Pharma R&D Annual Review 2019 Supplement: New Active Substances Launched During 2018 - Pharma Intelligence
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Pharmaprojects
Pharma intelligence |
Pharma R&D
Annual Review 2019
Supplement:
New Active Substances
Launched During 2018
Ian Lloyd
Senior Director, Pharmaprojects and Data Integration
Introduction
Following on from our review of trends in the and had to retire before the 10-mile mark, others
current pharmaceutical R&D pipeline, published have the finishing line in their sights when suddenly
in March 2019 (visit https://pharmaintelligence. their legs buckle and it all goes horribly wrong. Few
informa.com/resources/product-content/pharma- will be able to name any competitors who didn’t
rndannualreview-2019 to download the report successfully cross the finishing line, with a small
for free), this supplement takes a look at the number of high-profile exceptions. Even those that
industry’s success stories of 2018 – the drugs which do last the course range from Kenyan world-record
were launched on to the market for the first time holder Eliud Kipchoge, whose time at the 2018 Berlin
during the year. Our survey focuses exclusively on Marathon came close to beating the two-hour mark,
new active substances (NASs): new chemical or and those unfortunate ladies and gents who limp
biological entities where the active ingredient had home in 10 hours-plus. And some are remembered
received no prior approval for human use. This will for all the wrong reasons: lauded athlete Paula
include vaccines with novel antigenic components. Radcliffe is sadly likely to go down in history as much
As such, this list represents a subset of all the first for the infamous ‘toilet’ incident in the 2005 London
launches which Pharmaprojects reported during Marathon as for her many gold medals. In that event,
2018, excluding the 67 new drug launches with however, she did go on to complete the course, in the
reformulated or non-NAS moieties, or biosimilars. sporting equivalent of gaining approval even after a
So, to continue our sports theme this year, we’ll be disastrous initial Phase III trial readout.
looking at the drugs which successfully crossed the
finishing line, hit the bullseye, and lifted the trophy, to But we are here to celebrate the successes of the
become part of pharma’s elite 2018 team. 2018 pharma year. We will look first at the year’s
statistics, before taking a deeper dive into the real
In pharma as in sport, it’s all about winning. Pharma winners as opposed to the also-rans – the NASs with
notoriously has a higher drop-out rate than the most novel mechanisms of action, which, like sporting
gruelling of marathons. In a crowded field, many fall champions, furthered the achievements of human
by the wayside: some just didn’t have what it takes endeavour. First, what was the final score?
© Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) March 2019 / 3
68 New Active Substance Launches
Gold medal year sees pharma on the winners’ podium again
Figure 1 shows the number of NASs launched by Denver Broncos’ 606 points scored through the
year for the millennium thus far. And it reveals 2013 NFL season. The total of 61 non-vaccine NAS
2018 to have been a champion year. With no fewer launches surpassed 2014’s previous record by four,
than 68 NAS launches, the last 12 months saw the and one extra novel vaccine debut propelled 2018
highest number of NASs launched in a single year even further ahead. With the gold, silver and bronze
since our records began, and by some distance. It medals all going to years within the past five, is
truly was a spectacular year, akin to Manchester pharma finally solving its productivity issue? The
City’s highest ever English Premier League total of signs are certainly encouraging on this form.
100 points in the 2017/18 football season, or the
Figure 1: Number of NAS launches by year, 2000–18, with numbers excluding vaccines also shown
80
7
70 6
60
7
50 3
11
6 8 1 3
Drug Count
0 7
40
1
0 11
2 3 61
4 1 57
30
1 47
43
20 37 36 35 36 37 37
34
29 29 31
28
26 26 26
22
10
0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Other NASs Vaccines
Source: Pharmaprojects®, March 2019
If you take away the novel vaccines (the pink bars approvals late in the year can bolster a single year’s
in Figure 1) from this total, the scores from the last numbers at the expense of its successor. So perhaps
five seasons of drug-making present an industry a better indicator is to use five-year means. This
journey, from the 57 seen in 2014, to a nadir of 34 brings 2014–18’s average over all NASs (including
in 2016, and up to 61 by 2018. Of course, in a sense, vaccines) to 54.4, well ahead of 2009–13’s 41.0 and
the 12-month calendar period we are using here 2004–08’s 28.6. This puts the industry on a fairly
is somewhat arbitrary; a few faster-than-expected dramatic upward trajectory.
4 / March 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)
The 2018 NAS Statistics
It’s not the taking part that counts – it’s the winning
Let us now open our form book and examine in indications for which they were approved, their
detail the attributes that 2018’s winning team mechanism of action, the country and month of
had. First, it’s time for the full squad photo for the first launch, and indications of whether or not they
yearbook. Table 1 provides a full alphabetical list of are first-in-class, are for rare diseases, and/or had
the year’s new drugs, along with their trade names, orphan drug status.
the companies involved in their launch, the precise
Table 1: New active substance launches, 2018
Month First- Orphan
Trade Mechanism of Country of Rare
Drug name* Companies Indication of first in- drug
name action** first launch disease?
launch class? status?
