Introduction to Apex Early Phase 6/11/2020 · 6/11/2020 · Introduction to Apex Early Phase (c)...

Introduction to Apex Early Phase

(c) Apex Innovative Sciences 1

6/11/2020

1www.alliancesites.com

CNS Researchand

Hassman Research Institute


Apex Innovative Sciences

Apex was formed in 2019 through the merger of CNS Research and Hassman Research Institute (HRI), leading clinical research sites focused on central nervous system indications and variety of other therapeutic areas.

The merger enhances our ability to deliver scientific, technological, and clinical excellence at the speed needed to provide optimal value to our partners.

Harmonized clinical, operational, and scientific processes enable our two-site solution to ‘look like’ a single site.

Apex is led by Drs. Howard Hassman (Chief Executive Officer), Larry Ereshefsky (Chief Scientific Officer, Early Phase Development), and David Walling (Chief Clinical Officer). CNS Research Hassman Research

Institute



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Apex Early Phase

• Single- and two-site solutions for all your early phase study needs

• Two 60-bed state-of-the-art CRUs on East and West Coast

• Standardized biomarkers, imaging, and electrophysiologic assessments

• High-throughput healthy volunteer dosage formulation trials

• Rapid, quality enrollment of patient and special populations into PhaseI studies where healthy subjects are not the best strategy

• Thought-leader expertise in study design and execution

A partnership offering unique capabilities to accelerate drug development

Specialized Studies: FIH, SAD/MAD, POC, Driving Simulation, Asian Bridging, HAP, PK/PD, BA/BE, DDI, Biosimilars and more

Therapeutic Areas: Healthy, Psychiatry, Neurology, Pain, Sleep, Addictions, Internal Medicine, Dermatology, Respiratory


• On behalf of Apex and our sites, we hope all is well with you all.

• Our Policy and Procedures on managing COVID-19 risks are available online or by request.COVID-19 Policies and Procedures

• We have access to and utilize COVID-19 nasal swab and blood testing for all subjects

• We continue to operate and enroll healthy volunteers and patients into a variety of on the unit and outpatient studies. If you have additional questions or concerns, please let us know.

• We have also been approached by CROs and Pharma to 'rescue' Early Phase studies that many non-specialty Phase I units and Academic Centers cannot conduct due to closure or significant curtailment of activities.

• We have also been tracking our local hospital's capacities to insure that they are prepared to accept an EMS transfer for an SAE or Severe AE. Both in the New Jersey area surrounding our unit (HRI-Marlton) and in Los Angeles (CNS-Long Beach) they have ample beds and services.

COVID-19 and Apex Response

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Leadership

Larry Ereshefsky, Pharm.D.

CSO, Early Phase Development

Hassman Research Institute and CNS Research

David Walling, Ph.D.

Chief Executive Officer, Principal Investigator

CNS Research

Howard Hassman, D.O., AOBFP

Chief Scientific Officer, Principal Investigator



Therapeutic Areas

Dermatology

Alopecia, Acne, Psoriasis, Atopic Dermatitis, Rosacea, Aesthetics

Impairment

Cognitive Dysfunction, Validated Driving Simulation studies

Asian Studies

Bridging to Japanese, Chinese, and other Asian populations, enabling global development

Human Abuse Potential

Addictions, Exploratory assessments, Definitive HAL testing

Pain

Acute/Chronic, Fibromyalgia, Osteoarthritis, Migraine, Pain models such as UV and capsaicin

Healthy Volunteers

Including sub-populations of: Asian, elderly, post-menopausal females, tobacco users

Psychiatry

ADHD, Anxiety, Bipolar, Depression, PTSD, Schizophrenia

Neurology

Alzheimer’s, MS, Parkinson’s, Post-Stroke, Sleep Disorders

General Medical

Endocrinology, Immunology, Pulmonology, ENT, Ophthalmology, GI, NASH/NAFLD, and more

https://app.box.com/s/vxo8wm574slt5c4gwp9ng5zcamrjnuee

https://app.box.com/shared/4aplmydtul

https://app.box.com/s/90mfoq3n3q35wjz26hsfiwikqqzh2qil



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Specialized Studies• Elderly and target patient populations

