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1 PRELIMINARY EVIDENCE FOR PHARMACODYNAMIC EFFECTS OF RG7916 IN JEWELFISH A STUDY IN PATIENTS WITH SPINAL MUSCULAR ATROPHY WHO PREVIOUSLY PARTICIPATED IN A STUDY WITH ANOTHER SMN2-SPLICING TARGETING THERAPY CA Chiriboga 1, E Mercuri 2, D Fischer 3, D Kraus 4, M Alexander 5, G Armstrong 6, H Kletzl 4, M Gerber 4, Y Cleary 4, T Bergauer 4, K Gorni 4, and O Khwaja 4 1 Columbia University Medical Center, New York, NY, USA; 2 Pediatric Neurology and Nemo Center, Catholic University and Policlinico Gemelli, Rome, Italy; 3 Department of Neurology, University of Basel Hospital, Basel, Switzerland; 4 Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Switzerland; 5 Roche Pharmaceutical Research and Early Development, Roche Innovation Center New York, New York, NY, USA; 6 Roche Products Ltd, Welwyn Garden City, United Kingdom.

2 Disclosures CAC serves on advisory boards for AveXis, Biogen, and F. Hoffmann-La Roche, and receives royalties from Uptodate.com EM receives fees from AveXis, Biogen and F. Hoffmann-La Roche DK, MA, TB and KG are employees of F. Hoffmann-La Roche GA, HK, MG, YC and OK are employees of, and hold shares in, F. Hoffmann-La Roche DF declares no competing interests 2

3 Introduction RG7916 (RO ) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates SMN2 pre-mrna splicing towards the production of full-length SMN2 mrna resulting in an increase of SMN protein 1 Preclinical data show that RG7916 distributes into the CNS and peripheral tissues to modify SMN2 splicing to produce more functional SMN protein A. Poirier et al. April 26 th, S46, Presentation 007, 4:42 PM DNA SMN1 SMN2 Pre-mRNA RG7916 mrna 6 8 Functional SMN protein Unstable SMN protein rapidly degraded Functional SMN protein 3 CNS, central nervous system, SMN, survival of motor neuron. 1. Farrar MA, et al. Ann Neurol. 2017; 81:

4 Three Studies of RG7916 in People with SMA FIREFISH 1 Type 1 SMA Part 1: Dose-finding Several RG7916 dose levels n=21 RG7916 dose level 1 RG7916 dose level 2 Open-Label Extension Baranello G. et al April 24th Oral: 5:54 p.m. Poster: 6:15 7:00 p.m. Part 2: Confirmatory Open-label Dose level selected from Part 1 n=40* RG7916 dose selected for Part 2 Active treatment RG7916 Active treatment RG months 24 months Extension SUNFISH 2 Type 2 or 3 SMA Mercuri E. et al. April 25 th Poster 453, Session P4. Part 1: Dose-finding RG7916:placebo, 2:1 n=51 Part 2: Confirmatory Dose level selected from Part 1 RG7916:placebo, 2:1 n=168* RG7916 dose level 1 Placebo RG7916 dose level 2 Placebo RG7916 dose selected for Part 2 RG7916 Placebo 12 months Open-Label Extension RG months Extension JEWELFISH 3 Type 2 or 3 SMA Safety and PK/PD Non-naïve patients with Type 2 or 3 SMA Aged years n=24* (11 Patients to date) RG7916 ; no placebo (2 years) The RG7916 clinical program is designed to comprehensively assess PK, PD, safety and efficacy in a broad phenotypic and age range of patients with SMA 4 *Target enrolment; same dose as in SUNFISH. PK, pharmacokinetics; PD, pharmacodynamics; SMA, spinal muscular atrophy. Clinicaltrials.gov; 1. NCT ; 2. NCT ; 3. NCT (Accessed March 2018).

5 JEWELFISH Examines RG7916 in Non-Naïve Patients JEWELFISH (NCT ) is an open-label, exploratory study to assess the safety, tolerability, PK and PD of RG7916 in patients who have previously participated in a study with a therapy targeting SMN2 mrna splicing Rationale To evaluate the safety and PK/PD of RG7916 in patients who have received another SMN2 splicing agent The information collected will be valuable for patients that may wish to switch to RG7916 from other therapies JEWELFISH Type 2 3 SMA years old Primary endpoints Secondary endpoints Safety PK: Mean plasma concentration, C max, AUC and C trough of RG7916 and metabolites PK-PD relationship (PD investigations will include analyses of SMN2 mrna splice forms and SMN protein) 5 AUC, area under curve; C max, maximum observed plasma concentration; C trough, trough plasma concentration; PD, pharmacodynamics; PK, pharmacokinetics; SMA, spinal muscular atrophy; SMN, survival of motor neuron. Clinicaltrials.gov/show/NCT (Accessed March 2018).