Frontier
albuvirtide Aikening HIV infection GP41 antagonist China August N N N
Biotechnologies
Portola Factor Xa
andexanet alfa AndexXa Haemorrhage USA May N N Y
Pharmaceuticals stimulant
Androgen/
Johnson & Castration-resistant
apalutamide Erleada estrogen receptor USA February N N N
Johnson prostate cancer
antagonist
astodrimer Starpharma/ Hyaluronidase
Fleurstat Bacterial vaginosis Australia May N N N
sodium Aspen inhibitor
Dova Thrombopoietin
avatrombopag Doptelet Thrombocytopenia USA May N N N
Pharmaceuticals agonist
baloxavir Influenza virus Endonuclease
Xofluza Shionogi/Roche Japan March Y N N
marboxil infection inhibitor
Portola Venous
betrixaban Bevyxxa Factor Xa inhibitor USA January N N N
Pharmaceuticals thromboembolism
bictegravir* +
emtricitabine HIV integrase
Biktarvy Gilead Sciences HIV infection UK July N N N
+ tenofovir inhibitor
alafenamide
binimetinib Mektovi Array BioPharma Melanoma MEK inhibitor USA August N N Y
Albireo/Kyowa
Fibroblast
Hakko Kirin/ X-linked
burosumab Crysvita growth factor 23 USA March Y Y Y
Ultragenyx hypophosphataemia
antagonist
Pharmaceutical
Thrombotic
Factor VIII
caplacizumab Cablivi Ablynx thrombocytopenic Germany October Y Y Y
inhibitor
purpura
Regeneron/ Squamous cell
cemiplimab Libtayo PD-1 antagonist USA September N N N
Sanofi carcinoma
ErbB-2/4 & EGFR
Non-small cell lung
dacomitinib Vizimpro Pfizer tyrosine kinase USA December N N Y
cancer
inhibitor
© Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) March 2019 / 5
Month First- Orphan
Trade Mechanism of Country of Rare
Drug name* Companies Indication of first in- drug
name action** first launch disease?
launch class? status?
InterMune/ HCV nonstructural
danoprevir Ganovo Hepatitis C infection China June N N N
Ascletis protein 3 inhibitor
Austria,
Perianal fistula in Finland, the
darvadstrocel Alofisel TiGenix/Takeda Not applicable June N Y Y
Crohn's disease Netherlands
and Norway
Melinta Acute bacterial skin DNA
delafloxacin Baxdela Therapeutics/ and skin structure topoisomerase II/ USA January N N N
Ligand infections IV inhibitor
diphtheria-
Green Cross Diphtheria/tetanus
tetanus vaccine, Green Cross Immunostimulant S Korea January N N N
TD Vaccine prophylaxis
Green Cross
Non-nucleoside
reverse
doravirine Pifeltro Ligand HIV infection USA September N N N
transcriptase
inhibitor
Diphtheria,
DTaP5-IPV-Hib- MCM Vaccine
hepatitis-B, Germany,
HepB vaccine, Vaxelis (Sanofi/Merck Immunostimulant January N N N
pertussis, polio and Italy, Spain
Merck & Co & Co)
tetanus prophylaxis
Chronic lymphocytic
leukemia/small
Verastem lymphocytic PI3 kinase delta/
duvelisib Copiktra USA September Y N Y
Oncology lymphoma/ gamma** inhibitor
refractory follicular
lymphoma
Luteinizing
Neurocrine
hormone releasing
elagolix Orilissa Biosciences/ Endometriosis USA November N N N
hormone (LHRH)
AbbVie
antagonist
Ileal bile acid
Ajinomoto/ transport inhibitor/
elobixibat Goofice Mochida/EA Chronic constipation Sodium/bile acid Japan April Y N N
Pharma cotransporter
inhibitor
NovImmune/
Haemophagocytic Interferon gamma
emapalumab Gamifant Swedish Orphan USA December N Y Y
lymphohistiocytosis antagonist
Biovitrum
B-raf kinase
encorafenib Braftovi Array BioPharma Melanoma USA August N N Y
inhibitor
Protein 30S
Complicated intra-
eravacycline Xerava Tetraphase ribosomal subunit USA October N N N
abdominal infections
inhibitor
Calcitonin gene-
erenumab Aimovig Amgen/Novartis Migraine prophylaxis related peptide USA July Y N N
inhibitor
Sodium/glucose
Pfizer/Merck
ertugliflozin Steglatro Type 2 diabetes cotransporter 2 USA June N N N
& Co.
inhibitor
6 / March 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)Month First- Orphan
Trade Mechanism of Country of Rare
Drug name* Companies Indication of first in- drug
name action** first launch disease?
launch class? status?
