New challenges and opportunities in nonclinical safety testing of biologics

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<ul><li><p>12</p><p>4 cl5</p><p>6</p><p>7</p><p>8 Q1 ol9</p><p>10 Bayer Pharma AG, Berlin, Germany11 bGenentech, South San Francisco, USA12 cCiToxLAB, Evreux, France13 dMedImmune, Cambridge, UK14 e F. Hoffmann-La Roche Ltd, Basel, Switzerland15 fCovagen AG, Zuerich, Switzerland16 gUCB Pharma, Braine-lAlleud, Belgium17 h Pzer, La Jolla, USA</p><p>1819</p><p>2 1</p><p>222324</p><p>252627282930313233</p><p>3 435363738394041424344454647484950</p><p>5152</p><p>53</p><p>54</p><p>55</p><p>56</p><p>57</p><p>58</p><p>59</p><p>60</p><p>61 products. Beyond its general membership meetings in the U.S.,62 BioSafe has started to run in parallel yearly European Meetings</p><p>63</p><p>64</p><p>65embership66r 1819, 2675 from U68</p><p>69</p><p>70companies, small biotechnology companies and individual71contract research organizations. At this years meeting new72challenges in non-clinical development of biologics were73discussed, including animal use and species selection, unex-74pected toxicities, distribution behavior and specics of antibody75drug conjugate and non-traditional mAb development. At each76session, case examples were presented followed by podium77discussions.</p><p>q New challenges and opportunities in nonclinical safety testing of biologics werediscussed at the 3rd European BioSafe Annual General Membership meeting inNovember 2013, addressing scientic, strategic and experimental approaches inToxicology and Pharmacokinetics. Corresponding author.</p><p>E-mail address: andreas.baumann@bayer.com (A. Baumann).</p><p>Regulatory Toxicology and Pharmacology xxx (2014) xxxxxx</p><p>Contents lists availab</p><p>Regulatory Toxicology</p><p>.e</p><p>YRTPH 3029 No. of Pages 8, Model 5G</p><p>23 April 2014identifying and responding to key scientic and regulatory issuesrelated to the preclinical safety evaluation of biopharmaceutical</p><p>Japan) with toxicology, pathology or pharmacokinetic back-ground represented global big pharmaceutical/biotechnologyBioSafe is the Preclinical Safety expert group of the Biotechnol-ogy Industry Organization (BIO), which has been tasked with themission to serve as a resource for BIO members and BIO staff by</p><p>member companies.The 3rd Annual BioSafe European General M</p><p>ing was hosted by Bayer Pharma on NovembeBerlin. The 80 scientists (65 from Europe, 1http://dx.doi.org/10.1016/j.yrtph.2014.04.0050273-2300/ 2014 Published by Elsevier Inc.</p><p>Please cite this article in press as: Baumann, A., et al. New challenges and opportunities in nonclinical safety testing of biologics. Regul. Toxicol. Pha(2014), http://dx.doi.org/10.1016/j.yrtph.2014.04.005meet-013 in.S. andPEGylated proteinsDistributionBispecics</p><p>(iii) Mechanisms of nonspecic toxicity of antibody drug conjugates (ADC) and ways to increase thesafety margins.</p><p>(iv) Although biologics toxicity typically manifests as exaggerated pharmacology there are somereported case studies on unexpected toxicity.</p><p>(v) Specics of non-clinical development approaches of noncanonical monoclonal antibodies (mAbs),like bispecics and nanobodies.</p><p> 2014 Published by Elsevier Inc.</p><p>1. Introduction to foster face to face discussions with European colleagues of BIOa r t i c l e i n f o</p><p>Article history:Received 28 March 2014Available online xxxx</p><p>Keywords:BiologicsPharmacokineticsNon-clinical safetyMinipigsa b s t r a c t</p><p>New challenges and opportunities in nonclinical safety testing of biologics were discussed at the 3rdEuropean BioSafe Annual General Membership meeting in November 2013 in Berlin:</p><p>(i) Approaches to rene use of non-human primates in non-clinical safety testing of biologics andcurrent experience on the use of minipigs as alternative non-rodent species.</p><p>(ii) Tissue distribution studies as a useful tool to support pharmacokinetic/pharmacodynamic (PKPD)assessment of biologics, in that they provide valuable mechanistic insights at drug levels at thesite of action.Wolfgang F. Richter e, Frank-Peter Theil g, Marque Todd h</p><p>aWorkshop Report</p><p>New challenges and opportunities in nonof biologicsq</p><p>Andreas Baumann a,, Kelly Flagella b, Roy Forster c, L</p><p>journal homepage: wwwinical safety testing</p><p>ke de Haan d, Sven Kronenberg e, Mathias Locher f,</p><p>le at ScienceDirect</p><p>and Pharmacology</p><p>l sevier .com/locate /yr tphrmacol.