The Reef Biotech Ltd case What really happened

The Reef Biotech Ltd case  What really happened

The Reef Biotech Ltd case What really happened and take home messages Geert Jan Groeneveld, MD, PhD June 7, 2017 Castle Oud Poelgeest, Oegstgeest The Netherlands Reef Biotech Ltd. was Xenome Ltd. RB3285 was actually Xen-2174 Both CEO & head drug development leave Xenome Two board members (investors) leave Xenome $ 1.25 m investment Xenome is founded 1998 $ 1.25 m investment $ 3.75 m new share issue Xenome Ltd is founded $ 10 m equity finance $ 2.5 m

new funding Ziconotide lincensed by FDA for US market 1999 2000 2001 2002 Pre-clinical studies on Xen2174 (in vitro, rat and dog) 2003 End of Xenome Ltd $ 6.25 m new funding $6m new funding $5m new funding Ziconotide lincensed by EMA/EC for EU market 2004 2005 2006

Phase I/II trial oncology patients IT admin. Phase I trial HV IV admin. The rise and fall of a biotech company Japan patent US patent EU patent FDA/CDER IND approval for Xen2174 2007 2008 2009 2010 Additional dog studies (required by FDA) 1st Phase II trial bunion surgery IT admin. 2012 Phase I trial

HV, IT admin. pain tests & EEG 2nd Phase II trial bunion surgery IT admin. (n.d.) Phase I HV IT admin. / EEG FDA puts 1st Phase II on hold 2011 2013 hypothetical concentration in CSF in case of immediate and homogeneous distribution of Cmax intrathecally injected dose (mg/L) in CSF (0,26 mg/L) (0,30 mg/L) (2.4 mg/L) (3.1 mg/L) (3,2 mg/L) (3,6 mg/L) (4.7 mg/L) 26 mg/L (23.3 mg/L) (33.7 mg/L) (37.0 mg/L) (46.7 mg/L) (76.9 mg/L) (84.4 mg/L) (93.4 mg/L) (133 mg/L) (156.3 mg/L)

(154 mg/L) (200 mg/L) (308 mg/L) (333 mg/L) (267 mg/L) (267 mg/L) (370 mg/L) (385 mg/L) (615 mg/L) (741 mg/L) (769 mg/L) (1154 mg/L) (1481 mg/L) (2230 mg/L) (3076 mg/L) (3076 mg/L) AUC Cmax (mg/L) (ng*h/ml) in plasma in plasma In vitro rat EC50h 183nM EC50r 214nM 0.08 g/kg i.t.g i.t. 0.64 g/kg i.t.g i.t. 0.84 g/kg i.t.g i.t. IC50r 2,57g/kg i.t.M 0.86 g/kg i.t.g i.t. IC50h 2,26g/kg i.t.M 0.068 mg/L 93.6 0.097 mg/L 0.345 mg/L 516.2 dog 0.86 g/kg i.t.g i.t. 1 mg/animal i.t.

human 0,6 g/kg i.t.g/kg i.t. 7,7 g/kg i.t.g/kg i.t. 10 g/kg i.t.g/kg i.t. 50 g/kg i.t.g/kg i.t. 9.1 g/kg i.t.g i.t. 10 g/kg i.t.g i.t. 0.597 mg/L 855.8 1.58 mg/L 2152 22.8 g/kg i.t.g i.t. 42.2 g/kg i.t.g i.t. 257 mg/L 514 mg/L 0.12-0.15 mg/kg i.t. 200 g/kg i.t.g/kg i.t. 20 mg/subject 0.13 mg/L 2 mg/animal i.t. 2 mg/animal i.t. 0.243 mg/L 4 mg/animal i.t. 4 mg/animal i.t. 0.3 mg/kg i.t.