Mitsubishi
Tanabe Pharma/ Secondary Calcium-sensing
evocalcet Orkedia Japan May N Y N
Kyowa Hakko hyperparathyroidism receptor agonist
Kirin
Idiopathic Syk tyrosine kinase
fostamatinib
Tavalisse Rigel thrombocytopenic inhibitor**/Flt-3 USA May Y Y Y
disodium
purpura antagonist
Calcitonin gene-
Teva/Labrys
fremanezumab Ajovy Migraine prophylaxis related peptide USA November N N N
Biologics
inhibitor
VEGFR-1,2,3
Hutchison China
fruquintinib Elunate Colorectal cancer tyrosine kinase China November N N N
MediTech/Eli Lilly
inhibitor
Calcitonin gene-
galcanezumab Emgality Eli Lilly Migraine prophylaxis related peptide USA November N N N
inhibitor
Flt-3 antagonist/
Kotobuki Relapsed or
Axl receptor
gilteritinib Xospata Pharmaceutical/ refractory acute Japan October N Y Y
tyrosine kinase
Astellas Pharma myeloid leukemia
inhibitor
Acute myelogenous Hedgehog
glasdegib Daurismo Pfizer USA December N N Y
leukaemia pathway inhibitor
GW Dravet and Lennox- Cannabinoid
GWP-42003 Epidiolex USA November N Y Y
Pharmaceuticals Gastaut syndromes receptor agonist
hepatitis-B
Dynavax Hepatitis B infection Toll-like receptor 9
vaccine + 1018- Heplisav USA January N N N
Technologies prophylaxis agonist
ISS, Dynavax
Thymidine kinase
HSV-tk gene stimulant/DNA-
Graft-versus-host
therapy, Zalmoxis MolMed directed DNA Germany January N Y Y
disease
MolMed polymerase
inhibitor
CD4 antagonist**;
Thera- GP41 antagonist;
ibalizumab Trogarzo HIV infection USA April Y N N
technologies GP120env
antagonist**
influenza
vaccine
(egg-based), Influenza virus
Teratect Il-Yang Immunostimulant S Korea September N N N
quadrivalent, infection prophylaxis
inactivated,
Il-Yang
influenza
Influvac
vaccine, Influenza virus New
Quadriva- Abbott/Mylan Immunostimulant February N N N
quadrivalent, infection prophylaxis Zealand
lent
Abbott
Ionis
Transthyretin-
Pharmaceuticals/ Transthyretin Germany &
inotersen Tegsedi related hereditary November N Y Y
Akcea inhibitor USA
amyloidosis
Therapeutics
© Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) March 2019 / 7Month First- Orphan
Trade Mechanism of Country of Rare
Drug name* Companies Indication of first in- drug
name action** first launch disease?
launch class? status?
Agios
Isocitrate
Pharmaceuticals/ Acute myelogenous
ivosidenib Tibsovo dehydrogenase 1 USA August Y Y Y
CStone leukaemia
inhibitor
Pharmaceuticals
Hereditary
lanadelumab Takhzyro Dyax Kallikrein inhibitor USA August N Y Y
angioedema
Array BioPharma/ Solid tumours that
TrkA tyrosine
larotrectinib Vitrakvi Loxo Oncology/ have a NTRK gene USA December Y Y N
kinase inhibitor
Bayer fusion
Hypotension in
La Jolla Angiotensin II
LJPC-501 Giapreza septic or other USA March N N N
Pharmaceutical agonist
distributive shock
Anaplastic
Non-small cell lung lymphoma/ROS
lorlatinib Lorbrena Pfizer USA November N N Y
cancer receptor tyrosine
kinase inhibitor
moxetumomab Protein synthesis
Lumoxiti AstraZeneca Hairy cell leukemia USA December N Y Y
pasudotox antagonist
Adrenergic
transmitter uptake
Aerie
netarsudil Rhopressa Glaucoma inhibitor; Rho- USA April Y N N
Pharmaceuticals
associated kinase
2 inhibitor**
omidenepag Ube Industries/ Prostaglandin EP2
Eybelis Glaucoma Japan November N N N
isopropyl Santen receptor agonist
Transthyretin-
Transthyretin
patisiran Onpattro Alnylam related hereditary USA September N Y Y
inhibitor
amyloidosis
Phenylalanine
Hyperphenylala-
pegvaliase Palynziq BioMarin ammonia lyase USA July Y Y Y
ninemia
stimulant
Peroxisome
proliferator-
pemafibrate Parmodia Kowa Hyperlipidaemia Japan June N N N
activated receptor
alpha agonist
pertussis
acellular BioNet-Asia/DBV Pertussis infection
Viaskin PT Immunostimulant Thailand December N N N
vaccine, BioNet- Technologies prophylaxis
Asia
Ionis Protein 30S
Complicated urinary
plazomicin Zemdri Pharmaceuticals/ ribosomal subunit USA July N N N
tract infection
Achaogen inhibitor
Polyinosinic- Advanced solid
polycytidylic tumours, including
Yisheng Toll-like receptor 3
acid/inactivated Yivyka lung, breast, liver, Cambodia August Y N N
Biopharma agonist
virus, Yisheng colorectal and
Biopharma stomach
8 / March 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)Month First- Orphan
Trade Mechanism of Country of Rare
Drug name* Companies Indication of first in- drug
name action** first launch disease?
launch class? status?
EGFR/Erb-B2
pyrotinib Jiangsu Hengrui
SHR-1258 Breast cancer tyrosine kinase China August N N N
dimaleate Medicine
inhibitor
quadrivalent
inactivated
polymer-subunit Grippol Influenza infection
Petrovax Immunostimulant Russia September N N N
influenza Quadri prophylaxis
vaccine,
Petrovax
Theravance/ Chronic obstructive Muscarinic M3
revefenacin Yupelri USA December N N N
Mylan pulmonary disease antagonist
Glucagon-like
semaglutide Ozempic Novo Nordisk Type 2 diabetes peptide 1 receptor USA February N N N
agonist
sodium
Potassium Nordic
zirconium Lokelma AstraZeneca Hyperkalaemia December N N N
antagonist countries
cyclosilicate
ADP ribose
talazoparib Talzenna Medivation Breast cancer polymerase 1/2 USA October N N N
inhibitor
Merck & Co./
Sun Pharma Interleukin 23
tildrakizumab Ilumya Psoriasis USA October N N N
Advanced antagonist
Research
ALK-Abello/ Seasonal allergic
TO-206 Cedarcure Desensitizer Japan June N N N
Japan Tobacco rhinitis
Pheochromocytoma
ultratrace
or paraganglioma
iobenguane I Azedra Molecular Insight DNA inhibitor USA September N Y Y
neuroendocrine
131
tumours
umbilical cord
mesenchymal Heart failure and
Cellistem Cells for Cells Not applicable Chile July N N N
stem cells, Cells osteoarthritis
for Cells
Alpha
velmanase alfa Lamzede Chiesi Alpha-mannosidosis mannosidase II EU June Y Y Y
stimulant
Beta 3
Merck & Co./
vibegron Beova Overactive bladder adrenoreceptor Japan November N N N
Kyorin/Kissei
agonist
Spark Leber's congenital
voretigene
Luxturna Therapeutics/ amaurosis and RPE65 stimulant USA May Y Y Y
neparvovec
Novartis retinitis pigmentosa
* NAS in a combination drug
** Novel mechanism
Some timings are approximate
Source: Pharmaprojects®, March 2019
© Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) March 2019 / 9Which pharma teams brought home the most monoclonal antibody drug Ilumya (tildrakizumab)
silverware? Table 2 lists the top companies by and Beova (vibegron) for overactive bladder,
number of NAS launches for all of the Top 10 developed in partnership with Asian companies,
companies, plus any other companies which were India’s Sun Pharma Advanced Research and Japan’s
involved in the introduction of more than one Kyorin and Kissei, respectively.
