Massachusetts General Hospital

“The purpose of expanded access is to provide access to an investigational product (IP). Expanded Access Protocols (EAPs) should not interfere with the completion of clinical trials; therefore, EAPs are meant to be an option for patients who do not qualify for clinical trials. The criteria for participation in an EAP are broad, in-person visits may be infrequent, and there is no placebo. Expanded access is considered an extension of clinical care.”

“The Healey & AMG Center is committed to communicating news and updates about Expanded Access Protocols (EAPs).”

“The Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital has been awarded grant funding from the National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS) to conduct multiple intermediate size EAPs in ALS.”

“# About Expanded Access Protocols (EAPs) "apotentialpathway forapatientwith αseriousor immediatelylife-threateningdiseaseorconditionto gainaccessto aninvestigationalmedical product (drug,biologic,ormedicaldevice)fortreatment outsideofclinicaltrialswhennocomparableor satisfactoryalternativetherapyoptionsare available." An Expanded Access Protocol (EAP) can also be referred to as Compassionate Use.”

“# Expanded Access Program Update Suma Babu, MBBS., MPH Assistant Professor of Neurology Co-Director, Neurological Clinical Research Institute Massachusetts General Hospital Harvard Medical School, Boston, MA EAP overview Pridopidine EAP # agenda RAPA-501 EAP # The EAP Engine: Central Operations Team at Neurological Clinical Research Institute at MGH Admin & Communications Juliana Araujo, Jesse Rosenthal Allison Bulat, Judith Carey, Catherine Small # Expanded Access # FDA Definition: Sometimes called “compassionate use” Potential pathway for a patient with an immediately life-threatening or serious disease or condition Allows access to an investigational medical product outside of clinical trials Used when no comparable or satisfactory alternative therapy available # EAP paradigm is an extension of ALS clinical care Clinical Care Realm Research Realm Aligning EAP study visits with clinical visits and and clinical labs Aligning goals between IRB, FDA, industry sponsor, and ProviderPatient Including clinical and research staffing resources Utilizing clinic space for EAP study visits Some institutions may use EMR for source documentation Making sure protocol is followed for study conduct Safety reporting (SAEs) is done in a timely and FDA/IRB compliant manner Why EAP? Or Why not EAP? • Market gap: Trial population is often not representative of the postFDA approval consumers, creates insurance barriers. • Patient population: $90 %$ of ALS population in the US do not have access to experimental therapeutics nor do they have the opportunity to contribute to research • Financials: Drug development is time consuming and expensive for drug manufacturers and research sites. Unfunded EAPs may be out of reach for patients to cover drug costs. Industry apprehension: Long term safety of some experimental drugs are unknown in early stages of development. • Usability: Patients want less burdensome access to experimental therapeutics; clinics want to use their limited research staff and space resources carefully for trials, and observational research over EAPs # FDA’s encouraging perspective on EAPs in ALS # • Long term safety data: “During development, sponsors should collect safety data, including data from openlabel studies or expanded access programs, from patients across the spectrum of disease stages and severities, and whenever possible, data from patients who may not have been included in effectiveness studies but in whom, based on other data, the use of the drug following approval is likely. ” \[Page 4\] # Generalizability of safety and efficacy data: “There is a need to understand the safety and effectiveness of investigational drugs for ALS across disease stages….. An acceptable approach could include enrollment of a broad population with the conduct of the primary analysis in a study subset defined based on clinical characteristics and/or biomarkers, and analyses of the broader population being secondary and supportive” \[Page 3\] # Important FDA requirement for any EAP Providing drug will not interfere with clinical trials that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use # Two NIH funded EAPs (2023) Home-Neurology-ALS-News PRESS RELEASE $\cdot \cdot$ OCT\|5\|2023 SeanM.Healey&AMGCenterfor ALSawardedNIHUo1Grantto supportExpandedAccessto PridopidineinCollaborationwith PrileniaTherapeutics Home-Neurology-ALS-News PRESSRELEASE·OCT\|5\|2023 SeanM.Healey&AMGCenterfor ALSawardedNIHU01Grantto supportRapaTherapeutics ExpandedAccessProtocolof EpigeneticallyReprogrammed RAPA-501 # Pridopidine EAP More info: clinicaltrials.gov NCT06069934 45 sites Target enrollment: 200 ALS individuals who: ➢ do not qualify for clinical trials at the enrolling site and ➢ have established care at a specialized ALS center Same dose as platform trial: 45 mg twice daily, oral # Pridopidine EAP: Site Map | | | | | --- | --- | --- | | Pridopidine EAP 2 | | | Planned | Actual as of 9/10/24 | | Sites | 45 | 15 Nearing activation: 9 | | Participants | 200 | 54 Screening: 5 | # Multi-site EAPs: Complex and expensive central operations; Clinicians can join ongoing multi-site EAPs or create their own # Comparison of trial activation timelines | | | | | --- | --- | --- | | Study Startup Metrics | | Study Startup Stages | Pridopidine EAP 2 | Multi-Site Trials' Average \* | | Total Study Start Up Time (Funding to First Participant First Visit) | 186 days (6 months) | 214 days (7 months) | | Funding - IRB Submission | 25 days (1 month) | 103 days (3 months) | | IRB Submission - Approval | 40 days (1 month) | 60 days (2 months) | # Key Factors impacting Startup Timeline: Contract negotiations Sponsor, vendors, sites Site start up Study staff size and workload of multiple active projects Institutional paperwork and site staff training on the protocol and outcomes Local IRB cede approvals, in addition to central IRB Newer sites are unfamiliar with differences between EAP and trials RAPA-501 EAP More info: clinicaltrials.gov NCT06169176 # Up to 10 sites Target enrollment: 40 ALS individuals who: do not qualify for clinical trials at the enrolling site and have established care at a specialized ALS center and have a vital capacity $\leq 5 0 %$ predicted Treatment with RAPA-501 (4 infusions every 6 weeks, followed by 2 year safety monitoring) # RAPA-501-ALS-EAP Study Progress out of 10 clinical study sites ^ out of 40 participants”

The Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital has been awarded a three-year grant to support Rapa Therapeutics' intermediate size Expanded Access Protocol (EAP) in Amyotrophic Lateral Sclerosis (ALS) from the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH).

The Healey & AMG Center for ALS at Massachusetts General Hospital in collaboration with Prilenia Therapeutics B.V is thrilled to announce the enrollment of the first participant in the National Institutes of Health (NIH) – National Institute of Neurological Disorders and Stroke (NINDS) sponsored Expanded Access to Pridopidine Protocol (EAP) in Amyotrophic Lateral Sclerosis (ALS), supported by the U.S. government’s Accelerating Access to Critical Therapies for ALS Act (ACT for ALS).