6 JEWELFISH Patient Demographics All patients (N=10) Age at first dose, years, median (range) 24.5 (16 52) Gender, female/male, n (%) 3/7 (30%/70%) RG7916 treatment duration, days, median (range) 120 (26 294) SMA type, n (%) Type II: 5 (50%) Type III: 5 (50%) SMN2 copy number, n (%) 2: 1 (10%) 3: 2 (20%) 4: 1 (10%) 5: 1 (10%) Awaiting genotyping: 5 (50%) Ambulatory status, n (%) Ambulatory: 3 (30%) Non-ambulatory: 7 (70%) MFM at baseline, median (range) ( ) 6 Data-cut off: January 2018 MFM, Motor Function Measurement; SMA, spinal muscular atrophy; SMN, survival of motor neuron.

7 RG7916 Increases SMN Protein in Non-Naïve Patients Ratio FL SMN2/SMN2Δ7 mrna over time 5 SMN protein over time 5 SMN2 FL/SMN2Δ7 mrna fold change * Median fold change from baseline * Scheduled time (days) *N= Scheduled time (days) *N=3 Whole blood from these 10 patients showed an increase in the FL SMN2/SMN2Δ7 mrna ratio after RG7916 treatment initiation, with up to a 4-fold increase from baseline over 4 weeks This resulted in an up to 4-fold SMN protein increase versus baseline after 4 weeks of treatment 7 *Final data point represents three patients only. Patients in JEWELFISH have received the equivalent of RG7916 Dose 1 in the SUNFISH trial. Error bars represent min max values. FL, Full-length; SMN, survival of motor neuron.

8 Comparison of the Effects of RG7916 on SMN Protein in JEWELFISH and SUNFISH JEWELFISH 1 SUNFISH 2 JEWELFISH (N=10) SUNFISH (N=51) While the number of patients in the JEWELFISH study is limited, the PK and the magnitude of the SMN protein level increase thus far is similar to that seen in the SUNFISH Part 1 study SMN protein (ng/ml) 8 Patients in JEWELFISH have received the equivalent of RG7916 Dose 1 in the SUNFISH trial. AUC, area under the curve; PK, pharmacokinetics; SMN, survival of motor neuron. Clinicaltrials.gov/show/ 1.NCT ; 2. NCT (Accessed March 2018). AUC 0 24h RG7916 (ng*h/ml)

9 Safety Profile of RG7916 in JEWELFISH To date, RG7916 has been well tolerated, and there have been no drug-related adverse events leading to withdrawal in any SMA patients exposed to RG7916 Safety data is available from 10 patients exposed to study drug from days: ophthalmology monitoring did not show any evidence of the retinal findings seen in preclinical monkey studies 20 mild or moderate events were reported in 7 patients the most frequent events were nasopharyngitis (4 events in 2 patients), pyrexia and headache (2 events in 1 patient) no serious adverse events were reported; no adverse trends were reported after a review of all available safety labs, vital signs and ECG data study treatment was not changed in response to any adverse events While the number of patients in the JEWELFISH study is limited, the safety observations are similar to those from SUNFISH Part 1 9 ECG, electrocardiogram; SMA, spinal muscular atrophy.

10 Conclusions JEWELFISH is assessing the safety, PK and PD of RG7916 in a broad range of adolescent and adult SMA patients who have previously received an SMN2-targeting therapy Preliminary PD data in whole blood from 10 patients receiving RG7916 showed an up to 4-fold SMN protein increase vs baseline after 4 weeks of treatment To date, RG7916 has been safe and well tolerated There have been no drug-related adverse events leading to withdrawal in any SMA patients exposed to RG7916 The PK, magnitude of SMN protein increase, and safety observations (n=10) are similar to those seen in SUNFISH Part 1 10 PD, pharmacodynamics; PK, pharmacokinetics; SMA, spinal muscular atrophy; SMN, survival of motor neuron.

11 The JEWELFISH Protocol is Being Amended to Include More Patients The next JEWELFISH protocol amendment plans to: Include patients who have received nusinersen (FDA approval: Dec 2016) with SMA type I from 6 months of age Increase the total number of targeted patients to 40 Add an extension phase to the current 104-week treatment period Modify ophthalmologic assessments to lessen the overall burden to patients 11 FDA, Food and Drug Administration; PD, pharmacodynamic; PK, pharmacokinetic; SMA, spinal muscular atrophy.

12 Acknowledgments Many thanks to all the patients who participate in this study and their families 12