therapeutic. This shows that Pfizer and Merck &
Co tied to win the championship, being the only Also celebrating a victory lap, although only with
companies to deliver four new drugs to the market two scores each, were Eli Lilly, AstraZeneca, Novartis
during the calendar year. Pfizer probably wins and Sanofi. However, last year, unlike in 2017,
in a photo finish by virtue of having originated not all the Top 10 pharma companies took the
and developed three of its novel NASs by itself: chequered flag, with GlaxoSmithKline having failed
Daurismo (glasdegib), Lorbrena (lorlatinib) and to get anything over the line. And whereas the Top
Vizimpro (dacomitinib), all for cancers. Its one 10 pharma companies brought 21 NASs to market
collaboration was with Merck, on the antidiabetic in 2017, that figure fell to 19 in 2018. So, just as
Steglatro (ertugliflozin). Interestingly, all of Merck’s we saw that the Top 10 pharma companies are
four drug launches were developed through such contributing a smaller percentage of pipeline drugs,
collaborations, with two of these, the psoriasis last year they delivered fewer successes too.
Table 2: Top company NAS launch performance, 2018
Company Number of NAS launches 2018 Position by pipeline size
Pfizer 4 9
Merck & Co 4 8
Eli Lilly 2 10
AstraZeneca 2 4
Novartis 2 1
Sanofi 2 5
Roche 1 6
Johnson & Johnson 1 3
Takeda 1 2
GlaxoSmithKline 0 7
Array 3 153
Portola Pharmaceuticals 2 1,342
Mylan 2 52
Kyowa Hakko Kirin 2 46
Ionis 2 34
Ligand 2 22
Source: Pharmaprojects®, March 2019
10 / March 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)Of the six non-Top 10 companies who launched of the NASs by the therapeutic area of their
more than one NAS, Array BioPharma had an launched indication. Figure 2 shows that last year,
incredible year, producing three new drugs despite anti-infectives drew with anticancers as the pre-
only ranking at number 153 by pipeline size. Lowly eminent groups, with totals of 17 each, although
Portola Pharmaceuticals had the best strike rate, the anti-infective figure is, as in the preceding year,
with two launches out of a pipeline of four (it also bolstered by seven vaccines. It’s still another good
has two drugs in Phase II trials). The other teams result for this class though, with antivirals again
outperforming in the style of giant killers were the having significant success. These included four
more mid-table Ligand Pharmaceuticals, Ionis, new HIV therapies, one for hepatitis C, and a rare
Kyowa Hakko Kirin, and Mylan. anti-influenza therapeutic. That leaves four new
antibacterials, the best result for this category seen
Let’s move to see which disciplines pharma had the in years.
most success in during 2018, with an examination
Figure 2: 2018 NAS launches by therapeutic group
3 2 Alimentary/Metabolic
8
Blood & Clotting
6
Cardiovascular
5
1 Dermatological
Genitourinary
4 Hormonal
1 Immunological
2 Anti-infective
17 1 Anticancer
2
Musculoskeletal
Neurological
Respiratory
17 Sensory
Source: Pharmaprojects®, March 2019
© Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) March 2019 / 11Anticancers had an equally successful year in 2018 antibody-drug conjugate apiece. Notable in its
compared with the previous 12 months. However, absence this year was any further trophies for CAR-T
this category delivered just 24.2% of the new drugs cell therapeutics.
in 2018, despite accounting for 35.2% of the R&D
pipeline. Nonetheless, as we’ll see later, it’s here that Choice of venue in sports is usually a hotly
the highest level of innovation resides. contended, and sometimes contentious, issue.
