancer. A single arm, multicenter study to evaluate the efficacy and safety of IG-001 in female patients with anthracycline-resistant metastatic breast cancer (MBC). Fifty seven patients were recruited from 7 centers in South Korea where they received a 300 mg/m2 dose of IG-001 via a 3-hour infusion at each cycle using a q3w dosing regimen. This study showed thatIG-001, when administered to anthracycline resistant metastatic breast cancer patients, produced an objective response rate of 28.1% indicating that IG-001 would be an effective treatment for anthracycline-resistant breast cancer (Table 1). For the secondary efficacy end points,the median time to response was 41.5 days. The median response duration was 167.5 days (95% CI), the median time to tumor progression (TPP) was 198 days (95% CI), the median progression-free survival (PFS) was 169 days (95% CI) and the median overall survival was 568 days (95% CI).

GPMBC-202: A Phase 2 safety and efficacy study of IG-001 in anthracycline-resistant metastatic Breast cancer. This single arm, multicenter Phase 2 trial to evaluate the efficacy and safety of IG-001 in subjects with histologically confirmed metastatic breast cancer was conducted at 5 hospitals in Korea. Forty-one women received IG-001 by intravenous infusion at a dose of 300 mg/m2 over 3 hour every 3 weeks without routine premedication until disease progression, unacceptable, toxicity, or subject refusal.

A total of 331 chemotherapy cycles was administered, with a median of 8 cycles per subject (range, 1 - 16). The objective response rate for the

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Proceedings of the 7th IEEE InternationalConference on Nano/Molecular Medicine and Engineering

November 10-13, 2013, Phuket, Thailand

overall population was 58.5% (95% CI, 43.5 -72.3%), with 5 complete responses and 19 partial responses. Thirty-seven subjects who received IG-001 as a first-line therapy for their metastatic disease showed a response rate of 59.5% (95% CI, 43.5 - 73.7%), and two responses were reported in four subjects treated in the second-line setting for their metastatic disease. Mean dose intensity was 87.4 ± 16.7 mg/m2/week and the median was 100 mg/m2/week. Median TTP (time to progression) and OS for all subjects were 294 days (CI: 256 -

The duration of response was defined as the interval from the date PR criteria were satisfied to the date PD criteria were confirmed. A total of 24 (CR 5+PR 19) subjects (61.5%) were included in the duration of response analysis. Of these, a total of 4 subjects (16.7%) were confirmed with PD, and 20 subjects who did not have confirmed PD were censored and the study completion date was substituted for the end of observation date. The median survival time of the duration of response was not able to be estimated (PD was not confirmed in 50% or more of patients). The 95% confidence interval (Greenwood method) was 156 days.

GPMBC-301: A Phase 3 study of IG-001 inmetastatic Breast cancer.

This dual arm, multicenter Phase 3 study was conducted to compare safety and efficacy of IG-001 vs. Taxol. One hundred six patient per arm received either Taxol (175 mg/m2) or IG-001(300 mg/m2) over a 3 hour period every 3 weeks for 6 cycles. The study is to be completed in the first half of 2014. The interim analysis of the data from 209 patients has revealed a superior ORR of IG-001 (40%) vs. Taxol (26%). This superiority over Taxol is very comparable to the historical data from Abraxane® trials (Fig. 2).

Post-Marketing Surveillance of Genexol-PM/IG-001 in Breast Cancer.

IG-001 was launched as Genexol-PM in Korea in February 2007 and post-marketing surveillance for breast cancer has been completed. This was a post-marketing surveillance study of IG-001 in patients with locally recurrent or metastatic breast

cancer conducted to investigate the incidences and types of adverse events including unexpected and serious adverse events in clinical use. The study was also intended to monitor changes in the incidences and types of AEs, to assess clinical factors affecting safety and to assess clinical factors affecting efficacy in this setting.

