Diapositiva 1

Horizon Scanning: quali farmaci nel prossimo
futuro dell’oncologia
Joppi R, Pase D.
UOSD Ricerca Clinica & Valutazione Farmaci – Dipartimento Farmaceutico - Verona
3° Congresso SIFACT
SSN: Sostenibilità o Sopravvivenza? Le nuove frontiere dell’assistenza farmaceutica
Roma, 8-10 Ottobre 2015
ONCO Trials currently recruiting
Phase III
15%
Phase IV
5%
Phase I
31%
Total World: 2,377
Phase II
50%
Phase IV
9%
Phase I
21%
Phase III
25%
Total EU: 577
Phase II
45%
https://clinicaltrials.gov 09/10/2015
Sales Forecast by Therapeutic Areas
Host organization: Azienda ULSS 20 in Verona
EuroScan
The international information network on new and emerging health technologies
“A collaborative network of member agencies for the exchange of information on
important emerging technologies and the principal global forum for the sharing
and development of methods for the early identification and assessment “
18 Agencies in 14 different Countries in 4 continents:
Asia, Australia, Europe and North America
euroscan.org.uk
2007
2008
EUROSCAN
August 2006
IHSP kickoff
IHSP Chronology
2009 2010 2011
2012 2013 2014 2015
2016
Database
set up
- 36 reports
-
60
65
60
60
60
60
60
20
- 18 reports
-
39
34
29
26
30
25
31
11
-
9
9
9
9
9
7
9
8*
NPIR
Total IHSP documents (n): 739;
(*)reports ongoing
Update October 2015
Aims
TO ORGANIZE and EVALUATE available information on emerging drugs
BEFORE SUBMISSION of a MAA to Regulatory Agency and before any
decision on COSTS and POSSIBLE CLASS OF REIMBURSEMENT
Specific aims:
 to produce periodical lists of emerging drugs for which a MA will be
expected within 12-36 months
 to evaluate potential clinical impact and cost effectiveness in terms of
healthcare and cost for National Health Service
 to give well-timed
emerging drugs
information to improve regulatory
decisions about
 to identify further research fields needed to be investigated
IHSP Workflow
Database IHSP
Emerging drugs
- 36 months report
PRELIMINARY SELECTION (SC-IHSP)
Selected Drugs
-18 months report
New Product Information
Report - NPIR
(-12 months M.A.)
Evaluation
Team
PRIORITIZATION
SC-IHSP
MinSal
REGIONS
The IHSP Database, Oct. 2015
Priority-setting criteria used by SC-IHSP
AREA to INVESTIGATE
PARAMETERS
EVALUATION
Burden of disease
Epidemiology
Rare
Not rare
Severity
Severe
Not severe
Duration
Acute
Chronic
Treatment
Available
Absent
Efficacy vs. current treatments (mortality, morbility, quality of life, etc.)
Higher
Equal or Lower
Safety vs. current treatments
Higher
Equal or Lower
Compliance vs. current treatments
Higher
Equal or Lower
Social impact (Media, patients associations, lobbies ...)
YES
NO
Service reorganization and/or staff training required
YES
NO
Possible off-label use
YES
NO
Economic impact on the NHS
High
Low
Possible launch date
< 18 months
> 18 months
Drug in development for other indications of interest
YES
NO
Other drugs in development for the same indication
YES
NO
Patient impact
NHS Pressures
Others
IHSP
Outputs
-36
MONTHS
REPORT
Produced
annually
NPIR
general information

licensee

stage of development

possible submission date of the MAA

main proposed indication(s)

ongoing studies
“Drug Indication”
Drug/brand name /active substance
Company
ATC Group
Route of administration

general information

possible submission date of the MAA

proposed indication(s)

summary of the available data on clinical efficacy and safety

overview of all ongoing trials and completed studies not published

possible price and economic impact (if available)

alternative(s) already on the market

possible competitors in development

Active substance
Brand name
Company
ATC Group
general information
Dosage
Route of administration
Development state
……
clinical need and burden of disease

summary of efficacy/safety data from available clinical trials

clinical critical assessment

social / economic impact

ongoing trial(s) for the same or other indication(s)

(-12 months to
M.A.)
“Drug Name”
Drug/brand name/ active substance
Company
ATC Group