The decision to host the next football World Cup in
The therapeutic area with the second biggest 2022 in Qatar raised a few eyebrows, not only due
pipeline, neurologicals, had a much better result in to extreme heat there, but also amid controversies
2018 than in the previous year. Its six new drugs surrounding alleged corruption. As with pharma,
relight an Olympic torch that had been threatening it’s all about where the money is. And in the drug
to go out. Three of these were the new calcitonin industry, that means the US. Figure 3 shows that,
gene-related inhibitors for migraine prophylaxis, despite increasing internationalization, the drug
but there were also notable successes in epilepsy industry primarily launches its new drugs in the
and amyloidosis. Overall, there was a much better world’s biggest market. In 2018, 41 of the 68 NASs
therapeutic spread of NAS launches last year, with made their debut in the US: that’s a whopping 60%,
winners in every therapeutic area except the very although slightly down on the 63% seen in 2017.
smallest, antiparasitics. This is on the back of a record-breaking year in
approving drugs for the FDA, although it’s notable
In terms of the types of drugs brought to the that 2019 has started badly with the longest
market, biological drugs accounted for 24 (35%) of government shutdown in history running on into
the launches, down from 44% in the previous year, most of January. Japan again came in second in
and falling below their share of the pipeline (39.7%). 2018, but this time doubled the number of first
This breaks down into 10 monoclonal antibodies, launches there to eight from four the previous year.
four vaccines, three recombinant proteins, two cell Equal third (with Germany) this year is China, which
therapies, two gene therapies, and one antisense is now matching its burgeoning R&D field with a
oligonucleotide, RNA interference agent, and genuine presence as a first market to launch in.
Figure 3: 2018 NAS launches by country/region
1 111
4
1 Australia Netherlands
1
Austria New Zealand
4
Cambodia Nordic countries
1 Chile Norway
China Russia
41
8 EU S Korea
Finland Spain
1 Germany Thailand
1 Italy UK
1
1
1 Japan USA
2
1
11
Source: Pharmaprojects®, March 2019
12 / March 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)Pharma has for some time now been pursuing rare to around one in every 1,600 people). Meanwhile,
diseases with the vigour of a greyhound chasing over a third of the new drugs launched had orphan
the toy rabbit. Last year, just over a quarter of all drug designation for the disease which they were
NAS launches were indicated for a rare disease, launched for – a very significant proportion, and very
defined as a disease with a prevalence of less than slightly up on the previous year’s percentage. Figure
one in every 2,000 people in the EU, or affecting 4 has the details.
fewer than 200,000 people in the US (equivalent
Figure 4: Percentage of NAS launches with an orphan drug designation, 2012–18
60
52.2
50
% with orphan drug status (ODS)
40
36.1 37.0 36.8
35.2
30
27.5 27.1
20
10
0
2012 2013 2014 2015 2016 2017 2018
*2016–18 figures refer only to drugs with orphan drug status for their marketed indication in their marketed country.
Source: Pharmaprojects®, March 2019
© Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) March 2019 / 13The Novel NASs of 2018
Pharma scores a number of notable firsts, but the innovation run rate slows
Novelty in sport is a tough thing to achieve, but Beginning in cancer, we find that its innovative
those who find a way can often change the course drugs all come from somewhat obscure, specialist
of their chosen game. The infamous ‘bodyline’ companies. Generating a Mexican wave of
Ashes cricket series of 1932–33, where the English excitement in the crowd is Array BioPharma and
team deliberately bowled at the bodies of the Loxo Oncology’s Vitrakvi (larotrectinib). Not only is
Australian batsmen, changed a once ‘gentlemanly’ this drug the first TrkA tyrosine kinase inhibitor to
sport into the competitive event we see today, hit the market, it’s been approved for use in solid
and more recently the T20 form of the sport has tumours that have a neurotrophic receptor tyrosine
seen entirely new, innovative strokes, such as the kinase (NTRK) gene fusion. In other words, it’s tissue-
paddle sweep, come to the fore. In baseball, the agnostic – rather than being approved for use in a
Oakland A’s ground-breaking analytical approach particular tissue type, such as breast or prostate, it’s
to player evaluation, as immortalized in the book licensed for use in any solid tumour containing that
and later film Moneyball, changed the sport forever. particular oncogenic activating mutation. This is a
And innovation is right at the heart of the sport of new way of looking at approving cancer drugs, and
Formula 1 motor racing, although arguably it’s more Vitrakvi will surely be the first of many. Eli Lilly was
about technological advances in the cars these days so excited by Loxo that it is buying the company,
than it is about the drivers’ abilities. although Bayer got in first on Vitrakvi, exercising its
option to acquire full rights. The drug has received
Innovation in drug R&D is probably even harder, numerous orphan drug designations, and also
but 2018 fared well. Based on the strict definition benefitted from breakthrough therapy designation in
of novelty as being the first time a drug with a the US.
particular mechanism of action hits the market,
2018 produced 15 novel NASs, up from 14 in Tibsovo (ivosidenib) has been developed by US-
2017 (although two drugs in 2018 had two novel based Agios Pharmaceuticals and its licensee, the
mechanisms, ensuring that the new mode of action Chinese concern CStone Pharmaceuticals, and is
count was slightly higher). This also doesn’t take into the first isocitrate dehydrogenase 1 inhibitor to
account two newly marketed cell therapies, which hit the market. It follows on the back of the 2017
by definition don’t have a specific pharmacological first-in-class isocitrate dehydrogenase 2 inhibitor
action. However, given that there were more drug IDHIFA (enasidenib), also from Agios. Both drugs
launches, there is less novelty in our team of new were launched for acute myelogenous leukaemia,
drugs this time around. Adding in the cell therapies a rare and aggressive cancer that also saw Pfizer’s
gives an innovative drug percentage of 25.0% last Daurismo (glasdegib) and Kotobuki/Astellas’s
year, compared with 29.6% in 2017. With only a Xospata (gilteritinib) added to its armoury last year.
