molecular therapy for sma in clinical practice › ... ›...
TRANSCRIPT
2019
Molecular Therapy for SMA in Clinical Practice
2019
Introduction
Professor of Clinical Pediatrics and Neurologyat the University of ColoradoHaberfeld Family Endowed Chair in Pediatric Neuromuscular DisordersCo-Director, Neuromuscular Clinic
Assistant Professor of Pediatrics, Neurology andNeurotherapeutics at the University of TexasSouthwestern in DallasCo-Director, Neuromuscular Clinic
2019
Program Overview
Contact Start Time Duration Title
Castro, Diana 10/19/2019 8:00 5 Introduction
Castro, Diana 10/19/2019 8:05 25 Molecular basis of SMA
Castro, Diana 10/19/2019 8:30 25 Current Therapies and research for SMA
Parsons, Julie 10/19/2019 8:55 25 Complex Drug Program: One model
Discussion and Q & A 10/19/2019 9:20 10 Discussion and Q & A
2019
Molecular Basis for Spinal Muscular Atrophy
Diana Castro, MDAssistant Professor of Pediatrics, Neurology and Neurotherapeutics
University of Texas Southwestern Dallas
2019
Financial DisclosureResearch Support and/or Advisory Board
• Biogen Pharmaceutical• Avexis/Novartis• Sarepta Pharmaceutical• PTC Therapeutics• Fibrogen• ReveraGen• CINRG• Muscular Dystrophy Association• National Institute of Health• Guillain-Barre Syndrome/CIDP Foundation• Cure SMA
2019
WarningVideotaping or taking pictures of the slides associated with this presentation is prohibited. The information on the slides is copyrighted and cannot be used without permission and author attribution.
2019
Spinal Muscular Atrophy (SMA)• Group of disorders that affect the lower motor neuron • Caused by different genes
SMA
Proximal
5qSMARecessive SMA (Survival Motor
Neuron)
Non 5qSMARecessiveDominant
X-Linked (recessive)
Distal
RecessiveDominantX-linked
MitochondrialSporadic
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SMN Gene
SMA Region
SMN Protein and Functions
Outline
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Survival Motor Neuron Gene (SMN)• Chromosome 5q• SMN gene is duplicated in humans• SMN1 and SMN2 genes lie on a large,
inverted duplication on chromosome 5q13• The SMN1 gene lies within the telomeric
halve• The SMN2 gene lies within the centromeric
halve
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Arrangement of Genes in the SMA region
The gene can be arranged in a tandem duplication or with genes absent from one of the repeat units.
• SERF1, small EDRK-rich factor• SMN1, survival motor neuron 1• NAIP, Neuronal apoptosis inhibitory protein• BTF2p44, basic transcription factor 2 44-
kDasubunit
Burges, A, McGovern, V. Genetics of Spinal Muscular Atrophy. Molecular and Cellular Therapies for Motor Neuron Diseases.
2019
SMN GeneThe SMN gene is composed by 8 (9) exons
SMN1 and SMN2 share more than 99% nucleotide identity, and both are capable of encoding SMN
Burges, A, McGovern, V. Genetics of Spinal Muscular Atrophy. Molecular and Cellular Therapies for Motor Neuron Diseases.
2019
100% Full length SMN 10% Full length SMN 90% Truncated SMNΔ7
SMN Gene
Transcription
Translation
Disruption of a splice modulator
Modified from Neuromuscular.wustl..edu
2019
SMN ProteinHas a multidomain structure that provides a platform to recruit Gemins and small nuclear (sn)RNAs
Gemin2-binding domain (aa 19–44)Tudor domain (aa 91–142)Proline-rich domain (aa 195–248)Tyrosine- and glycine-rich region (YG box; aa 268–279)
Burges, A, McGovern, V. Genetics of Spinal Muscular Atrophy. Molecular and Cellular Therapies for Motor Neuron Diseases.