-18 MONTHS
REPORT
Produced every
6 months
ONCO-DRUGS COMING
4°QTR2015-1°QTR2017
Premessa
 Aumenta il numero di farmaci di tipo «biologico»;
 La durata degli RCT è insufficiente per conoscere i nuovi farmaci;
 I nuovi farmaci sono studiati per il loro effetto diretto, non come parte di
una strategia terapeutica (resezione/irradiazione o sospensione/ripresa in
relazione alla risposta);
 Aumenta il rischio di non utilizzare al meglio i farmaci disponibili e/o di
utilizzarli «off-label»;
 Sequenze/combinazioni di farmaci sono il presente, in futuro saranno
sostenibili?
 Se il target è assente: Chemioterapia più attiva della Target Therapy;
 La nuova Immunotherapy è una Target Therapy?
 Trattamento personalizzato è sempre più vantaggioso vs. trattamento non
personalizzato;
Qualche semplificazione….
….mab = anticorpo monoclonale che agisce bloccando un
recettore o il ligando di un recettore
….ib = piccola molecola che agisce togliendo energia ad un
«nodo» di trasmissione, in genere occupando la «tasca» dove
si va ad inserire l’ATP
Quali i «…mab/…ib» all’orizzonte?
Non-small cell lung cancer I
Drug
CERITINIB
(Zykadia)
RAMUCIRUMAB
MERELETINIB
NECITUMUMAB
Licencee
Novartis
Indication
Previously treated, locally advanced or
metastatic NSCLC with ALK
rearrangements.
ImClone Systems NSCLC (second-line)
AstraZeneca
Bristol-Myers
Squibb
Metastatic, EGFR T790M mutationpositive NSCLC progressed following
treatment with EGFR-tyrosine kinase
inhibitor
Stage IV squamous NSCLC
Primary
endpoint
Pivotal study
Phase I
(NCT01283516)
REVEL
(phase III)
AURA
(phase I/II)
SQUIRE
(phase III)
ORR; PFS
OS
Notes
1. Tyrosine kinase inhibitor of ALK.
2. Breakthrough Therapy designation
in US;
3. Insufficient data to evaluate the
drug;
4. Conditional M.A. in EU:
06/05/2015based on data of a Phase
I study, only.
Obbligation: submission of final
results of a phasae II and a phase III
studies
1. Anti-VEGF-receptor-2 monoclonal
antibody;
2. Clinical results are expected not to
be clinically relevant
ORR
1. EGFR tyrosine kinase inhibitor
Good ORR results;
2. To be monitored for patients with
brain metastases
OS
1. Fully human IgG1 monoclonal
antibody designed to block the ligand
binding site of the human EGFR
2. Fast Track status in US;
3. Modest OS and PFS results; no
alternatives
Non-small cell lung cancer II
Drug
Licencee
NIVOLUMAB
Bristol-Myers
(Nivolumab BMS) Squibb
PEMBROLIZUMAB
(LAMBROLIZUMAB) Merck & Co
(Keytruda)
ROCILETINIB
ATEZOLIZUMAB
Clovis Oncology
Roche
Indication
Advanced/metastatic, previously treated
NSCLC
EGFR mutation-negative and ALK
rearrangement- negative advanced
NSCLC, progressing on platinum-based
chemotherapy
Second-line treatment of locally-advanced
or metastatic, EGFR mutant NSCLC in
patients with T790M mutation
NSCLC expressing PD-L1 and progressing
during or after standard treatments
Primary
endpoint
Pivotal study
CheckMate-017
(phase III)
OS
Notes
1. Fully human IgG4 monoclonal
antibody that binds PD-1 on activated
immune cells to disrupt PD-1
interaction with PD-L1 and PD-L2
ligands;
2. Immunotherapy;
3. The drug is highly selective. Due to
the high discontinuation rate in the
phase II trial, safety has to be strictly
monitored;
4. M.A. in EU: 20/07/2015
5. In the L. 648/96 from the
22/09/2015
6. 24/09/2015: CHMP Positive Opinion
for Opdivo
KEYNOTE-001
Trial
(phase I)
1. First-in-class highly selective antiPD-1 humanized monoclonal antibody;
Preliminary
2. Immunotherapy;
antitumor activity:
3. Breakthrough Therapy designation
ORR;
and priority review in US;