limited supply of rookie players, pharma fell back
on some of the old warhorses and stalwarts of the The final US-launched novel cancer therapy is
squad. Verastem Oncology’s Copiktra (duvelisib). This is a
dual-acting PI3 kinase delta and gamma inhibitor,
The therapeutic area breakdown for novel and it’s the first time a drug targeting the gamma
NASs is as follows: four anticancers, four in receptor subtype has scored a goal. It was approved
alimentary/metabolic, two each for anti-infectives, for relapsed or refractory chronic lymphocytic
ophthalmologicals, and blood and clotting products, leukaemia, small lymphocytic lymphoma and
and one for neurologicals. Additionally, we have one follicular lymphoma, and benefitted from US
cell therapy in Crohn’s disease and another for heart orphan drug status and various expedited approval
failure and rheumatoid arthritis. In this section, designations.
we’ll take a look at each of these novel agents,
and highlight a few of the other more interesting Our other novel NAS in oncology is something a little
potential big hitters among the 2018 NASs. different. Chinese company Yisheng Biopharma’s
14 / March 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)Yivyka puts together an inactivated purified rabies Chiesi brought us Lamzede (velmanase alfa), which
virus with the firm’s proprietary double-stranded is alpha mannosidase II, while BioMarin’s Palynziq
RNA-based toll-like receptor 3 (TLR-3) agonist (pegvaliase) is a pegylated phenylalanine ammonia
adjuvant technology, PIKA. This immuno-oncological lyase. Unsurprisingly, both agents complete the hat-
approach induces antitumour cytokines, activates trick of being novel, for rare diseases, and receiving
NK cells, suppresses regulatory T-cells and regulates orphan drug status. As is often the case with such
macrophage polarization. It debuted for the agents, neither drug comes cheap – Palynziq’s
treatment of advanced solid tumours, including annual cost is estimated at a quarter of a million
lung, breast, liver, colorectal and stomach cancers, dollars per year, while Lamzede was rejected by the
in a somewhat unusual market – Cambodia. There UK’s health technology assessment agency, NICE,
are plans for Western development too, and orphan on the grounds of it not being cost-effective.
drug status in the US has already been granted
in both hepatocellular carcinoma and pancreatic Another somewhat niche, but no less important,
cancer. drug is the first of our two novel anti-infectives.
The HIV/AIDS market is now well served with an
The four novel NASs in the alimentary/metabolic array of reverse transcriptase inhibitors, protease
arena aren’t coming from any of the recognized inhibitors and integrase inhibitors, but there are
Big Pharma squad either. A collaboration between still some patients for whom therapy fails. Growing
Japan’s Kyowa Hakko Kirin and the emerging viral resistance to established classes of drugs,
Californian concern Ultragenyx delivered Crysvita exacerbated by poor compliance, means that even
(burosumab), whose novel mechanism of action is in 2019, lives are being lost to AIDS. That’s why
inhibiting fibroblast growth factor 23. The US was Theratechnologies’ Trogarzo (ibalizumab) is so
again the first market here, where it was approved important. It’s the first in a new class of drugs which
for the rare disease X-linked hypophosphatemia in inhibit the CD4/GP120env interaction, preventing
both adult and paediatric patients aged one year viral entry. It’s also, unusually for an HIV therapy, a
or older. It has subsequently gone on to the market monoclonal antibody, and therefore injectable. As
in Germany and the Netherlands, following EU such, this drug will be used as a ‘rescue therapy’, for
approval. The monoclonal antibody is not only the that small group of patients who are experiencing
first-to-market with this mechanism, it’s the only treatment failure. This might be a small population,
drug on the entire Pharmaprojects database which but for these individuals this drug is going to be a
we report to work in this way. lifesaver.
Also emanating from Japan was Ajinomoto, But it was another virus, influenza, which killed
Mochida and EA Pharma’s rather charmingly named the most people in the 20th century. We have just
Goofice (elobixibat), for chronic constipation. This marked 100 years since the most deadly single
drug has a dual mechanism of action, being an infectious disease event known in history – the
ileal bile acid transport inhibitor and sodium/bile Spanish flu pandemic. At least 40 million, and likely
acid cotransporter inhibitor, with neither of these closer to 100 million, deaths worldwide have been
activities having been found in a marketed drug attributed to the virus, most of them occurring
before. The former protein absorbs bile acids from in the 16-week period between September and
the intestinal lumen, bile duct and the kidney, while December 1918. Influenza can still kill today, and
the latter is a liver bile acid transporter. Bile acids direct antiviral drugs can be useful if the disease is
can function as natural laxatives, and can influence caught early enough. Most of the launched drugs
colon motor activity, either by affecting colon fall into the category of neuraminidase inhibitors,
secretion or via a prokinetic effect. It was one of the but Shionogi and Roche have collaborated to bring
eight new molecules to debut in Japan during the Xofluza (baloxavir marboxil) to the market, first in
year, and was developed there under licence from Japan and then subsequently in the US. It inhibits
its originator, AstraZeneca spin-out Albireo Pharma. the CAP-dependent endonuclease, and as such is
the first endonuclease inhibitor to be successfully
Enzyme replacement therapies are often the developed.
source of novel mechanisms, and last year was
no exception, with two stepping up to the plate. Moving to ophthalmology, in last year’s report, we
© Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) March 2019 / 15noted as highly significant the approval of Spark here, as it has the distinct advantage of both
Therapeutics and Novartis’s Luxturna (voretigene quarterly and monthly dosage forms.
