Pink Sheet: global policy and regulatory coverage
By Ian Schofield 27 May 2022
A list of EU biosimilar filings, CHMP opinions and EU marketing authorizations, including details of the biosimilar company, the brand...
Bluebird bio’s gene therapy Zynteglo, Akcea’s antisense drug Waylivra and BioMarin’s enzyme substitution therapy Palynziq were among the novel innovative medicines that were approved in Europe in 2019.
2019 SAW THE EU APPROVAL OF SEVERAL NEW INNOVATIVE DRUGS
A total of 28 medicines containing a new active substance received pan-EU marketing approval in 2019, marking a return to trend after a three-year peak of 45 NAS-containing product approvals was recorded in 2018.
Oncology medicines accounted for just under a quarter of EU new active substance1 approvals in 2019, slightly down on the previous year. Five orphan drugs were cleared for marketing, well down on the 17 seen in 2018.
Three products were approved via the EU’s accelerated assessment mechanism, while six received a conditional marketing authorization, meaning more data will have to be provided for them to receive a full marketing authorization (MA).
The NAS approval totals for 2017 and 2016 were 28 and 29 respectively, following another exceptional year in 2015, when 46 NAS-containing products were authorized for marketing.
The approval data are drawn from the European Commission’s register of centralized marketing authorizations (as of 14 January 2020), the Pink Sheet’s regularly updated new drug approvals tracker, and other sources. (Also see "New EU Approvals" - Pink Sheet, 4 Dec, 2019.)
Novelties & Orphans
Among the most eye-catching treatments granted an EU marketing authorization (MA) last year were bluebird bio Inc.’s Zynteglo gene therapy for beta-thalassemia and Merck & Co. Inc.’s Ervebo, the first Ebola virus vaccine ever to receive regulatory approval. Zynteglo and Ervebo were also among three products to receive approval after the European Medicines Agency fast-tracked its reviews of their MA applications under the accelerated assessment procedure2. The other product that was fast-tracked was Xospata (see below).
In the cancer area, Bayer AG’s Vitrakvi (larotrectinib) became the first therapy to receive a tumor-agnostic indication in the EU.
Akcea Therapeutics Inc./Ionis Pharmaceuticals Inc.’s antisense product Waylivra (volanesorsen) was the first drug to be authorized for treating familial chylomicronemia syndrome, while AbbVie Inc.’s Skyrizi (risankizumab) was approved as a first-in-class therapy for moderate to severe plaque psoriasis.
Other novelties included BioMarin Pharmaceutical Inc.’s Palynziq (pegvaliase injection), the only enzyme substitution therapy to be approved in Europe for treating the underlying cause of phenylketuronia, and Portola Pharmaceuticals Inc.’s Ondexxya (andexanet alfa), the first specific antidote for reversing the anticoagulant effects of the factor Xa inhibitors.
The five orphan medicines that made it onto the commission’s register of new drug approvals included Astellas Pharma Inc.’s Xospata (gilteritinib).
The other orphan approvals were for Zynteglo, Waylivra, Palynziq and AOP Orphan Pharmaceuticals AG’s Besremi (ropeginterferon alfa-2b) for the treatment of adults with polycythemia vera without symptomatic splenomegaly.
In the cancer area, the approval of Bayer’s Vitrakvi (larotrectinib) is notable for two reasons: it is a first in class oral tyrosine kinase inhibitor (TKI) designed to treat TRK fusion cancer, and is also the first therapy to receive a tumor-agnostic indication in the EU. The product has a conditional approval for use in adults and children with locally advanced or metastatic solid tumors with a neurotrophic receptor tyrosine kinase (NTRK) gene fusion who have no satisfactory treatment options. Securing EU authorization put Bayer ahead of Roche's rival TRK inhibitor, Rozlytrek (entrectinib), in Europe. The approval came 10 months after the US Food and Drug Administration granted accelerated approval for Vitrakvi, which Bayer licensed from Loxo Oncology Inc in 2017. (Also see "Bayer's Vitrakvi Is EU’s First Tumor-Agnostic Treatment " - Scrip, 24 Sep, 2019.)
Xospata (gilteritinib), Astellas’s orphan monotherapy for relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation, received an accelerated assessment at the EMA. EU approval was based on results of the Phase III ADMIRAL trial.This showed the product led to significantly longer overall survival, and the approval marked a significant advance for patients with relapsed or refractory FLT3-positive AML, Andrew Krivoshik, head of oncology at Astellas, said at the time. (Also see "Astellas Gets Europe Okay For AML Drug Xospata" - Scrip, 28 Oct, 2019.) Around a third of patients with AML have FLT3 mutations and the prognosis is particularly poor, with a median survival of less than six months following salvage chemotherapy.