The study was conducted at 12 medical institutions in Korea with expertise in the treatment of breast cancer from 08 Dec 2007 to 31 Dec 2010. 186 subjects were enrolled and had surveillance data sheets collected during this period. The starting dose of IG-001 was 300 mg/m2 with possible dose reductions in 2 stages based on hematological and non-hematological toxicities (except alopecia) to 240 mg/m2 and 190 mg/m2. IG-001 wasadministered as an intravenous infusion over 3 hours.

There were 185 females and 1 male subject in the safety population. The mean age of the subjects was 50.31 years with a range of 29 to 75 years. One hundred sixty subjects (90.32%) were < 65 years old and 18 subjects (9.68%) were 65 years or older. The disease duration ranged from 0.33 to 312 months with a mean duration of 64.44 months. One hundred eighty subjects (96.77%) had stage IV disease and 6 subjects (3.23%) had stage III disease. One hundred eighty four subjects (98.92%) had no medical history of allergies. One hundred eighty one subjects (97.31%) had prior treatment for breast cancer including 174 subjects (96.13%) with prior chemotherapy, 111 subjects (61.33%) with prior radiation therapy and 160 subjects (88.40%) with prior surgery.

In this PMS study of IG-001 in patients with breast cancer, the study drug was well tolerated with an excellent safety profile even though most of these patients had extensive prior chemotherapy. Most patients received close to the planned dose. The pre-medication regimen was effective in preventing hypersensitivity reactions and the incidence of rash and pruritus was low. There was only one case of a more serious hypersensitivity reaction (anaphylaxis) which was treated and resolved. Peripheral neuropathy was common but was not dose-limiting in most cases. Hematological toxicities were manageable and there were only 3 subjects with febrile neutropenia.

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CONCLUSIONS

A non-albumin-based paclitaxel formulation (IG-001/Genexol-PM) was shown here to have all the properties of the albumin-based paclitaxel formulation (nab-paclitaxel), including dissolution in plasma, high tumor plasma ratio, and dose-proportional PK [1-4]. These are consistent with IG-001 being capable of utilizing the albumin-mediated transport described for nab-paclitaxel (Abraxane®).

Taken together, in patients with metastatic breast cancer who have been previously treated with chemotherapy, including anthracycline containing regimens, the efficacy of IG-001 appears to be similar and at least equal to that of Abraxane®.Further development of IG-001 is therefore warranted in Breast cancer as well as other solid tumors.

Lastly, IG-001 is ideal for personalized paclitaxel therapy due to its expanded dose-proportionality and more gradual toxicity profile versus the currently available nanoparticle formulation of paclitaxel—namely Abraxane. Personalized paclitaxel therapy should allow for increased dosing without undue toxicity and therefore enhanced clinical efficacy. As such, it could give us the next generation paclitaxel nanoparticle formulation that can be more readily modified than nab-paclitaxel (Abraxane®).

REFERENCES

[1]. K. Motamed, C. Cheng, L. Hwang, C. Hsiao, V Trieu. 'A non-biologic nanoparticle paclitaxel (NBN-Pac) formulation with characteristics of albumin-based formulation—(nab-Pac)'. AACR-JCA Joint Conference: Breakthroughs in Basic and Translational Cancer Research. (2013), Abstract # D096,

[2]. N. K. Ibrahim, N. Desai, S. Legha, P. Soon-Shiong, R. L. Theriault, E. Rivera, B. Esmaeli, S. E. Ring, A. Bedikian, G. N. Hortobagyi, and J. A. Ellerhorst, 'Phase I and Pharmacokinetic Study of Abi-007, a Cremophor-Free, Protein-Stabilized, Nanoparticle Formulation of Paclitaxel', Clin Cancer Res, 8 (2002), 1038-44.

[3]. T. Y. Kim, D. W. Kim, J. Y. Chung, S. G. Shin, S. C. Kim, D. S. Heo, N. K. Kim, and Y. J. Bang, 'Phase I and Pharmacokinetic Study of Genexol-Pm, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies', Clin Cancer Res, 10 (2004), 3708-16.

