Cancer Drugs And Rare Diseases Top EU Approvals In 2015

• 46 new active substances approved
• First stem cell therapy
• First drug for mitochondrial dysfunction
• 12 new anticancers
• 16 drugs for rare diseases
• Five accelerated approvals
• Four conditional approvals
• Three exceptional circumstances approvals
• Second-highest number of CHMP recommendations

Oncology products again led the EU new drug approvals table in 2015, accounting for 12 of the 46 new active substances (NASs) that gained a marketing authorization from the European Commission. Cardiovasculars came second with six new drugs, and infectious diseases with five. In all, 90 new medicinal products were approved last year.

The figures are substantially up compared with 2014, which saw the approval of 80 new medicines including 34 NAS. Of the new drugs given the green light in 2015, a total of 16 (14 in 2014) were classified as orphan medicines for the treatment of rare diseases such as invasive aspergillosis, neuroblastoma and differentiated thyroid cancer.

Among the most notable advances last year were two landmark therapies for eye problems: Europe's first stem cell therapy, Chiesi's Holoclar, and Santhera's Raxone, the first treatment for a mitochondrial disease.

16 orphan drugs were approved, two more than in 2014, while four products were awarded conditional approvals and three were authorized under exceptional circumstances.

Novartis Europharm led the field in terms of NAS approvals, with a total of five (including three anticancers), followed by Amgen (four), Merck Sharp & Dohme (three) and Sanofi (three, including a Genzyme drug), then Boehringer Ingelheim, AbbVie and The Medicines Company (two each).

Several novel combinations of existing and/or new drugs passed muster, as did a range of marketed products with new uses and/or formulations for conditions like emphysema, weight management and severe keratitis.

About 20 generic medicines gained marketing authorization, including a range of oncology drugs.

Biosimilars, by contrast, fared very poorly, with no approvals at all in 2015. However, this area promises to show much greater activity in 2016, with Samsung Bioepis having gained an approval recommendation late last year for its version of Pfizer's Enbrel (etanercept), and 10 biosimilars now under evaluation at the European Medicines Agency.

Product assessment activity in general was high at the EMA, whose scientific committee, the CHMP, issued a total of 93 positive opinions in 2015, compared with 82 a year earlier. Of the 93, about a third were for anticancer medicines.

Judging by the recommendations delivered by the CHMP in the last few months of the year, approval can be expected shortly for the likes of AstraZeneca's lung cancer drug Tagrisso, Bioprojet Pharma's Wakix for narcolepsy, and Bayer's Kovaltry and Iblias for bleeding in hemophilia A (see below).

NAS approvals

As the first stem cell therapy to get the all clear in the EU, Chiesi's Holoclar was given a conditional approval for limbal stem cell deficiency due to ocular burns, a condition that affects about 3.3 out of 100,000 people in the EU and can eventually lead to blindness. It has both orphan drug status and advanced therapy designation.

Also in the ocular area, Santhera Pharmaceuticals' orphan drug Raxone (idebenone) became the first drug to be approved for Leber's hereditary optic neuropathy (LHON), a severe form of vision loss caused by mitochondrial dysfunction. The approval was granted under "exceptional circumstances" because of the severity of the disease and the lack of alternative treatment options, and is expected to spur further research in treating mitochondrial disease.

Two other new drugs were approved under exceptional circumstances. Obizur (susoctocog alfa), a NAS from Baxalta Innovations for bleeding episodes in patients with acquired hemophilia caused by antibodies to Factor VIII, had an orphan designation but this was removed at the time of approval because the company had not provided the necessary data to justify its "significant benefit". Alexion's Strensiq (asfotase alfa) was authorized as an orphan drug under exceptional circumstances for ERT in pediatric onset hypophosphatasia.

Marketing authorization under exceptional circumstances allows patients access to medicines that could not be approved under a standard authorization as comprehensive data cannot be obtained, either because the disease they target is too rare, the collection of complete information on the efficacy and safety of the medicine would be unethical, or there are gaps in the scientific knowledge.

Oncology

Oncology saw the approval of 12 new active substances. Three of the products were from Novartis Europharm: Odomzo (sonidegib) for basal cell carcinoma; Zykadia (ceritinib) for AKL-positive advanced NSCLC previously treated with crizotinib (conditional approval); and Farydak (panobinostat), an orphan drug, for relapsed/refractory multiple myeloma. The EMA noted that Farydak helped to keep genes that suppress the division and growth of the cancer cells switched "on", thereby stopping the cells from multiplying and activating processes that kill them.