Regeneron Pharmaceuticals Inc./Sanofi’s PD-1 inhibitor Libtayo (cemiplimab) was granted a conditional authorization in June 2019, becoming the first treatment available in Europe for metastatic or locally advanced cutaneous squamous cell carcinoma who cannot have surgery or radiation treatment. As part of the conditional approval, the companies will add a new patient group to the EMPOWER-CSCC-1 study on which the approval was based to further support the benefit-risk profile of Libtayo, and will report the results to the EMA.
Pfizer Inc. did well on the EU cancer drug approvals front last year, with three products getting the go-ahead for marketing. The PARP (poly ADP ribose polymerase) inhibitor Talzenna (talazoparib), for BRCA 1 and 2-positive, HER2-negative locally advanced or metastatic breast cancer, will compete with AstraZeneca/Merck’s class-leading Lynparza (olaparib). Lynparza was approved in the breast cancer setting just a couple of months earlier and was already fast becoming a blockbuster thanks to its ovarian cancer indication. (Also see "Pfizer's Talzenna To Compete With AZ's Lynparza In Breast Cancer After EU Okay " - Scrip, 24 Jun, 2019.)
Pfizer’s two other approvals were both for non-small cell lung cancer (NSCLC). Lorviqua (lorlatinib) received a conditional MA as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive advanced NSCLC whose disease has progressed after alectinib or ceritinib as the first ALK TKI therapy, or crizotinib and at least one other ALK TKI. Vizimpro (dacomitinib) is for use in adults with locally advanced or metastatic NSCLC with EGFR activating mutations.
Erleada (apalutamide), from Janssen-Cilag GMBH, was approved for treating men with non-metastatic castration resistant prostate cancer (NM CRPC) who are at high risk of developing metastatic disease. The approval was based on the pivotal Phase III SPARTAN study which showed that apalutamide plus androgen deprivation therapy significantly reduced the risk of developing distant metastasis or death (metastasis free survival) by 72% compared with placebo.
AOP Orphan Pharmaceuticals’ Besremi (ropeginterferon alfa-2b) is an orphan drug for adults with polycythemia vera (PV) without symptomatic splenomegaly, and is the first treatment to be approved for PV independent of previous hydroxyurea exposure. PV is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. The condition can result in cardiovascular complications such as thrombosis and embolism, as well as transformation to secondary myelofibrosis or leukemia.
The highlight of the year in the infectious disease area was the EU approval – the first worldwide – of Merck’s Ervebo (rVSV∆GZEBOV-GP, or recombinant vesicular stomatitis virus strain Indiana with a deletion of the VSV envelope glycoprotein replaced with the Zaire Ebola virus Kikwit 1995 strain surface glycoprotein). The EU approval was also the first worldwide. Because of the urgent need for an authorized Ebola vaccine, but also reflecting the need for further information on the manufacturing process, the Ervebo MA application underwent an accelerated assessment in Europe and was given a conditional approval. (Also see "First Ebola Vaccine Among Seven Products To Get EMA Nod" - Pink Sheet, 18 Oct, 2019.)
The other two anti-infectives were Menarini Group’s Quofenix (delafloxacin) for acute bacterial skin and skin structure infections, and Theratechnologies Inc.’s Trogarzo (ibalizumab) for multidrug-resistant HIV in combination with other antivirals where a suppressive antiviral regimen cannot otherwise be constructed.
In the metabolic disorders field, BioMarin’s orphan drug Palynziq was the first enzyme substitution therapy to be approved in Europe for treating the underlying cause of phenylketuronia in patients 16 years old and above. The product acts by reducing levels of phenylalanine in the blood.
Akcea Therapeutics' Waylivra, an orphan drug, became the first therapy to be approved for familial chylomicronemia syndrome, an ultra-rare life-altering genetic disease whose symptoms include severe abdominal pain and potentially fatal attacks of acute pancreatitis, as well as organ damage and diabetes. However, the product did not have an easy passage: the MA application was the subject of four sets of outstanding issues from the CHMP during 2018, and as part of the conditional marketing authorization, Akcea and partner Ionis will have to conduct a non-interventional post-authorization safety study.
Just one new drug was approved for diabetes in the EU last year: Sanofi/Lexicon Pharmaceuticals Inc.’s Zynquista (sotagliflozin) for type 1 diabetes mellitus in adult patients who cannot achieve adequate glycemic control with optimal insulin therapy. Zynquista is an oral dual inhibitor of two proteins responsible for glucose regulation: sodium-dependent glucose co-transporter types 1 and 2 (SGLT1 and SGLT2). SGLT1 is responsible for glucose absorption in the gastrointestinal tract, and SGLT2 is responsible for glucose reabsorption by the kidney.
In the blood disorders area, Portola’s Ondexxya (andexanet alfa) received a conditional approval as the first specific antidote for reversing the anticoagulant effects of the factor Xa (FXa) inhibitors, apixaban or rivaroxaban, in patients experiencing life-threatening or uncontrolled bleeding. As part of the conditional approval, Portola must provide final study reports from the ANNEXA-4 Phase IIIb/IV trial and a randomized controlled trial requested by the US FDA, as well as additional pharmacokinetic data.