3. To be considered in the November
PG-IHSP
Phase I/II study
(NCT01526928)
1. Potent, mutant-selective EGFR
inhibitor that targets the activating
mutations of EGFR (L858R and Del19),
Preliminary
while also inhibiting the dominant
antitumor activity: acquired resistance mutation, T790M;
ORR;
2. Breakthrough Therapy designation
in US;
3. To be considered in the November
PG-IHSP
POPLAR study
(phase II)
OS
1. Targets PD-L1 expressed on tumour
cells and tumour-infiltrating immune
cells, preventing it from binding to PD1 and B7.1 on the surface of T cells;
2. Breakthrough Therapy designation
in US;
3. To be considered in the November
IHSP-PG
Advanced melanoma
Drug
Licencee
PEMBROLIZUMAB
(LAMBROLIZUMAB) Merck & Co
(Keytruda)
Indication
Advanced melanoma
COBIMETINIB
Genentech
BRAFV600 mutation-positive unresectable
locally-advanced or metastatic melanoma
(in combination with Vemurafenib)
NIVOLUMAB
(Opdivo)
Bristol-Myers
Squibb
Advanced melanoma
Puma
Biotechnology
Adjuvant treatment of early stage, HER2positive breast cancer
Pfizer
First-line treatment for postmenopausal
women with ER-positive, HER2-negative,
advanced breast cancer (plus
LETROZOLE)
Primary
endpoint
Pivotal study
Phase Ib
(NCT01295827)
coBRIM
(Phase III)
ORR; OCR; PFS
PFS
CheckMate -037
ORR and OS
(phase III)
Notes
1. First-in-class highly selective antiPD-1 humanized monoclonal antibody;
2. Immunotherapy;
3. Breakthrough Therapy designation
in US;
4. Promising results;
5. M.A. in EU: 17/07/2015
1. MEK inhibitor;
2. EMA: accelerated assement;
3. No advantages, similar to the
already approved trametinib
1. Fully human IgG4 monoclonal
antibody that inhibits the PD-1, a
negative
regulator
of
immune
response to T-cell;
2. Immunotherapy
3. Breakthrough Therapy designation
in US;
4. Possible alternative;
5. M.A. in EU: 19/06/2015
Breast cancer
NERATINIB
PALBOCICLIB
ExteNET
(phase III)
PALOMA-1
(phase III)
DFS
1. Potent irreversible tyrosine kinase
inhibitor;
2. No advantages over exisiting
treatments; safety results are needed.
PFS
1. Selective inhibitor of cyclindependent kinases (CDK) 4 and 6,
preventing DNA synthesis by blocking
cell cycle progression;
2. No advantages over exisiting
treatments
Other solid Tumours
Drug
Licencee
Indication
Primary
endpoint
Pivotal study
AFATINIB
(Giotrif)
Boehringer
Ingelheim
Recurrent and/or metastatic head and
neck squamous cell carcinoma (HNSCC)
progressed on or after platinum-based
therapy
LENVATINIB
(Lenvima)
Eisai Co Ltd
Progressive radioiodine-refractory
differentiated thyroid cancer
SELECT
(phase III)
PFS
SONIDEGIB
(Odomzo)
Novartis
Basal cell carcinoma
BOLT
(phase II)
ORR
NIVOLUMAB
(Opdivo)
Bristol-Myers
Squibb
Advanced or metastatic clear-cell RCC after
prior anti-angiogenic therapy.
CEDIRANIB
AstraZeneca
First relapse of ‘platinum-sensitive'
ovarian cancer
LUX-Head & Neck
1
PFS
(phase III)
CheckMate-025
OS
(phase III)
ICON6 trial
(phase II/III)
PFS
Notes
1. Irreversible ErbB family blocker;
2. BSC would have been a better
comparator rathar then MTX;
3. M.A. 25/09/2013 for NSCLC with
EGFR mutation(s)
1. First-in-class multiple receptor
tyrosine kinase inhibitor;
2. Priority Review Status in US;
3. Nothing new with respect to
Sorafenib which is already approved
for this indication;
4. MA in EU: 28/05/2015
1. ORR defined as the proportion of pts
with CR or PR, or shrinkage;
2. Potent and selective smoothened
antagonist
3. BCC has a low impact;
4. Compared to Vismodegib, its
analogue already approved, SONI
