Overcoming the Road Blocks: Advancement of Block Copolymer

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Overcoming the Road Blocks; Advancement of Block Copolymer Micelles for Cancer Therapy in the Clinic Loujin Houdaihed, James C Evans, and Christine Allen Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 08 May 2017 Downloaded from http://pubs.acs.org on May 11, 2017

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Molecular Pharmaceutics

Overcoming the Road Blocks; Advancement of Block Copolymer Micelles for Cancer Therapy in the Clinic Authors Loujin Houdaihed1 James C. Evans1 Christine Allen*1 ¹Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.

*All correspondence relating to this paper should be addressed to: Professor Christine Allen, Leslie Dan Faculty of Pharmacy, University of Toronto, Canada. Tel: +1 416-946-0040 Fax: +1 416-978-8511 E-mail: [email protected]

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Abstract With countless pre-clinical studies on block copolymer micelles (BCMs) successfully demonstrating the superiority of these advanced drug delivery formulations over conventional formulations, it remains somehow discouraging that only a few have reached clinical evaluation and practice. With a critical eye, this review aims to compare and summarize the preclinical and clinical data available on several BCM formulations and to identify their primary role in drug delivery as ‘carrier’ or ‘solubilizer’. This review article focuses on polymeric micelles that have reached clinical evaluation and/or are being pursued commercially. While not always available, we aim to compare the pharmacokinetics, toxicity, and efficacy data obtained in preclinical studies to identify the factors that likely played a key role in a decision to move these formulations forward from bench to a first in human trial. Finally, we summarize clinical data obtained to date, when available, and conclude with the impact that each formulation has had on patients in terms of safety and efficacy. Keywords: Block copolymer micelles, targered delivery, EPR, nanoformulation, nano drug delivery systems, clinical translation.

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1. Introduction Block copolymer micelles (BCMs) encapsulating anti-cancer agents were first developed in the late 1980s, and since then have gained widespread interest as a viable drug delivery platform. During the past three decades, intense pre-clinical research on this nanoplatform has enabled a number of promising BCM formulations to enter clinical development with two receiving regulatory approval (Cynviloq and Nanoxel)1–3. Polymeric micelles were initially developed to improve the aqueous solubility of hydrophobic drugs. They were considered to be alternatives to the commonly used conventional excipients (e.g. Cremophor EL) that have been associated with significant toxicity. BCMs are advantageous as drug delivery systems in cancer therapy with optimized formulations having high drug to material ratios and enabling solubilization of drugs up to 10000 fold beyond their aqueous solubility 4–6. BCMs are best described as core-shell structures with hydrodynamic diameters ranging between 10 and 200 nm. They are composed of a hydrophobic core which encapsulates lipophilic drugs and a hydrophilic shell that is most commonly comprised of poly(ethylene glycol) (PEG) and provides a protective barrier between the core and the external medium 7,8. The self-assembly of block copolymers to form BCMs in aqueous solution is usually driven by hydrophobic interactions to minimize the interfacial free energy of the copolymer-water system. Self assembly is a thermodynamic process which depends on many factors including the composition and the concentration of the copolymer 9. The critical physico-chemical characteristics of drug-loaded BCMs that influence their performance in vivo include size, size distribution, morphology and stability. The stability of drug free BCMs is considered to include two components: namely, thermodynamic and kinetic stability. The thermodynamic component is primarily governed by the copolymer concentration such that when the total copolymer concentration in an aqueous solution is above the critical micelle concentration (CMC), the micelle is said to be thermodynamically stable. While, the kinetic component is largely determined by the nature and state of the hydrophobic core. For example, a solution of BCMs may be diluted to copolymer concentrations well below the CMC, and yet the micelles may remain intact due to kinetic stability (e.g. semi-crystalline core ) 10. The performance dependent parameters of BCMs can largely be tailored by optimizing the properties of the copolymer (i.e. nature, molecular weight, polydispersity, ratio of hydrophobic to hydrophilic block lengths) and method of preparation. Importantly, the properties of the drug and the ratio of drug to copolymer also play a significant role in determining performance. For example, the incorporation of drug into BCMs can alter their size, size distribution and morphology 10. A major challenge with BCM-based drug formulations is the design of micelles that act as true drug carriers and not only as solubilizers. In most cases, it is preferable that BCM-based drug formulations are highly stable in vivo in order to prolong their blood circulation lifetime 11. The compatibility between the drug and the core-forming block of the copolymer is an important parameter that has been shown to influence drug loading and retention as well as formulation stability 1,9. Given that each drug has unique physico-chemical characteristics it is unlikely that a BCM system formed from a single copolymer will serve as the ideal platform for the delivery of

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all drugs. As a result, a number of distinct polymer materials have been considered as the hydrophobic blocks of the copolymer 12. To date, the most commonly used hydrophobic blocks have been polyesters, poly(amino acids) (PAA), and polyether derivatives. Polyesters, such as poly(lactic acid) (PLA), and poly(Ɛcaprolactone) (PCL), are biocompatible and biodegradable and have been approved by the FDA for biomedical applications in humans. PAA, such as poly(aspartic acid) (PAsp) and poly(glutamic acid) (PGlu), are biodegradable and their multiple carboxy/amine functional groups enable conjugation of drugs and formation of complexes with various metals, or can be modified to optimize the core-drug compatibility, thus, increasing drug loading and formulation stability 12. Polyethers of pharmaceutical interest are copolymers of (poly(ethylene glycol)poly(propylene oxide)poly(ethylene glycol)) (PEG-b-PPO-b-PEG), known as poloxamers (Pluronic®). They are non-biodegradable but the individual polymer chains with a size of < 50 kDa can be excreted by the kidneys 12,13. 2. Carriers vs. Solubilizers The physico-chemical properties of BCMs can significantly influence the pharmacokinetics (PK) and biodistribution (BD) of their encapsulated cargo. However, the degree to which the drug’s in vivo fate is affected depends on the extent of drug retention in the micelles. Different factors that determine the stability and the resulting in vivo behavior of BCMs have been reviewed previously 7. Those factors can be divided into two main categories: the properties of the copolymer (chemical properties, molecular weight, ratio of hydrophobic to hydrophilic block length, and physical state of the core), and the physico-chemical properties of the copolymer aggregates (size, morphology and surface properties) 1. The stability of BCMs and their drug retention is significantly challenged by many factors following introduction into the systemic circulation including dilution of BCMs in the bloodstream, adsorption of blood proteins to the outer shell of the micelles and many others 1. We can distinguish between these two different classes of BCMs in terms of in vivo behavior depending on their stability: solubilizers and carriers. When BCMs have poor stability, release the drugs shortly after intravenous (i.v.) administration and act primarily by increasing the solubility of hydrophobic drugs, they are considered solubilizers. In this case, the PK and BD of the delivered drug will not be significantly different from that of a conventional formulation 7. Generally, the resultant rapid drug release from the micelles upon administration is undesired as it leads to a high volume of distribution for the drug and ensuing toxicities 7. However, solubilization is of great value to hydrophobic cancer drugs and many BCMs of low stability have been developed and some have made it to the market (Cynviloq and Nanoxel) for drug solubility enhancement purposes 2,14,15. The majority of small molecule therapies in oncology are hydrophobic and the administration of high doses of these drugs in aqueous solutions is a major challenge 14. Additionally, most of the conventional drug formulations currently used in the clinic, such as Taxol and Taxotere rely on surfactants such as Cremophor EL and Polysorbate 80 as solubilizers; these excipients have been associated with hypersensitivity reactions and other adverse events such as peripheral neuropathy and fluid retention 16–18. One of the important advantages of advanced drug delivery systems such as BCMs is that higher doses of drugs can be administered without inducing the hypersensitivity

