PTC Therapeutics
PTC THERAPEUTICS, INC. (Form: 8-K, Received: 01/29/2018 07:20:01)


UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): January 27, 2018
PTC THERAPEUTICS, INC.
(Exact Name of Company as Specified in Charter)

Delaware
 
001-35969
 
04-3416587
(State or Other Jurisdiction
of Incorporation)
 
(Commission
File Number)
 
(IRS Employer
Identification No.)
100 Corporate Court
 
 
South Plainfield, NJ
 
07080
(Address of Principal Executive Offices)
 
(Zip Code)
Company’s telephone number, including area code: (908) 222-7000
Not applicable
(Former Name or Former Address, if Changed Since Last Report)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions ( see General Instruction A.2. below):
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company     o
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.     o






Item 7.01.    Regulation FD Disclosure.
 
On January 27, 2018, PTC Therapeutics, Inc. (the “Company”) issued a press release (the “press release”) announcing the presentation of preliminary data from Part 1 of the FIREFISH trial in Type 1 SMA infants at the International Scientific Congress on Spinal Muscular Atrophy in Krakow, Poland. The full text of the press release issued in connection with the announcement is furnished as Exhibit 99.1 to this Current Report on Form 8-K (this “Report”). A copy of the presentation is also attached to this Report as Exhibit 99.2 and is incorporated by reference into this Item 7.01. Additionally, copies of three posters that were presented at the conference, 1) Mercuri et al. (L. Servais as presenting author), "Updated pharmacodynamic and safety data from SUNFISH Part 1, a study evaluating the oral SMN2 splicing modifier RG7916 in patients with Type 2 or 3 spinal muscular atrophy"  (the “SUNFISH poster”), 2) Chiriboga et al. (D. Kraus as presenting author) "Preliminary Evidence for Pharmacodynamics 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"  (the “JEWELFISH poster”), and 3) Poirier et al. (L. Mueller as presenting author), "Relationship Between Central and Peripheral SMN Protein Increase Upon Treatment with RO7034067 (RG7916)" (the “SMN protein poster”), are attached to this Report as Exhibits 99.3, 99.4 and 99.5, respectively, and are incorporated by reference into this Item 7.01.

The presentation was authored and given by Dr. Giovanni Baranello from the Fondazione Istituto Neurologico Carlo Besta in Milan, Italy, who is a third-party investigator in the trial, and was neither prepared nor presented by or on behalf of the Company. The SUNFISH poster was authored by Dr. Eugenio Mercuri from the Paediatric Neurology and Nemo Center at Catholic University and Policlinico Gemelli in Rome, Italy, who is a third-party investigator in the trial. The JEWELFISH poster was authored by Dr. Claudia A. Chiriboga from the Department of Neurology at Columbia University Medical Center in New York, NY, who is a third-party investigator in the trial. The SMN protein poster was authored by Dr. Agnes Poirier from the Roche Innovation Center in Basel, Switzerland. The SUNFISH poster and the JEWELFISH poster were neither prepared nor presented by or on behalf of the Company. The Company is providing the presentation and the posters as a convenience for investors for informational purposes.

The information in this Current Report on Form 8-K, including Exhibits 99.1, 99.2, 99.3, 99.4 and 99.5 shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such a filing.

Forward Looking Statements:  All statements, other than those of historical fact, contained in this Current Report on Form 8-K, including those contained in Exhibits 99.1, 99.2, 99.3, 99.4 and 99.5, are forward-looking statements, including regarding any advancement of the joint development program in SMA with PTC, Roche, and SMAF, in particular as related to the timing of enrollment, completion and evaluation of the Phase 2 clinical studies of RG7916 in SMA patients and the period during which the results of the studies will become available; the clinical utility and potential advantages of RG7916, including its potential to impact every aspect of the disease. The Company's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to the initiation, enrollment, conduct and availability of data from either the SUNFISH or FIREFISH studies and the outcome of such studies; and the factors discussed in the “Risk Factors” section of the Company's most recent Quarterly Report on Form 10-Q as well as any updates to these risk factors filed from time to time in the Company's other filings with the SEC. You are urged to carefully consider all such factors. The forward-looking statements contained herein represent the Company's views only as of the date of this Current Report on Form 8-K and the Company does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this Current Report on Form 8-K except as required by law.






Item 9.01.
Financial Statements and Exhibits.

(d) Exhibits

Exhibit No.
 
Description
99.1
 
99.2
 
99.3
 
99.4
 
99.5
 

Signature

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this Report to be signed on its behalf by the undersigned hereunto duly authorized.


 
PTC Therapeutics, Inc.
 
 
 
Date: January 29, 2018
By:
/s/ Mark E. Boulding
 
Name:
Mark E. Boulding
 
Title:
Executive Vice President and Chief Legal Officer





PTCLOGOIMAGE.JPG

Preliminary Data from FIREFISH trial in Type 1 SMA Infants Presented at the International Scientific Congress on Spinal Muscular Atrophy


SOUTH PLAINFIELD, N.J., Jan. 27, 2018 – PTC Therapeutics, Inc. (NASDAQ: PTCT) today announced the presentation of early interim data from Part 1, the dose-finding portion of the FIREFISH study. FIREFISH is a two-part seamless, open-label, multicenter study to investigate the safety and efficacy of RG7916 in infants and babies with Type 1 SMA. RG7916 has been safe and well tolerated at all doses and there have been no drug-related safety findings leading to withdrawal. In addition, data on the ability to swallow and requirements for tracheostomy or permanent ventilation, together with overall survival were also presented. Previously published natural history data indicate that in a comparable historic cohort the median age of event-free survival for SMA Type 1 infants to be between 8 and 10.5 months 1,2 . The presentation was given by Dr. Giovanni Baranello, Fondazione Istituto Neurologico Carlo Besta in Milan, Italy, at the International Scientific Congress on spinal muscular atrophy in Kraków, Poland, and will be made available via a link under the investor relations section of the PTC website. (www.ptcbio.com/smaeurope)

“It is exciting to show for the first time that an oral small molecule demonstrates early signs of clinical benefit,” stated Stuart W. Peltz, Ph.D., Chief Executive Officer of PTC Therapeutics. “We believe a drug that distributes to both the CNS and peripheral tissues can provide an important benefit to children suffering from this devastating, fatal disease. We anticipate that the trial will transition to the pivotal portion in the coming months.”