Amgen secured approval of two orphan cancer drugs: Blincyto (blinatumomab), for acute lymphoblastic leukemia (the product directs the immune system to attack cancer cells), which received a conditional marketing authorization; and Kyprolis (carfilzomib), a proteasome inhibitor used in combination with lenalidomide and dexamethasone for adults with multiple myeloma having received at least one prior therapy. Kyprolis was approved under an accelerated procedure.

Amgen also had a third (non-orphan) anticancer approved: Imlygic (talimogene laherparepvec) for the treatment of adults with melanoma that cannot be removed by surgery and that has spread either to the surrounding area or to other areas of the body without affecting the bones, brain, lung or other internal organs. The EMA noted that Imlygic is a first-in-class advanced therapy medicinal product (ATMP) derived from a virus that has been genetically engineered to infect and kill cancer cells.

Roche's Cotellic (cobimetinib), in combination with vemurafenib, was OK'd for unresectable or metastatic melanoma with the BRAF V600 mutation, and MSD's Keytruda (pembrolizumab) for advanced melanoma.

Other novel drugs included Bristol-Myers Squibb's PD-1 blocker Opdivo (nivolumab) for advanced melanoma (the drug was also approved as Nivolumab BMS for squamous non-small cell lung cancer). Nivolumab prevents the immune system from switching off T cells, increasing its ability to destroy cancer cells.

Unituxin (dinutuximab), an orphan drug from United Therapeutics, was authorized for high-risk neuroblastoma; Lenvima (lenvatinib) from Eisai Europe (also an orphan) for differentiated thyroid cancer (accelerated assessment); and Helsinn Birex Pharmaceuticals' Akynzeo (netupitant/palonosetron) for nausea and vomiting in cancer chemotherapy.

Cardiovascular

In the cardiovascular area, Novartis Europharm saw the approval of its angiotensin II antagonist combination Entresto (sacubitril/valsartan) for symptomatic chronic heart failure with reduced ejection fraction. The combination is classified as an NAS by the CHMP.

Other NAS approvals included GlaxoSmithKline's Nucala (mepolizumab) for severe refractory eosinophilic asthma; Sanofi's Praluent (alirocumab) for hypercholesterolemia; Amgen's Repatha (evolocumab) for hypercholesterolemia/mixed lipidemia; The Medicines Company's Kengrexal (cangrelor) for reducing thrombotic CV events in patients with coronary artery disease undergoing PCI; MSD's Zontivity (vorapaxar) for the reduction of atherothrombotic events in adults with a history of myocardial infarction; and Lixiana (exoxaban) from Daiichi Sankyo for the prevention of stroke and systemic embolism.

Infections

The treatment of infectious diseases in Europe will benefit from a number of new drugs such as Cresemba (isavuconazole) from Basilea Medical, an orphan drug for invasive aspergillosis and mucormycosis, and MSD's Zerbaxa (ceftolozane/tazobactam) for infections (ceftolozane is the NAS in the combination), as well as three products for acute skin infections: Cubist (UK) Ltd's Sivextro (tedizolid phosphate); Orbactiv (oritavancin) from The Medicines Company; and Durata Therapeutics' Xydalba (dalbavancin).

Hepatitis C saw just two advances last year, both from AbbVie: Viekirax, a fixed-dose combination of two new substances (ombitasvir and paritaprevir) with ritonavir, and Exviera (dasabuvir). Viekirax itself is judged to be an NAS as the individual substances were not approved as single agents. Exviera and Viekirax were approved in the EU as one regimen for patients with genotype 1.

In the HIV area, Gilead Sciences received approval for Genvoya, its new product combining the NAS tenofovir alafenamide with elvitegravir, cobicistat and emtricitabine.

Two new drugs were OK'd for psoriasis and psoriatic arthritis: Celgene Europe's Otezla (apremilast) and Novartis Europharm's Cosentyx (secukinumab). One new product was approved for treating the underlying cause of cystic fibrosis: Vertex Pharmaceuticals' Orkambi, which combines the NAS lumacaftor with ivacaftor.

Orphans And Some Other New Drugs

A number of new orphan drugs were authorized for a range of rare conditions: Horizon Therapeutics' drug for urea cycle disorders, Ravicti (glycerol phenylbutyrate); Genzyme Europe's Cerdelga (eliglustat) for Gaucher disease; Synageva BioPharma's Kanuma (sebelipase alfa) for long-term enzyme replacement therapy in lysosomal acid lipase deficiency (accelerated assessment); Biogen Idec's Elocta (efmoroctocog alfa) for bleeding in hemophilia A patients; Hetlioz (tasimelteon) from Vanda Pharmaceuticals for non-24-hour sleep-wake disorder in blind adults; and Boehringer Ingelheim's Ofev (nintedanib) for idiopathic pulmonary fibrosis.