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reactions that are seen with conventional formulations. Indeed, BCM-based systems that act as solubilizers are of value for their good tolerability and the improvement in the toxicity profile that results from the elimination of small molecule surfactants and other excipients. However, their low stability, to some extent limits their exploitation of the enhanced permeability and retention (EPR) effect, and therefore their efficacy is typically comparable to that of conventional formulations 11,19. On the other hand, if the BCM-based drug formulation is stable following IV administration with good drug retention then the drug’s in vivo fate will mirror that of the micelles 1,7. Importantly, in order to achieve site-specific delivery, it is crucial to have the drug retained within the core of BCMs 1,11. Micelles that act as true carriers are preferable as their high stability prolongs their blood circulation lifetime and enables effective exploitation of the EPR effect resulting in selective and increased tumor accumulation— a prerequisite for improving the anti-tumor efficacy of the formulation. Stable BCMs also limit systemic drug exposure and the ensuing toxicity that results 11. However, despite their improved pre-clinical efficacy, as observed in animal models in comparison to conventional treatments and unstable micelles, BCMs functioning as carriers failed to achieve the same results in humans 20 As we now have learned, there is tremendous heterogeneity associated with the EPR effect. Accordingly, tumor accumulation of BCMs and other nanotechnologies can vary significantly from patient to patient with the same and different tumor types 21. Thus delivery systems that are engineered to exploit the EPR effect alone do not guarantee significant anti-tumor efficacy in all patients 22. Beyond bulk tumor accumulation there are many other factors that influence efficacy including effective drug release from the carrier, intratumoral distribution of drug, and cellular internalization or transport to the drug’s target site of action 11,19. Herein we review several of the BCM formulations that have reached clinical development with a focus on identifying their role as either carrier or solubilizer and highlighting their strengths and limitations. The focus here is on formulations delivering platinum-based chemotherapy (cisplatin and oxaliplatin), doxorubicin, and taxanes (paclitaxel and docetaxel), that have been advanced to clinical trials and/or the clinic (Table 1). All formulations discussed were initially developed for cancer therapy; one formulation (Paxceed) was further investigated for other indications including rheumatoid arthritis and psoriasis. 3. Block Copolymer Micelle-Based Drug Formulations in Clinical Development 3.1.Platinum-Based Chemotherapy (Cisplatin and Oxaliplatin) Platinum (Pt)-based drugs act by crosslinking with the purine bases of DNA which prevents DNA repair leading to apoptosis 23. Cisplatin (cis-dichlorodiammineplatinum (II)) (CDDP), the first member of the classical Pt complexes, is widely used as first line chemotherapy for many cancers, including lung, ovarian, gastrointestinal, and cervical cancer 24–27. Treatment with CDDP is often discontinued due to major toxicities, specifically, nephrotoxicity and neurotoxicity 28,29. In addition, intrinsic (in colorectal, lung and prostate cancer patients) or acquired (in ovarian cancer patients) drug resistance has been observed in a high fraction of patients 30. This has led to the development of second and third generation Pt complexes. Oxaliplatin (1,2-diaminocyclohexane Pt (II) ((DACH-Pt) oxalate) is a member of the third

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generation of Pt complexes with higher solubility and less toxicity than CDDP 31. Oxaliplatin has been shown to be active against refractory ovarian cancer, germ-cell cancers, anthracyclineresistant metastatic breast cancer (MBC), and non-small cell lung cancer (NSCLC) 32–35. Oxaliplatin is currently used as a standard treatment for colorectal cancer; however, the use of this drug has been associated with severe peripheral neuropathy characterized by limb numbness 36 . Therefore, several BCM formulations encapsulating Pt-based therapeutics have been developed in an effort to improve the safety of the drug and overcome resistance. 3.1.1

NC-6004

First reported in 2003, NC-6004 is a BCM formulation of CDDP that was originally developed by Kataoka’s group at the University of Tokyo and licensed to NanoCarrier (Japan). In 2008, NanoCarrier out-licensed NC-6004 to Orient Europharma (Taiwan) 37. NC-6004 is unique relative to other BCM formulations that have reached clinical development in that the drug is complexed to the core-forming poly(glutamic acid) block of the poly(ethylene glycol)poly(glutamic acid) block copolymer [PEG-b-P(Glu)] (12000: 6000 g/mol) with a [CDDP]/[Glu] molar ratio of 0.71 28. The micelles are spontaneously formed by complex formation between Pt(II) and carboxy groups in the P(Glu) block. This formulation has shown high stability relative to other block copolymer-drug aggregates (with a copolymer CMC < 5 x 10-7) 28, and provides sustained release of CDDP for over 150 h in physiological saline. NC-6004 drug loaded BCMs are 28 nm in diameter with a narrow size distribution and high drug loading level (39% w/w) with a drug to copolymer ratio of 27. The micelles were found to maintain a diameter of approximately 25 nm for up to 50 h when incubated in physiological saline at 37 °C 38. Preclinical Studies In preclinical evaluation of NC-6004, its administration was shown to prolong the circulation lifetime of the CPPD and resulted in a 20-fold increase in its accumulation at the tumor site in a murine Lewis lung carcinoma (LLC) xenograft model, relative to free drug administered at the same dose 38. In a PK study, the plasma area under the curve (AUC) and Cmax values were 65and 8-fold higher, respectively, in NC-6004 treated rats compared to rats administered free drug (at an equivalent CDDP dose) 28. NC-6004 resulted in high accumulation in the liver and the spleen compared with CDDP; however, kidney Pt levels were 3.8-fold lower. Importantly, the tumor Cmax and AUC were 2.5- and 3.6-fold higher, respectively, with NC-6004 relative to CDDP 28. The maximum accumulation of NC-6004 in the tumor was seen at 24 h, with approximately 10% of dose/g of tissue. The Pt level in the plasma was reported to be approximately 60% of the injected dose at 8 h and 13 % at 24 h after administration of NC-6004 38 . Toxicities that are typically seen with CDDP including neurotoxicity, nephrotoxicity and ototoxicity were found to be significantly reduced 28,29,39. While sensory nerve conduction velocities were normal in NC-6004 treated animals, they were significantly lower in CDDP treated animals. As well, histological studies showed that the NC-6004 treated group had significantly lower Pt levels in the sciatic nerve relative to that found in the CDDP group resulting in reduced neurotoxicity for NC-6004 28. Creatinine and blood urea nitrogen levels were normal with NC-6004 but increased with CDDP 28. In another study, the number of apoptotic renal cells in the NC-6004-treated mice was significantly lower than that in the CDDPtreated group by approximately 66%, clearly demonstrating significantly less nephrotoxicity

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associated with NC-6004 39. Additionally, ototoxicity studies in guinea pigs showed that NC6004, unlike CDDP, did not cause any changes in auditory responses 29. The most significant antitumor activity for NC-6004 was observed in a model of colon cancer (C26) in mice. In this study, treatment with NC-6004 led to complete tumor regression, which was not obtained with free CDDP when administered at the same dose 38. NC-6004 significantly inhibited tumor growth of gastric carcinoma (MKN-45) and oral squamous cell carcinoma (OSC-19) in mice; however, when administered at the same dose, results were comparable to that obtained with free drug 28,39. Likely drivers for clinical translation Based on findings from pre-clinical studies the main advantages associated with NC-6004, relative to free drug, are its prolonged circulation lifetime and improved toxicity profile. These advantages are attributed to its high degree of plasma stability and good drug retention following i.v. administration. Despite the improved tumor accumulation associated with NC6004, the efficacy was reported to be comparable in most tumor models when NC6004 and free drug were administered at chemically equivalent doses of Pt. This may be indicative of poor or limited drug release from the carrier once at the tumor site. As a result, the superior safety profile of NC-6004 relative to that of CDDP—namely, reduced nephrotoxicity, neurotoxicity and ototoxicity— was likely the key factor that motivated translation of this formulation into clinical development. Clinical Studies A Phase I clinical trial evaluating NC-6004 in 17 patients with advanced solid tumors was completed in 2011 40. In this study, the PK of total plasma Pt, gel-filterable Pt (encapsulated Pt), and ultrafilterable Pt (extra-micellar Pt) were evaluated. For both total and encapsulated Pt, the PK profiles were similar with an 11-fold increase in plasma AUC and a prolonged plasma halflife following administration of NC-6004 in comparison to previously reported values for free drug (at the same dose). For ultrafilterable Pt, a 230-fold increase in the plasma half-life and an 8.5-fold increase in plasma AUC were reported, suggesting that NC-6004 provides sustained release of Pt after administration. Consistent with preclinical observations, toxicities such as, nephrotoxicity, neurotoxicity, and ototoxicity, were less frequent and less severe in patients treated with NC-6004 relative to those treated with free drug. Although nephrotoxicity was reduced, it was still observed in patients who received the highest dose (120 mg/m2) even with a hydration regimen. Standard treatment with CDDP requires 8 hours of both pre and posthydration in order to reduce nephrotoxicity. For this reason, the decreased nephrotoxicity of NC6004 is considered a major advantage over CDDP as it reduces the need for hydration. However, unanticipated hypersensitivity reactions were observed with NC-6004. Although, not fully understood, the rapid binding of plasma protein to released CDDP and the subsequent prolonged blood circulation time of the protein-bound CDDP was suggested as a mechanism underlying the hypersensitivity reactions to NC-6004. The maximum tolerated dose (MTD) was not identified as per protocol due to the severe and unexpected hypersensitivity reactions. 120 mg/m2 was considered to be close to the MTD (similar to the previously reported MTD of the free drug), and the recommended dose was identified as 90 mg/m2 40. Another Phase I/II study was conducted to evaluate the combination of NC-6004 with Gemcitabine (GEM) in patients with pancreatic cancer. In this trial, patients were premedicated with oral steroids prior to administration of NC-