FIREFISH (NCT02913482) is a multi-center, open-label, seamless pivotal study evaluating the safety and efficacy of RG7916 in babies aged 1–7 months at enrollment with Type 1 SMA and two SMN2 gene copies. The exploratory Part 1 (n=8–24) is assessing the safety, tolerability, pharmacokinetics and pharmacodynamics of RG7916 at different dose levels. In Part 1, patients receive RG7916 for at least
4 weeks (or 2 weeks after steady-state is achieved) of daily administration; patients then enter an extension phase with RG7916. The confirmatory Part 2 (n=40) will assess the safety and efficacy of RG7916 at the dose level selected from Part 1 over 24 months. The primary endpoint for Part 2 is the proportion of infants sitting without support for 5 seconds, assessed by the Gross Motor Scale of the BSID-III, after 12 months of treatment.





“This early interim analysis of survival and the delay to milestone events that are hallmarks of the progression of SMA in infants are promising,” stated Dr. Giovanni Baranello, Fondazione Istituto Neurologico Carlo Besta in Milan, Italy. “These data, in conjunction with earlier poster presentations at the Congress from the trials in patients with type 2/3 SMA, are supportive of safety and sustained increase in SMN protein levels. Clinical trials in SMA patients require a globalization of clinical research; particularly, it is essential for a coordinated multidisciplinary team to support the babies and their families and to ensure the best standard of care to promote the higher benefit to affected children from potential new treatments.”

In addition to the oral presentation, three posters were on display during the Congress: updated pharmacodynamic and safety data from SUNFISH part 1, preliminary evidence for pharmacodynamic effects of RG7916 in JEWELFISH, and preclinical data demonstrating the relationship between central and peripheral SMN protein increase upon treatment with RG7916. The data presented demonstrate systemic and dose-dependent increase of SMN protein levels. The data from mice and other species suggest that SMN protein level increases seen in the blood of patients following RG7916 treatment reflect SMN protein level increases in the CNS, muscle and other key issues affected in SMA. In addition, RG7916 has been safe and well tolerated at all doses and there have been no drug-related safety findings leading to withdrawal.

The U.S. Food and Drug Administration granted orphan drug designation to RG7916 for the treatment of patients with SMA. RG7916 directly targets the underlying molecular deficiency of SMA by modulating SMN2 splicing to increase expression of full-length SMN2 mRNA from the SMN2 gene. An interim analysis from the first part of SUNFISH of the five cohorts treated with RG7916 for 28 days or longer demonstrated an exposure-dependent increase in SMN protein. SMA is characterized by reduced levels of SMN protein, motor neuron loss, and muscle atrophy. To date, RG7916 remains well-tolerated in patients at all doses and there have been no drug-related safety findings leading to withdrawal.

The SMA program was initially developed by PTC Therapeutics in partnership with the SMA Foundation in 2006 to accelerate the development of a treatment for SMA. In November 2011, Roche gained an exclusive worldwide license to the PTC/SMA Foundation SMN2 alternative splicing program. The development of these compounds is being executed by Roche and overseen by a joint steering committee with members from PTC, Roche, and the SMA Foundation.

1 Kolb S, et al. Amer Neuro Assoc 2017; 883-891
2 Finkel R, et al. Amer Acad Neur 2014; 810-817

About Spinal Muscular Atrophy (SMA)
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder that is the leading genetic cause of mortality in infants and toddlers caused by a missing or defective survival of motor neuron 1 (SMN1) gene, which results in reduced levels of SMN protein. The homologous SMN2 gene is predominantly spliced to a truncated mRNA, and only produces small amounts of functional SMN protein. Insufficient levels of SMN protein are responsible for the loss of motor neurons within the spinal cord leading to




muscle atrophy and death in its most severe form. It is estimated that this devastating disease affects 1 in every 11,000 children born. 
About the SMA Clinical Trials
FIREFISH
: An open-label, two-part clinical trial. Part 1 is a dose escalation study in at least 8 infants for a minimum of 4 weeks. The primary objective of Part 1 is to assess the safety profile of RG7916 in infants and determine the dose for Part 2. Part 2 is a single-arm study in approximately 40 infants with Type 1 SMA for 24 months, followed by an open-label extension.
SUNFISH : A double‐blind, two‐part, placebo‐controlled trial. Part 1 enrolled patients with Type 2 or 3 SMA to evaluate safety, tolerability, and PK/PD of several RG7916 dose levels. The pivotal SUNFISH Part 2, in non‐ambulant patients with Type 2 or 3 SMA, will evaluate safety and efficacy of the RG7916 dose level selected from Part 1.
JEWELFISH : An exploratory, open-label study to establish the safety and tolerability of RG7916 in people who have previously participated in a study with another therapy targeting SMN2 splicing.

About PTC Therapeutics
PTC is a global biopharmaceutical company focused on the discovery, development, and commercialization of novel medicines using our expertise in RNA biology. PTC's internally discovered pipeline addresses multiple therapeutic areas, including rare disorders and oncology. PTC has discovered all of its compounds currently under development using its proprietary technologies. Since its founding 20 years ago, PTC's mission has focused on developing treatments to fundamentally change the lives of patients living with rare genetic disorders. The company was founded in 1998 and is headquartered in South Plainfield, New Jersey. For more information on the company, please visit our website www.ptcbio.com.

For More Information:

Investors:
Emily Hill
+ 1 (908) 912-9327
ehill@ptcbio.com

Media:
Jane Baj
+1 (908) 912-9167
jbaj@ptcbio.com

Forward Looking Statements:
All statements, other than those of historical fact, contained in this press release, are forward-looking statements, including statements regarding: any advancement of the joint development program in SMA with PTC, Roche, and SMAF, in particular as related to the timing of enrollment, completion and evaluation of the Phase 2 clinical studies of RG7916 in SMA patients and the period during which the




results of the studies will become available; the clinical utility and potential advantages of RG7916, including its potential to impact every aspect of the disease; the timing and outcome of PTC's regulatory strategy and process; PTC's strategy, future expectations, plans and prospects, future operations, future financial position, future revenues or projected costs; and the objectives of management. Other forward-looking statements may be identified by the words "potential," "will," "promise," "expect," "plan," "target," "anticipate," "believe," "estimate," "intend," "may," "project," "possible," "would," "could," "should," "continue," and similar expressions.
PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to: the initiation, enrollment, conduct and availability of data from either the SUNFISH or FIREFISH studies and the outcome of such studies; events during, or as a result of, these studies that could delay or prevent further development of RG7916, including future actions or activities under the SMA joint development program; our expectations for regulatory approvals; PTC's scientific approach and general development progress; and the factors discussed in the "Risk Factors" section of PTC's most recent Quarterly Report on Form 10-Q as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors.
As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products, including with respect to PTC's joint development program in SMA with Roche and the SMAF. There are no guarantees that any product candidate under the joint development program will receive regulatory approval in any territory or prove to be commercially successful.
The forward-looking statements contained herein represent PTC's views only as of the date of this press release and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this press release except as required by law.




© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. FIREFISH, A MULTI-CENTER, OPEN-LABEL TRIAL TO INVESTIGATE THE SAFETY AND EFFICACY OF RG7916 IN BABIES WITH TYPE 1 SMA: STUDY UPDATE AND REAL-LIFE EXPERIENCE OF STUDY IMPLEMENTATION G Baranello1, J Day2, A Klein3, E Mercuri4, L Servais5, N Deconinck6, R Masson1, H Kletzl7, C Czech7, M Gerber7, Y Cleary7, F Lee7, K Gelblin7, S Nave7, K Gorni7 and O Khwaja7 1. Carlo Besta Neurological Research Institute Foundation, Developmental Neurology Unit, Milan, Italy; 2. Department of Neurology, Stanford University, Palo Alto, CA, USA; 3. University Children’s Hospital Basel, Basel, Switzerland; Inselspital, Bern, Switzerland; 4. Paediatric Neurology and Nemo Center, Catholic University and Policlinico Gemelli, Rome, Italy; 5. Institute of Myology, Paris, France; Reference Center for Neuromuscular Disease, Centre Hospitalier Régional de La Citadelle, Liège, Belgium; 6. Queen Fabiola Children's University Hospital and Université Libre de Bruxelles, Brussels, Belgium; Neuromuscular Reference Center UZ Ghent; Ghent, Belgium; 7. Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Basel, Switzerland.


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. Disclosures GB is PI in the following clinical trials in SMA: BP39055 and BP39056 (Roche); CLMI070X2201 (Novartis); AVXS-101-CL-302 (Avexis); SMA- 001 (Catalyst); PI in the following clinical trials in Duchenne Muscular Dystrophy: FOR_DMD; DSC/14/2357/48 (Italfarmaco); VBP15-004 (Reveragen); PTC124-GD-025o_DMD (PTC Therapeutics). JD reports grants from: AMO Pharmaceuticals; aTyr; AveXis; Biogen; Bristol Meyers Squibb; Cytokinetics; Ionis Pharmaceuticals; Roche Pharmaceuticals; Sanofi-Genzyme; and Sarepta Therapeutics. He has served as a consultant for: AMO Pharmaceuticals; AveXis; Biogen; Cytokinetics; Ionis Pharmaceuticals; Roche Pharmaceuticals; Pfizer; Sarepta Therapeutics; Santhera Pharmaceuticals. He has patents licensed to Athena Diagnostics for genetic testing of myotonic dystrophy type 2 (US patent 7442782) and spinocerebellar ataxia type 5 (US patent 7527931). AK has received speaker and consulting fees from Biogen, PTC, Roche and Santhera and is PI for F. Hoffmann-La Roche and Santhera studies. EM is a consultant for F. Hoffmann-La Roche, AveXis, IONIS and Biogen, and PI for Biogen/IONIS and F. Hoffmann-La Roche studies. LS is a PI of SMA studies for Roche, Biogen, and Avexis. He has attended SAB of Biogen and Avexis and received consultancy fees from BiogenND. RM has no disclosures to report. HK, CC, MG, YC, FL, KGelblin, SN, KGorni and OK are current employees of F. Hoffmann-La Roche. RG7916 is an investigational medicine and benefit/risk profile has not been fully established. The information presented is early interim data.


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. Introduction • SMA is a severe, progressive neuromuscular disease leading to loss of motor function and reduced life expectancy1 • Increasing evidence suggests that SMA may be a multi-system disorder, where cells and tissues throughout the body, including motor neurons may be selectively vulnerable to low SMN protein levels3,4 • RG7916 is an orally administered, centrally and peripherally distributed SMN2 pre-mRNA splicing modifier that increases SMN protein levels • Preclinical data show similar RG7916 concentrations in blood, brain, and muscle tissue (Poster P48, A. Poirier et al.) • Similar SMN protein increase in brain and muscle in SMA mouse models following RG7916 administration (Poster P48) • Proof-of-mechanism of oral SMN2 splicing modifiers was previously established in preclinical models5 and in Type 2 and 3 SMA patients with RG79166 (Poster P46, E. Mercuri et al.) • The FIREFISH study aims to assess the safety and efficacy of RG7916 in babies with Type 1 SMA. This study is sponsored by F. Hoffmann-La Roche Ltd. SMA, spinal muscular atrophy; SMN, survival of motor neuron. 1. Mercuri E, et al. Lancet Neurol 2012;11:443–452; 2. Acsadi G, et al. J Neurosci Res 2009;12:2748–2756; 3. Singh RN, et al. Biochim Biophys Acta 2017;1860:299–315; 4.Hamilton G and Gillingwater TH. Trends Mol Med 2013;19:40–50; 5. Naryshkin N, et al. Science 2014; 345:688–693; 6. Clinicaltrials.gov NCT02633709 Accessed December 2017


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. RG7916 mechanism of action SMN1 6 8 7 DNA Pre-mRNA mRNA Functional SMN protein 6 8 7 6 8 7 SMN2 6 8 7 6 8 7 6 8 7 6 8 7 6 8 Functional SMN protein Unstable SMN protein rapidly degraded RG7916 Pinard E, et al. J Med Chem; 2017;60:4444–4457. RG7916 modifies SMN2 splicing to produce functional SMN protein in central and peripheral compartments


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. *Comprises minimum two dose-ranging cohorts; Patients to be enrolled in a stepwise fashion based on PK findings to minimize exposure. https://clinicaltrials.gov/ct2/show/NCT02913482, accessed Jan 2018. FIREFISH: Study overview FIREFISH Type 1 SMA 1–7 months old Part 2: Confirmatory Open-label Dose level selected from Part 1 n=40 Active treatment RG7916 12 months 24 months Extension Part 1*: Dose- finding Several RG7916 dose levels n=8–24 RG7916 dose selected for Part 2 Continued treatment RG7916 Open-Label Extension RG7916 dose level 1 RG7916 dose level 2 Key inclusion criteria • Genetic confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of SMN1 • Clinical history, signs or symptoms attributable to SMA type 1 after 28 days but prior to 3 months • Adequate nutrition at time of enrolment and willing to consider tube if required • Two SMN2 gene copies (confirmed by central testing during screening) Key exclusion criteria • Concomitant or previous participation in a SMN2 targeting or gene therapy study • Invasive ventilation or tracheostomy • Awake non-invasive ventilation or with awake hypoxemia (SaO2 < 95%) with or without ventilator support • Hospitalization for pulmonary event within the last 2 months, or planned at the time of screening • Recent history (< 1 year) of ophthalmological disease Detailed study information: clinicaltrials.gov/ct2/show/NCT02913482 www.roche-sma-clinicaltrials.com


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. Part 1 Part 2 Primary endpoint • Safety, tolerability, PK and PD of RG7916 • Dose selection for Part 2 % infants sitting without support for 5 seconds at 12- months assessed by Gross Motor Scale of the BSID-III Secondary endpoints • Motor function (HINE-2, CHOP-INTEND) • Pharmacodynamics/PK • Safety • Time to death or permanent ventilation • Respiratory Plethysmography (RP) • Compound Muscle Action Potential Negative Peak Amplitude (CMAP) FIREFISH: Outcome measures https://clinicaltrials.gov/ct2/show/NCT02913482, accessed Jan 2018. BSID-III, Bayley Scales of Infant and Toddler development Third Edition; CHOP-INTEND, Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE-2, Hammersmith Infant Neurological Examination Module 2.


