The document provides an overview of clinical research at the Rett Clinic, including several ongoing and planned clinical trials. It summarizes: 1) Clinical trials in Rett syndrome testing ketamine, cannabidiol, trofinetide, and Anavex2-73, as well as planned gene therapy trials. 2) Clinical trials in CDKL5 Deficiency Disorder testing ganaxalone and TAK-935, with goals of reducing seizures. 3) Planned deliverables from the NIH-funded Natural History Study of Rett and related disorders, which has followed over 1000 patients.

1. Rett Clinic: Clinical
Research Overview
Tim Benke, M.D., Ph.D.
Prof. Pediatrics, Neurology, Otolaryngology and
Pharmacology
University of Colorado School of Medicine and
Medical Director, Rett Clinic
Research Director, Neurosciences Institute
Children’s Hospital Colorado
Tristen Dinkel, BSN RN; Rett Clinic Coordinator
Scott Demarest, MD

2. Disclosures
R21 NS101288(Benke)
NIH/NINDS
Exploratory determination of the role of L-type calcium
channels in mediating abnormal plasticity and behavior
after early life seizures Role: PI.
Ponzio Family Chair in Neurology Research
Children’s Hospital Colorado Foundation
Questcor Pharmaceuticals (Benke)
Whole-exome sequencing and ACTH responsiveness in
Infantile Spasms
Role: PI.
U54 HD061222 (Percy)
NICHD
Rett syndrome, MECP2 Duplication Disorder, and Rett-
related Disorders Natural History.
Role: Site Director, Co-I, 5212 sub-protocol CoI.
Rett Clinic at Children’s Hospital Colorado (Benke)
Rocky Mountain Rett Association
Role: PI/Medical Director
CDKL5 Center of Excellence (Benke)
International Foundation for CDKL5 Research
Role: PI
CURE (Traynelis). Functional and clinical evaluations of
glutamate receptor mutations in epileptic
encephalopathies.
Role: site PI
Scientific Advisory
Avexis, Neuren/Acadia, Marinus, Ovid/Takeda
IRSF, LouLou, IFCR, GRIN2B, CureGRIN, GW, LGS

3. Topics today
• Clinical trials 101
• Clinical trials in the Rett Clinic
• Rett
• CDKL5 Deficiency Disorder
• FOXG1
• MECP2 Duplication Syndrome

4. Clinical Trials: Basics (101)
What is a clinical study? Clinical trial?
A process by which subjects consent to participate in a
defined study designed to produce information that can be
used to understand (study) or help (trial) the population as
a whole. This data is peer-reviewed and published to
advance the knowledge and effective and safe treatments
of the disease. Trials are interventions.
You do not HAVE to participate in a clinical trial unless you
WANT to participate: participating involves consent (in
some cases using de-identified data you “opt out” versus
“opt in”)
A review board must approve the trial before any subjects
are contacted or enrolled; international rules of standards
and ethics are applied.

5. Clinical Trials: Phases
Phase 1: Testing healthy volunteers, multiple doses. May
be in patients with advanced stages of a disease or diseases
with no known treatments.
Phase 2: Testing on patients for efficacy and safety
Phase 3: Confirmatory: Testing on patients for efficacy,
effectiveness, and safety

6. Clinical trials: Types
Placebo controlled: a placebo is used to make sure the effects
are real. Patients with epilepsy can see a 25% reduction in
seizures with a placebo
Randomized: Who gets placebo or drug is a flip of the coin.
Double blind: Subjects and Study personnel do not know who is
getting drug.
Open Label: everyone getting drug
Cross-over: Those getting drug then get placebo and vice-versa.
Usually Randomized and Double blind too
Extension: access to drug after trial ends (usually an open label
continuation of the trial)

7. Clinical trials: Other
Gold standard: randomized, double-blind, placebo
Screening visit: first visit to make sure subject meets
inclusion/exclusion criteria
Inclusion/exclusion criteria: usually age, weight, disease specifics,
other medication use, recent trial experience, etc
Duration: The duration of treatment during the trial
Endpoints/Outcomes: The measurables to determine safety and
efficacy

