Pink Sheet: global policy and regulatory coverage
By Francesca Bruce 24 Sep 2020
Industry access to real world data for regulatory and market access purposes in Asia Pacific compares poorly with the US.
2018 was a bumper year for new drug approvals in the EU, with 45 products containing a total of 42 new active substances authorized for marketing, well up over the 2017 total of 28 new products containing 29 NASs.
Orphan-designated medicines also put in a strong showing, with the number of approvals more than doubling to 17, compared with just eight a year earlier.
The last time this kind of tally was seen was in 2015, when products containing a total of 46 NAS were authorized for marketing, of which 16 were for orphan indications. The figures are drawn from the European Commission’s register of centralized marketing authorizations (as of Jan. 8, 2019) and from Informa’s regularly updated new drug approvals tracker. (Also see "New EU Approvals" - Pink Sheet, 30 Nov, 2018.)
Anticancer medicines topped the EU approvals table in 2018, with 11 marketing authorizations, followed closely by drugs for infectious diseases (nine) and metabolism/diabetes (eight).
The oncology approvals included the first two CAR-T cell medicines, Novartis’s Kymriah and Gilead Sciences’ Yescarta, both of them orphan drugs for blood cancers.
Among new medicines in other therapeutic categories that made a splash last year were Roche’s multiple scelerosis therapy, Ocrevus, and Spark Therapeutics’ orphan drug Luxturna for inherited retinal dystrophy.
Other orphan approvals included Alnylam’s Onpattro and Ionis/Akcea's antisense product Tegsedi, both forhereditary transthyretin (hATTR) amyloidosis. There were also two new drugs for migraine prophylaxis: Lilly’s Emgality and Novartis’s Aimovig.
Of the 45 NAS-containing products approved last year, five underwent an accelerated assessment: Kymriah, Onpattro, Tegsedi, Roche/Chugai’s hemophilia A drug Hemlibra, and Shire Pharmaceuticals’ Takhzyro for hereditary angioedema.
As in 2017, two products received a conditional approval, meaning the sponsor must provide more data post-authorization. They were Clovis Oncology’s Rubraca for ovarian neoplasms and Kyowa Kirin’s Crysvita for X-linked hyperphosphatemia.
Two drugs were approved under exceptional circumstances (three in 2017): Chiesi Farmaceutici’s Lamzede for alpha-mannidosis, and Ultragenyx’s mucopolysaccharidosis VII (MPS VII; Sly syndrome) drug Mepsevii. Exceptional approval is granted where the applicant is unable to provide comprehensive safety and efficacy data because the condition is rare or the collection of full information is not possible or is unethical.
Some 25 of the products were classed by the European Medicines Agency as medicines and 14 as biologics, while four were advanced therapy medicinal products (ATMPs) and two were vaccines.
Arguably the most important drugs approved in the oncology segment last year – at least in terms of breaking new therapeutic ground – were Novartis AG’s Kymriah(tisagenlecleucel) and Gilead Sciences Inc.’s Yescarta(axicabtagene ciloleucel), the first CAR-T cell therapies to gain marketing authorization in the EU.
Kymriah is indicated for pediatric and young adult patients up to 25 years of age with refractory B cell acute lymphoblastic leukemia and for adult patients with relapsed or refractory diffuse large B cell lymphoma after two or more lines of systemic therapy.
The products, which both have orphan designation, carry a high price tag – around £280,000 in the UK, for example – but the health authorities in Europe are likely to look favorably on characteristics such as their innovative nature, the small patient populations affected, and the lack of alternative effective therapies. Indeed, in some member states the products are already being funded under special access systems. (Also see "CAR-T Therapies Should Impress EU Reimbursement Bodies" - Pink Sheet, 22 Oct, 2018.)
Among the other new oncology approvals were two lung cancer therapies, Takeda Pharmaceutical Co. Ltd.’s Alunbrig(brigatinib), which underwent an accelerated assessment for use in adult patients with anaplastic lymphoma kinase-positive advanced non-small cell lung cancer previously treated with crizotinib, and AstraZeneca PLC’s Imfinzi(durvalumab) for locally advanced, unresectable non-small cell lung cancer in adults whose tumors express PD-L1 on ≥ 1% of tumor cells and whose disease has not progressed following platinum based chemoradiation therapy.