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6004 and no hypersensitivity reactions were reported. Treatment with NC-6004 in combination with GEM was relatively well tolerated and exhibited modest efficacy in this patient population 41 . Taken together, the clinical data obtained to date has confirmed that NC-6004 is a relatively stable formulation of CDDP that results in a significantly different PK profile of the drug. NC6004 is advantageous over CDDP primarily due to a reduction in toxicity to normal tissues and a relative improvement in the patient’s quality of life. Patients may undergo therapy with minimal hydration and treatment of cisplatin-related toxicities. Yet to this point the formulation has only resulted in modest efficacy 40,41. NanoCarrier is currently undertaking five clinical trials on this formulation including a Phase III trial for various cancer indications including head and neck (NCT02817113), and pancreatic cancers (NCT02043288) in Asia and the US, respectively (Table 2) 42. 3.1.2. NC-4016 NC-4016, invented by Professor Kataoka of the University of Tokyo and currently licensed by NanoCarrier (Japan), was developed to improve the anti-tumor effects and decrease the peripheral neuropathy of oxaliplatin, a member of the third generation of Pt agents. Similar to NC-6004, NC-4016 micelle formation is driven by polymer–metal complexation between the Pt of (DACH-Pt) and carboxylic acid groups of poly(ethylene glycol)-poly(glutamic acid) block copolymers (PEG-b-P(Glu)) (12000: 6700 g/mol). The drug loaded BCMs of NC-4016, with a [DACHPt]/[Glu] molar ratio of 0.75 and drug loading level of 32% (wt%), were reported to have a hydrodynamic diameter of 40 nm and a narrow size distribution 43. The micelles were reported to provide sustained drug release in phosphate buffer saline (pH 7.4) at 37 °C over 96 hours after an induction period of 15 h (no release). The BCMs in NC-4016 were also found to maintain their size for 240 h in vitro (only 50 h for NC-6004). Thus, compared with NC-6004, the stability of NC-4016 is elevated and this is attributed to the hydrophobicity of (DACH-Pt) 43,44. Preclinical Studies When NC-4016 and oxaliplatin were administered at chemically equivalent doses of Pt in C-26 tumor bearing mice, NC-4016 resulted in elevated Pt levels in the circulation relative to the administration of free drug. The plasma and tumor AUC for elemental Pt released from NC-4016 were significantly higher than that achieved with administration of oxaliplatin (up to 7 days). This generated high and extended Pt levels at the tumor site with peak levels of 11% of the injected dose/g tumor reached at 48 h post-administration. Plasma Pt levels were reported to be > 80% of the injected dose at 9 h and >16% at 27 h after administration of NC-4016 (higher than those seen with NC-6004 43. In another study, NC-4016 resulted in 20-, 4-, and 25-fold greater accumulation of Pt in the liver, spleen, and tumor, respectively, than oxaliplatin at 48 h after administration 44. Correspondingly, when tested in rats, NC-4016 did not cause any signs of acute neuropathy, unlike oxaliplatin which caused cold induced allodynia (i.e. elevated sensitivity to pain) 36. Importantly, and while free oxaliplatin failed to suppress tumor growth, much greater antitumor efficacy was observed with NC-4016 in mice bearing colon carcinoma (C-26) even at lower doses of Pt 44. NC-4016 also induced significant tumor growth inhibition in oral carcinoma (KB)-bearing mice compared with oxaliplatin when administered at equivalent

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doses of Pt 36. This superior antitumor activity of NC-4016 in comparison to oxaliplatin was made possible by the preferential accumulation of the micelles in the tumor tissue 36,44. Likely drivers for clinical translation In conclusion, preclinical data demonstrated that NC-4016 shows considerably high stability, and has significantly improved the PK profile of oxaliplatin, resulting in superior anti-tumor effects and reduced peripheral neuropathy—a major toxicity associated with oxaliplatin. The significant tumor growth inhibition afforded by NC-4016, relative to free drug, was attributed to the elevated and extended accumulation of Pt in tumors. In contrast, reduced peripheral neuropathy seen with NC-4016 is a result of the high stability of the micelles and reduced exposure of normal tissue to Pt. Overall, the combination of the enhanced safety profile and antitumor efficacy likely served as the basis for pursuing clinical development of this formulation. A Phase 1 clinical trial (NCT01999491) in the US evaluating NC-4016 in patients with advanced solid tumors or lymphoma is now recruiting. 3.2. Taxane-Based Chemotherapy (Paclitaxel and Docetaxel) Taxanes are widely used as first-line treatment for many cancers and act by binding to β-tubulin and stabilizing microtubules resulting in G2/M arrest and subsequent apoptosis 45. Paclitaxel (PTX), a plant derivative of the Pacific Yew tree (taxus brevifolia), is an essential component of standard treatments in ovarian, breast, and lung cancers. However, administration of PTX is associated with dose-limiting adverse effects such as neurotoxicity. In addition, the conventional formulation of PTX (Taxol) has been shown to cause severe hypersensitivity reactions which have been attributed to the excipients used to solubilize the drug (Cremophor El and ethanol) 16. Docetaxel (DTX), a second-generation semi-synthetic taxane, is administered as Taxotere and used for treatment of cancers of the breast, prostate, lung, head and neck, and stomach 46. Taxotere is known to be associated with significant adverse effects such as fluid retention syndrome, injection site reactions, and peripheral neuropathy 17. Therefore, several polymeric micelle systems have been explored in order to improve the toxicity profile associated with PTX and DTX administration 47. 3.2.1. NK105 NK105, originally developed by NanoCarrier and later licensed to Nippon Kayaku, in Japan 48, is a micelle formulation which was developed primarily to overcome the pitfalls associated with Taxol 49. It consists of poly(ethylene glycol)-poly(aspartate) block copolymers (PEG-b-P(Asp)) (12 000: 8000 g/mol) wherein the core-forming block, P(Asp), is modified with 4-phenyl-1butanol to increase core-drug compatibility. NK105 has a high drug loading level of 23% (w/w) and includes BCMs with a diameter of 85 nm 5. Preclinical Studies In mice bearing C-26 tumor xenografts, administration of PTX in NK105 resulted in an extended circulation lifetime with a 90-fold higher plasma AUC than that obtained with free drug at an equivalent dose. The prolonged blood circulation lifetime of NK105 resulted in a significant increase in tumor AUC (25-fold higher compared to free drug) 5. In the same study, NK105 demonstrated superior tumor growth inhibition in HT-29 tumor xenografts (relative to free drug). 9



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Investigating NK105 PK parameters in rats, the volume of distribution at steady state (Vss) was found to be 100-fold lower than that of free PTX, leading to a reduction in neurotoxicity (characterized by demyelination of nerve) in these animals 5. Likely drivers for clinical translation The stable structure of NK105 substantially altered the PK profile of the drug, significantly reducing the distribution of PTX into normal tissues and, as a result, improving the toxicity profile of the drug. In particular, neurotoxicity (commonly observed with Cremophor EL-based formulations), was significantly reduced with NK105. The stable structure of NK105 in the circulation also resulted in high and extended PTX levels in plasma and tumor leading to superior anti-tumor efficacy relative to free PTX 5. The improvements seen in both safety and efficacy provided strong justification for advancing this formulation into the clinic. On a separate note, NK105 shares a common advantage with other PTX-loaded BCM dosage forms that have been advanced to clinical trials, which is the avoidance of using excipients found in the conventional formulation of PTX (Taxol) (Cremophor El and ethanol). These excipients have been shown to be responsible for the severe hypersensitivity reactions associated with the use of Taxol 16. NK105 differs from many of the other BCM formulations of PTX due to its high degree of stability which in turn results in significantly higher plasma and tumor AUCs for the drug and leads to greater antitumor effects. Clinical Studies In a Phase I clinical trial, and consistent with preclinical findings, administration of NK105 resulted in significantly increased plasma and tumor concentrations of drug relative to administration of PTX as Taxol (plasma AUC of NK105 at 150 mg/m2 was 15-fold higher than that previously reported of Taxol at 210 mg/m2) 50. Hematologic toxicities associated with NK105 were comparable to those of Taxol, yet the hypersensitivity reactions were significantly reduced even when prophylactic premedication was not used. Based on this study, the MTD was determined to be 180 mg/m2. The recommended dose for Phase II was defined at 150 mg/m2 and the dose limiting toxicity (DLT) as neutropenia 50. This trial demonstrated the advantages of NK105 over Taxol; namely the reduction in hypersensitivity reactions and the tri-weekly short infusion time (1h instead of 3h), thus providing a better quality of life for patients 50. A Phase II clinical trial was conducted in 57 patients with previously treated advanced stomach cancer. Despite the markedly improved PK profile of PTX following administration in NK105 in comparison to administration of free drug, clinical efficacy was modest (overall response rate (ORR) observed was 25%, median progression free survival (PFS) was 3.0 months, and median overall survival (OS) was 14.4 months) 51. Further interpretation of the results from this trial is difficult as there was no comparison to free drug. In a Phase III clinical trial NK105 was compared to PTX in patients with metastatic or recurrent breast cancer. Results from this trial were released in July 2016 showing that the primary endpoint of the study (statistical noninferiority of PFS) could not be achieved 48. Taken together, in spite of the significantly improved pharmacokinetic profile of PTX following administration in NK105, this formulation