8. Clinical trials: Where to get information?
Facebook?
Email?
Internet?
Blogs?
Me? I do not endorse any particular trial though will
participate in some.
Trust but verify! The only real sources:
Clinicaltrials.Gov
Company website
The consent form for the study
The study investigator(s), after IRB approval

9. The NIH-funded Natural History Study (NHS)
• NIH-funded Natural History Study of Rett and Rett-related
disorders has followed over 1000 patients through 2013
• MECP2, CDKL5, FOXG1
• Genotype/phenotype, Epilepsy, GI, Scoliosis, life-expectancy:
published standards
• Funding through: 9/2020 (not renewed)
 5211: parent protocol
 5212: neurophysiological biomarkers
 5213: genetic and metabolic biomarkers
 5214: Behavioral analyses
• Study visits occur separately from regular Rett Clinic
• Biomarker: objective measure of disease severity or predictive
of disease progression or response to treatment

10. Participating Institutions and
Investigators
Consortium Study Chair: Alan K. Percy, MD, UAB
Study Administrator and CoPI: Jeff Neul MD, PhD, UCSD
CoPI: Walter Kaufmann, MD, Greenwood Genetics
Site PIs
Eric Marsh, MD, PhD, Children’s Hospital of Philadelphia
Tim Benke, MD, PhD, University of Colorado
Mustafa Sahin, MD, PhD, Boston Children’s Hospital
Sarika Peters, PhD, Vanderbilt University
Alexander Paciorkowski, MD, University of Rochester
Steve Skinner MD, Greenwood Genetics
Dan Glaze MD, Baylor College of Medicine
Peter Heydemann and Elizabeth Berry-Kravis, Rush
Mary Jones MD, UCSF
Steven Kaminsky, PhD, Rettsyndrome.org
Data Management and Coordinating Center Principal Investigator:
Jeffrey Krischer, PhD, University of South Florida
National Institutes of Health:
NICHD: Program Officer: Melissa Parisi, MD, PhD;Project Scientist: Danuta Krotoski, PhD
NINDS: Program Officer: Laura Mamounas, PhD

11. 5211: Enrollment
Current enrollment (2013 to now):
All ages
749 MECP2+ subjects with RTT and atypical RTT and ID
69 subjects with MECP2 duplication
55 with FOXG1
63 with CDKL5
< 10 years of age: Annual
10-20 years of age: Bi-annual
>20 years old: Every four years (twice during funding cycle)
Challenge: Older and sicker patients

12. 5212: Enrollment (co-enrolled in 5211)
153 enrolled/140 analyzed
• RTT: 71 female subjects (34 with repeat studies)
• CDKL5: 19 female subjects (5 with repeat studies)
• MECP2 dup: 16 male subjects
• FOXG1: 7 male/female subjects
• 27 Age-matched controls
• Summary: AEPs and VEPs are different between groups
and compared to controls, but unclear yet if this can be
used as a biomarker

13. NHS Deliverables
50+ papers on Rett, CDD, MDS, FOXG1
Delivered recently
• MECP2 males
• MDS: comparisons
• CDD: clinical summary
• CDD: CVI
• CDD: Severity Assessment
Planned/in process deliverables
• Disorder comparisons, clinical: RTT, CDD, MDS, FOXG1
• Biomarker evaluation: AEP, VEP
• Disorder comparisons, metabolomics
• Heath-care supervision guidelines

14. Rett: Ketamine
“A Randomized, Double-blind, Placebo-controlled, Cross-
over Study to Assess the Safety, Tolerability and Efficacy of
Oral Ketamine for Patients With Rett Syndrome”
Ketamine, phase 2: 5 days drug/placebo; wash-out; 5 days
drug/placebo; wash-out (8-10 weeks total)
6-12 years old. Pre-menarche.
Primary endpoint: safety; Secondary: CGI-I, MBA, RSBQ, etc
Goal: 48 subjects; local 4+, active

15. Rett: GW-CBD
“A Randomized, Double-blind, Placebo-controlled Trial to
Investigate the Efficacy and Safety of Cannabidiol Oral
Solution (GWP42003-P, CBD-OS) in Patients With Rett
Syndrome”
CBD, phase 3, 40 weeks treatment
2-18 years old. > 9 kg.
Primary endpoint: RSBQ and CGI-I
Goal: 252 subjects; local 10+, startup