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. Patient demographics and baseline characteristics from the first 13 patients and study status IQR=interquartile range. Data current as of December 7, 2017. RG7916 is an investigational medicine and benefit/risk profile has not yet been fully established. The information presented is from early interim analysis. All Treatments (N=13) Age at first dose (months) Median (IQR) 6.9 (6.3–6.9) Gender Female, n (%) 10 (76.9) Weight at baseline (g) Median (IQR) 6720 (5650–7600) Age at diagnosis (months) Median (IQR) 3.5 (2.1–4.6) • Part 1 (dose-finding) screening ongoing with a total of 16 patients enrolled* • 10 active sites: Italy, France, USA, Belgium, Switzerland, Turkey • Data presented here are from the first 13 patients recruited • Part 2 expected to start Q1 2018 *Status Jan 5, 2018


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. Age of patients and duration of exposure to treatment Study duration is measured from start date of first dose to date of data extraction. Data current as of December 7, 2017. RG7916 is an investigational medicine and benefit/risk profile has not yet been fully established. The information presented is from early interim analysis. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Death Death Age (months) Before first dose After first dose


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. No patient has lost the ability to swallow Data current as of December 7, 2017. RG7916 is an investigational medicine and benefit/risk profile has not yet been fully established. The information presented is from early interim analysis. Visit All Treatments Baseline N=13 Able to swallow, n 12 Unable to swallow, n 1 Week 8 N=9 Able to swallow, n 8 Unable to swallow, n 1 Week 17 N=4 Able to swallow, n 4 Unable to swallow, n 0 Week 26 N=4 Able to swallow, n 4 Unable to swallow, n 0 Week 35 N=3 Able to swallow, n 3 Unable to swallow, n 0 Summary of clinical outcomes No patients have required tracheostomy or permanent ventilation* *Permanent ventilation defined as ≥ 16 hours of assisted ventilation per day for more than 2 weeks or continuous intubation ≥ 30 days


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. Summary of safety outcomes • Overall 10 (77%) out of 13 patients experienced at least one adverse event. Most events were mild in intensity and resolved despite ongoing treatment • Adverse events reported in more than one patient were pyrexia (n=5), upper respiratory tract infection (n=3), diarrhea (n=2), vomiting (n=2), erythema (n=2) • Serious adverse events were reported in four patients: respiratory tract infection viral, pneumonia & neutropenia, acute respiratory failure and hypoxia • Ophthalmological monitoring conducted every 2 months did not show any evidence of the retinal toxicity seen in preclinical monkey studies in any patient exposed to RG7916 • Fatal events were reported in two patients: • Respiratory tract infection viral with fatal outcome on study Day 21 • Cardiac arrest and respiratory arrest with fatal outcome on study Day 236* *Event reported after cut off date November 15, therefore not included in serious adverse events count. Reference: interim safety summary BP39056 part 1 dated 08/01/2018


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. • Working with patients with Type 1 SMA presents several challenges, mainly related to the age and the severity of the disease • Challenges can affect the infants, family, and staff involved in the studies • As SMA (and especially Type 1) is a rare and devastating disease, we are facing a GLOBALIZATION of clinical research • Families in countries where competing trials and therapies (eg, nusinersen) are not available may ask to be recruited to studies or to access therapies • This may accelerate recruitment and development of new treatments • Give access to potential treatment to a higher number of patients Tips from real-life experience during the implementation of the FIREFISH study


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. • Real-life experience from investigators must be used to best support patients and families during the FIREFISH trial • The importance of support from advocacy groups and patient/family organizations • Key considerations when conducting a study in Type 1 SMA include: • The need to coordinate a multi-disciplinary team of healthcare specialists dealing with such young babies • The support to relocate families away from their home country • The importance of assuring standard-of-care practices whilst patients participate in the trial Tips from real-life experience during the implementation of the FIREFISH study


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. • Families in countries where competing trials and therapies (eg, nusinersen) are not available may ask to be recruited to studies or to access therapies • Resource limitations and cultural differences • Relocation is important for the safety of the child and for the good conduct of the study Family relocation


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. SMA standard of care implementation has increased survival and improved quality of life of children and their families   Increased survival   Improved quality of life Rehabilitation Orthopedic Care/ Orthosis Psycho-social support Nutritional care (growth/ under-nutrition) Pulmonary care Respiratory support Gastro-intestinal management Intensive Care/ Emergency Patient with SMA & family Bone health Other organ involvement


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. • A proactive and anticipatory approach is essential to modify the course of the disease • Changing phenotype should be paralleled and supported by the implementation of standard of care (eg, postural control or standing frame as long as the child reaches new motor milestones, etc) The application of SoC remains essential despite the emerging therapies • Need of consistency of management within the study (involving different sites in different countries) • Need for training and dissemination of experience among sites and countries SoC, standard of care. Clinical trials involving relocation should ensure multidisciplinary management


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. Conclusions • To date, RG7916 has been safe and well tolerated at all doses and there have been no drug-related safety findings leading to withdrawal in any SMA patients exposed to RG7916 • Ophthalmologic monitoring did not show any evidence of the retinal toxicity seen in preclinical monkey studies in any patient exposed to RG7916 • Early interim clinical data reported:  No patient lost the ability to swallow  No patient has required tracheostomy or reached permanent ventilation • Important considerations in conducting such clinical studies:  Co-ordination of a multi-disciplinary team  Family relocation  Application of standard-of-care practices • Study updates will continue to be communicated at congresses in 2018 • Part 2 of the study is expected to start in Q1 2018


 
© 2018 F. Hoffmann-La Roche Ltd. All rights reserved. We thank all the patients who participate in these studies and their families. We thank our collaborators PTC Therapeutics and SMA Foundation. We thank the FIREFISH, SUNFISH, and JEWELFISH investigators and trial staff. Acknowledgments