Other NAS receiving approval in various conditions were: Keryx Biopharma's Fexeric (ferric citrate coordination complex) for hyperphosphatemia in patients with chronic kidney disease; Sanofi Pasteur's Gardasil 9 (human papillomavirus 9-valent vaccine); Zambon's Xadago (safinamide) for add-on therapy in Parkinson's disease; Shionogi's Senshio (ospemifene) for vulvar vaginal atrophy in post-menopausal women; and Lumark (lutetium isotope) from IDB Radiopharmacy for the radiolabeling of carrier molecules.

Boehringer Ingelheim's Praxbind (idarucizumab) received accelerated approval for reversing the effects of the company's anticogulant, Pradaxa (dabigatran exexilate). The approval of Praxbind is expected to boost sales of Pradaxa, which have been declining since 2014 as a result of a lack of physician confidence in prescribing the drug.

New Uses, New Combinations, And Other Novelties

A range of other products, containing known substances for new uses or in new combinations, received the EU seal of approval in 2015.

They included two products for lung infections in CF patients: Raptor Pharmaceuticals' orphan drug Quinsair (levofloxacin), the first inhaled fluoroquinolone antibiotic for respiratory infections in CF, and PARI Pharma's Vantobra (tobramycin).

Vantobra hit a barrier in November 2014 when, following a review of its positive opinion in June of that year, the CHMP concluded that the product was similar to the TOBI Podhaler (an orphan drug from Novartis), meaning that it could not be approved for the same indication. However, after PARI submitted some new data, the committee decided in January 2015 that while Vantobra was similar to the Podhaler, it was clinically superior because of its greater safety in a substantial portion of the target population and the fact that it offers shorter treatment times. It was duly authorized in March.

In the weight management area, Novo Nordisk gained approval of liraglutilide, as Saxenda, for weight management in overweight or obese patients. The substance is already approved as Victoza for diabetes, but is often used off-label for weight loss in patients without diabetes.

In the same category, but proving more controversial, was the March 2015 approval of Orexigen Therapeutics' Mysimba (naltrexone plus bupropion, prolonged-release) for weight management in obesity. The approval was granted despite objections raised by France and Ireland over issues such as doubts about limited efficacy, rebound potential after therapy cessation, lack of long term CV data, and neuropsychiatric risks such as depression and suicide¹. Mysimba succeeded where competitor weight loss products have failed: Arena/Eisai's Belviq (lorcaserin) filing was withdrawn in 2013, and the CHMP has twice rejected Vivus's phentermine/topiramate combination Qsymia.

In the diabetes area itself, Boehringer Ingelheim gained approval for its new single-pill combination Synjardy (empagliflozin/metformin) for type 2 disease. Empagliflozin alone was first approved in the EU in May 2014 as Jardiance.

Other interesting new approvals included Respreeza, a new generation human alpha-1 proteinase inhibitor from CSL Behring, for use in slowing progression of emphysema in adults with alpha-1 antitrypsin deficiency (AATD). According to the company this is the first alpha-1 proteinase inhibitor to significantly reduce loss of lung tissue and slow progression of emphysema due to AATD.

Otsuka Pharmaceutical's Jinarc (tolvaptan) was approved for autosomal dominant polycystic kidney disease (ADPKD). Although the substance has been available for hyponatremia as Samsca since 2009, this is a new dosage and a new indication that the CHMP said brought a significant clinical benefit over existing therapies for this condition.

A couple of new combinations of existing substances were approved for the treatment of HIV: BMS' Evotaz (atazanavir/cobicistat), a new fixed-dose once-daily combination of its Reyataz with Gilead's Tybost; and MSD's Dutrebis (lamivudine/raltegravir).

Omeros London Ltd's Omidria (phenylephrine/ketorolac) was authorized as a new combination treatment for maintaining pupil dilation and reducing pain in lens replacement surgery.

As well as its two NAS, The Medicines Company (through its ProFibrix arm) saw its Raplixa (human fibrinogen/thrombin) sealant powder approved to control bleeding in surgery where standard surgical techniques are insufficient. The key benefit of Raplixa, according to the EMA, is that it can reduce time to hemostasis compared with a gelatin sponge alone in patients undergoing spinal, vascular, liver and soft tissue surgery.

2015 saw the arrival of a new treatment option for severe keratitis in patients with dry eye disease that has not responded to tear substitutes, when Santen Oy's Ikervis became the first topical eye drop formulation of ciclosporin to be approved for this indication.