16. Rett: Trofinetide
From the company website
“In the fourth quarter of 2019, we plan to initiate the LAVENDER 12-
week Phase 3, double-blind, randomized, placebo-controlled study to
evaluate efficacy and safety of trofinetide and placebo in approximately
180 females ages 5 to 20 years with Rett syndrome. Half of the study
participants will receive trofinetide and half will receive placebo. The
study will use the Rett Syndrome Behaviour Questionnaire (RSBQ), a
caregiver assessment and the Clinical Global Impression Scale-
Improvement (CGI-I), a clinician assessment of the improvement of Rett
syndrome as co-primary efficacy endpoints.
The LAVENDER Phase 3 study will be followed by LILAC, a 40-week
open-label extension study. All participants completing the 12-week
LAVENDER study may be eligible to enroll in the LILAC study, in which all
study participants will receive trofinetide and followed to evaluate long
term tolerability and safety of the drug.
Trofinetide has been granted Fast Track Status and Orphan Drug
Designation for Rett syndrome in the U.S. and Orphan Drug Designation
for Rett syndrome in Europe.”
Local goal: 10+, start-up

17. Rett: Anavex
“A Double-Blind, Randomized, Placebo-Controlled, Dose
Titration Study of ANAVEX2-73 in Patients With Rett
Syndrome”
Anavex2-73, phase 2: 7 weeks treatment , 12 week open
label extenstion
18+ age
Primary endpoint: safety, pharmacokinetics; Secondary:
CGI-I, RSBQ
Goal: 15 subjects; local: not participating

18. Rett: Sarizotan
“A Randomised, Double-Blind, Placebo-Controlled 6-month
Study to Evaluate the Efficacy, Safety, and Tolerability of
Sarizotan in Patients With Rett Syndrome With Respiratory
Symptoms”
Active, not recruiting, not participating

19. Rett: Gene Therapy
From Avexis/Novartis Press release:
https://reverserett.org/avexis-novartis-release-statement-on-avxs-201/
“Due to the data integrity concerns related to a specific animal testing
procedure used in the development of Zolgensma and included in the
application, we have decided to also review data quality and
compliance with the preclinical work performed for AVXS-201, our Rett
Syndrome gene therapy candidate. Out of caution, and to ensure that
we have a robust data package for the FDA we have chosen to repeat
and add additional pivotal preclinical studies as well as new quality
controls. Once these studies are completed, we will submit the revised
IND (investigational new drug application) to the FDA with the goal of
rapidly progressing to clinical trials in Rett Syndrome patients. We
expect that conducting these additional studies and completing the IND
will take until the middle of 2020. At that time we will be in a position
to provide further updates to the Rett Syndrome community.”
Local: we hope so

20. CDD: Ganaxalone
“Study of adjunctive ganaxalone treatment in Children and
Young Adults with CDKL5 deficiency disorder (Marigold)”
• Positive GABA-R allosteric modulator
• Phase 3
• Recruiting
• Marinus Pharmaceuticals
• Double blind-placebo controlled: baseline, 17 week add-
on (placebo or ganaxalone), open-label with ganaxalone
• Primary endpoint: reduction in seizures
• Goal: 100 participants (age 2yo-21yo)
• Local: 5 (5 more by end of year), active/participating

21. CDD: TAK-935 (OV935)
“A multicenter, open-label, pilot study of TAK-935 (OV935) in
participants with 15Q Duplication Syndrome of Cyclin-Dependent
Kinase-Like 5 (CDKL5) Deficiency Disorder (ARCADE STUDY)
• 24Cholesterol hydroxylase inhibitor: reduces expression of
NMDARs
• Phase 2
• Takeda/Ovid Therapeutics
• Open label: baseline, 20 week treatment, open label
extension
• Primary endpoint: reduction in seizures
• Goal: 30 participants (15 with CDD, age 2yo to 35 yo)
• Local: 2 participants (5 more by end of year), active,
participating

22. CDD: Gene Therapy
Local: we hope so

23. Topics today
• Clinical trials 101
• Clinical trials in the Rett Clinic
• Rett
• CDKL5 Deficiency Disorder
• FOXG1
• MECP2 Duplication Syndrome