• PK/PD relationships with QEEG/ERP, fMRI/PET

• Sleep and Arousal with PSG, MWT, MSLT

• Eye tracking, sway balance

• QTc, TQTc, cardiac monitoring

• 505(b)(2) program strategies

• Biologics and biosimilars

• Bioequivalence/DDI/Food Effect

• Digital Device and Software Technologies

• Orphan indications

• Impairment, driving simulators

• Safety: Cognitive/Motor/Driving impairment, Capnography, Pulse Ox, Telemetry

• First into Human, SAD, MAD studies

• Translational and experimental medicine studies:

o Precision medicine

o NIH Research Domain Criteria

o Neurocircuitry applications

o Biomarkers

o CSF sampling

• Enrichment strategies

• Adaptive and umbrella designs

• Pain models in HNV and patients


Technology/Capabilities

• Imaging (PET, MRI, fMRI, MRS, MRE, MRI-PDFF, DEXA-scan, DAT-Scan, FibroScan)

• Electrophysiology (EEG, PSG, MWT, MSLT, and QEEG / ERP)

• Pain models in HNVs and patients

• Digital Therapies (health devices, software, and applications)

• Safety (capnography, pulse ox, spirometry, safety EEGs, telemetry, biomarkers)

• Cognitive and behavioral assessments, including impairment of function

• Eye tracking, balance assessments

• CSF collection



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Evaluating Drug Impairment: Driving Simulation

Driving labs set up at both HRI and CNS – six simulators at each site

State-of-the-art CRCDS MiniSim driving simulators at both sites – used to evaluate the effectsof a wide variety of drugs on driving performance in both normal and patient populations

What drugs need to be evaluated?

• Drugs intended for chronic (or chronic-intermittent)outpatient use by adults who drive

• Drugs that might increase risk-taking

Driving studies may also be needed if a drug approvedfor a particular use is proposed for:

• a different indication

• a different dose or dosing schedule

• a new patient population


Illustrative approaches to accelerate development

Identify Study Needs; Adapt design and tools

as new data is reviewed

• Joint Review of Data • Go/No-Go Decision –

How to proceed forward

SAD/MAD MTD

• PK/PD

• ECG; Vital Signs

• QEEG/EP; Cognition

• CSF collection (‘backup plan’)

• Imaging (PET, sMRI, fMRI)

• Behavioral and pain models

• Measure efficacy effect size

POC

Go Decision

SAD HNV FIHIncorporate first generation AsiansCombine FEExplore elderly or target populationsProof of CNS Penetration

MAD HNV → Patients (MTD, titration)Proof of Mechanism, Biomarker dose responseFocused PD ‘sub-studies’

Mini-POC using target patient population. Multiple populations in one trial (transdiagnostic) or 2 or more IMPs

MAD can overlapPharmacodynamic (PD) panels can overlap

POC



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Illustrative Site - Pharma InteractionsConsulting and Assisting in Clinical Trials Over the Entire life cycle

of Drug Development – embed CRO and Technology CapabilitiesCritical Path for

Clin Pharm Studies

FIH

MAD/MTD

pts or HNVs

EEG/fMRI/CSF/

biomarkers

BE/BA - FE

DDI/Impairment

Human Abuse

Asian/Special

populations

QTc

Clinical consultants and

External Content Experts

Technology Partners

Established CRO support

Sponsor

Data review and

recommendations for

‘critical path’

Technology

Platforms

Parallel process:

Conduct rate limiting studies

Ongoing Regulatory/Scientific

Consultation

HRI/CNS EP

Units provide

input in areas of

expertise

Approval

We support drug development

from FIH to post-approval2 x 60 beds CRUs

11 Phase IIa-IV sites


FIH Trials: Risk Identification and Mitigation

Safety FIH

Trials

Drug

Study Design

Study population

Study Environment

ExperiencedStaff

Risk Mitigation

Process

Key Principals

• Early assessment of key program risks and address

• Collaborative sponsor and CRO discussions to increase safety for human volunteers

• Review of safe first dose, dose escalation, toxicokinetics by Clinical Pharmacology expert and Principal Investigator

• Consensus with sponsor re first safe dose, confirm the ‘human equivalent dose estimate’, and review appropriate safety assessments

• Risk assessment and mitigation strategy for dosing

• Sentinel dosing based on current regulatory and ethical standards



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Ph1-01 Combination study (HNV-SAD; HNE-SAD; FE; MAD;CSF)This scheme has been used multiple times at AEP

Cohort 1 (Dose A) Cohort 2

(Dose B) Cohort 3 (Dose C) Cohort 4

(Dose D)

