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Rare disease therapies head the ‘class of 2015’

Last year’s approvals included a number of first-in-class compounds
NME approvals

In 2015, a total of 44 New Molecular Entities (NMEs) were approved for marketing in countries around the world, maintaining the high output from pharma industry pipelines of the last few years.

While a little shy of the 2014 tally of 49 NMEs - the highest level for almost 20 years - last year's collection (see table) includes a similarly impressive array of new drugs, including a number of first-in-class compounds and therapies for rare diseases.

By PME's reckoning, 17 (39%) of the 44 NMEs approved in 2015 worked in a new way to prior therapies, continuing the recent trend towards the development of innovative therapies and moving away from the clusters of 'me too' drugs that was often seen in NME lists from the 1990s and 2000s.

There was also once again a preponderance of drugs for 'orphan' or rare diseases, which have become increasingly popular targets for the pharma industry as they can command high prices, despite having small patient populations. All told, 19 NMEs were in this category, accounting for 43% of the total for the year.

Interestingly however, some of the notable first-in-class therapies are for diseases that affect millions of people worldwide, and as a result have blockbuster sales potential. 

One class - the PCSK9 inhibitors for elevated cholesterol - actually saw two new entrants, namely Regeneron/Sanofi's Praluent (alirocumab) and Amgen's Repatha (evolocumab), which became the first new cholesterol therapies to enter the market in more than a decade.

Indicated for use in patients who cannot meet treatment targets with statins (as well as for a rare, genetic form of elevated cholesterol), the two drugs are predicted to eventually achieve sales of several billion dollars a year as an estimated two-thirds of people with elevated cholesterol fall into this category.

2015 also saw the first completely new class of drug for chronic heart failure for many years with the approval of Novartis' Entresto, which combined the established angiotensin II receptor antagonist valsartan with sacubitril, the first in a new class of neprilysin inhibitors. Also tipped as a blockbuster, Entresto has been shown in trials to reduce the risk of cardiovascular death and hospitalisations in CHF patients, improving survival by around 15% compared to current therapies.

Man of the new NMEs in 2015 were for rare and orphan diseases that promise to make a massive impact for the patients involved

GlaxoSmithKline (GSK) also scored a big new approval in the form of Nucala (mepolizumab), the first in a new class of asthma medications that work by inhibiting interleukin-5. It will be used as an add-on therapy for the sizeable proportion of eosinophilic asthma patients who experience breakthrough attacks despite current treatment.

Many of the new NMEs in 2015 were for rare and orphan diseases that promise to make a massive impact for the patients involved as they often have few or no drugs available to treat their conditions.

Highlights of the year include a brace of approvals for Alexion. These were Kanuma (sebelipase alfa), the first-ever treatment for the rare, inherited disorder lysosomal acid lipase deficiency - and Strensiq (asfotase alfa), the first enzyme replacement therapy for patients with infantile- and juvenile-onset hypophosphatasia, a serious and sometimes fatal bone disease.

There was also good news for patients with hereditary orotic aciduria (HOA) - a condition that can result in blood abnormalities, urinary tract obstruction, failure to thrive and developmental delays - who finally have a treatment option in the form of Wellstat Therapeutics' Xuriden (uridine triacetate).

While not working via new molecular pathways, two other drugs are also worthy of mention. Kythera Biopharma created a new therapeutic category in the pharma/cosmetic area with Kybella (deoxycholic acid), the first drug for reducing double chin, while Sprout Pharma chalked up the first approval for 'female Viagra' after the FDA backed Addyi (flibanserin) for hypoactive sexual desire disorder in women.

A product in a new class of cancer therapies that harness the power of viruses also debuted in 2015

Looking at the approvals by therapeutic category, the largest grouping was for new oncology drugs, which account for 13 (around 30%) of the 2015 crop of NMEs, with no fewer than four new therapies for multiple myeloma. The four are Genmab/Johnson & Johnson's Darzalex (daratumumab), AbbVie/Bristol-Myers Squibb's Empliciti (elotuzumab), Takeda's Ninlaro (ixazomib) and Novartis' Farydak (panobinostat), the first HDAC inhibitor to be approved for myeloma.