 


 
Presented at the International Scientific Congress on Spinal Muscular Atrophy, Krakow, Poland, 25 – 27 January 2018. Updated pharmacodynamic and safety data from SUNFISH Part 1, a study evaluating the oral SMN2 splicing modifier RG7916 in patients with Type 2 or 3 spinal muscular atrophy Eugenio Mercuri1, Giovanni Baranello2, Janbernd Kirschner3, Laurent Servais4, Nathalie Goemans5, Maria Carmela Pera1, Anne Marquet6, Gillian Armstrong7, Heidemarie Kletzl6, Marianne Gerber6, Christian Czech6, Yumi Cleary6, Margaret Chan8, Sangeeta Jethwa6, Stephane Nave6, Ksenija Gorni6 and Omar Khwaja6 1Paediatric Neurology and Nemo Center, Catholic University and Policlinico Gemelli, Rome, Italy; 2Carlo Besta Neurological Research Institute Foundation, Developmental Neurology Unit, Milan, Italy; 3Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Freiburg, Germany; 4Institute of Myology, Paris, France; Reference Center for Neuromuscular Disease, Centre Hospitalier Régional de La Citadelle, Liège, Belgium; 5Neuromuscular Reference Centre, Department of Paediatrics and Child Neurology, University Hospitals Leuven, Belgium; DVC St Jozef Antwerp, Antwerp, Belgium; 6Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Switzerland; 7Roche Products Ltd, Welwyn Garden City, United Kingdom; 8Roche Pharmaceutical Research and Early Development, Roche Innovation Center New York, New York, NY, USA Background • Spinal muscular atrophy (SMA) is a severe, progressive neuromuscular disease leading to loss of motor function and reduced life expectancy.1 • SMA is caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene; a second SMN gene, SMN2, only produces low levels of functional SMN protein.2 • SMA has traditionally been described as a disease of lower motor neurons; however, cells and tissues throughout the body may be vulnerable to reduced levels of SMN protein, and increasing evidence suggests that SMA is a multi-system disorder.3,4 • RG7916 is an orally administered, centrally and peripherally distributed SMN2 pre-mRNA splicing modifier that increases SMN protein levels. • The SUNFISH study aims to assess the safety and efficacy of RG7916 in people with Type 2 or 3 SMA. • Here, we report data from Part 1 of the SUNFISH study. Methods • SUNFISH study is currently recruiting participants (NCT02908685). • Study design: SUNFISH is a multicenter, randomized, placebo-controlled, operationally seamless, Phase 2 study evaluating the efficacy and safety of RG7916 in patients with Type 2 or Type 3 SMA (Figure 1 and Table 1). — Part 1. Exploratory: dose-finding; blinded RG7916 or placebo (2:1) in patients with Type 2 or ambulatory and non-ambulatory Type 3 SMA. First patient dosed October 20th 2016. — Part 2. Confirmatory: efficacy and safety at the selected dose from Part 1; blinded RG7916 or placebo (2:1) for 12 months followed by open-label RG7916 until commercial availability, in patients with Type 2 or non-ambulatory Type 3 SMA. First patient dosed October 11th 2017. Figure 1: SUNFISH study design *Part 1 of SUNFISH comprises 2 age groups (2–11 and 12–25 years); for each age group a minimum of two doses will be tested. Table 1: SUNFISH study overview; Type 2 or 3 SMA, 2–25 years Part 1 (n=51) Part 2 (n=168) Inclusion/exclusion criteria Key inclusion criteria • Confirmed genetic diagnosis of SMA* • Confirmed genetic diagnosis of SMA* • Non-ambulant • Able to sit independently and can raise hand to mouth Key exclusion criteria • Previous participation in an SMN2-targeting study or gene therapy study • Planned (within 18 months) or previous (<1 year prior) surgery for scoliosis or hip fixation Endpoints Primary endpoints • Safety, tolerability, PK and PD of RG7916 • Dose selection for Part 2 • Change from baseline in MFM32 at Month 12 Selected secondary endpoints Motor function at 12 months • HFMSE, RULM, stabilization or improvement in MFM32, MFM domain scores Respiratory function at 12 months • SNIP, MIP†, MEP†, FEV1 †, FVC† and PCF† PK/PD • SMN2 mRNA and SMN protein in blood • Cmax, Ctrough and AUC of RG7916 QoL at 12 months • SMAIS‡ Safety *5q-autosomal recessive SMA. †Patients aged 6–25 years only. ‡In patients aged ≥12 years only. Conclusions • To date, RG7916 has been safe and well tolerated at all doses, and there have been no drug- related safety findings leading to withdrawal in any SMA patients exposed to RG7916. • Analysis of the SUNFISH Part 1 cohorts treated with RG7916 showed dose-dependent increases in the SMN2 FL/SMN2∆7 mRNA ratio. • RG7916 treatment resulted in increased SMN protein up to a median of 2.5 fold in patients with SMA. • These safety, tolerability and PK/PD data were sufficient to inform the selection of a RG7916 dose level predicted to lead to clinically