Cohort 3b1

(Dose C)Fed

Fasted

Fed

Fasted

Cohort 3c2

(Dose C)

HNV - SAD(N=8; 6:2/cohort)

HNV - FE(N=8; 6:2/cohort)

Cohorts 1 -24

(Dose C and ? TBD)

Pharmacodynamic measures – depending on objective, incorporated in SAD and/or MAD to demonstrate exposure; or occasionally in separate cohort(s)

TIME

1. HNV-FE accounts for possible increase of exposure, initiate after SAD Cohort 4 has 24 hour safety2/3. Panels staggered for possible increase of exposure, these cohorts start only after a higher dose has been tolerated in the HNV-SAD 4. Separate cohorts for complex PD measures, such as imaging or CSF

HNV Elderly - SAD(1 up to 3 cohorts) (N=8; 6:2/cohort)

Cohort 5 (Dose E)

Cohort 13

(Dose C)

Cohort 2 (Dose Y)

Cohort 3 (Dose Z)

HNV or HNE or patient population - MAD(N=8; 6:2/cohort)

– depending on objective, add, biomarkers; translational/experimental medicine evaluations

Cohort 3B-3C (Dose Y -Z)


CNS Research

• Founded in 2000

• Largest clinical research provider in Southern California

• Operates three outpatient clinics located in Long Beach,Garden Grove, and Torrance

• Long Beach facility includes a 60 bed Clinical PharmacologyUnit, 20 bed Asian inpatient unit, and Licensed PsychiatricHealth Facility

• Database of over 90,000 subjects; dedicated recruitmentstaff comprised of 20+ outreach and recruitment specialists

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Long Beach Inpatient Unit

• 40,000 sq. ft. state-of-the-art facility

• Specially designed for early phase research

• 60+ beds for healthy subjects and stable patients

• Provides an array of services that are critical to the successful completion of complex and adaptive design studies

• Secure medication dispensary and CLIA Waived lab

• Six driving simulators dedicated to clinical trials

• Affiliated with a large neurology practice in same building


Patient Populations

ADHD – 1,400+

Alzheimer’s Disease – 3,150+

Asian – 1,200+

Asthma/Allergy – 1,275+

Bipolar – 2,570+

Chronic Pain – 7,475+

Depression – 2,000+

Diabetes – 4,035+

Fibromyalgia – 1,410+

Generalized Anxiety Disorder – 2,435+

Healthy Normal Volunteers – 8,220+

Migraine – 9,340+

Multiple Sclerosis – 1,765+

Obese – 3,450+

Parkinson’s Disease – 2,500+

Post-menopausal women – 700+

PTSD – 830+

Schizophrenia – 8,300+

Sleep Disorders – 345+

Substance Abuse – 5,925+



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Collaborative Neuroscience Research – Asian Bridging


Asian Bridging

Asian sensitivity and bridging in Japanese, Chinese, and Korean first-generation subjects

CNS is uniquely qualified to successfully conduct these studies.

• Dr. Ereshefsky co-created the ex-Japan, US-based strategy, and has been designer/investigator on 100+ Asian studies

• Experienced clinical/medical leadership

• Asian staff, bilingual

• Custom-built Asian inpatient unit

• Referral relationships with Asian community groups

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Asian Studies Strategy• Conduct early phase studies supporting global drug development

o Simultaneous conduct of SAD/MAD using Asian and Caucasian volunteers, can beaccomplished in same cohort

o First generation Japanese, Chinese, and Korean studies with all grandparents, parents,and volunteer born in country of origin (typically passport holding) can be conductedin Los Angeles

• Perform separate complementary SAD/MAD studies running in parallel or lagging behindfull development program

• True Bridging study takes a drug in later development and performs SAD/MAD PK andsafety study to enable approval in Asia

• Adds value to compound by including Asian data in Phase I enabling global Phase II


Recruitment

Why Los Angeles for Asian Studies?

CNS Research resides in the center of largest Asian-American populated metropolitan region in the entire US.