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seems to surpass conventional PTX formulations only in terms of safety in the clinical setting. Therefore, NK105 represents another example of a seemingly promising BCM formulation failing to provide greater efficacy in clinical trials. 3.2.2. Cynviloq Cynviloq (Genexol-PM, IG001, Paclitaxel PM), a BCM formulation of PTX, was the first BCMbased drug formulation to be approved for human use. It was approved exclusively in South Korea for patients with MBC, NSCLC and ovarian cancer. Cynviloq is now on the market in India, the Philippines and Vietnam for treatment of patients with MBC and metastatic NSCLC, and is currently making its way through clinical trials in many countries including a Phase IV trial in South Korea for MBC 3. The BCMs in Cynviloq are formed from the copolymer PEG-bpoly(D,L-lactide) (mPEG-b-PDLLA) (2000:1750 g/mol) using the solid dispersion method 52. The micelles are 20 to 50 nm in diameter and have 16.7% drug loading. In vitro stability studies of Cynviloq were not published but further preclinical and clinical evaluation indicated that the formulation has relatively low stability 6,52. Preclinical Studies In a pre-clinical study in healthy mice, Cynviloq was found to have unique PK and BD profiles; the plasma AUC for PTX following administration as Cynviloq was 30% lower than that obtained for the drug when administered as Taxol. The rapid clearance of the drug from the bloodstream was attributed to the kinetic instability of the formulation, which leads to a rapid release of PTX upon administration 52. When tested in mice bearing B16 melanoma xenografts, Cynviloq was found to have a 3-fold greater MTD. Cynviloq was also well tolerated in rats with a significantly lower LD50 value relative to Taxol 52. The increase in MTD allowed for the treatment of mice bearing MX-1 (breast) and SKOV-3 (ovarian) tumor xenografts with a higher drug dose, leading to superior tumor growth inhibition relative to Taxol.52 Likely drivers for clinical translation The PK profile of Cynviloq indicates that the BCMs in this formulation are rapidly cleared from blood circulation upon i.v. administration. Therefore, this formulation is serving more as a solubilizer for PTX rather than a true drug carrier. However, despite the lack of stability of Cynviloq (which prevents its full exploitation of the EPR effect), this formulation induced significantly greater anti-tumor effects in animal tumor models relative to Taxol. The biocompatibility of the copolymer used and the absence of allergenic excipients (Cremophor El and ethanol) improved the MTD of Cynviloq compared with that of Taxol (3-fold increase) and allowed for higher doses of PTX to be administered, resulting in superior anti-tumor activity 52,53. Indeed, Cynviloq showed promising preclinical data with significantly improved toxicity and efficacy afforded for PTX in breast and ovarian tumor models which warranted pursuing clinical trials. Clinical Studies Consistent with observations from preclinical studies, the first Phase I trial showed the unique PK profile of Cynviloq — lower plasma AUC and a shorter plasma half-life in comparison to

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Taxol suggesting rapid dissociation of the micelles after i.v. administration and enhanced partitioning of Cynviloq into tissues and tumors. Importantly, the MTD of Cynviloq was determined to be 390 mg/m2 which was significantly higher than that for Taxol and the nabpaclitaxel formulation (Abraxane) (200 and 300 mg/m2, respectively). Regarding toxicities, and despite the absence of premedication, Cynviloq showed a favorable toxicity profile with no hypersensitivity reactions as observed with Taxol 6. Several Phase II clinical trials evaluated Cynviloq for different indications including advanced breast cancer and NSCLC (Table 2) 15,54,55. Of note, the administered dose of Cynviloq in these trials ranged from 230 to 435 mg/m2 which is higher than the dose commonly employed for Taxol (~ 170 mg/m2). In agreement with the results obtained in preclinical studies, a single arm trial in 41 patients with MBC, confirmed antitumor activity for Cynviloq in chemo naïve patients and patients pretreated with anthracyclines. The overall response rate for patients in this trial was 58.5% which is higher than that for Abraxane (47.6% at the same dose) and Taxol (21–54%), as a first line therapy for patients with MBC 15. In another single arm Phase II trial, 71 patients with advanced NSCLC received a combination of Cynviloq and CDDP as a first-line therapy. Data from this study were more favorable in terms of response rate and survival duration than most Phase II or Phase III clinical trials using Taxol in combination with CDDP 55. However, another Phase IIb trial which evaluated this combination in 276 patients with advanced NSCLC showed non-inferiority in terms of PFS and OS in comparison to Taxol in combination with CDDP 56. The clinical data led to the approval of Cynviloq, originally developed by Samyang Biopharmaceuticals, in Korea. Approval was granted in the Philippines, India and Vietnam for the treatment of a range of cancers (MBC, NSCLC, and ovarian). The exclusive distribution rights to Cynviloq were acquired by Sorrento Therapeutics (merged with IgDraSol) in the 27 countries of the European Union (EU), North America and Australia in 2013 57–59. Cynviloq is currently in clinical development for multiple indications and is often combined with other chemotherapeutic agents such as doxorubicin, carboplatin, and gemcitabine (Table 2). Bioequivalence studies were carried out to compare Cynviloq and Abraxane in patients with metastatic or locally recurrent breast cancer (NCT02064829) as well as NSCLC. Positive preliminary data, from a total of eight patients, that supported potential bioequivalence was reported in 2014 60. These studies concluded in July 2015, with no updates provided as of yet. Bioequivalence between Cynviloq and Abraxane could potentially allow for the approval of Cynviloq by the FDA through the 505(b)(2) pathway, which would eliminate the need for independent trials evaluating efficacy versus the standard of care 61,62. Several roadblocks might inhibit this however, most notably, the fact that Celgene (the supplier of Abraxane) has filed a Citizens Petition with the FDA highlighting the unique and complex characteristics of nanotechnology and reiterating the FDA’s own stance that the “technical assessments of such products should be product-specific” 63. Abraxane (currently on the market in the EU, North America and India for the treatment of breast cancer) is Cremophor-EL free and comprised of albumin-bound PTX nanoparticles 64. Of note, Cynviloq was acquired by the NantWorks company for up to $1.3 billion in May 2016; this company was founded by Dr. Patrick SoonShiong who is the inventor and developer of Abraxane 64. A recently published Phase III trial (NCT00876486) has evaluated the efficacy and safety of Cynviloq in comparison with conventional PTX in 212 patients with metastatic HER2-negative