</p></li><li><p>78</p><p>79</p><p>80</p><p>81</p><p>82</p><p>83</p><p>84</p><p>85 Q3</p><p>86</p><p>87</p><p>88</p><p>89</p><p>90</p><p>91</p><p>92</p><p>93</p><p>94</p><p>95</p><p>96</p><p>97</p><p>98</p><p>99</p><p>100</p><p>101</p><p>102</p><p>103</p><p>104</p><p>105</p><p>106</p><p>107</p><p>108</p><p>109</p><p>110</p><p>111</p><p>112</p><p>113</p><p>114</p><p>115</p><p>116</p><p>117</p><p>118</p><p>119</p><p>120</p><p>121</p><p>122</p><p>123</p><p>124</p><p>125</p><p>126</p><p>127</p><p>128</p><p>129</p><p>130</p><p>131</p><p>132133</p><p>134</p><p>135</p><p>136</p><p>137</p><p>138</p><p>139</p><p>140</p><p>141</p><p>142</p><p>143</p><p>144</p><p>145</p><p>146</p><p>147</p><p>148</p><p>149</p><p>150</p><p>151</p><p>152</p><p>153</p><p>154</p><p>155</p><p>156</p><p>157</p><p>158</p><p>159</p><p>160</p><p>161and total number is often high (300). The satellite animals were162not used for any other endpoints, other than TK or PD (no pathol-163</p><p>164</p><p>165</p><p>166</p><p>167</p><p>168</p><p>169</p><p>170</p><p>171</p><p>172</p><p>173</p><p>174</p><p>175</p><p>176</p><p>177</p><p>178</p><p>179</p><p>180</p><p>181</p><p>182</p><p>183</p><p>184</p><p>185</p><p>186</p><p>187</p><p>188</p><p>189</p><p>190</p><p>191</p><p>192</p><p>193</p><p>194</p><p>195</p><p>196</p><p>197</p><p>198</p><p>199</p><p>200</p><p>201</p><p>202</p><p>gy a</p><p>YRTPH 3029 No. of Pages 8, Model 5G</p><p>23 April 20142. Animal use in biologics development</p><p>With the increasing importance of biologics in drug develop-ment, non-human primates (NHP) have been identied as the mostsuitable and relevant toxicology species leading to a higherdemand of this species for non-clinical safety testing of biologics.Beyond the increasing ethical and public pressure to explore andadvance approaches to reduce the number of NHPs (Bluemel,2012), it was recently questioned why NHPs are used in biologicsdevelopment, when pharmacology-mediated adverse effects ofmonoclonal antibodies (mAbs) are highly predictive from in vitrostudies (Van Meer et al., 2013). In the introduction of this sessionchaired by Jenny Sims (Integrated Biologix) and Andreas Baumann(Bayer Pharma), it was questioned if this statement is only a futuredream or if it has some realistic components. If pharmacology-mediated adverse effects and PKPD relationships are understoodwith short-term animal studies, what is gained from furtherchronic toxicity studies. The following two lectures reviewedapproaches to rene NHP use in non-clinical safety testing inbiologics development without compromising the risk benetassessments for human use.</p><p>Kathryn Chapman (U.K. National Centre for 3Rs, NC3Rs)presented approaches to minimize the use of NHPs in biologicsdevelopment. There has been particular interest in animal use inbiologic testing since it was recognized that the NHP may be theonly relevant non-clinical toxicology species for many of theseproducts. The NC3Rs, in collaboration with up to 30 organizationsfrom the pharmaceutical, biotechnology, contract research andregulatory environment, have facilitated cross-company data-sharing initiatives to minimize the increase in NHP use(Chapman et al., 0000). These evidence-based approaches havefed into regulatory addendums e.g., ICH S6 (R1) and ICH M3 (R2)and continue to support the eld in using appropriate studydesigns to answer the scientic questions at hand. Two currenthot topics in this area with a focus on the 3Rs (replacement, rene-ment and reduction of animals in research) are (i) how oftenrodent models can support biologic development and (ii) howand when recovery animals should be included on studies. Unpub-lished data shows that company portfolios for mAbs range fromhaving no products with rodent potency to a third of their pipelinehaving the potential to use the rodents for some studies. This islinked to therapeutic area, for example less frequent rodentpotency for immunology products. Also the company strategy inscreening for