shows similar efficacy with a dosedependent safety profile;
5. MA in EU: 14/08/2015
1. Fully human IgG4 monoclonal
antibody that binds PD-1 on activated
immune cells to disrupt PD-1
interaction with PD-L1 and PD-L2
ligands;
2. Immunotherapy;
3. To be considered in the November
IHSP-PG
1. Potent inhibitor of VEGFR-1,-2,-3
and inhibits VEGF signalling;
2. Currently under evaluation by
CHMP-EMA;
3. To be considered in the November
IHSP-PG
Leukemia
Drug
VENETOCLAX
Licencee
AbbVie and
Genentech
BLINATUMOMAB Micromet Inc
Indication
Relapsed/refractory CLL, in pts with 17p
deletion
Ph-negative relapsed/refractory acute
lymphoblastic leukemia
Primary
endpoint
Pivotal study
Phase II
(NCT01889186)
MT103-211
(phase II)
Notes
ORR
1. Selectively binds and inhibits BCL-2,
an important regulator of apoptosis;
2. Breakthrough Therapy designation
in US;
3. To be considered in the November
IHSP-PG
CR or CR with
partial
hematological
recovery within
the first 2 cycles
1. Specific T-cell engaging antibody
that directs cytotoxic T-cells to CD19expressing target cells;
2. First specific therapy in this
indication
ORR
1. Low molecular weight histone
deacetylase inhibitor;
2. Priority review status in US;
3. The development of the association
BELI + CHOP has to be monitored
Lymphoma
BELINOSTAT
Spectrum
Relapsed or refractory peripheral T-cell
Pharmaceuticals lymphoma
BELIEF
(phase II)
Multiple Myeloma
Drug
CARFILZOMIB
PANOBINOSTAT
(Farydak)
Licencee
Indication
Relapsed refractory multiple myeloma
Onyx
(combination therapy with lenalidomide
Pharmaceuticals
and dexamethason)
Novartis
Relapsed and/or refractory multiple
myeloma, after at least one prior therapy
(in combination with bortezomib and
dexamethasone)
Primary
endpoint
Pivotal study
ASPIRE
(phase III)
PANORAMA1
(phase III)
PFS
PFS according to
mESBMT criteria
Notes
1. Inhibitor of chymotrypsin-like
proteasome and immunoproteosome
activities;
2. Unclear possible place in therapy
1. Potent pan-deacetylase inhibitor;
2. In Nov 2014 negative opinion from
FDA oncology drug advisory
committee;
3. Clinical results were considered
modest;
4. MA in EU: 28/08/2015
Multiple Myeloma II
Drug
Licencee
Indication
Multiple myeloma in pts who have
received >3 prior lines of therpapy
(including both a proteosome inhibitor
DARATUMOMAB Janssen Biotech and an immunomodulatory agent) or are
double refractory to a proteosome
inhibitor and an immunomodulatory
agent.
IXAZOMIB
ELOTUZUMAB
Millenium
Relapsed and/or refractory multiple
Pharmaceuticals myeloma
Bristol-Myers
Squibb
Relapsed or refractory multiple myeloma
Primary
endpoint
Pivotal study
Phase II study
(NCT01985126)
TOURMALINEMM1
(phase III)
ELOQUENT-2
(phase III)
ORR
PFS
Coprimary end
points: PFS and
ORR
Notes
1. Monoclonal antibody binding to the
transmembrane ectoenzyme, CD38, on
the surface of multiple myeloma cells;
2. Breakthrough Therapy designation
in US;
3. To be considered in the November
IHSP-PG
1. Proteasome inhibitor;
2. Still ongoing;
3. First pre-specified interim analysis:
improving PFS;
4. To be considered in the November
IHSP-PG
1. First-in-class humanized
immunoglobulin
G1 immunostimulatory monoclonal
antibody targeted against signaling
lymphocytic activation molecule F7
(SLAMF7), a glycoprotein expressed on
myeloma and natural killer cells but
not on normal tissues;
2. Breakthrough Therapy Designation
in US;
3. Available in the US under an
expanded access programme
4. EMA: accelerated assessment
5. Currently under evaluation by CHMPEMA;
6. To be considered in the November
IHSP-PG