[4]. W. T. Lim, E. H. Tan, C. K. Toh, S. W. Hee, S. S. Leong, P. C. Ang, N. S. Wong, and B. Chowbay, 'Phase I Pharmacokinetic Study of a Weekly Liposomal Paclitaxel Formulation (Genexol-Pm) in Patients with Solid Tumors', Ann Oncol, 21 (2010), 382-8.

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Fig. 1. Evolution of Paclitaxel Therapy. Abraxane® improved the MTD of Taxol by 48% as the 1st

solvent-free, albumin-bound nanoparticle paclitaxel. IG-001 paclitaxel polymeric micelles can improve the MTD of Abraxane® by 15-30% , hence can be labeled as the 3rd generation paclitaxel therapy.

Table 1. GPMBC-201: Objective Response of Patients with Anthracycline Resistant Metastatic Breast Cancer Treated with IG-001—ITT and PP Analysis

TUMOR RESPONSE ITT (N=57) ITT*(N=55) PP**(N=53)

Partial Response 16 (28.1%) 16 (29.1%) 16 (30.2%)

Stable Disease 29 (50.9%) 29 (52.7%) 27 (50.9%)

Progressive Disease 10 (17.5%) 10 (18.2%) 10 (18.9%)

Non evaluable subjects 2 (3.5%) - -

Response (CR+PR) 16 (28.1%) 16 16 (30.2%)

* Excluding Non-evaluable subjects

** Per protocol population was defined as the subjects who did not have major violation and were treated at least 2 cycles and received tumor evaluation more than once.

IG-001 Mean size

25 nm

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Table 2. GPMBC-202: The Efficacy of IG-001 with Metastatic Breast Cancer—ITT and

PP Analyses

Tumor Response ITT (N=41) ITT *(N=39) PP** (N=33)

Complete Response 5 (12.2%) 5 (12.8%) 4 (12.1%)

Partial Response 19 (46.3%) 19 (48.7%) 17 (51.5%)

Stable Disease 13 (31.7%) 13 (33.3%) 10 (30.3%)

Progressive Disease 2 (4.9%) 2 (5.1%) 2 (6.1%)

Non evaluable subjects 2 (4.9%)

Response (CR+PR) 24 (58.5%) 24 (61.5%) 21 (63.6%)1 Excluding non-evaluable subjects.2 Defined as the subjects who did not have major violation and were treated at least 2 cycles.

Fig. 2. IG-001 and Abraxane® Show Similar Overall Response Rates (ORR) vs. Taxol.

* Data presented for IG-001 is interim results of an ongoing phase 3 study in MBC conducted in South Korea. Comparison is made to that of pivotal registration trials of Abraxane® vs. Taxol in the US and China.

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Table 3. Summary of Efficacy Assessments for PMS of IG-001.

Clinical Response Subjects

N (%)

CR (complete response) 0 (0.00)

PR (partial response) 36 (24.32)

SD (stable disease) 53 (35.81)

PD (progressive disease) 58 (39.19)

Unevaluable 1 (0.68)

Total 148 (100.00)

Table 4. Summary of Efficacy Assessments of IG-001 in MBC.

Clinical

Trial Phase

Clinical

Trial Design

Study/ No. of

Patients

Treat.

Regimen

Dose

(mg/m2), scheduling

Infusion

Time (min)

%

ORR

PFS/TTP (months)

OS

(months)

Remarks

MBC

Ph 2

S. Korea

Single arm,

Multi- center

GPMBC201 57

Mono- therapy

300, q3w

180

28.1

ND

ND Anthracyclin-

resistant MBC

Ph 2

S. Korea

Single arm,

Multi-center

GPMBC202

43

Mono-therapy

300, q3w

180

58.5

ND

ND

Ph 3 S. Korea (Interim)

Dual arm,

Multi-center

GPMBC-

202 106/arm

Mono-therapy

IG=300, q3w vs.

Tax=175, q3w

180

40 vs. 26

ND

ND

PMS S. Korea

Single arm,

Multi- center

186 Enrolled/

143 Treated

Mono-therapy

Up to 300,

q3w (185-300)

180

24.3

ND

ND

Locally-

recurrent or MBC

100