2019
Biochemical Function of
SMN ComplexSMN complex consist of
o SMNo Gemins2–8o Unrip (unr-interacting protein)
o Sm proteinsSMN localizes to both nuclear and cytosolic compartments Functions: Formation of small nuclear
ribonucleic proteins(snRNP) critical for the correct splicing of all genes
Assembly of other RNP complexes
www.med.upenn.edu
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Types of Defects
Phenotypic Severity
Molecular Testing
Loss of SMN1
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Types of Defects
95% Homozygous deletion of exon 7 and/or 8 or gene conversion from SMN1 to SMN2**
5% compound heterozygosity for a point mutation within the SMN1gene on one chromosome and a deletion/gene conversion of SMN1
<1% subtle intragenic point mutations within the SMN1 gene on both chromosomes. Rare and is most likely due to consanguinity
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Gene Conversion from SMN1
to SMN2
• **Severe missense mutations disrupt the ability of SMN to efficiently oligomerize and therefore act much like SMN lacking the sequence encoded by exon 7 (SMN1 converting to SMN2)
• This form of SMN is rapidly degraded and results in minimal amounts of SMN protein
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Phenotypic Severity
Determinants
SMN2 copy number Type of SMN2
Trans-Acting Modifiers: PLS3
Other Phenotypic Modifiers• Neuronal apoptosis
inhibitory protein (NAIP) gene
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SMN2 Copy Number
Type Highest Motor Function SMN 2 copy number Type 0
1aNever sits or walks 1 copy
Type 1 1 b 1c
No independent sitting 1 or 2 copies (85%)3 copies (15%)
Type 2 Independent sitting, some stand but never walk 3 copies ( 82%)2 copies ( 11%)4 copies( 7%)
Type 3 Independent walking but may lose ambulation 3 or 4 copies (96%) 2 copies (4%)Type 4 Walks during adult years but may lose ambulation ≥4 copies
Wang CH, et al. J Child Neurol. 2007;22:1027-1049
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Type of SMN2 Gene
The output of SMN2 is critical to determinate the phenotype
The ability to identify an intact SMN2 gene is not possible with the current diagnostic testing
The variant c.859G>C in exon 7 of SMN2 results in approx. 20% increase in full-length SMN protein and a mild SMA phenotype (Type 2 or 3)
With current screening procedures we cannot obtain precise information on whether these SMN2 genes are fully intact and functional
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Molecular Testing
SMN1 deletion/ copy number
SMN1 sequencing
• Now routinely performed within the setting of diagnostic or carrier testing for SMA
• SMN2 copy number analysis is important stratifying patients who are more likely to respond to therapeutic strategies
• Value within the setting of clinical trials
SMN2 copy number :
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Carrier Status
(1/40 to1/60)
• Category 1: SMN1 exon 7 copy number of 1 and presumes the presence of a SMN1 deletion/gene conversion on the other chromosome (heterozygous)
• Category 2 : two SMN1 genes in cis on a single chromosome along with a deletion/gene conversion of SMN1 exon 7 on the opposite chromosome resulting in a SMN1 exon 7 copy number of 2
• Category 3: subtle intragenic point mutation on one chromosome resulting in an SMN1 exon 7 copy number of ≥2
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Prenatal Testing
• 25% risk for the fetus to be affected• Amniocentesis can be performed after the
14th week of pregnancy, and is associated with a risk of miscarriage 1 in 200
• Chorionic Villus Sampling can be performed as early as the 10th week of pregnancy
2019
Newborn Screening
• Approved in the US at national level in 2018
• Implementation is at discretion of each state
CureSMA
2019
Current Therapies and Research on SMADiana Castro, MD
Assistant Professor of Pediatrics, Neurology and NeurotherapeuticsUniversity of Texas Southwestern Dallas
2019
Copyright © motifolio.com
Modulation of the low functioning SMN2 ”back up copy”
Replacement of SMN1 (gene transfer)
Neuroprotective Agents
Therapeutic ApproachesMotor Neuron
**Myostatin Inhibitor
2019
Modulation of the low functioning SMN2
• Branaplan(LMI070 )• Risdiplam (RO7034067)
• FIREFISH• SUNFISH• JEWELFISH
ORAL
• Nusinersen
INTRATHECAL
2019
Risdiplam• Recruiting• Oral medication- small molecule• Selective SMN2 splicing modifier designed to bind with specificity to SMN2 pre-mRNA• Promote inclusion of exon 7 and increase the production of functional SMN protein
FIREFISH SUNFISH JEWELFISH RAINBOWFISH
2019
FIREFISH• SMA Type 1 with 2 SMN2 copies• 1-7 months • Open label• Part 1: safety, tolerability, dose selection -
completed• Part 2: safety and efficacy in 40 participants• Estimated study completion September 2020
ClinicalTrials.gov. CureSMA Annual Meeting 2019
2019
FIREFISH
RESULTS
6.5-fold increase increase in SMN protein levels in blood after 4 wks.
