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Daniel S Lorrain, Michael Poon, Karin J Stebbins, Geraldine Cabrera, Alex Broadhead, Jon Seiders, and Jeff Roppe Pipeline Therapeutics, San Diego, CA

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Daniel S Lorrain, Michael Poon, Karin J Stebbins, Geraldine Cabrera, Alex Broadhead, Jon Seiders, and Jeff Roppe Pipeline Therapeutics, San Diego, CA Discovery of PIPE-505, a small molecule therapeutic for the treatment of sensorineural 304.01 hearing loss (SNHL) associated with cochlear synaptopathy *Daniel S Lorrain, Michael Poon, Karin J Stebbins, Geraldine Cabrera, Alex Broadhead, Jon Seiders, and Jeff Roppe Pipeline Therapeutics, San Diego, CA Introduction Neurite outgrowth mediated by Netrin/DCC pathway PIPE-505 increases hair cells via Notch inhibition Ex vivo explant In vivo drug treatment Isolated SGN PIPE-505 is a gamma secretase inhibitor in development PIPE-505 DMSO 3 Atoh1 Hes5Hes5 ↓ ↑ Atoh1 ** for the treatment of SNHL associated with cochlear 1.0 synaptopathy. A series of in vitro and in vivo studies in PIPE-505 2 γ-secretase 1 Atoh Hes5 Hes5 0.5 animal models of auditory loss have demonstrated two 1 ) (fold increase/vehicle) (fold 9 Fold Increase/vehicle Fold distinct mechanisms of action (MOA) leading to (folddecrease/vehicle) 1 1 .0 l 0 p 0.0 R PF2 0.2% 2% vehicle 0.2% 2% o t restoration of hearing function. Specifically, PIPE-505 1) m r ↓Hes5 0 .5 Brain Research Bulletin 2016 Notch o n ( facilitates SGN neurite growth via the Netrin/DCC pathway 5 s e OHC *** H ↑ 4 *** P<0.001, 1-way ANOVA, Tukeys post-hoc analysis 0 .0 leading to regeneration of inner hair cell ribbon synapses v e h ic le .0 3 .3 3 1 0 ** * n P I P E - 5 0 5 M o i 3 g m µ and 2) increases Atoh1 expression via reduced Notch e 0 r / Hes5↓ 0 55 PIPE-505 restores synapses in vivo, mouse model 1 C r 2 e OHC ↑ H p signaling leading to outer hair formation. These cellular O s 50 C # H 1 O # IHC synapses DCC α-fragment regenerative effects together, restore auditory function. + 45 P=0.0013 A 7 O 0 P<0.0001 Y 16 M 40 untreated Veh 0.02% 0.2% 2% ↑Atoh1 .001 .01 .1 1 C PIPE-505 M PIPE-505 H I 14 / a t c PIPE-505 improves auditory measures n u 12 p 2 P B 10 t C ABR Wave 1 ABR Threshold 8 PIPE-505 restores ABR PIPE-505 improves ABR e B 5 5 vehicle 2% PIPE-505 iv d 0 0 a 8 -5 -5 wave 1 amplitude, a measure threshold, a measure of OHC N 9 E E IP IP P P % % of AN function function .2 2 0 PIPE-505 restores auditory nerve synapses and hair cells CtBP2/GluR2 98dB 1 .5 9 0 V e h ic le P I P E - 5 0 5 , 2 % ) I B PIPE-505 causes dose dependent type I spiral PIPE-505 restores synapses in vivo, guinea pig model N a iv e a n im a l d e 1 .0 ( 8 0 v d a ganglion neurite outgrowth * l o W * * * * h R s * * * * # IHC synapses autoradiography * * * * e B 0 .5 r 7 0 A G041 h Notch- T C o n t r o l e a r NXT1505 neurite outgrowth DRC sparing 20 P I P E - 5 0 5 , 2 % 0.008 0.010 0 .0 6 0 *** 1 0 2 0 3 0 4 0 . 5 0 6 0 7 0 . 8 0 . 4 8 1 6 2 4 3 2 0.008 0.006 h 225 Human PK prediction t BACEi 15 *** d B S P L g 5% dose level F r e q u e n c y ( k H z ) n >30d sustained exposure e 0.006 l g 0.004 n e In summary, PIPE-505 restores SGN connections to inner hair i t i r 0.004 10 d 150 u n neurite length neurite i e cells and regenerates outer hair cells. These effects are b 0.002 N * Neurite length Neurite 0.002 I S Synapses/IHC 5 mediated via two distinct γ-secretase substrates, DCC and G *** 0.000 0.000 ] 75 H Notch, respectively. A first-in-human study is planned to 1 le 5 3 9 9 9 9 9 9 3 3 3 3 3 3 0.1 10 c 0 T 3 3 3 3 3 3 6 6 6 6 6 6 NT3 0.01 i 5 N 8 8 8 8 8 8 1 1 1 1 1 1 3 0.001 h 1 3 3 3 3 3 3 8 8 8 8 8 8 e 0 0 0 0 0 0 [ vehicle 0.0001 M D D D D D D 7 7 7 7 7 7 V µ Z Z Z Z Z Z - - - - - - 1 A A A A A A S S S S S S 0 [NXT1505](µM) M M M M M M evaluate PIPE-505 in patients with SNHL associated with M M M M M M p p n n n µ B B B B B B PIPE-505 (μM) 0 0 1 0 0 1 M M M M M M 1 0 1 0 p p n n n µ 1 1 0 0 1 0 0 1 1 0 1 0 naive vehicle 0.02% 0.2% 2% 0 1 1 Vehicle 0.02% 0.2% 2% cochlear synaptopathy. Measures of audibility as well as PIPE% NXT1505-505 IT injection (30l) speech intelligibility will be assessed. P <0.05 1-way ANOVA, Tukey's post-hoc