28 New Drug Approvals In EU: Cancer Dominates, But RA, Skin & Blood Disorders Well Served Too

Twenty-eight new products containing a total of 29 new active substances were authorized for marketing in the EU in 2017, very much line with the 2016 tally. As in that year, oncology dominated the 2017 approvals, which also included new drugs for rheumatoid arthritis, skin & blood disorders, and hepatitis C.

A total of 28 products containing a new active substance were authorized for marketing in the EU in 2017. As in previous years, the approvals were dominated by oncology, which accounted for 11 (more than a third) of all marketing authorizations granted by the European Commission for NAS-containing products. One of the new products, AbbVie Inc.’s Maviret for hepatitis C, contained two substances new to the market, bringing the total number of new active substances to 29.

The figures are based on data extracted from the commission’s approvals database. They are almost identical to those for 2016, when 29 products containing a total of 30 NASs were approved, 10 of them for cancer indications.

Of the NAS-containing products approved in 2017, two were given conditional approvals, three underwent an accelerated assessment, and there were three approvals under “exceptional circumstances.” The number of orphan drugs declined substantially, though, with eight of the newly approved NAS-containing drugs aimed at rare diseases, compared with 14 in 2016. (Also see "EU Orphan Designations Fall Sharply In 2017" - Pink Sheet, 28 Dec, 2017.) A ninth orphan drug, EUSA Pharma/Apeiron Biologics AG’s Qarziba (dinutuximab beta), was also approved but it was not classed as a NAS by the European Medicines Agency.

By contrast, the tally of biosimilars rose sharply to 16, four times as many as in the previous year. They included the first versions of five biologic blockbusters: Herceptin, Humalog, Humira, MabThera and Forsteo.

Also given the go-ahead for marketing were half a dozen new combinations, about 20 generics, and a range of other novelties including new formulations and uses.

The data are drawn from the European Commission’s drug approvals database as of Jan. 4, 2018.

Oncology Approvals

Eleven of the newly authorized drugs, accounting for more than a third of the total, were approved for oncology indications.

Among the newcomers in oncology was Roche’s Alecensa (alectinib), a second-generation anaplastic lymphoma kinase (ALK) inhibitor, which received a conditional marketing authorization in February 2017 for second-line treatment of adults with ALK-positive NSCLC previously treated with crizotinib. The following December it received EU approval for first-line treatment, and the conditional MA was converted to a standard one. The first-line approval was based on results from the Phase III ALEX study, which showed Alecensa significantly reduced the risk of disease worsening or death by 53% compared with crizotinib. The study also showed that the drug reduced the risk of tumors spreading to, or growing in the brain or central nervous system compared with crizotinib by 84%. The product is seen as a key part of Roche’s defense against biosimilar competition to Avastin (bevacizumab), Rituxan (rituximab) and Herceptin (trastuzumab).

Fotivda (tivozanib), from Aveo Oncology/EUSA Pharma, is an oral, once-daily, potent and highly-selective vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) for treating advanced renal cell carcinoma in adults. Approved in August, the product had its first commercial launch in November, with sales beginning in Germany. That same month, Aveo president and chief executive officer Michael Bailey said the company was planning expand the drug’s availability in Europe through its partner, EUSA Pharma, and potentially in North America, where it plans to file for approval with the Food and Drug Administration pending the results of the pivotal TIVO-3 study.

Novartis’s Kisqali (ribociclib) was approved for first-line use in combination with an aromatase inhibitor in postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) locally advanced or metastatic breast cancer, based on the MONALEESA-2 study. In December 2017, updated data from the MONALEESA-7 study showed the extent of progression-free survival benefit in premenopausal women with advanced breast cancer. (Also see "Novartis' Kisqali Impresses In Premenopausal Breast Cancer As Market Crowds" - Scrip, 7 Dec, 2017.) Novartis has priced the drug competitively in order to compete with Pfizer’s Ibrance (palbociclib), which was approved in 2015. The product will also face competition from Lilly’s Verzenio (abemaciclib), which has yet to be approved in the EU (it was approved in the US last year).