100 g/kg i.t.g/day i.t. 1445 mg/L 0.797 mg/L 0.2 mg/animal/day 400 g/kg i.t.g/day i.t. 100 g/kg i.t.g/kg i.t. 30 mg/subject 40 mg/subject 40 mg/subject 5 mg/animal/day i.t. for 14 days dose up to 8 mg/animal i.t. 8 mg/animal i.t. 10 mg/animal/day i.t. for 14 days 15 mg/animal/day i.t. 29 mg/animal i.t. 40 mg/animal i.t. 40 mg/animal i.t. CNS effects EC50 human NET in vitro EC50 rat NET in vitro ED50 for anti-nociception in Brennan model for post-operative pain ED50 for anti-allodynia effect in CCI model for tactile allodynia IC50 rat NET in vitro IC50 human NET in vitro PK-study PK-study PK-study anti-allodynia effect plateaued at this level in Chung model for peripheral neuropathic pain plateau of post-operative nociception in Brennan model PK-study no adverse effects observed (NOAEL for single i.t. administration) ED50 for combined anti-nociception and anti-allodynia in CCI model PK-study

safe and well-tolerated in at least 3 subjects anti-allodynia observed for up to 48 hours in CCI model seizures in 1 dog (in cohort of n=10) PK-study safe and well-tolerated in at least 4 subjects seizures in 2 dogs (in cohort of n=10) PK-study no adverse effects observed (NOAEL for single i.t. administration) aseptic drug-induced meningitis (1 subject in 6 subjects dosed) seizure (1 subject in 6 subjects dosed) no effects on rotarod performance seizure in 1 dog (in cohort of n=3) no seizures and no effects on EEG in Beagle dogs PK-study "significant mortality" seizure in 1 dog (in cohort of n=3) no effects on Functional Observational Battery seizures upper motor neuronal deficits and seizures upper motor neuronal deficits and seizures death Study design Randomized, double-blind, placebo-controlled, serial-cohort, single ascending dose of Xen2174 or placebo PK/PD study, administered intrathecally in HV Cohort Xen2174 dose Placebo 1 0.50 mg (n=8) n=3 2

1.00 mg (n=8) n=3 3 2.50 mg (n=8) n=2 Pharmacokinetics: CSF PK up to 32 hours (via intrathecal catheter) Plasma PK Pharmacodynamics: Pain threshold and tolerance levels for each of a battery of nociceptive tests Safety 24h EEG PainCart; multidimensional pain test battery Electrical Stimulation Olofsen and Dahan, 2005

Arendt-Nielsen et al., 2007 Pneumatic Pressure Polianskis, 2001 Cold Pressor Eckhardt et al. 1998 and Jones et al. 1988 Conditioned Pain Modulation DNIC Electrical pre/post cold pressor Thermal stimulation Medoc TSA-II 30Thermode CHEPS UVB model Capsaicin (chemical allodynia model) PD results: electrical stair PTT Placebo XEN0.50 XEN1.00 XEN2.50 6 Delta Electrical Stair PTT (mA): change 4 2 0 -2 -4

-6 0:00 12:00 24:00 36:00 48:00 Time (hh:mm) 60:00 72:00 84:00 96:00 108:00 PD results: cold pressor PTT Placebo XEN0.50 XEN1.00 XEN2.50 60 40 Cold PTT (sec): % change

20 0 -20 -40 -60 0:00 12:00 24:00 36:00 48:00 Time (hh:mm) 60:00 72:00 84:00 96:00 108:00 PD results: pressure PTT Placebo XEN0.50 XEN1.00

XEN2.50 90 Pressure PTT (kPa): % change 60 30 0 -30 -60 0:00 12:00 24:00 36:00 48:00 Time (hh:mm) 60:00 72:00 84:00 96:00 108:00 PD results: Electrical burst PTT

Placebo XEN0.50 XEN1.00 XEN2.50 120 Electrical Burst PTT (mA): % change 80 40 0 -40 -80 0:00 12:00 24:00 36:00 48:00 Time (hh:mm) 60:00 72:00 84:00

96:00 108:00 PK results CSF concentrationtime profiles of Xen 2174 Safety issues human equivalent doses of Xen-2174 CSF concentrations humans vs dogs Out-of-pocket costs Xenome Ltd. 1998-2013 Study phase Costs preclinical $ 2,000.000 Discovery and pharmacology GLP preclinical $ 4,500.000 Toxicology and PK $ 10,500.000 Phase I study in HV: plasma PK and safety Phase I/II study in cancer patients with pain Phase II study in 200 bunionectomy patients Phase I study in HV with EEG recording (no CSF PK!)

$ Phase I PK/PD study in HV; CSF PK and pain tests clinical Total 975.000 $ 16,975.000 Take home messages Fail early to fail cheap QBCD: which question needs to be answered first? More (quality) information early on leads to better informed decisions MTD is not (that) relevant for non-cytotoxic drugs Allometric scaling leads to estimates that still have to be confirmed

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