Small molecule inhibition of the muscarinic M1 acetylcholine receptor by potent, selective antagonists facilitate 206.19 OPC differentiation *Michael M Poon1, Kym I Lorrain1, Ariana O Lorenzana1, Karin J Stebbins1, Alexander Broadhead1, Thomas O Schrader2, Yifeng Xiong2, Jill Baccei2, Ari J Green4, Jonah R Chan4, Daniel S Lorrain3; 1Biol., 2Chem., 3Pipeline Therapeutics, San Diego, CA; 4Neurol., UCSF, San Francisco, CA Introduction Calcium mobilization Lysolecithin mouse brain slice Human brain slice Inhibition of the muscarinic acetylcholinergic receptors by Fold selectivity against M1 Compound M1 IC50 (nM) M2/M1 M3/M1 M4/M1 non-selective muscarinic antagonists (e.g., clemastine, 3.19 Benztropine 16.9 11.2 4.78 Compound EC50 (nM) MBP M1 Figure 4 Pipeline M1 benztropine) accelerates the differentiation of Compound 57 0.716 343 763 430 5 antagonists induced Mbp ) PIPE-359 7.9 t PIPE-359 1.69 102 43 26 C d * in a naïve human cortical oligodendrocyte precursor cells (OPCs) into oligodendrocytes d - * 2.1 2 Compound 77 98.8 1270 212 ( 4 PIPE-307 10 brain slice assay. Slices e (OLs). Subsequent work has implicated the M1 isoform as l PIPE-307 2.35 555 64.2 54.2 c i were incubated in MT7 or h being a key driver of this phenomenon. In-house chemistry 6.69 Compound 107 30 e 3 Compound 29 57.4 347 91.9 v compound for 9 days prior s v PIPE-683 7.45 698 175 292 efforts have identified a number of potent, selective M1 PIPE-683 36.2 e 2 to RNA isolation and g Compound 107 8.91 178 117 313 n a QPCR. antagonists. Using these, we have characterized the effects of h 13.5 c Compound 51 417 1590 24.5 Compound 77 44.3 1 d [PIPE-307](logM) l inhibiting M1 in a diverse set of in vitro assays, including OPC Compound 25 19.6 128 199 241 o F 0 differentiation, cortical myelination, and organotypic brain Compound 14 51.5 124 217 58.4 300nM 11µMµM 11µMµM Vehicle MT7 OPC359 OPC797 slice. Our data show that a selective, small molecule inhibitor Table 2 Pipeline compounds are potent and selective in a cellular PIPE-359 Cmpd 77 of M1 is sufficient to drive OPCs towards differentiation and setting. Compounds were evaluated in CHO-K1 cells overexpressing one of M1-4 receptors for inhibition of ACh-induced calcium release at EC Figure 2 Pipeline compounds induced Mbp in cultured cortical mouse that the resulting oligodendrocytes express myelin basic 80 Dunnett's multiple concentrations. brain slice demyelinated with lysolecithin. Slices were cultured at comparisons test Significant? Summary Adjusted P Value protein. Moreover, these OLs are functional, i.e., capable of postnatal day 17, demyelinated and treated with compound. Mbp was Vehicle vs. MT7 Yes * 0.0136 axonal wrapping and induction of nodes of Ranvier. Of note, Rat OPC differentiation measured by quantitative PCR. The highly M1 selective peptide MT7 was Vehicle vs. PIPE-359 No ns 0.1802 an M3 selective antagonist (Sagara et al., 2006) was not active used as a positive control. 100 Compound EC50 (nM) Vehicle vs. Compound 77 Yes * 0.0444 n ) in a rat OL differentiation assay. In concert with our in vivo o i 3 t T a PIPE-683 18.9 i data (also presented at this meeting), a strong case can be t o t n 50 e PIPE-359 20.3 Rat cortical myelination d made that the development of an M1 selective small r e e f z Cortical coculture (myelination) Conclusion f i i molecule antagonist is a promising approach for treating l PIPE-307 25.4 a D ) 40 0 L m C O r demyelinating diseases such as multiple sclerosis. Compound 107 78.5 / P h o MT7 t MT7 Selective inhibition of M1 results in the differentiation of g IC 25.4 x O EC 25.4 nM n 50 50 e n ( e d Compound 77 175 l 30 n % OPCs into mature oligodendrocytes. Here, we described the i t -50 n n e o i t -9 -8 -7 -6 -5 M3 selective* > 3.00E+03 m identification of potent, selective small molecule M1 a g n e 3 [PIPE-307](logM) i l 3 log[OPC-0001307], M s [ H]NMS membrane binding e 20 antagonists as evaluated by [ H]NMS binding and calcium P y B M vehiclevehicle M Vehicle T3 1µM PIPE-307 mobilization assays and further showed that these molecules g EC50 16.2nM v a Fold selectivity against M1 ( 10 induce myelination-competent oligodendrocytes.
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