neparvovec). This became the first ever US-approved
in vivo gene therapy, targeting patients with the While that concludes our round-up of drugs winning
ophthalmological genetic disorder of confirmed their new MOA-based races, there are a few other
biallelic RPE65 mutation-associated retinal elite athletes which deserve a mention. In the cell
dystrophy. However, it wasn’t until May 2018 that therapy arena, TiGenix and Takeda collaborated
the drug finally hit the market, at an – if you pardon to deliver Alofisel (darvadstrocel), an expanded
the pun – eye-watering price of $425,000 per eye, allogenic adipose-derived adult stem cell therapy
or $850,000 per patient, and thus it comes under which was approved for the treatment of complex
our current set of novel NASs. As a one-off cure, perianal fistulae in Crohn’s disease patients. The
that price is probably justifiable, but the companies other cell therapy launched was Chilean company
are going to have to box clever to come up with Cells for Cells’ Cellistem, another allogeneic
strategies for its funding in non-first world countries. expanded therapy, here using umbilical cord stem
cells delivered intravenously to treat heart failure
The other new ophthalmological first-in-classer and osteoarthritis.
arrives for the rather more prosaic disease of
glaucoma. Aerie Pharmaceuticals delivered Of the other non-novel MOA NASs, there are a
Rhopressa (netarsudil), which adds the novel Rho- few other stand-outs in the rare disease squad.
associated kinase 2 inhibitor activity to the ways Two drugs were launched for transthyretin-
to treat this common condition. The drug was related hereditary amyloidosis; Ionis and Akcea’s
launched in the US in April, and is currently being Tegsedi (inotersen) was another rare success for
looked at in the EU, where a decision is expected in an antisense therapeutic, while, more excitingly,
the second half of this year. Alnylam weighed in with Onpattro (patisiran).
This became the first RNA interference drug to be
There were two novel launches for the different successfully brought to the market. Pharmaprojects
forms of thrombocytopenic purpura, thrombotic reports 533 such drugs in total – this initially
and idiopathic. For the former, Ablynx produced the promising strategy has seen many casualties leaving
Factor VIII inhibitor Cablivi (caplacizumab). As the the pitch on a stretcher, so it’s good to see a drug of
name suggests, it’s another monoclonal antibody, this type finally hitting the back of the net.
and in fact is a more specialized ‘nanobody’.
Nanobodies are the smallest fragment of naturally Another drug of interest for orphan diseases is
occurring single-domain antibodies which are fully Epidiolex, GW Pharmaceuticals’ therapy for seizures
functional in the absence of a light chain. Being associated with the rare forms of epilepsy, Dravet
smaller than MAbs, they can penetrate target syndrome and Lennox-Gastaut syndrome. It’s
tissues more effectively. The idiopathic treatment is significant not only as it’s for these niche indications,
Tavalisse (fostamatinib disodium), from Rigel, which but also because it’s the first time a cannabinoid has
is the first example of a Syk tyrosine kinase inhibitor been approved for therapeutic use in the US.
to reach the market (the drug also hits Flt-3).
Finally, three drugs for rare cancers can’t pass
Last but not least is our single CNS success, although without comment, as success here can be as
in fact there were three drugs launched with the lucrative as a sports sponsorship deal. Showing us
same mechanism here. We’re talking about the the money here we have Kotobuki and Astellas’s
new calcitonin gene-related peptide inhibitors Xospata (gilteritinib) for relapsed or refractory
for migraine prophylaxis, which were racing to be acute myeloid leukaemia, AstraZeneca’s Lumoxiti
first-to-market in 2018. Breasting the tape and (moxetumomab pasudotox) for hairy cell leukaemia,
getting gold was Amgen and Novartis’s Aimovig and Molecular Insight’s Azedra (ultratrace
(erenumab), which made it across the line in the iobenguane I 131) for the ultrarare neuroendocrine
US in July. Hot on its heels in the autumn were Eli tumours, pheochromocytoma and paraganglioma.
Lilly’s Emgality (galcanezumab) and Teva’s Ajovy This completes a formidable year of additions to
(fremanezumab). The latter may have come in third, pharma’s very own Hall of Fame.
but there may be an element of hare and tortoise
16 / March 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)Lap of Honour for Pharma as it Enjoys the Applause for a
Record-Breaking Year
But will this be the peak of its performance?
At the conclusion of a championship season, every drugs is going to be the key, and further pushback
sports team, no matter how successful, has to could endanger the prospects of such projects being
rebuild and start from scratch again. Has 2019 pursued. More uncertainty comes with the imminent
got off to a bad start thanks to the prolonged US and unexpected departure of FDA Commissioner
government shutdown which impacted the FDA Scott Gottlieb. Gottlieb was generally considered
through most of January? Nielsen Hobbs, executive to have successfully walked the tightrope between
editor for regulation and policy at Informa’s Insight being pro-industry but pushing forward the pricing
publication Pink Sheet, thinks maybe not, although debate in a way which also satisfied President
2018’s record may be hard to break. “I don’t Trump’s populist tendencies towards Big Pharma-
think the shutdown will impact things much,” he bashing. He might prove a tough act to follow –
says. “Reviews of existing products continued with pharma stocks took a dive after his announcement
carryover funds (though they were close to running due to fears about who might replace him.
out by the end), and it doesn’t seem as though too
many new applications were held up from filing Might 2018’s record-breaking 68 NASs prove hard
because of the closure. It’s hard to break records to beat then? The record almost certainly won’t
every year, and approvals have been limited so far stand as long as what is reckoned to be the longest-
in 2019, though the agency has about the same standing world record in sports, that of Frances
number of applications under review as it did this Keddie, who was a student at the University of
time last year, so it would be possible to set another California, Berkeley, when she set a triple jump
record. I just think it unlikely given the laws of mark of 11.83 metres on 2 December 1926. That
averages.” In addition to this, the relocation of the record was not broken until 9 May 1981 – 55 years
EMA to Amsterdam due to Brexit has also disturbed later! But despite the pressures described above,
the work of drug approval in Europe. Politics sure pharma is more likely to behave like a sport such as
isn’t helping things here. swimming, where world records are more regularly
beaten. Even if 2019 isn’t another world-beater,
Speaking of Brexit (which is pretty much all everyone this year’s Figure 1 I think gives us a certain degree
in the UK is currently doing), at the time of writing, of confidence that the underlying trend is currently
all options are on the table: Theresa May’s deal, no firmly on the up.
deal, a delay to departure or a second referendum.