19/21 infants (90%) remain alive with 2 having discontinued due to the fatal progression of their disease
3 patients are now over 24 m/old
None of the participants loss of ability to swallow, got tracheostomy or permanent ventilation
Most common AEs were fever, diarrhea, URI, ear infections, pneumonia, constipation, vomiting and cough
2019
CHOPType of Patient
CHOP INTEND
Score
Age at the beginning of
the study
Age at the beginning of
SMA SxHealthy Infants
(n=14)50.1 points
(range: 32-62)3.3 months
Infants with SMA with 2
copies of SMN2 (n=16)
20.2 Points(range:10-33)
3.7 months <1 month: 61-2 months: 52-3 months: 34-5 months: 1
Kolb SJ, et al; NeuroNEXT Clinical Trial Network on behalf of the NN101 SMA Biomarker Investigators. Ann Neurol. 2017;82(6):883-891.
1 Spontaneous movement (upperextremity)
2 Spontaneous movement (lower extremity)
3 Hand grip
4 Head in midline with visual stimulation
5 Hip adductors6 Rolling: elicited from legs7 Rolling: elicited from arms
8 Shoulder and elbow flexion and horizontal abduction
9 Shoulder flexion and elbow flexion
10 Knee extension11 Hip flexion and foot dorsiflexion12 Head control13 Elbow flexion14 Neck flexion15 Head/neck extension16 Spinal incurvation
Risdiplam: 10/17 infants (59%) achieved CHOP scores ≧40 points
2019
Natural Hx. HINE SMA Type 1Voluntary Grasp No grasp Uses whole
hand
Ability to kick No kickingKick
horizontal, legs do not lift
Head control Unable to maintain upright Wobbles
Rolling No rollingSitting Cannot sit
Crawling Does not lift head
Standing Does not support weight
Walking No walking
Score = 0 Score = 1
14/33(42%) 19/33(58%)
18/33(55%) 15/33(45%)
20/33(61%) 13/33(39%)
33 patients:
• 2 stronger infants received a score of 1, which persisted >2 years
• 7 weaker infants received a score of 0 in all the developmental milestones
All patients scored 0
Risdiplam: • 7/17 can sit without support for ≧ 5 sec• 1/17 stand up with support
Sanctis, RD et al. Neuromuscul Disord. 2015;26(11):754-759.
2019
SUNFISH• SMA type 2 or 3 ambulant or not• Randomization: placebo or drug• 2- 25 years• Part 1: ideal dose (n=51)• Part 2: safety and efficiency (n=158)• Estimated completion: July 2020
ClinicalTrials.gov. CureSMA Annual Meeting 2019
2019
SUNFISH
RESULTS
2-fold increase in SMN protein levels in blood
AE have been mostly mild and resolved despite ongoing treatment
58% had an improvement in Motor Function Measure (MFM32) over baseline of 3 points or more after 1 year Improvements were seen both in patients <12 years old (71%; n=24) and > 12 years old (42%; n=19)
ClinicalTrials.gov. CureSMA Annual Meeting 2019
2019
JEWELFISH• All types of SMA• Open label• 6 months to 60 years• 125 participants • Previously treated with an splicing modifier
(Nusinersen) or Olesoxime • Estimated study completion December 2020
ClinicalTrials.gov. CureSMA Annual Meeting 2019
2019
JEWELFISH
RESULTS
>2- fold increase of SMN protein levels in blood
12 patients with type 2 or 3 SMA have been treated
To date, no drug-related AE’s leading to withdrawal have been reported