efficacious levels of SMN protein; this dose level will be assessed in Part 2 of SUNFISH in children and young adults with SMA. Abbreviations AUC, area under curve; Cmax, maximum plasma concentration; Ctrough, trough plasma concentration; FEV1, forced expiratory volume in 1 second; FL, full-length; FVC, forced vital capacity; HFMSE, Hammersmith Functional Motor Scale Expanded; MEP, maximum expiratory pressure; MFM, Motor Function Measure; MIP, maximum inspiratory pressure; PCF, peak cough flow; PD, pharmacodynamic; PK, pharmacokinetic; QoL, Quality of Life; RULM, Revised Upper Limb Module; SMA, spinal muscular atrophy; SMAIS, Spinal Muscular Atrophy Independence Scale; SMN, survival of motor neuron; SNIP, sniff nasal inspiratory pressure. Acknowledgments We would like to thank the patients and their families who participated in this study, as well as the investigators and trial staff involved in the SUNFISH study. We thank Tobias Bergauer, Anna-Katharina Wiegers and Johann Karl of the Roche Biomarker Team for their contributions to this study. We thank Dr. Riccardo Masson of the Carlo Besta Neurological Research Institute Foundation, Developmental Neurology Unit, Milan, Italy for his support of this study. We would also like to thank our collaborators at PTC Therapeutics and the SMA Foundation. The study was sponsored by F. Hoffmann-La Roche AG, Basel, Switzerland. Writing and editorial assistance was provided by MediTech Media, UK. Results • To date, RG7916 has been safe and well tolerated at all doses assessed. • There have been no deaths and no drug-related safety findings leading to withdrawal • Bi-monthly ophthalmological monitoring did not show any evidence of retinal toxicity seen in preclinical monkey studies. • Adverse events were mostly mild, resolved despite ongoing treatment and were reflective of the underlying disease. • RG7916 produced a dose-dependent increase in SMN2 FL mRNA and a concomitant decrease in SMN2Δ7 mRNA (Figure 2). • In patients with SMA, SMN protein was increased in a dose-dependent manner up to a median of 2.5 fold (Figure 3). • Increases in SMN protein were sustained up to 250 days (Figure 3). Table 2: Adverse events occurring in ≥2 patients in at least 1 dose group, Day 1 to 84 by starting dose Aged 2–25 years Aged 2–11 years Aged 12–25 years Placebo n=16 Dose 1 n=7 Dose 2 n=7 Dose 3 n=7 Dose 1 n=7 Dose 2 n=7 Patients with at least one event, n Pyrexia 2 0 1 1 2 1 Oropharyngeal pain 2 0 0 1 1 2 Vomiting 1 2 0 0 0 1 Upper respiratory tract infection 0 0 1 2 0 0 Fatigue 0 0 0 1 2 0 Figure 2: SMN2 mRNA levels versus plasma concentrations of RG7916. Time-matched concentration of RG7916 versus (A) the ratio of SMN2 FL mRNA to SMN2Δ7 mRNA, (B) SMN2 FL mRNA, or (C) SMN2Δ7 mRNA is plotted. 0 0 2 4 20 40 60 80 100 120 140 160 6 8 10 12 14 16 18 20 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 0.0 0.2 0.4 0.6 0.8 1.2 1.0 1.4 1.6 1.8 2.0 A B CSMN2 FL/∆7 ratio Placebo 12–25 years, dose 1 12–25 years, dose 2 2–11 years, dose 1 2–11 years, dose 2 2–11 years, dose 3 2–11 years, dose 4 0 20 40 60 80 Time-matched plasma RG7916 concentration (ng/mL) 100 120 140 160 SMN2 F L ratio (ratio from baseline ) SMN2 FL 0 20 40 60 80 100 120 140 160 SMN∆7 SMN2 FL /∆ 7 ratio (ratio from baseline ) SM N ∆ 7 ratio (ratio from baseline ) Figure 3: SMN protein levels. (A) Concentration of SMN protein in blood by dose. Ratio of SMN protein change from baseline in blood is plotted by dose in (B) and median values (range) are displayed in (C). Day 0 2 3 4 5 6 7 50 100 SMN protein (ng/mL ) A B 150 200 250 Day 0 0 1 2 3 4 50 100 SMN protei n (ratio from baseline ) 150 200 250 2–11 years, dose 4 2–11 years, dose 1 2–11 years, dose 2 2–11 years, dose 3 12–25 years, dose 1* Placebo 12–25 years, dose 2 C Median [range] SMN protein in blood (n=51 patients), ratio at Day 28 versus baseline 2–11 years 12–25 years Placebo Dose 1 Dose 2 Dose 3 Dose 4 Dose 1 Dose 2 SMN protein ratio at Day 28 versus baseline; median [range] 0.958 [0.714–1.38] 1.09 [0.813–1.47] 1.51 [0.97–2.30] 1.67 [1.20–1.87] 1.96 [1.17–2.50] 2.25 [1.43–2.52] 2.51 [1.49–3.51] *Not all samples available for all time points. References 1. Mercuri E, et al. Lancet Neurol 2012;11:443–452. 2. Acsadi G, et al. J Neurosci Res 2009;12:2748–2756. 3. Singh RN, et al. Biochim Biophys Acta 2017;1860:299–315. 4. Hamilton G and Gillingwater TH. Trends Mol Med 2013;19:40–50. 12 months 24 months Placebo to active switch Extension Open-label Extension at pivotal dose Placebo Placebo RG7916 RG7916 dose level 1SUNFISHType 2 or 3 SMA Part 1: Dose-finding* RG7916:placebo, 2:1 n=36–72 Part 2: Confirmatory Dose level selected from Part 1 RG7916:placebo, 2:1 n=168 Placebo RG7916 dose level 2 RG7916 dose selected for Part 2