When a sports team has one of its star players sent But as any successful sports team coach will tell you,
off, it often adversely affects the cohesiveness of the complacency is the enemy of success. “Complacency
team and can lead to it conceding points, goals or is a disease,” Sir Alex Ferguson, one of the most
tries to the opposition. Many feel that it’s inevitable successful UK football managers of all time, has
that both the UK and EU will be weaker apart, and been quoted as saying. “Two-nil at half time is a
that there is potential for the effects to ripple across dangerous game; you can’t give an inch.” And the
world economies. So far, UK pharma appears to industry needs not just bums on seats (quantity),
be unfazed, with little sign of shifting resources but also an exciting match to watch (quality). We
overseas, but it’s very early days as yet. saw more of the former than the latter last year,
and in pharma as in sports, it is the right mixture of
Further pricing pressures could hold back success skill and innovation which is ultimately going to drive
too. Just as professional athletes’ salaries seem success. A steady flow of NASs with novelty is what’s
almost incomprehensible to the average worker, really needed.
some of the costs of innovative, niche drugs for rare
diseases tend to bring many outside the industry As any sports psychologist will tell you, positivity
out in more of a sweat than the average workout is also paramount. So, let’s end by looking at
does. Finding ways to pay for such undeniably useful some of the exciting drugs which the new 2019
© Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) March 2019 / 17season is likely to bring. Of seven confirmed IL-3 recombinantly fused to truncated diphtheria
2019 NAS launches so far, we’ve seen three toxin; Daiichi Sankyo’s Tarlige (mirogabalin) for
monoclonal antibodies, one apiece for non- peripheral neuropathic pain; and Johnson &
Hodgkin’s lymphoma, osteoporosis and paroxysmal Johnson’s esketamine for treatment-resistant
nocturnal haemoglobinuria, in the form of Innovent depression. There’s also a new gene therapy,
and Eli Lilly’s Tyvyt (sintilimab), UCB, Amgen and AnGes’s Collategene (beperminogene perplasmid),
Astellas’s Evenity (romosozumab), and Alexion’s which expresses hepatocyte growth factor to treat
Ultomiris (ravulizumab), respectively. Drugs which critical limb ischaemia.
are already approved and expected to launch this
year include Elzonris (tagraxofusp) from Stemline Some of the more promising prospects passing
Therapeutics for blastic plasmacytoid dendritic cell through pharma’s youth academy and expected to
neoplasm, which is a targeted therapy of human gain approval this year are summarized in Table 3.
Table 3: Important approvals expected in 2019
Drug Company Indication Notes
brolucizumab Novartis Wet AMD Once q 12wk dosing
givosiran Alnylam Acute hepatic porphyria RNAi therapeutic
Community-acquired
lefamulin Nabriva Oral/IV antibacterial
pneumonia
LentiGlobin Bluebird Bio ß-thalassemia ß-globin gene therapy
Diffuse large B-cell
lisocabtagene maraleucel Juno/Celgene CAR-T therapy
lymphoma
onasemnogene
Novartis Spinal muscular atrophy Gene therapy
abeparvovec
selinexor Karyopharm Multiple myeloma First XPO1 inhibitor
tenapanor Ardelyx IBS with constipation First NH3E inhibitor
Source: Pharmaprojects®, March 2019
18 / March 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.)So, even as the class of 2018 completes its victory better comes along. This is part of what makes both lap after an undeniably champion year, it must be sport and pharma so utterly riveting. And in both, looking over its shoulder at the young guns coming you are only as good as your last win. Predicting through. Pharma, like sport, thrives via renewal. the next season’s results is never going to be a sure Even the most robust of sports stars, such as US thing. Rest assured, however: Pharmaprojects has boxer Bernard Hopkins, who won the WBA light all the match stats and the inside track, and we’ll heavyweight title aged 49, knows that their time is be back again to commentate on the next year’s limited, just as pharmaceuticals have to make their exciting games and highlights. money before their patent runs out or something About the Author Ian Lloyd Senior Director, Pharmaprojects & Data Integration Ian Lloyd is the Senior Director of Pharmaprojects and Data Integration, overseeing the content and analyst services for our drug development solution. He supports clients in their drug pipeline data requirements and inquiries, providing insight into the best search strategies to answer their drug-related business questions and also identifying and analyzing trends in pharma R&D. For over 25 years, he has authored the “Pharma Annual R&D review” and its new active substances (NAS) launches supplement. This has become a must-have industry report for those seeking to identify the changing fortunes of drug R&D. Ian joined Pharmaprojects in 1987, when it was part of PJB Publications. It was acquired by Informa in 2003. He previously worked in molecular biology as a research assistant at the University of Bristol. © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) March 2019 / 19
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