Orphan Cancer Drugs

The five NAS-containing orphan cancer drugs were as follows:

• Pfizer Inc.’s Besponsa (inotuzumab ozogamicin) is the first CD22-directed antibody-drug conjugate indicated for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. While the EU approval is an important step for Pfizer, the market for Besponsa is limited: ALL is an aggressive type of leukemia with a poor prognosis and it is uncommon in adults, representing about 15% of all diagnosed leukemias. About 10,000 new adult ALL cases are diagnosed in Europe each year; 20%-40% of newly diagnosed cases are cured with current treatment regimens, although some 20% of adult patients will be refractory or resistant to treatment.
• Novartis’s Rydapt (midostaurin) for acute myeloid leukemia. This is the first targeted treatment to be approved in the EU for use in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by Rydapt single agent maintenance therapy, for adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive. It was also cleared for use as monotherapy for the treatment of adults with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN) or mast cell leukemia. There are more than 18,000 estimated new cases of AML diagnosed each year in the EU, and about a third of AML patients have an FLT3 gene mutation. Novartis confirmed in September that the pricing model for Rydapt will be close to that in the US where the price in AML will be different from that charged for the SM indication. It added that it was “still discussing reimbursement with government agencies and third-party payers to provide access to Rydapt for patients as quickly as possible.” (Also see "EU Moves To RATIFY Novartis' Rydapt for AML" - Scrip, 20 Sep, 2017.)
• Pfizer/Merck KGAA’s Bavencio (avelumab) for metastatic Merkel cell carcinoma (mMCC). The conditional marketing authorization is based on data from the JAVELIN Merkel 200 trial, an international, multicenter, single-arm, open-label, Phase II study. The JAVELIN clinical development program for Bavencio involves at least 30 clinical programs and more than 6,300 patients evaluated across more than 15 different tumor types, according to the companies. Some 2,500 Europeans are affected by MCC each year, with metastatic disease diagnosed in 5-12% of patients. Fewer than 20% of patients with mMCC survive beyond five years.
• Zejula (niraparib), an orphan drug for maintenance therapy in ovarian cancer from Tesaro Inc. This is the first oral, once-daily PARP inhibitor to be approved in Europe for patients with recurrent ovarian cancer regardless of BRCA mutation of biomarker status. The company said in November that the first commercial launches were planned before the end of the year in Germany and the UK. The product’s approval gives Tesaro an advantage over AstraZeneca PLC’s competitor drug, Lynparza (olaparib), which was approved in Europe in 2014 for a more limited indication (although an expanded approval is expected). The CHMP said the main benefit of Zejula was its ability to improve progression-free survival compared with placebo. Datamonitor Healthcare analyst Zachary McClellan estimates the product’s revenues in the EU will reach $135m by 2025.
• Ipsen’s Xermelo (telotristat), the first oral treatment in the EU for carcinoid syndrome diarrhea in patients inadequately controlled by somatostatin analogue therapy.

Three other NAS-containing cancer drugs were given the all-clear for marketing:

• Tesaro’s Varuby (rolapitant) for prevention of delayed nausea and vomiting in chemotherapy. The company says the product is a selective and competitive antagonist of human substance P/neurokinin 1 (NK-1) receptors that is rapidly absorbed and slowly eliminated, with a plasma half-life of seven days. Results from three global Phase III trials of Varuby showed a significant reduction in episodes of vomiting or use of rescue medication during the 25 to 120 hour period following administration of emetogenic chemotherapy, including cisplatin, carboplatin and anthracycline/cyclophosphamide-based regimens, Tesaro noted.
• Steba Biotech’s Tookad (padeliporfin), a vascular-targeted photodynamic therapy for adenocarcinoma of the prostate.
• Axumin (fluciclovine) from Blue Earth Diagnostics, a diagnostic radiopharmaceutical for the detection of recurrence of prostate cancer in adult men.

Rheumatoid Arthritis

Three new drugs were approved for moderate to severe rheumatoid arthritis patients who have failed or not responded adequately to disease-modifying antirheumatic drugs (DMARDs) – Eli Lilly & Co.’s Olumiant (baricitinib), Pfizer’s Xeljanz (tofacitinib), and Sanofi/Regeneron Pharmaceuticals Inc.’s Kevzara (sarilumab).