•Ophthalmology monitoring did not show any evidence of the retinal findings seen in preclinical monkey studies
2019
RAINBOWFISH• 2019• Open label • Asymptomatic infants• Birth to 6 weeks of age (at first dose) • 2 to 4 SMN2 copies • All infants will receive Risdiplam for 24 months, followed by a 3-
year extension phase • Primary endpoint: proportion of infants sitting without support x
5 sec. after 12 months of treatment (BSID-III)• Secondary endpoints: long-term evaluation (2-5 years) of motor
milestone achievements and other developmental milestones (CHOP, HINE)
ClinicalTrials.gov. CureSMA Annual Meeting 2019
2019
Modulation of the low functioning SMN2
•Branaplan(LMI070 )•Risdiplam (RO7034067)
•FIREFISH•SUNFISH•JEWELFISH
ORAL
•Nusinersen
INTRATHECAL
2019
AON Exon Inclusion
SMN1 100% full length SMN protein
ASO- binds to ISS-N1 (splice silencer dependent on hnRNP protein) located
in intron 7.ASO displaces hnRNP
Exon 7
90% Full length SMN protein
Transcription
Translation
Facilitating accurate splicing of SMN2 transcripts: increasing transcripts containing exon 7
Modified from Neuromuscular.wustl..edu
2019
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
LaterOnset
Infantile Onset
Other SMApopulations
CS1: SAD
CS2: MAD
CS12: CS10 & CS2 Re-dosing
CS10: CS1 Re-dosing
CS4 CHERISH: P3 Later-Onset
CS3A: P2 open label
CS3B ENDEAR: P3 Infantile-Onset
FDA approval 23Dec16
NURTURE: P2 open label pre-symptomatic newborns
CS7 EMBRACE: OLE:
Phase 1 or 2 IONIS
Phase 2 Biogen
Phase 3 IONIS
EMBRACE: P1 Infants/Children
CS11 SHINE: OLE
Arrows do not accurately reflect timing
Biogen Clinical Program
2019
NURTURE
Phase 2 open label
25 infants aged ≤ 6 weeks with pre-symptomatic, genetically confirmed SMA
15 with 2 copies of SMN2 and 10 with 3 copies of SMN2
Primary endpoint
• All 25 patients are alive • No participants required permanent ventilation, including
tracheostomy• 4/25 (16%) participants required respiratory intervention
(>6 hrs./day continuously for >7days)
2019
Pre-Symptomatic (NURTURE) HINE Motor Milestones
0
5
10
15
20
25
30
Head control Sitting withoutsupport
Walking withassistance
Walking alone
2 SMN2 Copies (n=15) 3 SMN2 Copies(n=10) Total (n=25)
2019
Mea
n (S
E) C
HO
P IN
TEN
D
tota
l sco
re
NURTURE CHOP INTEND
Kolb SJ, et al; NeuroNEXT Clinical Trial Network on behalf of the NN101 SMA Biomarker Investigators. Ann Neurol. 2017;82(6):883-891.
Study visit day
NURTURE infants
Highest individual observed score over the 2-year period was 33 in a natural history cohort with 2 SMN2 copies
Highest mean (SE) score over the 2-year period was 19.9 (1.7) in a natural history cohort with 2 SMN2 copies
Max CHOP INTEND score = 64a
In healthy infants, mean (SD) total score was 47.2 (10.0) at Month 0 and 56.7 (5.8) at the 3-month
0
10
20
30
40
50
60
70
2 SMN2 copies 3 SMN2 copies2 SMN2 copies
1 64 183 302 365 421 540 659 700 778
132 SMN2 copies, n
3 SMN2 copies, n
15
10
15
10
15
10
15 15
10 10
15
9 7
10 9 7
3 SMN2 copies
Mean (min, max) CHOP INTEND3 SMN2 copies = 62.6 (58, 64)2 SMN2 copies = 61.0 (46, 64)
2019
NURTURE
Summary
At the time of the interim analysis (May 2018), patients were 14 to 34 mo.