Breast cancer patients can also now benefit from two new arrivals.Lilly Research Laboratories’s Verzenios(abemaciclib) is indicated for the treatment of women with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy.
Puma Biotechnology Inc.’s Nerlynx (neratinib) is for the extended adjuvant treatment of adult patients with early stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab based therapy. Interestingly, the EMA's drug evaluation committee, the CHMP, initially rejected the drug in early 2018. Puma said the benefit-risk assessment was negative because the trial results were “based on evidence from a single pivotal trial and the two- and five-year invasive disease free survival (iDFS) benefits observed to-date may lack sufficient clinical relevance.” (Also see "Puma's Neratinib Gets CHMP Turnaround But Slow EU Uptake Expected" - Scrip, 27 Jun, 2018.) However, the committee later changed its mind and gave it the all-clear.
Pierre Fabre Medicament saw two new NAS approvals, each for use in combination with the other: Mektovi(binimetinib) and Braftovi(encorafenib). The products are for treating adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
Kyowa Hakko Kirin Co. Ltd.’s orphan drug Poteligeo (mogamulizumab) was approved for adults with mycosis fungoides or Sézary syndrome who have received at least one prior systemic therapy. The product is a humanized monoclonal antibody (MAb) directed against the CC chemokine receptor 4 (CCR4), which is frequently expressed on leukemic cells of certain hematologic malignancies including cutaneous T-cell lymphoma. The company plans to begin launching it in various EU markets this year.
The other two oncology approvals last year were Pfizer Inc.’s Mylotarg /(gemtuzumab ozogamicin) for acute myeloid leukemia, and
Clovis Oncology Inc.’s PARP inhibitor Rubraca(rucaparib), which received a conditional marketing authorization for use in relapsed or progressive high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Both products have orphan designation.
The anti-infective category saw the second largest number of approvals last year, with nine NAS-containing products. Only one of them had orphan designation: Merck Sharp & Dohme Ltd.’s Prevymis (letermovir) for the prophylaxis of cytomegalovirus reactivation and disease in adult CMV-seropositive recipients of allogeneic hematopoietic stem cell transplant. The product is one of a new class of non-nucleoside CMV inhibitors that inhibits viral replication by targeting the viral terminase complex.
MSD also received approval for two HIV drugs containing the NAS doravirine: Pifeltro (doravirine) and Delstrigo (doravirine/lamivudine/tenofovir disoproxil), for use with other antiretrovirals for the treatment of adults infected with HIV without past or present evidence of resistance to the NNRTI class.
A third HIV treatment, Gilead’s Biktarvy, was approved, containing the NAS bictegravir in combination with emtricitabine and tenofovir alafenamide.
The other anti-infective approvals were Rempex Pharmaceuticals Inc.’s Vabomere(a combination of the NAS vaborbactam with meropenem) for various infections,TetraPhase Pharmaceuticals Inc.’s Xerava(eravacycline) for complicated intra-abdominal infections, and BioCryst Pharmaceuticals Inc.’s flu treatment Alpivab(peramivir).
The metabolic diseases class saw the approval under exceptional circumstances of Ultragenyx Pharmaceutical Inc.’s orphan drug Mepsevii (vestronidase alfa) for non-neurological manifestations of MPS VII. According to Ultragenyx, MPS VII is one of the rarest MPS disorders, affecting an estimated 200 patients in the developed world. Mepsevii, an enzyme replacement therapy, is intended to provide or supplement beta glucuronidase, an enzyme that helps with the degradation of glycosaminoglycans and prevents their accumulation in various tissues in the body.
Another orphan, Kyowa Kirin’s Crysvita (burosumab), was one of just two drugs to receive a conditional approval last year – for X-linked hyperphosphatemia. The product is a human monoclonal antibody that binds to and inhibits the activity of fibroblast growth factor 23. According to the EMA, the benefits of Crysvita are its ability to reduce the loss of phosphate from the kidney, to improve abnormally low serum phosphate concentrations, and to reduce the severity of rickets as shown in X-rays.