Another new treatment option, this time in ADHD, came with the approval of Shire Pharmaceuticals' Intuniv (guanfacine prolonged-release tablets) for patients in whom stimulants are unsuitable, not tolerated or ineffective.

A number of generic medicines were approved in 2015, including the anticancers pemetrexed, bortezomid and docetaxel, as were generic versions of pregabalin, duloxetine, cinacalcet, fentanyl, sufentanil, voriconazole and aripiprazole.

Biosimilars In The Doldrums, But 2016 Looks Brighter

While no new biosimilar products were approved in 2015, a livelier 2016 is in prospect, judging by activity at the EMA.

In November, Samsung Bioepis gained a CHMP positive opinion for Benepali, its version of Pfizer's TNF-inhibitor Enbrel (etanercept). If authorized by the commission – which would be expected sometime in the first quarter of this year – it will be the second biosimilar MAb to gain EU approval, after Celltrion/Hospira's biosimilar versions of infliximab (Johnson & Johnson's Remicade).

Moreover, as of the beginning of January 2016, the CHMP had 10 biosimilars under evaluation, including four monoclonal antibody products:

• Two versions of AbbVie's Humira (adalimumab). One of these will be the product filed by Amgen late last year (its first biosimilar submission in Europe).
• Celltrion's biosimilar rituximab – the first filing in Europe for a version of the CD20-targeted oncology antibody, Roche's Rituxan/Mabthera.
• Samsung Bioepis' SB2 (infliximab).
• Sandoz' biosimilar etanercept.
• Two versions of Amgen's neutropenia drug Neulasta (pegfilgrastim), one from Richter, the other probably from either Sandoz or Apotex.
• An insulin glargine.
• Two enoxaparin sodium products.

93 CHMP Opinions – And Imminent Approvals

In 2015, the CHMP delivered 93 positive opinions, compared with 82 in 2014. This is the second-highest number of recommendations since the agency was set up in 1995, trumped only by the 117 seen in 2009. Of the 93 opinions, 39 were for new active substances.

13 of the NAS (a total of 14 products, including Nivolumab BMS) were for cancer indications, five for infections and hematology, and three each for cardiovascular and metabolism. 18 products had orphan designation.

Positive opinions are generally followed up by a marketing authorization within two to three months. On this basis, here are some likely impending EU approvals of new products that gained the CHMP green light in the closing months of last year:

• AstraZeneca's Tagrisso (osimertinib), a daily tablet for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a T790M mutation in the EGFR gene, which was reviewed under the accelerated assessment program and received conditional approval. The drug was approved by the US Food and Drug Administration in November, also under an accelerated procedure.
• Another AZ drug, Zurampic (lesinurad), in combination with a xanthine oxidase inhibitor (XOI), for the adjunctive treatment of hyperuricemia in adult gout patients who have not achieved target serum uric acid levels with an adequate dose of an XOI alone.
• Bayer's Kovaltry and Iblias (both octocog alfa). The products are intended for the treatment of bleeding in patients of all ages with congenital factor VIII deficiency in hemophilia A. They have been registered with two brand names as Bayer plans to market BAY 81-8973 as Kovaltry, while CSL Behring has marketing rights under the Iblias brand name.
• Sanofi Pasteur's Vaxelis, a vaccine against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive diseases caused by Haemophilus influenzae type B.
• Laboratoires CTRS' Neofordex (dexamethasone acetate) for symptomatic multiple myeloma. This was a hybrid orphan drug application (relying partly on results carried out with a reference drug and partly on new data). The EMA said the key benefit of the product was its ability to improve survival and response in combination with other medicinal products in symptomatic disease.
• Feraccru (ferric maltol) from Iron Therapeutics for the treatment of iron deficiency anemia in patients with inflammatory bowel disease.
• Bioprojet Pharma's Wakix (pitolisant) for narcolepsy (a first-in-class compound with orphan designation).
• UCB Pharma's Briviact (brivaracetam) for partial-onset epilepsy seizures.

110 Applications Forecast For 2016

The number of applications for initial marketing authorization in 2016 is expected to remain stable, with 110 applications in 2016 versus 112 in 2015, as is the number of applications for medicines containing a new active substance, according to data from the EMA management board's December meeting.

The EMA also expects a stable level of pre-authorization activities for human medicines in 2016, with around 546 requests for scientific advice on medicine development being received compared with 510 in 2015. Among these, EMA expects approximately 33 requests for parallel advice with heath technology assessment (HTA) bodies.

New active substance approvals in EU in 2015

References

1. France fights to prevent EU approval of obesity drug, Scrip Regulatory Affairs, 13 February 2015

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