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breast cancer. Cynviloq was administered i.v. over 3 hours, once every 3 weeks, without premedication. Cynviloq administered dose started at 260 mg/m2 and was increased to 300 mg/m2, while conventional PTX was administered at 175 mg/m2. Compared with conventional PTX, Cynviloq demonstrated improved ORR (39.1% for Cynviloq vs 24.3% for conventional PTX) 65. However, Cynviloq did not result in significant increases in PFS and OS relative to Cremophor EL-based PTX. Interestingly, both groups had similar toxicity profiles with higher neutropenia rates observed with Cynviloq. Hypersensitivity reactions were seen in both groups and premedication was used as required 65. In conclusion, Cynviloq was superior to Taxol in terms of enabling administration of higher doses of drug in the absence of additional toxicities. Doses of 300-435 mg/m2 can be administered safely in patients 6 in comparison to Abraxane which has an MTD of 300 mg/m2 66. In terms of clinical efficacy, Cynviloq has shown improved ORR compared to Cremophor ELbased PTX; however, the promising efficacy results seen in pre-clinical studies have not translated into significant clinical benefit (i.e. PFS and OS). 3.2.3. Paxceed Paxceed, developed by Burt’s lab at the University of British Columbia and licensed by Angiotech Pharmaceuticals (Canada), is another BCM formulation that physically encapsulates PTX. Paxceed consists of PEG-b-poly(D,L-lactide) (mPEG-b-PDLLA) (2000:1333 g/mol) and is prepared by the film hydration method 67. The micelles are less than 50 nm in size and have a PTX loading level of 10% (w/w). In vitro biocompatibility studies showed the micelles to be biocompatible. The micelles were found to have good physical stability at room temperature with no drug precipitation for over 24 h, however, physiologically relevant stability studies and drug release studies were not available 67,68. Preclinical Studies Preclinical studies in nude mouse models of lung carcinoma (MV-522) compared the PK and BD profiles for Paxceed to that of Taxol. A key difference was that the blood levels of micellar PTX were lower in Paxceed-treated mice (5.5-fold lower plasma AUC). when administered at the same dose 67. This was explained by the rapid (within minutes) dissociation of PTX from micelles following its i.v. administration in rats. 53. Consequently, Paxceed has a similar safety profile to that of Taxol following i.v. administration based on similar MTD values and body weight losses. Interestingly, upon i.p. administration, Paxceed was found to have up to a 5-fold higher MTD relative to Taxol which could be due to slower PTX transfer to the circulation 67. Accordingly, when administered i.v. at their MTDs, Paxceed failed to result in an improvement in tumor growth inhibition in comparison to Taxol, yet it resulted in significantly greater tumor growth inhibition, in comparison to Taxol, following i.p. administration 67. Likely drivers for clinical translation Paxceed and Cynviloq are similar in terms of copolymer composition (i.e. mPEG-b-PDLLA) differing only slightly in the molecular weight of the polymer blocks (2000:1333 in Paxceed vs 2000:1750 g/mol in Cynviloq) and method of preparation employed for drug loaded micelle

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preparation 52,68. Therefore, it was unsurprising that Paxceed showed a lack of stability and low residence time in the blood circulation in animal models. Unlike Cynviloq, however, i.v administration of Paxceed resulted in similar anti-tumor efficacy and toxicity profile to that of Taxol (similar MTD). Therefore, there was no evident advantage to use of Paxceed over conventional PTX via i.v administration in animal tumor models. As a result, this formulation has not been advanced to clinical evaluation for oncology indications 67. However, Paxceed entered clinical trials for a number of non-oncology indications including psoriasis (NCT00006276), rheumatoid arthritis (NCT00055133), and multiple sclerosis. However, since 2004, there have been no updates provided on clinical evaluation of Paxceed 3. 3.2.4. Nanoxel Nanoxel was developed by Dabur Pharma (India) and was later acquired by the Fresenius Kabi (Germany). Nanoxel is a Cremophor-EL free BCM formulation of PTX which was first approved in India in 2006 as an alternative to Taxol for use in MBC, NSCLC, ovarian cancer, and AIDS-related Kaposi's sarcoma 2,69. The micelles are composed of the pH sensitive copolymer polyvinyl pyrrolidone (PVP) and poly(N-isopropyl acrylamide) (NIPAM) (PVP-bPNIPAM). The spherical micelles have a diameter of 80–100 nm and are said to release the drug by erosion of the copolymer which occurs more rapidly at low pH 70. It was hypothesized that after cellular internalization of Nanoxel by endocytosis, the pH sensitive polymer is degraded in lysosomes and the drug then released inside the cell. In vitro cellular uptake studies in three different human cancer cell lines, A549, HBL-100 and PA-1, representing NSCLC, breast cancer and ovarian cancer, respectively, revealed that Nanoxel had significantly higher cellular uptake compared with Cremophor EL-based PTX formulations and similar uptake to that of Abraxane 71 . It should be noted that in vitro stability studies of Nanoxel have not been published. Preclinical Studies Published in vivo preclinical evaluation of Nanoxel is limited to one study which compared the efficacy and toxicity of Nanoxel to that of Abraxane 72. Following i.v administration in healthy mice, no mortality was seen in Abraxane-treated animals while 100% mortality occurred in Nanoxel-treated animals (at the same doses). Abraxane induced significantly greater tumor growth inhibition compared with that of Nanoxel in mice bearing HT29 colorectal carcinoma tumors when administered at equitoxic doses 72. The antitumor activity of Abraxane was still significantly higher even when half of the equitoxic dose of Abraxane was used 72. Likely drivers for clinical translation While in vitro studies revealed a significant increase in cellular uptake of PTX when incubated with cells in the Nanoxel formulation in comparison to incubation with the Taxol formulation and similar uptake to the obtained with Abraxane, Nanoxel showed significantly reduced safety and anti-tumor activity in comparison to that of Abraxane in vivo. This could be attributed to a lack of Nanoxel stability which prevented full exploitation of the EPR effect and reduced accumulation of the micelles at the tumor site. Further interpretation of in vivo data is difficult as there is no published comparison to the clinically used formulation of PTX (Taxol). Thus, overall there is no clear advantage associated with use of Nanoxel in terms of safety or efficacy, at least in published preclinical studies, to support forward movement into clinical evaluation.

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Clinical Studies Nanoxel has been evaluated clinically; yet, at this time limited clinical data on the formulation has been published 73. In the clinical trial that led to the approval of Nanoxel in India, higher response rates were seen in patients treated with Nanoxel in comparison to those treated with Taxol. However, the study design, in particular the small number of patients accrued, restricted statistical analysis of the differences observed 2. This study also revealed high tolerability for Nanoxel as no premedication of patients was required to prevent hypersensitivity reactions 70. A retrospective study published in 2013 assessed the incidence of hypersensitivity reactions and other adverse effects induced by Nanoxel administration compared with Taxol in common practice (i.e. not in a clinical trial setting). This study found that Nanoxel results in the same adverse reactions as Taxol but with a lower incidence and less severity. This study confirmed what was found earlier, that Nanoxel administration is not associated with hypersensitivity reactions even in the absence of prophylactic premedication 2. Taken together, accessible data shows that Nanoxel is better tolerated and less expensive than Taxol —a reported $400 less per cycle— both due to its lower direct acquisition cost and because it does not require premedication for hypersensitivity reactions 2,73. Nanoxel was later approved in several countries in Asia and Latin America. However, the lack of well-designed and adequately sized clinical trials comparing Nanoxel to Taxol and Abraxane have delayed its approval in other countries. It was previously argued that regulatory rules controlling new medications in low- and middle-income countries (LMICs) are less strict than in the USA and Europe, which raises safety and efficacy concerns 73. 3.2.5. Nanoxel-M Nanoxel-M, also known as Nanoxel-PM, Doxetaxel-PM or SYP-0704A, was developed in an effort to find an alternative for the conventional DTX formulation Taxotere. In this formulation, Samyang Biopharmaceuticals applied its proprietary “PM technology” used to produce Cynviloq for solubilization of DTX. As a result, this formulation eliminates the excipient Tween 80 which is included in Taxotere and associated with hypersensitivity reactions and fluid retention 74. Similar to Cynviloq, Nanoxel-M is composed of methoxy-poly(ethylene glycol)-poly(D,Llactide) (mPEG-b-PDLLA) (2000:1765 g/mol) block copolymers and prepared using the solid dispersion method. The micelles have a diameter of 25 nm with a narrow size distribution. The micelles were found to be stable after reconstitution in saline for 6 h 74. Preclinical Studies Preclinical studies in mice, rats and beagle dogs revealed that Nanoxel-M and Taxotere had similar PK profiles 74. Additionally, the amount of unmetabolized DTX excreted in feces and urine following i.v administration of Nanoxel-M was comparable to that of Taxotere in rats. The MTD of Nanoxel-M was found to be similar to that of Taxotere and both formulations had comparable toxicities in terms of hematology and body weight loss, however, micellar DTX did not cause the severe hypersensitivity reactions and fluid retention that are seen with conventional DTX. Regarding antitumor efficacy, tumor growth reduction induced by Nanoxel-M was

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equivalent to that obtained with Taxotere in xenograft mouse models of human lung cancer (i.e. H-460 tumors) 74. Likely drivers for clinical translation Nanoxel-M exhibited an equivalent PK profile to that of Taxotere, indicating that the micelles acted as solubilizers with most of the drug released immediately upon i.v. administration. There was no significant difference in anti-tumor efficacy between Nanoxel-M and Taxotere in animal tumor models. In terms of toxicity, however, Nanoxel-M has shown a superior toxicity profile over Taxotere; the hypersensitivity reactions and fluid retention usually associated with Taxotere were not seen with Nanoxel-M. Based on these results, it was expected that Nanoxel-M could provide a safer treatment than Taxotere while retaining antitumor efficacy in cancer patients. Indeed, the significant improvement in the safety profile of Nanoxel-M was the main advantage of this formulation and supported proceeding to clinical trials. In 2012, Nanoxel-M completed a Phase I trial for advanced solid tumors but no results have yet been published (NCT01336582). Nanoxel-M is now recruiting for a Phase II trial in patients with recurrent or metastatic head and neck squamous cell carcinoma (NCT02639858), and for a Phase III trial to evaluate Nanoxel-M in non-muscle invasive bladder cancer patients (NCT02982395). Both trials are being conducted in South Korea (Table 2). 3.2.6.