Among the other notable new cancer drugs is Pfizer's Ibrance (palbociclib), first-in-class cyclin-dependent kinase (CDK) 4 and 6 inhibitor, a new candidate for oestrogen receptor-positive/HER2-negative breast cancer. Around 60% of breast cancer patients have this receptor profile - which is poorly addressed by current therapies - and could be eligible for treatment with the new drug.

A product in a new class of cancer therapies that harness the cell-killing power of viruses also debuted in 2015 in the form of Amgen's Imlygic (talimogene laherparepvec), the first oncolytic virus therapy to be registered in the US.

Imlygic is a genetically modified live herpes virus used to treat melanoma lesions that cannot be removed completely by surgery, and works by replicating inside cancer cells, causing them to rupture and die. It is not the first oncolytic virus to be approved worldwide however - that distinction goes to Rigvir, a therapy for melanoma that was registered in Latvia in 2004.

The tally of cancer drugs was well ahead of cardiovascular and cholesterol therapies (six NMEs), central nervous system (CNS) therapies (four) and antidiabetic agents (three), and in general the spread of indications is very broad, perhaps to be expected given the high preponderance of orphan diseases. Notably, after a flurry of activity last year. antimicrobials had something of a lean year - disappointing given the ongoing concerns about drug resistance.

31 of the 44 NMEs approved during 2015 were given the nod by the US [FDA] regulator first

Countries and companies
Once again, the importance of the US market was underscored by the sheer number of drugs that were first approved by the US FDA. All told, 31 of the 44 NMEs approved during 2015 were given the nod by the US regulator first, with just five cleared in Japan and four in the EU.

One contributory factor could be the FDA's efforts to accelerate the review times for new medicines in order to get them to patients more quickly. For example, the number of approvals for drugs designated as 'breakthrough' therapies by the FDA - and therefore qualifying for expedited review - was eight, exactly in line with 2014.

Around half were granted a priority review by the FDA, with nearly two-thirds making use of expedited review processes (ie breakthrough, priority review accelerated approval or fast-track).

The NMEs were split between 40 companies - with only a few drugmakers managing to bring more than one new drug to market in 2015. Leading the pack on this measure were Novartis and Takeda - with three new approvals - while Amgen, AstraZeneca, Alexion, Allergan and Otsuka each managed two apiece.