Two oral thrombopoietin receptor agonists were approved last year for use in severe thrombocytopenia in adults with chronic liver disease (CLD) undergoing invasive procedures: Dova Pharmaceuticals Inc.’s Doptelet (avatrombopag), and Shionogi & Co. Ltd.’s Mulpleo (lusutrombopag) – previously known as Lusutrombopag Shionogi. Doptelet had just been approved in the US for the additional indication of adults with chronic immune thrombocytopenia, a bigger market than CLD; Dova said it would begin talking to the EMA about a similar extension in the EU.
Ultomiris (ravulizumab) was approved for the rare condition, paroxysmal nocturnal hemoglobinuria. Its manufacturer, Alexion Pharmaceuticals Inc., hopes the product will become the standard of care for the disorder. Ultomiris had originally been designated an orphan drug, but was removed from the EU orphan register at the sponsors’ request in June 2019, shortly before it received its marketing authorization. The EMA said Alexion had not shown a clinically relevant advantage over the comparator drug eculizumab (Alexion’s own Soliris) or a major contribution to patient care. The company said last year it planned to submit the drug for atypical hemolytic uremic syndrome (aHUS) in the EU and Japan, having already made a US filing.
Esperoct (turoctocog alfa pegol) is Novo Nordisk AS’s long-acting Factor VIII replacement for the treatment and prophylaxis of bleeding in patients 12 years and over with hemophilia A. The product originally had an EU orphan designation but this was withdrawn in May at the company’s request.
Bluebird bio's Zynteglo (autologous CD34+ cells encoding βA-T87Q-globin gene), a first-of-its-kind therapy, was the only advanced therapy medicinal product (ATMP) to receive EU approval in 2019. An orphan therapy that received a conditional marketing authorization, it is indicated for transfusion-dependent beta thalassemia in patients 12 years and older. Zynteglo also underwent an accelerated review under the EMA’s PRIME (priority medicines) scheme, and was evaluated in just 150 days, “the fastest ATMP review time to date,” according to the EMA.
Dermatology, Cardiovascular, Musculoskeletal
Just one dermatological anti-inflammatory drug was cleared for marketing last year: AbbVie’s Skyrizi (risankizumab) for moderate to severe plaque psoriasis. This was an important approval: the product is a first-in-class humanized immunoglobulin antibody that is designed to selectively inhibit interleukin-23 by binding to its p19 subunit. Indicated for moderate to severe plaque psoriasis, Skyrizi is seen as a follow-up to the company’s blockbuster drug Humira (adalimumab), which has lost patent protection in Europe and is facing biosimilar competition in the US from 2023.
Two new drugs were approved for cardiovascular indications: Teva Pharmaceutical Industries Ltd.’s Ajovy (fremanezumab), for the prophylaxis of migraine in adults who have at least four migraine days per month, and La Jolla Pharmaceutical Co.’s Giapreza (angiotensin II acetate) for refractory hypotension in adults with septic or other distributive shock.
In the musculoskeletal area, AbbVie received approval for its JAK (Janus kinase) inhibitor, Rinvoq (upadacitinib), for treating moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or are intolerant of, one more disease modifying anti-rheumatic drugs.
Evenity (romosozumab), a bone-forming monoclonal antibody from UCB Pharma SA and Amgen Inc., was authorized in December for severe osteoporosis in postmenopausal women at high risk of fracture, with first launches of the product due in the first half of 2020. Wider use of effective osteoporosis therapies could lead to significant savings for national health care systems in Europe, according to the companies, which said at the time that €37bn US$41bn) is spent annually on the care of patients with fragility fractures in just six EU markets. (Also see "EU Approvals: Evenity Cleared For Severe Osteoporosis" - Scrip, 12 Dec, 2019.))
Other NAS-containing drug approvals last year were Aerie Pharmaceuticals Inc.’s Rhokiinsa (netarsudil) for reducing elevated intraocular pressure in adults with primary open-angle glaucoma or ocular hypertension, Shionogi & Co. Ltd.’s Rizmoic (naldemedine tosilate) for opioid-induced constipation in adult patients who have previously been treated with a laxative, and Macimorelin Aeterna Zentaris (macimorelin acetate) for diagnosing growth hormone deficiency in adults.
1The status of “new active substance” is determined by the European Medicines Agency’s drug evaluation committee, the CHMP.
2The EU’s accelerated assessment mechanism can cut the time it takes the European Medicines Agency to evaluate a marketing authorization application from up to 210 days to up to 150 days (not counting clock stops when applicants have to provide additional information). The EMA reserves accelerated assessment for drugs it believes to be of major public health interest, particularly from the point of view of therapeutic innovation.
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