rodent potency in candidate selection and develop-ment varies depending on therapeutic area. There are case studiesshowing that rodent models do support biologic programs andhave the potential to provide more relevant data and reduce theuse of NHP on some occasions. With the revision of ICH S6 (R1)Guideline (Preclinical Safety Evaluation of Biotechnology-DerivedPharmaceuticals), which describes the potential for only usingthe rodent in (sub) chronic studies if the toxicity prole of therodent and NHP is the same in short term studies, the predictionis that the rodent will be used more for development of theseproducts. In addition, technological advances such as microsam-pling mean that rodent data is likely to be used more frequentlyto support clinical trials.</p><p>The use of recovery animals has been identied as another areawhere animal use is increasing. Often recovery animals areincluded on all studies conducted and more than one dose group.The question is whether the reasons behind this are scienticallydriven or whether it is upward creep. A cross-company data shar-ing group has looked at 259 studies from 137 compounds and 22companies and these data show wide variation in the number of</p><p>2 A. Baumann et al. / Regulatory Toxicolorecovery animals used. Analysis shows that there are opportunitiesto reduce the use of recovery animals in certain circumstanceswhich would not impact drug development.</p><p>Please cite this article in press as: Baumann, A., et al. New challenges and oppor(2014), http://dx.doi.org/10.1016/j.yrtph.2014.04.005ogy and no intercurrent clinical pathology). In contrast to rodentstudies, large animal experiments are conducted much moretranslationally, where self baselines are routinely available. Inthese cases, far fewer large animals are used (30).</p><p>It would be optimal to gain all data from each (rodent) animalutilized in toxicology studies, and correlate a given animalstoxicity and PD measures, with its own TK. The only way to achievemore insight from each animal, depends on two advances; rst rened, methods for taking repeated blood draws from the rodent;and second developing assay methods that utilize far smallersamples of blood (Powles-Glover et al., 2014).</p><p>This way, dynamic insights into animals TK, PD, and clinicalpathology effects might be gained, without undue stress to the ani-mal, or confounding toxic effects from repeated blood draws. Suchadvances have been developed in many labs using capillary basedmicrosampling of only 32 ll of blood, generally referred to asmicrosampling. Micro-ELISA methods have also been developed,and have not posed severe technical hurdles; typically, serum frombiologic drug-treated animals must be diluted anyway, to enableassays to fall within standard curves.</p><p>With improved insight, interpretation, and translation, moreinsightful toxicity studies may be designed in rodents, whichmay alleviate some need for NHP work.</p><p>3. Use of minipigs in non-clinical safety testing with biologics Quo vadis ?</p><p>Minipigs are increasingly used as non-rodent species fortoxicity testing of pharmaceuticals, in particular in Europe(Svendsen, 2006; Ganderup et al., 2012). However, the focus islargely on small molecule-based therapeutics and dermal adminis-tration (Ganderup, 2011); only few data exist on repeat-dose IVadministration of biologics. The session chaired by Sven Kronen-berg (Hoffmann-La Roche) and Roy Forster (CiToxLAB) providedan overview about the use of minipigs in safety testing of biologics.A gap analysis on the use of mAbs in the minipig by Kronenbergemphasized that the minipig immune system has a largely analo-gous structure and function to the human immune system (Bodeet al., 2010), but a better understanding on how sensitive minipigsare towards infusion-related reactions and FccR-mediated effectorfunction is yet missing. This includes possible (side) effects of IVadministration of mAbs, such as cytokine release, complementIn addition to the in vivo approaches there is also ongoing workto identify the benets and limitations of in vitro technologies toassess the safety prole of biologics. A holistic, integrated approachto get the best data from the most appropriate technology orspecies is a must have in the future of biologics products.