Los Angeles-Long Beach Combined Statistical Area:

• Highest Korean population in the US

o Over 300,000 Korean Americans (226,000 born in Korea)

• Second highest Chinese population in the US

o Over 528,000 Chinese Americans

• Second highest Japanese population in the US

o Over 135,000 Japanese Americans (52,000 born in Japan)

o The city of Torrance holds the densest Japanese American population in the 48 contiguous states



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Retention

• Units designed specifically for research, with patient comfort andsafety in mind

• Private rooms for caregiver accommodations as needed

• 32” LCD flat screen TVs with cable in every room, and in lounge areas

• Wireless internet for personal laptops and community computers

• Board games, video games, and DVD players

• Lounge, break room, dining room with full kitchen

• Site owned vans and town car service provide patient transportationto and from visits as needed

• Dedicated staff for regular contact with patient/family duringwashout periods


Best Practices for Asian Bridging Studies

• Cultural Sensitivity – Cultural sensitivity to the Asian population is acritical factor in successful recruitment and retention.

• Care and Comfort – We strive to make volunteers comfortable in ourenvironment, providing them with excellent customer service.

• Asian Staff – We have Asian staff members available not just during thescreening and consent process but throughout the study.

• Asian Diet – We provide Asian meals to allow volunteers to adjust betterto the unit environment.

• Respect – We are mindful of their usual customs and behavior.

• Fair Compensation – We show that we value their time and contributionto the study by providing a fair stipend.

• Repeat Volunteers – Asian subjects who have done studies with us inthe past want to return. We also receive many word-of-mouth referrals.



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Recent Metrics

An Investigator/Subject Blind, Randomized, Placebo-Controlled Study to Investigate the Safety, Tolerability,Pharmacokinetics and Pharmacodynamics of Single Doses of ***** in Healthy Japanese Subjects

Contracted for 24, screened 103, enrolled 24 in five months.

Screened over 100 but only randomized 24 due to a specific eye exam I/E criteria.

A Phase 1b, Randomized, Controlled, Double-blind Trial to Evaluate the Safety and Immunogenicity of***** in Healthy Japanese Adults Aged 18 to 49 Years

Contracted for 20, screened 20, enrolled 20 in three weeks.

A Rising Single and Multiple Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of *****in Healthy Adult Japanese Subjects

Contracted for 16, screened 36, enrolled 16 in three months.



• Over 35 years of experience conducting Phase I-IV trials

• Locations in Berlin and Marlton, NJ

o Marlton is home to new 60-bed state-of-the-art Inpatient Unit

• Affiliated with a large network of multi-specialty practices in the SouthJersey and Philadelphia area, which offers unique access to a widerange of patient populations

• Locations use separate patient databases

o Berlin: Family Practice Database with 75,000+ subjects

o Marlton: Research Database with 65,000+ subjects

• Full-time enrollment staff using sophisticated outreach, social andtraditional media, access to clinical practice

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Marlton Inpatient Unit

• 21,000 sq. ft. of space with 60 inpatient beds

• Purpose-built facility constructed in 2011

• Provides an array of services that are critical to the successful completion of complex and adaptive design studies

• Pharmacy with laminar flow hood and compounding capabilities

• 3 CLIA Waived labs

• Offers safety resources required for the unique needs of Human Abuse Liability (HAL) studies


HRI Phase I Experience

Healthy – 52

13 First into Human SAD | 20 SAD and/or MAD combination | 20 BA/BE PK studies

Schizophrenia – 39

Hep C – 18

Depression – 11

HAL – 9

OUD/Addiction – 7

Diabetes – 7

Analgesia/pain models – 6

Obesity – 5

Hypertension – 4

Renal/Hepatic Impairment – 4

Tourette’s – 3

Parkinson’s – 3

Alzheimer’s – 3

Atopic Dermatitis – 3

NASH – 3

Cancer Pain – 2

Multiple Sclerosis – 2

Osteoarthristis – 2

Bipolar Disorder – 2

Psoriasis – 1

Insomnia – 1



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Studies at the Marlton location are enrolled with patients from HRI’s research database, many of whom have been cared for Drs. Howard Hassman and Steven Glass for 25+ years.

HRI Marlton Recruitment Model

Research Database – 65,000+

Addiction– 8,940

ADHD – 5,500

Alzheimer’s – 650

Bipolar – 10,500

Depression – 11,000

Diabetes – 2,850

HNVs – 5,500

NASH – 505+

Pain – 4,520

Parkinson’s – 554

Recreational Users – 5,300

Schizophrenia – 9,500

Major Metropolitan Area:

The Philadelphia-Camden-Wilmington MSA:

• Home to both HRI's locations

• One of the largest in the US

• Over 6M residents


HRI Pharmacy

• Schedule I-IV drug storage

• Triple locked drug storage

• Surveillance cameras monitor all access

• Blinding of Investigational product

• Services include a multitude of administration routes and formulation preparations (USP 795, 797)