All participants were alive and none required permanent ventilation, including tracheostomy
All (100%) participants have achieved sitting without support and most (88%) have achieved walking with assistance and 77% are walking alone
Early treatment of the pre-symptomatic infant allows for progressive gains in motor function
Nusinersen was well tolerated and no specific drug-related safety concerns were identified
2019
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
LaterOnset
Infantile Onset
Other SMApopulations
CS1: SAD
CS2: MAD
CS12: CS10 & CS2 Re-dosing
CS10: CS1 Re-dosing
CS4 CHERISH: P3 Later-Onset
CS3A: P2 open label
CS3B ENDEAR: P3 Infantile-Onset
FDA approval 23Dec16
NURTURE: P2 open label pre-symptomatic newborns
CS7 EMBRACE: OLE:
Phase 1 or 2 IONIS
Phase 2 Biogen
Phase 3 IONIS
EMBRACE: P1 Infants/Children
CS11 SHINE: OLE
Arrows do not accurately reflect timing
Biogen Clinical Program
2019
SHINE
ENDEAR
Symptomatic
<6 months
SMN2 copies: 2
Sham n=41
Sham in ENDEAR
Sham in ENDEAR
Nusinersen in SHINE
Nusinersen n=81Nusinersen in ENDEAR and
SHINE
2019
CHOP
CSMA (2019) Cure SMA - 2019 Annual Conference I Jun 28-Jul 1, 2019 I Anaheim, CA. Poster 6
2019
Nusinersen: Long-term ResultsMean change from baseline in HFMSE
score
Darras BT, et al. Neurology. 2019;92:e2492–e2506
Mean change from baseline over ~3 years of treatment
• CMAP values remained relatively stable• No children discontinued treatment due
to AEs
Motor assessment SMA Type II SMA Type IIIHFMSE Score +10.8 points +1.8 pointsUpper Limb Module Score +4 points Not reported
Six-minute Walk Test Distance Not reported +92 meters
2019
These materials are provided to you solely as an educational resource for your personal use. Any commercial use or distribution of these materials or any portion thereof is strictly prohibited.
Nusinerseno FDA approved in 2016 for pediatrics and adultso Baseline labs and prior to each dose: PLT count, PT, and U/Ao Administered intrathecally
• Recommended dosage is 12 mg/5 mL per administrationoFirst 3 loading doses should be administered at 14-day intervalsoFourth loading dose should be administered 30 days after the 3rd doseoMaintenance dose should be administered once every 4 months thereafter
• SPINRAZA® PI 2016. 49
2019
Dosing Information
• Lumbar puncture• Nusinersen is administered over 1-3 minutes• Dose 12 mg (5 ml)• Labs: CBC, PT, PTT, urine protein
Inj. 1
Inj. 2
Inj. 3
Inj. 4
2 weeks 30 days2 weeksInj. Every 4 months
4 months
{Loading doses} {Maintenance}
2019
Videos
2019
Copyright © motifolio.com
Modulation of the low functioning SMN2 ”back up copy”
Replacement of SMN1 (gene transfer)
Neuroprotective Agents
**Myostatin Inhibitor
Therapeutic ApproachesMotor Neuron
2019
AVXS- 101 Gen Transfer
Completed Phase 1 (2017)15 patients SMA type 12 copies of SMN26 male, 9 femaleIV 1 hr. infusion
• Self-complementary AAV9 (A non-replicating adeno-associated virus)
• Delivery functional human SMN gene
Cohort-1 (6.3 m) n =3 small doseCohort-2 (3.4 m) n =12 large dose
SMN1
• Safety, tolerability• Time to death
and permanent ventilation
AAV9 Vector
2019
AVXS-101
Results
• Safe (4.6 years)• Improves survival • All patients are alive and only 1 patient (Cohort 1)
reached the pulmonary endpoint at 28 months• None of the patients in Cohort 1 were able to sit
without support, or to stand or walk • Patients in Cohort 2 demonstrated improvements in
motor function: o 11/12 have head controlo 11/12 sit unassisted > 30 seco 2 patient stand with assistance o 2 patients can crawl, stand and walk
independently
24th International Annual Congress of the World Muscle Society, Copenhagen, Denmark, 1–5 October 2019
2019
STR1VE• Phase 3• SMA type 1 with 2 SMN2• <6 months
24th International Annual Congress of the World Muscle Society, Copenhagen, Denmark, 1-5 October 2019
2019
SPR1NT• Phase 3• Pre-symptomatic SMA < 6wks• 2 copies of SMN2: 15• 3 copies of SMN2: 12
24th International Annual Congress of the World Muscle Society, Copenhagen, Denmark, 1-5 October 2019
2019
STRONG
EPNS Congress, Athens, Greece, September 17-21 2019
2019
STRONG• 30 Patients enrolled• Dose A: 3• Dose B:
o 6-24 m: 13o 24-60 m: 12
• Dose C: 2
EPNS Congress, Athens, Greece, September 17-21 2019
2019
FDA
Onasemnogene Abeparvovec-xioi• Approved May 31st for patients < 2years of age• No weight limit• AAV9 < 1:50• Baseline Labs: LFTs , Troponin, CBC, PT, PTT and Q1 wks. x 4, Q2 wks. x 2months• Dose: 1.1x 10¹⁴ vector genomes (vg) per Kg of body weight• IV infusion over 60 min• Prednisone 1mg/kg/day pre and post treatment for 1 month then taper over 2 months
2019
Videos
2019
SRK - 015
Phase 2 active treatment study to evaluate the efficacy and safety of SRK-015 in patients with later-onset SMA
