Onder 2.9.2. Rechtbank Den Haag 16 januari 2019

Role of folic acid in the antitumor activity of LY231514 against the L5178Y murine lymphoma. (…) The exquisite sensitivity of the L5178Y/TK-/HX- tumor model to LY231514 treatment allowed us to evaluate the effect of low folate diet on the therapeutic activity of this compound. For mice on LFD, LY231514 at 0.3 and 1.0 mg/kg/day (i.p. qd x10) produced 100% inhibition of tumor growth for tumors measured one day after the completion of a single course of drug treatment (Figure 2). As noted in Figure 1, higher drug levels yielded unacceptable toxicity. For mice on LFD that received a folate supplement of 15 mg/kg/day via oral gavage, significant inhibition of tumor growth was noted over a broad dose range (10- 1000 mg/kg/dose). Moreover, 100% inhibition of tumor growth was observed at 30 to 1000 mg/kg/dose without any lethality. This antitumor dose response (with folate supplementation) was virtually identical to that observed for mice receiving standard diet. However, the lethality was signicantly [sic] greater for the mice on standard diet (lethality at 400 and 800 mg/kg/day of 10% and 100%, respectively). Mice on standard diet received approximately one-tenth of the

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