• USP 1163 QA

• USP 800 in progress



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Pain Models of Neuronal Sensitisation:Assessment Techniques Performed at HRI

Pinprick Hyperalgesia Touch-evoked Allodynia

UVB Sunburn Inflammatory Model

(induction: physical)

Ref Poster: Francke K et al. Pain Therapeutics Summit, 2012

Electrical Hyperalgesia Model

(induction: electrical)

Capsaicin Hyperalgesia Model

(induction: chemical (patch/intradermal)


Berlin Campus

Unit 1: CNS/Neuroscience

Unit 2: Early Phase/Inpatient

Unit 3: General Medicine, Pain, and Addiction

1

2

3



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HRI Berlin Recruitment Model

Acne – 1,650

ADHD – 3,300+

Alzheimer’s Disease – 430

Atopic Derm – 1,300+

Bipolar – 5,600+

Depression – 5,000+

Diabetes – 3,200+

Diabetic Foot Ulcer – 485

HNVs – 5,700+

Hypertensive Patients – 10,000+

NASH – 400+

Obese – 9,000+

Osteoarthritis – 7,000+

Pain – 8,500+

Parkinson’s Disease – 110

Post Menopausal Women – 8,000+

Psoriasis – 550

Schizophrenia – 7,000+

Senior Citizens – 15,000+

Substance Abuse – 5,000+

Family Practice Database – 75,000+

Affiliate:

Advocare Berlin Medical Associates

• Large network of multi-specialty practices in the South Jersey / Philadelphia area

• 4 addiction treatment units


HRI Addiction Study Experience• Total Experience

• 35 'illicit' drug studies over the past 8 years, including 10 OUD studies, several alcohol, and 7 opioid

addiction studies.

• Consistently a top-enrolling site; #1 enrolling site on at least 9 trials in the last 5 years

• Study Performance

• Recruiting patients with OUD • Over 5 years experience successfully recruiting quality OUD subjects

• Managing patients with OUD during their residency period in the clinical unit

• Longest residency period with vulnerable population was over 60 days

• Multiple OUD trials requiring a residency period, all with a higher than average retention rate

• Managing follow up of patients after their residency period through to their EOS/ET visit

• Multiple successful OUD trials completed with higher than average retention rates

• Subjects were provided with a 24-hour number to call for support and/or questions

• Recruiting smokers and managing for the type of study during the residency period

• Completed many trials with smoking subjects

• Two secure, monitored smoking areas with regularly scheduled smoke breaks

• Currently implementing an OUD craving study using fMRI, PSG, and ERP



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Dependence & Abuse Potential

Experienced Staff:

• PIs with decades of substance abuse clinical experience

• Full time Psy. D. Specialist in Addiction and Pain

• Full-time clinical research pharmacist

• Doctorate and Masters-level dedicated raters with decades of experience

Capabilities and Services:

• HAL /HAP studies including opioids, methadone/buprenorphine, alcohol interaction, stimulants, hypnotics

• Physiologic monitoring, i.e., capnography/pulse ox, pupilometry and biophysical testing

• A multitude of administration routes and formulation preparations

Recruitment:

• Large research database of recreational drug users

• Referral relationship with network of addiction treatment centers

HRI is a leader in the conduct of substance abuse and abuse liability trials.


NASH* Center of Excellence

HRI is a top-enrolling site for NASH/NAFLD studies.

• Rapidly expanding patient database

• Referrals from multi-physician gastroenterology practice

Free FibroScan® Screenings Offered Daily

Dedicated technicians identify and pre-screen potential NASH/NAFLD patients by offering

free FibroScan® screenings daily.

Capabilities:

• Imaging:MRI-PDFF, MRE with T1/T2 Mapping, SWE, Ultrasound

• Liver Biopsies

*Non-alcoholic steatohepatitis

https://app.box.com/s/nm8rx0rrjagge2yc9hky3a09eor8aqo5



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Contact

Bobbie Theodore, M.S.

Alliance Executive Director

[email protected]

M: 916-803-7149

mailto:[email protected]

Introduction to Apex Early Phase 6/11/2020 · 6/11/2020 · Introduction to Apex Early Phase (c)...

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Transcript of Introduction to Apex Early Phase 6/11/2020 · 6/11/2020 · Introduction to Apex Early Phase (c)...