alirocumabPraluenthypercholesterolaemiaPCSK9 inhibitorRegeneron/SanofiUSA
aripiprazole lauroxilAristadaschizophreniaatypical antipsychotic (D2 partial agonist)AlkermesUSA
asfotase alfaStrensiqhypophosphatasiaalkaline phosphatase replacementAlexionJapan
avibactamAvycazbacterial infections (with ceftazidime)beta-lactamase inhibitorAllerganUSA
brexpiprazoleRexultidepression/schizophreniaserotonin 5-HT1a / dopamine D2 partial agonistOtsuka/LundbeckUSA
cangrelorKengrexalpercutaneous coronary intervention (PCI)P2Y12 inhibitorThe Medicines CompanyEU
cariprazineVraylarschizophrenia / bipolar disorderdopamine D3/D2 receptor partial agonistGedeon Richter/AllerganUSA
cholic acidCholbambile acid synthesis disorderscholic acid replacement therapyRetrophinUSA
cobimetinibCotellicBRAF V600-positive malignant melanomaMEK inhibitorRoche/ExelixisSwitzerland
daratumumabDarzalexmultiple myelomaanti-cd38 antibodyGenmab/Janssen BiotechUSA
deoxycholic acidKybellasubmental contouring (double chin)destruction of fat cellsKythera BiopharmaUSA
dinutuximabUnituxinneuroblastomaanti-GD2 antibodyUnited TherapeuticsUSA
elotuzumabEmplicitimultiple myelomaanti-SLAMF7 antibodyAbbVie /  Bristol-Myers SquibbUSA
eluxadolineViberzidiarrhoea-predominant irritable bowel syndromemu opioid receptor agonist / sigma opioid receptor antagonistAllerganUSA
evogliptinSuganontype 2 diabetesonce-daily DPP-4 inhibitorDong-ASouth Korea
evolocumabRepathahypercholesterolaemiaPCSK9 inhibitorAmgenEU
flibanserinAddyihypoactive sexual desire disorderserotonin 5-HT1a agonist / 5-HT2a antagonistSprout PharmaceuticalsUSA
idarucizumabPraxbindPradaxa reversal agentanti-dabigatran antibodyBoehringer IngelheimUSA
isavuconazoleCresembaInvasive aspergillosis/mucomycosistriazole antifungalBasilea/AstellasUSA
ixazomibNinlaromultiple myelomaoral proteasome inhibitorTakedaUSA
lenvatinibLenvimathyroid cancermultikinase inhibitorEisaiUSA
lesinuradZurampicgoutxanthine oxidase inhibitorAstraZenecaUSA
lumacaftorOrkambicystic fibrosis (with ivancaftor)CFTR protein misfoldingVertex PharmaUSA
lusutrombopagMulpletathrombocytopenia in chronic liver diseaseoral thrombopoietin receptor agonistShionogiJapan
mepolizumabNucalasevere eosinophilic asthmaanti-interleukin-5 antibodyGlaxoSmithKlineUSA
necitumumabPortrazzanon-small cell lung cancerEGFR inhibitorAstraZenecaUSA
omarigliptinMarizevtype 2 diabetesonce-weekly DPP-4 inhibitorMerck & CoJapan
osimertinibTagrissonon-small cell lung cancerEGFR inhibitorAstraZenecaUSA
palbociclibIbranceER+/HER2- breast cancerCDK 4/6 inhibitorPfizerUSA
panobinostatFarydakmultiple myelomaHDAC inhibitorNovartisUSA
parathyroid hormone (recombinant)Natparahypocalcaemia in hypoparathyroidism
parathyroid hormone replacement
patiromerVeltassahyperkalaemiapotassium ion binderRelypsaUSA
rolapitantVarubichemotherapy-induced nausea and vomiting (CINV)neurokinin-1 receptor antagonistTesaroUSA
sacubitrilEntrestochronic heart failure (in combination with valsartan)neprilysin inhibitorNovartisUSA
safinamideXadagoParkinson's diseaseMAO-B inhibitorNewron PharmaEU
sebelipase alfaKanumalysosomal acid lipase deficiencyrecombinant lysosomal acid lipaseAlexionEU
selexipagUptravipulmonary arterial hypertensionIP prostacyclin  receptor agonistActelionUSA
sonidegibOdomzobasal cell carcinomaSMO receptor antagonistNovartisSwitzerland
talimogene laherparepvecImlygicmalignant melanomaoncolytic virusAmgenUSA
tenofovir alafenamideGenvoyaHIV (in combination with cobicistat, emtricitabine and elvitegravir)nucleotide reverse transcriptase inhibitorGilead SciencesUSA
trelagliptin succinateZafatektype 2 diabetesonce-weekly DPP-4 inhibitorTakedaJapan
uridine triacetateXuridenhereditary orotic aciduria (HOA)uridine prodrugWellstat TherapeuticsUSA
vonicog alfaVonvendivon Willebrand diseasevon Willebrand factor (recombinant)BaxaltaUSA
vonoprazan fumarateTakecabacid-related diseasespotassium-competitive acid blockerTakeda/OtsukaJapan
Source: PME Research

Article by
Phil Taylor

is a freelance journalist specialising in the pharmaceutical industry

8th March 2016

From: Regulatory



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