CriPec Docetaxel:

CriPec Docetaxel, developed by Crystal Therapeutics, is a proprietary polymeric technology encapsulating DTX. Crystal Therapeutics indicates that this formulation was developed to overcome the side effects associated with the conventional formulation of DTX (Taxotere) and to result in better antitumor efficacy which other DTX-loaded nanomedicines have failed to show 75. In this formulation, DTX is covalently conjugated to core-cross-linked polymeric micelles (DTX-CCL-PMs) composed of poly(ethylene glycol)-b-poly[N-(2hydroxypropyl)methacrylamide-lactate] (mPEG-b-p(HPMAm-Lacn)) copolymers, by a hydrolysable ester bond. The micelles are 66 nm in diameter and have a 12% (w/w) DTX loading level. In vitro drug release studies revealed that the covalent conjugation of DTX to the CCL-PMs allows for sustained release of the drug when tested in PBS (pH 7.4), rat blood and human blood at 37° C following first-order kinetics 75. Preclinical Studies The PK studies evaluating the DTX-loaded CriPec formulation, carried out in healthy rats, showed elevated and extended levels of DTX in the blood stream (t1/2 =16.2 h). Additionally, DTX could still be detected in blood up to seven days after i.v. administration, successfully demonstrating that DTX, due to covalent conjugation of drug to the copolymer, was retained within the micelles for several days. In terms of toxicity, the DTX-CCL-PM formulation was tested in healthy rats and compared to conventional DTX (Taxotere). DTX- related toxicities (such as diarrhea and panleukopenia) were seen in both groups, however, these toxicities were significantly reduced in the DTX-CCL-PMs group despite administration of a 45% higher dose of drug 75.

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Importantly, DTX-CCL-PMs were found to achieve superior antitumor efficacy in mice bearing MDA-MB-231 tumor xenografts in comparison to Taxotere. Surprisingly, a single i.v. injection of DTX-CCL-PMs resulted in complete regression of tumors for over 56 days. The superior efficacy observed with DTX-CCL-PMs was attributed to their significantly increased tumor accumulation compared to Taxotere—20-fold higher when administered at chemically equivalent doses of drug and 40-fold higher at equitoxic doses. Interestingly, DTX-CCL-PMs were also found to reduce tumor stromal components such as pericytes and fibroblasts after a single dose administration, suggesting that the superior efficacy of DTX-CCL-PMs could be partially attributed to the depletion of tumor stroma. Likely drivers for clinical translation Preclinical studies of CriPec Docetaxel formulation revealed that the covalent conjugation of the drug to the cross-linked micelles allowed for this formulation to act more as a carrier for DTX as reflected by the high in vitro stability and extended circulation lifetime of the drug in the blood stream following IV administration 75. Regarding tolerability, DTX-CCL-PMs were much better tolerated compared to conventional DTX (Taxotere). The dose limiting toxicities of DTX that are typically encountered in the clinic such as diarrhea and hematological changes occurred with less severity and/or incidence in DTX-CCL-PMs treated rats in comparison to Taxotere treated rats. The volume of distribution of drug has been significantly reduced (0.06 L/kg) in comparison to that obtained with Taxotere (4 L/kg) 75. Importantly, DTX-CCL-PMs have significantly improved the antitumor efficacy of DTX compared to Taxotere. This was mainly attributed to the enhanced tumor accumulation, as well as the anti-stromal activity of the formulation. Taken together, was successful in improving the efficacy as well as the tolerability of DTX in tumor bearing mice. These data strongly supported further clinical investigation of CriPec Docetaxel formulation and indeed, this formulation was advanced to Phase I clinical trial (NCT02442531) in Belgium (currently recruiting) to be evaluated in patients with solid tumors 76,77. 3.3. Doxorubicin Doxorubicin (DOX) is an anthracyline drug acting primarily by stabilizing Topoisomerase II, leading to inhibition of DNA replication. Since its approval, DOX has been used in the treatment of several cancers including breast, lung, gastric, ovarian, thyroid, and pediatric cancers. However, DOX is associated with DLTs with the most severe being cardiotoxicity 78. Doxil, a liposomal formulation of DOX, and the first FDA-approved nanomedicine (in 1995), results in a prolonged circulation lifetime for the drug in vivo and a significantly improved toxicity profile, in comparison to free drug. Doxil has also been shown to result in an increase in tumor accumulation of drug, yet its efficacy is in part limited by poor drug release once at the tumor site 79. In addition, the clinical use of Doxil has been associated with palmar plantar erythrodysthesia as a DLT 80. Block copolymer micelle formulations of DOX were developed as a means to address these challenges—with the goal of attaining good formulation stability in the bloodstream and complete release of drug once at the tumor site. So far, only two of the BCM formulations that have been developed for delivery of DOX have reached clinical evaluation (NK911, SP1049C).

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3.3.1. NK911 NK911, developed by Nippon Kayaku and Prof. Kazunori Kataoka from University of Tokyo, is a DOX-loaded polymeric micelle formulation comprised of PEG-poly(aspartic acid) (5000:4000 g/mol) block copolymers with DOX conjugated to the poly(aspartic acid) (P(Asp)) core-forming block (45% of P(Asp) repeat units are conjugated with DOX). The conjugation of DOX in the core serves to increase the affinity of the core for the physically incorporated drug, resulting in a high drug loading level and a stable formulation. NK911 has a small particle size, with a diameter of 40 nm. The micelles were found to gradually release the physically entrapped drug from the inner core within 8–24 h; however, conditions of the release studies were not reported and stability studies under physiological conditions are not published 4. Preclinical Studies Preclinical evaluation of NK911 in mice bearing subcutaneous murine C26 colon carcinoma xenografts revealed a significant increase in plasma AUC(0–24 h), Cmax for DOX (28.9- and 36.4fold higher than those of free DOX, respectively) and a 3.4-fold increase in tumor accumulation relative to administration of free drug. Accordingly, NK911 resulted in superior efficacy in comparison to free DOX in C26, M5076 and P388 tumor-bearing mice when administered at the same dose. However, in Lu-24 and MX-1 tumor bearing mice the anti-tumor activity was not superior to that of the free drug 4. In terms of toxicity, NK911 had a superior toxicity profile to that of free DOX. When both were administered at the highest equivalent dose, free DOX induced a significantly higher number of deaths due to toxicity compared with NK911 encapsulated DOX. Of note, in preliminary experiments leading to the development of NK911, the anti-tumor activity of BCMs containing both chemically and physically encapsulated DOX resulted in significantly higher efficacy in mice bearing C26 tumor compared with the free drug and BCMs containing only chemically encapsulated drug. Based on this, the authors of the study suggest that the chemically conjugated DOX does not play a significant role in the observed pharmacological activity of the formulation. However, further studies are needed to confirm this hypothesis 81. The stability and biological behaviour of NK911 were compared with that of Doxil in tumor spheroids. The study suggested that Doxil resulted in preferential distribution of DOX to the surface of the spheroids, while NK911 demonstrated greater release of DOX which was distributed more uniformly throughout the spheroids 82. Accordingly, NK911 exhibited significantly higher cytotoxic effects when evaluated in spheroids of a human colon cancer cell line (HT-29) compared with Doxil (at the same dose and after 24 hours exposure) 82. Likely drivers for clinical translation Preclinical data revealed that NK911 has significantly changed the PK profile of DOX and acted more as a carrier of the drug. As a result, the blood circulation lifetime of DOX was extended leading to a significant increase in drug accumulation at the tumor site. Consequently, NK911 showed promising results with superior anti-tumor efficacy in colon, sarcoma, and leukemia tumor models and a significantly improved toxicity profile compared with free DOX. Interestingly, cytotoxicity studies conducted in tumor spheroids revealed that NK911 has surpassed Doxil in inducing a greater cytotoxic effect. This was attributed to the fact that NK911