 
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 C.A. Chiriboga1, E. Mercuri2, D. Fischer3, D. Kraus4, M. Alexander5, G. Armstrong6, H. Kletzl4, M. Gerber4, Y. Cleary4, K. Gelblin4, T. Bergauer4, K. Gorni4 and O. Khwaja4 1Department of Neurology, Columbia University Medical Center, New York, NY, USA; 2Paediatric Neurology and Nemo Center, Catholic University and Policlinico Gemelli, Rome, Italy; 3Department of Neurology, University of Basel Hospital, Basel, Switzerland; 4Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Basel, Switzerland; 5Roche Pharmaceutical Research and Early Development, Roche Innovation Center New York, New York, NY, USA; 6Roche Products Ltd, Welwyn Garden City, UK Table 1: JEWELFISH study overview JEWELFISH Type 2 or 3 SMA Key inclusion criteria • Confirmed diagnosis of 5q-autosomal recessive SMA • Previous participation in a study with an antisense oligonucleotide targeting SMN2 splicing or an SMN2 splicing modifier other than RG7916 • Any number of SMN2 gene copies allowed Key exclusion criteria • Concomitant participation in any investigational drug or device study • Participation in any investigational drug or device study, other than an antisense oligonucleotide targeting SMN2 splicing or SMN2 splicing modifier study, within 90 days of screening or 5 half-lives of the drug, whichever is longer • History of gene or cell therapy • Recently initiated treatment (>6 months prior to enrollment) with oral salbutamol or another beta 2-adrenergic agonist taken orally • Recent history (>1 year) of ophthalmologic disease Primary endpoints Safety PK: Mean plasma concentration, Cmax, AUC and Ctrough of RG7916 and metabolites Secondary endpoints PD: SMN mRNA and protein levels in blood Figure 1: SMN2 FL/SMNΔ7 mRNA ratio over time Figure 2: SMN protein concentration over time Figure 3: The SMN protein ratio over time Background • Spinal muscular atrophy (SMA) is a rare hereditary neuromuscular disease caused by loss of function of the survival of motor neuron 1 (SMN1) gene.1 • SMA is characterized by progressive degeneration of spinal cord α-motor neurons, leading to muscle weakness and atrophy.2 • While SMN1 produces full-length (FL) SMN protein, a second gene, SMN2, produces only low levels of functional SMN protein.1 • RG7916 is an orally available, centrally and peripherally distributed investigational small molecule designed to modify the splicing of the SMN2 pre-mRNA, resulting in increased production of SMN2 FL mRNA, and subsequently SMN protein.3 • Although SMA has traditionally been viewed as a disease of motor neurons, increasing evidence indicates that SMA is a multi-system or whole-body disorder.4 Therapies that increase SMN protein levels systemically may have the potential to have broader therapeutic benefit than those targeting the motor neurons alone. • JEWELFISH is an exploratory, open-label study (NCT03032172) to establish the safety and tolerability of RG7916 in people who have previously participated in a study with another therapy targeting SMN2 splicing.5 Study design • JEWELFISH is a multicenter, open-label study primarily evaluating the safety and tolerability of once-daily oral administration of RG7916 in patients aged 12–60 years with Type 2 or 3 SMA who have previously participated in a study with therapy targeting SMN2 splicing (Table 1). — This includes patients previously enrolled in the MOONFISH study with RG7800 and those previously enrolled in studies with nusinersen. — Planned enrollment is 24 patients, to include 16 previous MOONFISH patients and 8 previous nusinersen study patients. • JEWELFISH will also investigate the pharmacodynamics (PD) and pharmacokinetics (PK) of RG7916 treatment in non-naïve patients. • As planned in the study protocol, a Safety Monitoring Committee reviews all safety information from all JEWELFISH participants. Results • Data from 3 patients with up to 4 weeks’ exposure are shown. • To date, no drug-related adverse events leading to study discontinuation have been observed in JEWELFISH, and no stopping rules have been met. • Preliminary PD data from 3 JEWELFISH patients show a rapid increase in the SMN2 FL/SMNΔ7 mRNA ratio, with an approximately 2-fold increase at 4 hours after treatment onset. The SMN2 FL/SMNΔ7 mRNA ratio increased up to 4-fold from baseline over 4 weeks of RG7916 treatment (Figure 1). • SMN protein analysis indicated an increase in SMN concentration over 4 weeks of RG7916 treatment (Figure 2), with an up to 4-fold increase in the SMN ratio compared with baseline in 1 patient and up to 2-fold increase in the other 2 patients (Figure 3). Conclusions • All 3 patients showed increases in SMN2 FL/SMNΔ7 mRNA ratio and SMN protein increases of up to 4-fold. • The JEWELFISH protocol will be amended to the dose level selected for the pivotal Part 2 of SUNFISH6. • Safety and PK/PD data from SUNFISH Part 1 informed the selection of a pivotal RG7916 dose level; see Mercuri E et al. SUNFISH poster. • To date, RG7916 has been safe and well tolerated at all doses and there have been no drug-related safety findings leading to withdrawal in any SMA patients exposed to RG7916. Acknowledgments We would like to thank the patients and their families for participation in these studies. This study is funded by F. Hoffmann La-Roche. The authors thank Paul Grimsey, Yumi Cleary and Marianne Gerber of Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Basel, Switzerland for data analysis support. We would also like to thank our collaborators at PTC Therapeutics and the SMA Foundation. The authors thank Craig O'Hare, PhD, of MediTech Media UK for providing medical writing support, which was funded by F. Hoffmann La-Roche Basel, Switzerland, in accordance with Good Publication Practice (GPP3) guidelines. Abbreviations AUC, area under curve; Cmax, maximum observed plasma concentration; Ctrough, trough plasma concentration; FL = full-length; PD, pharmacodynamics; PK, pharmacokinetics; SMA, spinal muscular atrophy; SMN, survival of motor neuron. References 1. Tisdale S, et al. J Neurosci. 2015;35(23):8691-8700. 2. Mercuri E, et al. Lancet Neurol. 2012;11(5):443-452. 3. Naryshkin NA, et al. Science. 2014;345(6197):688-693. 4. Hamilton G & Gillingwater TH. Trends Mol Med. 2013;19(1):40-50. 5. ClinicalTrials.gov. NCT03032172. Updated 2017. Accessed January, 2017. 6. ClinicalTrials.gov. NCT02908685. Updated 2017. Accessed January, 2017. 1 0 1 2 3 4 2 3 4 mRNA SMN2 FL/SMNΔ 7 (fold increase from baseline ) Time (weeks) Patient 1 Patient 2 Patient 3 Baseline 2 0 1 2 3 4 6 4 SMN protein (ng/mL ) Time (weeks) Patient 1 Patient 2 Patient 3 1 0 1 2 3 4 2 3 4 S MN protein rati o (fold increase from baseline ) Time (weeks) Patient 1 Patient 2 Patient 3 Baseline Presented at the International Scientific Congress on Spinal Muscular Atrophy, Krakow, Poland, 25–27 January 2018