Olumiant is the first JAK inhibitor to gain approval in Europe for RA. While the data are impressive, pricing will be key to the uptake of the drug, according to Datamonitor Healthcare analyst Christina Vasiliou. Olumiant faces competition from well-established products such as adalimumab (AbbVie’s Humira) and etanercept (Amgen’s Enbrel), which also now have cheaper biosimilar versions available in Europe, Vasiliou adds that Olumiant will compete well against Xeljanz. "Based on baricitinib's strong and comprehensive clinical trial program and promising clinical performance to date, Datamonitor Healthcare forecasts baricitinib to be the most commercially successful JAK inhibitor in RA, with estimated 2025 sales of approximately $1.9bn," Vasiliou said. (Also see "Lilly's Olumiant To Be EU's First RA JAK Inhibitor, But Pricing Is Key" - Scrip, 16 Dec, 2016.)

As for Kevzara, Vasiliou said that its clinical performance to date had been comparable to that of Roche’s Actemra (tocilizumab), and that key opinion leaders would consider using it in the same treatment setting where they currently use Actemra – primarily in non-responders to anti-TNF biologics, and as a first-line biologic in rare cases of high disease activity or comorbidities. However, “its lack of differentiation from Actemra will prevent it from capturing significant market share," Vasiliou predicted in April 2017. (Also see "Sarilumab Set To Clear EU Hurdle In RA But Actemra Specter Remains" - Scrip, 24 Apr, 2017.)

Skin Disorders

Three products received marketing approval for skin disorders – Leo Pharma’s Kyntheum (brodalumab), Janssen Cilag’s Tremfya (guselkumab), and Sanofi’s Dupixent (dupilumab). The first two were for moderate to severe plaque psoriasis.

Kyntheum became the first biologic to be approved that selectively targets the IL-17 receptor subunit A. By binding to this specific receptor subunit on the cells of the skin, rather than targeting free inflammatory mediators, Kyntheum blocks the biological activity of several pro-inflammatory IL-17 cytokines involved in plaque formation. Rights to the product were licensed to Leo Pharma by AstraZeneca in 2016. Brodalumab is currently approved in the US (under the brand name Siliq) and in Japan for adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy.

Tremfya was also approved for plaque psoriasis; the product is a first-in-class interleukin-23 inhibitor.

The third skin disorder drug, Dupixent, was authorized for moderate-to-severe atopic dermatitis in adult patients who are candidates for systemic therapy. This product is the first systemic therapy for this disease, and is already a big seller in the US.

Blood Disorders

Two new products received approval for treating blood disorders: Novo Nordisk AS’s Refixia (nonacog beta pegol) for the treatment and prophylaxis of bleeding in patients aged 12 years and over with hemophilia B (congenital Factor IX deficiency); and Afstyla (lonoctocog alfa) from CSL Behring for the treatment and prophylaxis of bleeding in patients with hemophilia A (congenital Factor VIII deficiency).

Hepatitis C

Two new combination hepatitis C products were approved. AbbVie’s Maviret contains two NASs – glecaprevir and pibrentasvir – and is billed as a “once-daily, ribavirin-free, eight-week option for patients without cirrhosis and who are new to treatment across all genotypes,” according to the company. The product was approved under the EMA’s accelerated assessment procedure for drugs that address unmet medical needs.

Gilead Sciences Inc.’s Vosevi (sofosbuvir/velpatasvir/voxilaprevir) is a pan-genotypic combination product in which voxilaprevir is the NAS.

Other NAS-Containing Products

A range of other NAS-containing drugs were approved last year:

• Brineura (cerliponase alfa), a drug from BioMarin International for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) (also known as tripeptidyl peptidase 1 (TPP1) deficiency). This orphan drug was approved under exceptional circumstances and via the accelerated assessment mechanism. As a condition of the approval, BioMarin has to carry out certain post-authorization safety and efficacy studies – PASS (long-term safety including serious hypersensitivity reactions and anaphylaxis) and PAES (further evaluation of effectiveness in delaying progression of CLN2 motor-language clinical scale as well as safety and tolerability).
• Veltassa (patiromer sorbitex calcium) is a new treatment for hyperkalemia in adults, from Vifor Fresenius. Marketing authorization applications for Veltassa have been submitted and are under review in Switzerland and Australia, and plans are under way to submit applications in other markets worldwide. Veltassa was approved by the US FDA for the treatment of hyperkalemia in October 2015, becoming the first new medicine for this condition in more than 50 years.
• Oxervate (cenegermin eye drops), an orphan drug from the Italian firm Dompe Farmaceutici, is a recombinant human NGF for moderate or severe neurotrophic keratitis in adults. It is the first biologic drug to be authorized in the EU for this condition.
• Gedeon Richter PLC’s Reagila (cariprazine) is a novel antipsychotic for schizophrenia in adults. The product was launched in the US as Vraylar in March 2016 for schizophrenia and bipolar mania, and in August 2016 Richter and Recordati signed an exclusive license agreement to commercialize cariprazine in Western Europe, in Algeria, in Tunisia and in Turkey.
• Merck Sharp & Dohme’s Zinplava (bezlotoxumab) was approved for the prevention of recurrence of Clostridium difficile infection in adults at high risk of recurrence of CDI. Zinplava is a human monoclonal antitoxin antibody that binds with high affinity to Clostridium difficile toxin B and neutralizes its activity.
• Biogen Idec’s Spinraza (nusinersen), an antisense oligonucleotide targeted to the SMN2 gene, was approved for 5q spinal muscular atrophy. The orphan product is the first approved treatment in the EU for SMA, a leading genetic cause of death in infants that is marked by progressive, debilitating muscle weakness. Spinraza is the third of the products approved last year that were reviewed under the accelerated assessment mechanism.
• Spherox (spheroids of human autologous matrix associated chondrocytes) from CO.DON AG, is an advanced therapy medicinal product (ATMP) for the repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee. The EMA said that knowledge on the long-term effects of the medicine is still awaited. The company will continue the first clinical study to obtain more information about the long-term safety and effectiveness of Spherox; it will also carry out two other studies on the manufacture of Spherox, which will look, among other things, at the consistency of the finished product.

Combinations And Other Products

Other new EU approvals last year included a number of combinations of known substances:

• Sanofi’s Suliqua (insulin glargine plus lixisenatide) for type 2 diabetes.
• Chiesi Farmaceutici’s Trimbow (beclomethasone/formoterol/glycopyrronium bromide) and GlaxoSmithKline PLC’s Trelegy Ellipta and Elebrato Ellipta (fluticasone furoate/umeclidinium/vilanterol), both for COPD.
• Zentiva BV’s efavirenz/emtricitabine/tenofovir disoproxil and Janssen-Cilag’s Symtuza (darunavir/cobistat/emtricitabine/tenofovir alafenamide fumarate), both for HIV infection.

Other notable approvals included Vemlidy (tenofovir alafenamide fumarate) from Gilead Sciences for chronic hepatitis B. This is a targeted prodrug of Viread (tenofovir disoproxil fumarate) – the company says it is the first new treatment for CHB in Europe “in almost a decade” and that it has shown antiviral efficacy similar to Viread but at one-tenth the dose. Actelion Pharmaceuticals’ Ledaga (chlormethine (mechlorethamine) is an orphan drug for the topical treatment of mycosis fungoides-type cutaneous T-cell lymphoma in adults – a rare, potentially life-threatening immune system cancer.

EUSA Pharma/Apeiron Biologics’ Qarziba (dinutuximab beta), is something of a novelty. An orphan chimeric MAb for pediatric neuroblastoma that targets ganglioside antigen GD2, it was approved under exceptional circumstances, becoming the only anti-GD2 monoclonal antibody authorized in the EU (although it was not classed by the EMA as a NAS). Dinutuximab beta was developed by Apeiron and is marketed by the company’s global licensing partner, EUSA Pharma. It was previously available in Europe under a managed access program; following a positive CHMP opinion in March 2017, it was granted expedited EU approval.

Almirall SA’s Skilarence is a new oral formulation of dimethyl fumarate for the first-line treatment of adults with moderate to severe chronic plaque psoriasis. Marketing in the EU was due to start in Q3 2017. The company says it is the first fumaric acid ester to be approved for psoriasis in the EU.

Biosimilars

The large clutch of biosimilars approved in the EU in 2017 included the first versions of five major products – Roche’s Herceptin and MabThera, AbbVie’s Humira, and Lilly’s Humalog and Forsteo – as well as new versions of reference drugs that already face biosimilar competition. Further details will be published in a future Pink Sheet article.

From the editors of Scrip Regulatory Affairs.