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can release DOX uniformly within the tumor spheroids— a major advantage over Doxil which has been associated with limited drug release at the tumor site 79. Taken together, encapsulation of DOX in NK911 has improved DOX safety and anti-tumor effects in animal models and has shown promise in overcoming the limited antitumor efficacy associated with Doxil. Clinical Studies Of note, NK119 was the first polymeric micelle formulation to be advanced to clinical trials. In a Phase I clinical trial of NK911 in 23 patients, a 2.5-fold increase in the plasma half-life of DOX was reported with a 2-fold increase in plasma AUC in comparison to the free drug. The volume of distribution (Vss) and total clearance (Cltot) of NK911 were lower than that of free DOX. However, plasma AUC and t1/2 of DOX in NK911 were significantly lower than those previously reported for Doxil. Importantly, the toxicity spectrum of NK911 resembled that for free DOX with neutropenia as the DLT 83. As a consequence, the MTD for NK911 (67 mg/m2) was comparable to that of free DOX. However, infusion-related reactions common with Doxil 84,85 were not seen with NK911. In terms of anti-tumor efficacy, a partial response was only seen in one patient 83. Based on the lack of infusion-related reactions and initial signs of efficacy, NK911 moved into a Phase II clinical trial. The results of this study have yet to be reported and the latest publicly available updates are several years old 3,83. 3.3.2. SP1049C SP1049C, developed by Kabanov’s group and Supratek Pharma, was the first Pluronic-based polymeric micelle formulation of DOX to enter clinical trials. The formulation consists of a mixture of two pluronic block copolymers, poly(ethylene oxide)-poly(propylene oxide)poly(ethylene oxide) (PEO-b-PPO-b-PEO), L61 and F127 (1:8 w/w). Pluronic L61 was primarily chosen to sensitize resistant cancer cells to DOX, while Pluronic F127 was used to stabilize the formulation by preventing aggregation of Pluronic L61. Formation of the Pluronic micelles is driven spontaneously after reconstitution of DOX in a 0.9 % NaCl carrier solution containing 0.25 % (w/v) Pluronic L61 and 2 % (w/v) Pluronic F127 86,87. The micelles have a final drug loading level of 8.2% (w/w) and a size of < 30 nm. Dynamic light scattering revealed that the micelles maintain their diameter under physiological conditions (duration not reported); however, further in vitro stability studies of the formulation and the drug release profile were not accessible 86,87. Preclinical Studies In preclinical studies in normal mice, the plasma AUC for DOX in the SP1049C-treated group was 2.7-fold higher than that for free DOX. When administered in Lewis lung carcinoma (3LL M-27) bearing mice, SP1049C and free DOX exhibited a similar AUC in the liver, kidney, heart and lungs, but AUC values were higher in the tumor and brain for the SP1049C-treated group, indicating a tumor targeting effect 86,88. In addition to increased tumor accumulation, SP1049C showed longer residence in tumor tissues resulting in increased anti-tumor activity and survival in different tumor models (9 out of 9)— both sensitive and resistant to DOX— whereas free DOX was effective in only 2 out of 9 models. Importantly, in vitro studies suggest that the improved efficacy of SP1049C compared with free DOX could also be attributed to Pluronic

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L61, particularly in multidrug-resistant tumors. The use of Pluronic L61 resulted in alterations in the transmembrane transport and intracellular trafficking of DOX in multidrug-resistant cancer cells generating a high level of active DOX inside the cell 86. Toxicity studies in rats and rabbits revealed that SP1049C and free DOX have similar MTDs and exhibit comparable toxicity profiles 86. Likely drivers for clinical translation Preclinical studies demonstrated that SP1049C did not significantly alter the PK profile of DOX, indicative of rapid dissociation of micelles and drug release following i.v. administration. Accordingly, the toxicity profile of free DOX was comparable to that of micellar DOX. However, SP1049C surpassed free DOX in terms of antitumor efficacy in sensitive and resistant animal tumor models. Therefore, it was expected that SP1049C could be used for primary as well as relapsed and multidrug resistant cancers and this distinguished SP1049C from other DOX-based formulations. Indeed, the potential to overcome drug resistance and to exhibit not only a significantly higher but also a broader spectrum of anti-tumor activities compared with non-micellar DOX served as the basis for proceeding to a clinical trial 86,88. Clinical Studies Preclinical findings enabled a Phase I clinical trial for SP1049C in Canada in 1999 [25]. Patients with metastatic or recurrent solid tumors refractory to conventional chemotherapy or for which no suitable conventional therapy existed were eligible for this study. SP1049C was found to have a similar PK profile and toxicities to DOX with neutropenia as the principal DLT. The MTD was defined as 70 mg/m2 which is similar to that for free DOX. Importantly, hand-foot syndrome, an adverse effect commonly encountered with Doxil was not observed 87. Due to the small number of patients enrolled in the trial and the diversity of previous treatments, the cardiac safety of SP1049C could not be accurately evaluated in this study. In terms of antitumor efficacy, partial responses were seen with SP1049C in several patients with advanced Ewing’s sarcoma, carcinosarcoma, and oesophageal adenocarcinoma 87. In a subsequent Phase II clinical trial SP1049C was evaluated in 21 patients with advanced carcinoma of the esophagus and gastroesophageal junction. This trial concluded that SP1049C has high activity as a single agent in this patient population with a response rate of 47% and clinical benefit (response rate plus stable disease) of 89% 89. Median OS was 10 months, and PFS was 6.6 months which were generally comparable to values seen with standard combination regimens of DOX 89. SP1049C was granted an orphan drug designation by FDA in 2008 and was planned to move into a Phase III clinical trial. However, since 2008, no updates regarding SP1049C are available 90. 4.

Conclusions

In conclusion, the preclinical and clinical development of nine BCM formulations has been investigated in this review. The three key parameters that were evaluated (for both preclinical and clinical studies) were; 1) PK profile, 2) anti-tumor efficacy and 3) toxicity profile of the encapsulated drug. For the majority of these formulations, the PK profile of the encapsulated drug was improved when included in BCM formulations in the preclinical setting. In general, (where the data was available), these results seem to transfer well to in patient studies. Even

20


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though two-thirds of the formulations investigated showed improved anti-tumor efficacy in animal studies, this did not translate well into the clinic, with results showing either modest levels of improvement (in the case of Cynviloq), or else being similar to the standard of care (in the majority of the cases). A key area where BCM formulations appear to be successful is in improving the toxicity profile of the drug. In clinical trials, where toxicity information was reported (for seven of the formulations), the BCM formulations in general showed an improved toxicity profile; this was manifested as a reduction in the rate of side effects, a reduced need (in most cases) for prophylactic medications and faster infusion times. All of these factors improve the quality-of-life for patients and increase compliance to a chemotherapy regimen. A key area of concern from reviewing these studies is the lack of translatability of anti-tumor efficacy between preclinical animal models and clinical trials. With regards to improving efficacy, it may be necessary to optimise the design of future clinical trials by stratifying patients according to their EPR status in order not to mask any potential therapeutic benefits. The implementation of standardized guidelines as well as optimal pre-clinical models will all aid in overcoming the road blocks associated with BCMs and facilitate their release into the market.

21



1 2 3 4 5 6 7 BCM 8 Formulation 9 10 11 12 13 NC-6004 14 15 16 NC-4016 17 18 19 NK105 20 21 22 23 Cynviloq 24 25 26 27 Paxceed 28 29 Nanoxel 30 31 32 Nanoxel-M 33 34 CriPec 35 Docetaxel 36 37 38 NK911 39 40 SP1049C 41 42 43 44 45 46 47 48

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Table 1. Major preclinical and clinical findings on block copolymer micelle formulations of drugs, in comparison to intravenous administration of the respective free drugs or their conventional formulations. Preclinicala PK

Biodistribution

Clinical Toxicity

AUC

Cmax

t1/2

Tumor accumulation

Accumulation in normal organs

↑

↑

↑

↑

Liver↑ Spleen↑ Kidneys↓

Neurotoxicity ↓ Nephrotoxicity↓ Ototoxicity↓

↑

↑

↑

↑

Liver↑ Spleen↑

↑

↑

↑

↑

na

Antitumor Efficacy

PK

Toxicity

AUC

Cmax

t1/2

MTD

↑c

↑

↑

↑

Similar to the previously reported MTD of free drug

Neurotoxicity ↓ Nephrotoxicity↓d Ototoxicity↓ Hypersensitivity↑

Acute neuropathy↓

↑

na

na

na

na

na

Neurotoxicity ↓

↑

↑

↑

↑

↓ Hypersensitivity↓ No premedication 1 h tri-weekly infusion

↓

↓

↓

↑

↓

na

na

na

na

Efficacyb

Only modest efficacy was seen in combination with Gemcitabine 41

na

Clinical efficacy was modest (overall response rate (ORR) observed was 25%, median progression free survival (PFS) was 3.0 months, and median overall survival (OS) was 14.4 months) 50 . The overall response rate for patients was 58.5% which is higher than that for Abraxane (47.6% at the same dose) and Taxol (21–54%) as first line therapy for patients with MBC 6. na