 
Relationship between central and peripheral SMN protein increase upon treatment with RO7034067 (RG7916) Agnès Poirier1, Marla Weetall2, Hasane Ratni1, Katja Heinig1, Nikolai Naryshkin2, Sergey Paushkin3, Lutz Mueller1 1 Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland 2 PTC Therapeutics, South Plainfield, NJ, USA 3 SMA Foundation, New York, NY, USA Figure 1: RO7034067 tissue vs. plasma concentration RO7034067 plasma concentration vs. concentration in brain (Figure 1A; n=190), muscle (Figure 1B; n=44) and CSF (Figure 1C; n=35) of mice, rats and monkeys following single or repeat PO or IP administration. Conclusions • RO7034067 distributes well into the CNS, CSF and peripheral tissues, including muscle, blood and brain, in mice, rats and monkeys following single or repeat oral or IP dosing. • Oral administration of RO7034067 increased SMN protein levels to a similar magnitude in the brain and muscle of C/C and Δ7 mouse models of SMA. • In addition, oral administration of a structurally similar SMN2 splicing modifier, RO6885247, resulted in parallel increases in SMN protein levels in the blood, brain, and muscle of C/C-allele mice. • The data from mice and other species suggest that SMN protein level increases seen in the blood of patients following RO7034067 (RG7916) treatment reflect SMN protein level increases in CNS, muscle and other key tissues affected in SMA. Abbreviations • AAALAC, Association for Assessment and Accreditation of Laboratory Animal Care International; CNS, central nervous system; CSF, cerebral spinal fluid; IP, intraperitoneal injection; PO, per oral; MRD1, multi-drug resistance gene; SMA, spinal muscular atrophy; SMN, survival motor neuron. References 1. Lunn MR and Wang CH. Lancet 2008; 371:2120–2133. 2. Hamilton G and Gillingwater TH. Trends Mol Med. 2013; 19:40–50. 3. Feng Z et al. Hum Mol Genet. 2016; 25:964-75. 4. Sivaramakrishnan M et al. Nat Commun. 2017; 8:1476,017-01559-4. Acknowledgements • We would like to thank the Jackson Laboratory for providing the FVB.129(B6) Smn1tm5(Smn1/SMN2)Mrph/J strain and FVB.Cg-Tg(SMN2*delta7)4299Ahmb Tg(SMN2)89Ahmb strain; and the Charles River Laboratories for providing the Wistar Hannover Crl:WI (Han) strain. We would also like to thank our collaborators at PTC Therapeutics and the SMA Foundation. The study was sponsored by F. Hoffmann-La Roche AG, Basel, Switzerland. Writing and editorial assistance was provided by Vassia Schiza, PhD, of MediTech Media, UK and was funded by F. Hoffmann La-Roche Basel, Switzerland, in accordance with Good Publication Practice (GGP3) guidelines. All animal experiments were carried out in AAALAC-certified facilities, and protocols were approved by the Institutional Animal Care and Use Committee. Background • Spinal muscular atrophy (SMA) is caused by deletion and/or mutation of the Survival Motor Neuron 1 (SMN1) gene, resulting in insufficient levels of the SMN protein, which is critical to the survival of motor neurons.1 • Increasing evidence suggests SMN depletion directly affects cells and tissues in both the CNS and the periphery, suggesting that SMA may be a multi-system disorder.2 • RO7034067 (RG7916) is an orally administered, centrally and peripherally distributed SMN2 pre-mRNA splicing modifier that increases SMN protein levels.3-4 — RO7034067 is under investigation in the SUNFISH (Type 2/3 SMA), FIREFISH (Type 1 SMA) and JEWELFISH (non-naïve Type 2/3 SMA) clinical studies. • RO7034067 was designed to penetrate the CNS (avoiding transporter protein interaction which would restrict this) and peripheral tissues on oral administration • We assessed the tissue and CSF distribution of orally administered RO7034067 and effects on SMN protein levels in the CNS and peripheral tissues of preclinical models; this will inform the significance of increases in blood SMN protein levels seen in patients receiving RO7034067. Methods • RO7034067 tissue and CSF (to serve as surrogate for free concentration in the brain) distribution were assessed in adult and juvenile, wildtype FvB mice, Brown Norway BN/Crl rats, Wistar Hannover Crl:WI (Han) rats and cynomolgus monkeys (Macaca fascicularis). • C/C-allele mouse model of mild SMA was derived from FVB.129(B6)-Smn1tm5(Smn1/ SMN2)Mrph/J strain and dosed from ~7 weeks old. The Δ7 mice was derived from FVB.Cg-Tg(SMN2*delta7)4299Ahmb Tg(SMN2)89Ahmb strain and dosed from post-natal Day 3. • Levels of RO7034067 were quantified using liquid chromatography−tandem mass spectrometry (LC-MS/MS) on triple quadrupole mass spectrometers. • SMN protein levels were quantified using Homogeneous Time Resolved Fluorescence (Human SMN Assay Kit Cisbio) as previously described, and normalised to total protein concentrations. Fold increase was calculated vs vehicle. Results • Single or repeated, daily oral (PO) or intraperitoneal (IP) administration of RO7034067 for up to 39 weeks showed similar total drug levels in brain, muscle and CSF of mice (n=90), rats (n=148) and monkeys (n=24) (Figure 1). — An excellent correlation was observed between plasma levels of RO7034067 and levels in brain, muscle and CSF over a wide range of concentrations. • Following oral administration for 7 days in cynomolgus monkeys, RO7034067 distributed to key tissues and organs including the CNS and muscle that could be affected in SMA (Figure 2). — Total plasma concentrations (794 ng/ml) were very similar to those in brain (783 ng/g) and muscle (668 ng/g), whereas CSF drug levels (53.5 ng/ml) were within the range of free compound in plasma (119 ng/ml). • After oral administration of RO7034067 to adult C/C-allele mice (n=4 per dose; 1, 3 or 10 mg/kg/day for 10 days), and Δ7 mice (n=6 or 7 per dose; 0.1, 0.3, 1 or 3 mg/ kg/day for 7 days), the SMN protein increase from baseline was parallel in brain and muscle (Figure 3). • Following oral administration of a structurally similar SMN2 splicing modifier, RO6885247 (RG7800) in C/C-allele mice, comparable fold increases in SMN protein levels in blood, muscle and brain were observed in (Figure 4). Figure 2. RO7034067 tissue distribution in cynomolgus monkeys RO7034067 concentration in plasma (ng/ml), CSF (ng/ml) and tissues (ng/g) of cynomolgus monkeys (n=2) at Day 7 following daily PO dosing (3mg/kg/day for 7 days). RO7034067 (ng/ml or ng/g) 10000100010010 Plasma AUC0–24h@day6 = 8740 ng/h/ml Monkey 1 Monkey 2Muscle Brain Heart Bone marrow Spleen Kidney Liver CSF Free plasma Figure 4. SMN protein fold increase from baseline in blood, brain and muscle of adult C/C-allele mice after oral administration of RO6885247 Fold increase from baseline in SMN protein levels in blood vs. brain (Figure 4A; n=74) and fold increase in SMN protein levels in brain, muscle and blood over time (Figure 4B, n=5 per time point) in adult C/C-allele mice following a single or repeat doses of RO6885247 (10 mg/kg/day) PO for up to 30 days. 0 0 1 2 3 4 2 1 3 4 SMN protein bloo d (fold inc ) SMN protein brain (fold inc) 0 0 5 10 2015 25 30 2 Brain Muscle Blood 1 3 4 SMN protei n (fold increase ) Time (days) 1 1 10 100 1000 100 10 1000 Monkeys Rats Mice 3-fold identity line n = 190 Brain (ng/g ) 1 1 10 100 1000 100 10 1000 n =44 B Plasma (ng/ml) A n = 35 C )Plasma (ng/ml) 1 1 10 100 100 10 CSF (ng/ml ) Free Plasma (ng/ml) Muscle (ng/g ) Figure 3. SMN protein levels fold increase from baseline in brain vs. muscle of SMA mouse models following oral administration of RO7034067 SMN protein levels fold increase from baseline in brain vs. muscle in adult C/C-allele mice (n=4 per dose) dosed 1, 3 or 10 mg/kg/day PO for 10 days, and in Δ7 mice (n=6 or 7 per dose) dosed 0.1, 0.3, 1 or 3 mg/kg/day PO from post-natal 3 through 9. 0 0 1 2 3 4 2 1 3 4 SMN protein brain (fold inc) SMN protein muscl e (fold inc ) Presented at the International Scientific Congress on Spinal Muscular Atrophy, Krakow, Poland, 25–27 January 2018