Enrolling
Estimated completion April 2021
SRK-015 is a fully human anti-pro Myostatin monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/lambda isotype that binds to human pro/latent myostatin
IV infusion every 4 weeks
ClinicalTrials.gov NCT03921528
2019
SRK-015
Cohort 1: SMA Type 3 ambulatory (n:20) on or off another SMA therapy. Open-label, 20 mg/kg SRK-015
Cohort 2: SMA Type 2 and non-ambulatory Type 3 (n:15). Patients already receiving an approved SMN up regulator therapy initiated at age 5 or older. Open-label, 20 mg/kg SRK-015
Cohort 3: SMA Type 2 < 5 years (n:20). Patients receiving an approved SMN up regulator therapy initiated before the age of 5 years old. Double-blind, randomized 1:1 to: 20 mg/kg or 2 mg/kg SRK-015
ClinicalTrials.gov NCT03921528
2019
Are You Ready?Julie A. Parsons, MDHaberfeld Endowed Chair in Pediatric Neuromuscular DisordersProfessor of Clinical Pediatrics and NeurologyUniversity of Colorado School of Medicine
2019
WarningVideotaping or taking pictures of the slides associated with this presentation is prohibited. The information on the slides is copyrighted and cannot be used without permission and author attribution.
2019
Financial DisclosuresI have participated in clinical trials for:• Biogen• Isis/Ionis• Cytokinetics• AveXis• Genentech/Roche• Sarepta• PTC Therapeutics• Scholar Rock
2019
System Challenges with the Introduction of New Therapies
2019
Objectives
• Understand some of the challenges of start up when a trial drug is approved for a rare disease
• Understand some of the key aspects of system development to support a treatment plan
• Identify barriers to clinical treatment
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Introduction
• Basic science allows development of specialized drugs for rare disorders
• These drugs or products are carefully tested for safety and efficacy in clinical trials
• Some of these drugs are then approved and brought into the commercial market to be used for treatment
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Challenges in Trials to Treatment• Providing prompt and effective education about the disease,
treatment, delivery system, and possible medical issues
• Establishing a protocol for treatment
• Establishing an Administrative infrastructureo Schedulingo Preauthorizationo Insuranceo Payment
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Challenges in Trials to Treatment
• Clinical trials are run in a very rigidly controlled environment which is monitored and regulated closely
• Adequate staffing and oversight is guaranteed both by internal and by external oversight
• Patient safety and outcomes are closely watched and documented
• Ideally all costs are budgeted for and compensated
2019
Differences between Trials and Treatment
• Finances and Controlled Environment
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Control• Clinical trial process and regulation guarantees that there
is a standardized, controlled environment for drug delivery and outcome evaluation.
• Then the schema changes to free market with commercial and financial interests at play.
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Finances• Clinical trials are fully funded
• Research and medical team are compensated
• Institutional and administrative costs are paid
• Pharmacy procurement and processing is specified
• Patient travel and expenses are reimbursed
2019
The Players
Patients
HospitalAdministrati
on
PharmaCompany
Medical TeamThird Party
Payers
2019
• These are rare diseases!!
Reminder
2019
Patients
• Want treatment immediately as soon as it is available
• Not always fully informed as to risks and benefits
• Many times do not fully understand the medical or financial implications of treatment
• Social media plays a prominent role
2019
Medical Team Providers• Change from research team to clinical medicine team
• Want to safely provide the approved novel therapy
• Not always familiar with the drug, delivery system, risks and benefits
• No organized safety reporting or sharing experience and standardized outcomes
2019
Hospital Administration• Cost of novel medication requires upper level management be
involved early in discussions about treatment• Look to limit financial risk and liability
oChief Financial OfficeroChief Medical Officero Pharmacy Managero Finance and revenue recovery specialistso Business Manager/Operations coordinatoroGovernment advocate
2019
Pharmacy• Pharmacy and Therapeutics committee must approve addition of
the drug to formulary
• Process of “white bagging”, “buy and bill”, specialty pharmacy
• Special preparation, processing and handling of drug when it is dispensed or administered.