LD50 ↓

↑

↓

↓

↓

↑

Hypersensitivity↓ No premedication

na

Liver↑ Spleen↑ Kidneys↑ Lungs↑ Heart↑ Liver↑

Similar to Taxol

Similar to Taxol

na

na

na

na

na

na

na

na

na

na

na

na

na

na

Similar to Taxol

Similar to Taxotere

na

na

Hypersensitivity↓ Fluid retention ↓

Similar to Taxotere

na

na

na

na

Hypersensitivity↓ No premedication Infusion time 1 h instead of 3 h Hypersensitivity↓ Fluid retention ↓ No premedication

↑

na

na

na

na

na

na

↑g

↑

↑

↑

Close to that of free DOX

Infusion-related reactions ↓

na

↑

na

No hand-foot syndrome

SP1049C had a response rate of 47% and clinical benefit (response rate plus stable disease) of 89%. Median overall survival was 10 months, which is

na

na

↑e

↑

Vdss↓f

↑

↑

↑

↑

Similar to free DOX

Diarrhea↓ Pan-leukopenia↓ Effects on immunologically related tissues↓ Toxicities ↓

Similar to DOX

↑

Brain ↑

Similar to DOX

↑

Similar to DOX

22


na

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comparable to that s combination regime

a. Preclinical data for Paxceed, Cynviloq and Nanoxel-PM were compared to conventional formulation (not free drugs). b. Efficacy results were gathered from Phase II clinical trials when available. c. Superior antitumor efficacy compared to free drug was seen in one tumour model (C26). In other tumour models, however, similar antitumor activity was seen for both NC-6004 and CDDP when administered at the same dose 28,38,39. d. Although nephrotoxicity was reduced, it was still observed in patients who received the highest dose (120 mg/m2) even with a hydration regimen 40. e. The pharmacokinetics parameters of CriPec Docetaxel were not compared to Taxotere or free drug. Therefore, AUC and Cmax values could not be compared to another control (t1/2 was compared to a previously reported t1/2 of Taxotere) 75. f. Significantly reduced volume of distribution at steady state (Vdss) indicates less distribution of the drug to the normal tissues 75. g. Superior efficacy was seen in comparison to free DOX in C26, M5076 and P388 tumor-bearing mice when administered at the same dose. However, in Lu-24 and MX-1 tumor bearing mice the anti-tumor activity was non-superior to that of the free drug 4.

Table 2. BCM formulations under clinical development and/or approved for clinical use. Only completed, recruiting, active and not yet recruiting trials have been included. Data compiled from information provided by clinicaltrials.gov and corporate websites. Date of access: November 2016.

23



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

Block copolymer

Trade Name

Manufacturer

Drug

Indication

PEG-b-poly(glutamic acid)

NC-6004

NanoCarrier

Cisplatin

•

•

•

•

Locally advanced or metastatic pancreatic cancer in combination with gemcitabine Head and neck cancer in combination with 5-FU and cetuximaba Advanced solid tumors or nonsmall cell lung, biliary and bladder cancer in combination with gemcitabine Locally advanced or metastatic pancreatic cancer in combination with gemcitabine

Page 24 of 36

Phase (place)

Status

ClinicalTrials.gov Identifier

•

Phase III (Asia)

•

Recruiting

•

NCT02043288

•

Phase I (Japan, Taiwan, USA)

•

Recruiting

•

NCT02817113

•

Phase I/II (USA)

•

Recruiting

•

NCT02240238

•

Phase I/II (USA)

•

Completed

•

NCT00910741

PEG-b-poly(glutamate)

NC-4016

NanoCarrier

Oxaliplatin

Advanced solid tumors or lymphoma

Phase I (USA)

Recruiting

NCT01999491

PEG-b-poly(aspartate)

NK-105

NanoCarrier / Nippon Kayaku

Paclitaxel

Metastatic or recurrent breast cancer

Phase III (Japan)

Active, not recruiting

NCT01644890

PEG-b-poly(D,L-lactide)

Genexol-PM

Samyang Pharmaceuticals, IgDrasol (USA)

Paclitaxel

• •

Metastatic breast cancer Metastatic or locally recurrent breast caner

• •

•

Taxane-pretreated recurrent breast cancer Gynecologic cancer Advanced breast cancer in combination with doxorubicin Recurrent and metastatic adenocarcinoma of the pancreas in combination with gemcitabine Advanced urothelial cancer previously treated with gemcitabine and platinum Advanced ovarian cancer in combination with carboplatin 24

•

Approved (Korea) Bioequivalence study vs Abraxane® (International) Phase IV (Korea)

• •

Phase I (Korea) Phase II (Korea)

• •

•

Phase II (Korea)

•

Phase II (Korea)

• • •

•

•


•

Completed

•

NCT02064829

•

Enrolling by invitation Recruiting Recruiting

•

NCT00912639

• •

NCT02739529 NCT01784120

•

Not yet open for recruitment

•

NCT02739633

•

Completed

•

NCT01426126

Page 25 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48


•

•

Advanced non-small-cell lung cancer in combination with gemcitabine Unresectable locally advanced or metastatic pancreatic cancer

•

Phase I (Korea)

•

Completed

•

NCT00877253

•

Phase II (Korea)

•

Completed

•

NCT01770795

•

Phase II (Korea)

•

Completed

•

NCT00111904

PEG-b-PDDLA

Paxceed

Angiotech

Paclitaxel

• •

Psoriasis Rheumatic arthritis

• •

Phase II (USA) Phase II (USA)

• •

Completed Completed

• •

NCT00006276 NCT00055133

PEG-b-PDDLA

Nanoxel-M

Samyang Biopharmaceuticals

Docetaxel

•

Recurrent or metastatic head and neck squamous cell carcinoma Advanced solid cancer Non Muscle Invasive Bladder Cancer

•

Phase II (Korea)

•

Recruiting

•

NCT02639858

• •

Phase I (Korea) Phase III (Korea)

• •

Completed Recruiting

• •

NCT01336582 NCT02982395

Metastatic cancer and solid tumors

•

Phase I (Belgium)

•

Recruiting

•

NCT02442531

• •

mPEG-b-p(HPMAm-Lacn)

CriPec Docetaxel

Crystal Therapeutics

Docetaxel

•


NK911b

Nippon Kayaku

Doxorubicin

Metastatic pancreatic cancer

PEO-b-PPO-b-PEO (Pluronic)

SP1049Cb

Supratek Pharma

Doxorubicin

• • •

Gastrointestinal cancer Colorectal cancer Non-Small cell lung cancer

• • •

Phase II Phase I Phase I

PEG-b-poly(glutamate)

NK012

Nippon Kayaku

SN-38

• •

Relapsed small cell lung cancer Advanced, metastatic triple negative breast cancer Refractory solid tumors Colorectal cancer in combination with 5-FU Advanced solid tumors, metastatic triple negative breast cancer

• •

Phase II (USA) Phase II (USA)

• •

Completed Completed

• •

NCT00951613 NCT00951054

• •

Phase I (USA) Phase I (USA)

• •

Completed Completed

• •

NCT00542958 NCT01238939

•

Phase I (USA)

•

Completed

•

NCT01238952

Advanced or metastatic solid tumors

•

Phase I (Japan)

• • •


NC‐6300/ K‐912b

Nippon Kayaku

Epirubicin

•

25


Phase II (Japan)


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

a. Partnered with Orient Europharma b. No trials listed in clinical trials.gov

26


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NC-4016

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Paxceed

Nanoxel-PM

CriPec Docetaxel Cynviloq NK105 NK911

Nanoxel

Pre-clinical studies SP1049C

NC-6004 Drivers for clinical translation

Risk

Benefits

• • • • •

Release kinetics In vitro toxicity In vitro efficacy In vivo PK study In vivo efficacy study

•

Improved PK profile

•

Improved toxicity profile

•

Improved efficacy


Clinical studies

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Overcoming the Road Blocks: Advancement of Block Copolymer

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