</p><p>Lauren Black (Charles River Laboratories) gave some furtherinsights on the use of satellite groups and blood sample volumereduction. For many years different animals were used for toxicityevaluation (satellite animals) than those assayed for blood levels(toxicokinetic = TK groups). Assays of the TK were done in satellitegroups because the analytical methods were not sensitive andrequired up to 500 ll of blood to be drawn for each sample. Suchhigh blood volumes would deplete the rodents hematocrit ifdrawn multiple times from the same animal, and this would con-found interpretation of toxicity if performed in the main studyanimals designated for pathology. So, until very recently, therodent numbers used for satellite TK and or pharmacodynamics(PD) could end up being half of the animals utilized on the study,</p><p>nd Pharmacology xxx (2014) xxxxxx203activation and ADCC. Some of the effects can be caused also by204polymer excipients used in biologics formulations: minipigs,205similar to dogs, show acute cardio-pulmonary reactions to some</p><p>tunities in nonclinical safety testing of biologics. Regul. Toxicol. Pharmacol.</p></li><li><p>206</p><p>207</p><p>208</p><p>209</p><p>210</p><p>211</p><p>212</p><p>213</p><p>214</p><p>215</p><p>216</p><p>217</p><p>218</p><p>219</p><p>220</p><p>221</p><p>222</p><p>223</p><p>224</p><p>225</p><p>226</p><p>227</p><p>228</p><p>229</p><p>230</p><p>231</p><p>232</p><p>233</p><p>234</p><p>235</p><p>236</p><p>237</p><p>238</p><p>239</p><p>240</p><p>241</p><p>242</p><p>243</p><p>244</p><p>245</p><p>246</p><p>247</p><p>248</p><p>249</p><p>250</p><p>251</p><p>252</p><p>253</p><p>254</p><p>255</p><p>256</p><p>257</p><p>258</p><p>259</p><p>260</p><p>261</p><p>262</p><p>263</p><p>264</p><p>265</p><p>266</p><p>267</p><p>268</p><p>269</p><p>270</p><p>271</p><p>272In the last talk, Andrew Makin (CiToxLAB Scantox) focused on273practical considerations for the use of minipigs with biologics, as274well as some examples and case histories. On the practical side,275concerns focus on the size of minipigs (test item requirements)276and the issue of venous access for administration and or blood277sampling (now largely overcome with the availability of new cath-278eter and access port materials). Case histories were given related to279the value of a minipig segment II (teratology) study for the evalu-280ation of a peptide-based drug for metabolic disease, and the use of281minipigs in the efcacy and safety evaluation of a recombinant282bone morphogenetic protein. CiToxLAB experience with biologics283testing in minipigs is summarized in Table 1, and includes several284products (such as peptides, protein hormones, monoclonal anti-285bodies and clotting factors). In no case was the minipig subse-286quently judged to be an inappropriate model. Most of this287information is not in the public domain, and it was concluded that288if just some of these studies/projects were published, we would289probably have a different impression of the value of minipigs in290the testing of biologics.291</p><p>292</p><p>293</p><p>294</p><p>295</p><p>296</p><p>297</p><p>298</p><p>299space and are not athletic like dogs, nor arboreal like NHPs. Despite300</p><p>301</p><p>302</p><p>303</p><p>304</p><p>305</p><p>306</p><p>307</p><p>308</p><p>309</p><p>310</p><p>311</p><p>312</p><p>gy and Pharmacology xxx (2014) xxxxxx 3</p><p>YRTPH 3029 No. of Pages 8, Model 5G</p><p>23 April 2014IV administered drug carriers and polymers (liposomes/lipid-basedexcipients) due to complement activation, which do not reproducein the normal human physiological response to such medication(Szebeni et al., 2007, 2012). However, different to dogs, no undueeffects were seen when typical biologics excipients such as polox-amer and polysorbate 20 and 80 were intravenously administeredto the minipig (Festag et al., 2013), supporting the use of minipigsfor typical mAb formulations. A major gap highlighted was theobvious lack of placental transfer of macromolecules (Szebeniet al., 2007) in the minipig that may limit their role in developmen-tal toxicity testin...</p></li></ul>

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