2019
Pharma Company• Offer support systems to patients
• Offer support systems to providers
• Believe all patients should be treated with their product
• Change from research medical team to commercial team • Internal communication not always consistent
2019
Colorado Experience
• Participated in clinical trials for nusinersen and onasemnogene abeparvovec for spinal muscular atrophy patients
• Medical research team Medical care team
2019
Rocky Mountain Region
2019
Complex Drug Program
• Medical Director
• Operations Coordinator
• Nurse Manager
2019
Neurology Complex Drugs Program• Operations Coordinator
oCentral point of contactoManages all of the complex schedulingo Interfaces with the hospital preauthorization and finance team.oManages the status of insurance referrals, denials, appeals, etco Partners with Nurse Coordinator
2019
Neurology Complex Drugs Program• Clinical Nurse Coordinator
o Medical point of contact for patientso Provides education to nursing personnelo Meets with patient and family to review the Memo of Understanding
and answer questions prior to initiation of therapyo Pends laboratory and medication orders to be reviewed and signedo Often sees patient on the procedure dayo Post procedure follow up phone calls
2019
Neurology Complex Drugs Program• High Risk Medical Team
o Neurologisto Anesthesiologisto Gastroenterologist/Nutritiono Pulmonologist/RTo Interventional Radiologisto Neurosurgeono Orthopedic Surgeono Social Worko Complex Drug Program Team
2019
Memo of Understanding
• States our team’s responsibilities
• States the patient and family responsibilitieso Following consensus guidelineso ImmunizationsoNutritionoRoutine follow up appointments
2019
SMA Consensus Care Guidelines
2019
Consensus of Care Guidelines for SMA
• Important that in light of new therapies, care guidelines continue to be followed.
• New therapies are not a replacement for good general health care.
• Reminder: There is no cure for SMA
2019
Third Party Payers• Often have little knowledge about the rare disorder or the treatment• Might not have a code or policy in place to approve the drug or
delivery system for that drug• Includes Medicaid for many patients• May require journal articles and published results for evidence
based medicine requirements• Dictate strict outcome measurement monitoring that might not be
needed• May be slow in developing a policy regarding treatments
2019
Spinraza ProcessNeurology
•Patient is evaluated in the Neuromuscular Clinic to determine interest in treatment•Letter of Medical Necessity is developed
InsuranceVerification
•Prior Authorization or Pre-determination Request is submitted to insurance•Authorization must be received prior to scheduling
ManagedCare
•Verify payer is contracted with hospital•Verify payer reimbursement is sufficient for both procedure and medication•Negotiate Single Case Agreement if needed
High Risk Eval
•Patient is evaluated by High Risk team to determine the best procedure treatment plan•Pertinent information related to treatment (anesthesia plan, pulmonary concerns, recovery plan) documented in chart (EMR)
Scheduling
•Scheduling orders are placed•Medication and safety lab orders are placed in chart
Pharmacy
•Pharmacy buyers order medication for each scheduled appointment•Our institution is a “buy-and-bill” institution
IR or PC
•Safety labs are obtained before the procedure•Medication is administered
Patient Financial Services
•Submit claim to payer•Confirm correct payment is made to hospital
2019
Lessons Learned• Engage hospital administration early • Patients want treatment now. Keep them informed and up to date• P and T committees take time for investigation and approval• Pharma access to care programs have benefits and challenges• White bagging vs buy and bill, specialty pharmacies• Insurance is a complex field to navigate• Peer to peer calls are time consuming
2019
Conclusions• Clinical treatment is a complex process
• Advanced planning is necessary
• Teamwork is a requirement
• Good communication and education of all parties involved is key
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2019
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2019
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Record your attendance hours after each session or do it all at once after the meeting is complete! Credit not recorded by December 15, 2019 will not be reported to ABPN and ABPMR. The AANEM will report ALL Annual Meeting attendees’ credit to ABPN and ABPMR by December, 31, 2019.