Also in this therapeutic class ,Aegerion Pharmaceuticals Inc.’s orphan drug Myalepta (metreleptin) was approved as an adjunct to diet as a replacement therapy to treat the complications of leptin deficiency in lipodystrophy (LD) patients. AstraZeneca’s Lokelma (sodium zirconium cyclosilicate), an oral potassium removing agent, was approved for use in patients with hyperkalemia.
MSD received approval for three products containing its new compound for type 2 diabetes, ertugliflozin: Steglatro (ertugliflozin), Steglujan (ertugliflozin/sitagliptin) andSegluromet (ertugliflozin/metformin hydrochloride). Novo Nordisk ASsecured the other 2018 diabetes drug approval with Ozempic (semaglutide) – the product was approved for use in the EU in a multi-dose Ozempic pen, the latest generation of Novo Nordisk's prefilled devices, although the company said last year that it intended to submit a variation application to the EMA for the approval of an updated pen to "help facilitate reimbursement for patients with type 2 diabetes using Ozempic.” (Also see "Seven New Drugs Approved In EU In First Two Months of 2018" - Pink Sheet, 28 Feb, 2018.)
Four new therapies for genetic disorders were approved in the EU last year, including Novartis/Spark Therapeutics Inc.’s highly innovative ATMP, Luxturna(voretigene neparvovec). This is the first gene therapy to be approved for the treatment of retinal disease: the specific indication is adult and pediatric patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations and who have sufficient viable retinal cells. Luxturna works by delivering a functional RPE65 gene into the cells of the retina through a single retinal injection to restore the production pathway for the required enzyme, thereby improving the patient's ability to detect light. The product is likely to command a high price, and Novartis said in November that it was exploring "a range of resources and innovative reimbursement and access approaches" in the various EU countries. (Also see "Luxturna's EU Approval Highlights Gene Therapy Pricing Challenges" - Pink Sheet, 23 Nov, 2018.)
Chiesi Farmaceutici SPA’s orphan drug Lamzede (velmanase alfa) received an exceptional circumstances approval for alpha-mannidosis. However, it hit something of a stumbling block in the UK last year when the HTA body, NICE, issued draft guidance pointing out “important limitations” in the available evidence on velmanase alfa and saying that the size and nature of the clinical benefits offered by the treatment over the short and long term were “highly uncertain.” The company’s economic modelling also failed to convince NICE’s highly specialized drugs evaluation committee, which expressed concern that the model was “based on expert opinion rather than clinical evidence.” (Also see "More Evidence Needed For Chiesi’s Ultra Orphan Lamzede, Says NICE" - Scrip, 24 May, 2018.)
Another orphan,Shire PLC’s Takhzyro (lanadelumab), was approved under an accelerated assessment for the routine prevention of recurrent attacks of hereditary angioedema in patients aged 12 years and older.
Vertex Pharmaceuticals Inc.’s orphan medicineSymkevi, which contains the NAS tezacaftor in combination with ivacaftor, is for us in cystic fibrosis patients aged 12 years and over.
Two innovative orphan drugs were approved under accelerated review for hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy:Alnylam Pharmaceuticals Inc.’s RNAi product Onpattro (patisiran) and Ionis Pharmaceuticals Inc./Akcea Therapeutics Inc.s’Tegsedi (inotersen).
The other neurologic drug approval was Otsuka Pharmaceutical Co. Ltd.’s Rxulti(brexpiprazole) for schizophrenia in adults.
Three new drugs were approved for hemophilia A:Bayer AG’s orphan medicineJivi(damoctocog alfa pegol), Roche/Chugai Pharmaceutical Co. Ltd.’s Hemlibra(emicizumab), and Shire’s Adynovi (rurioctocog alfa pegol).
The fourth approval in the blood disorders category was Cablivi (caplacizumab), an orphan drug from Ablynx NV/Sanofi for use in adults experiencing acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression.
Other important new approvals in 2018 included Roche’s Ocrevus (ocrelizumab), the first disease-modifying therapy for relapsing and primary progressive multiple sclerosis to get the all-clear in the EU. However, it is only approved for early-stage and not all primary progressive MS patients. When giving it the all-clear in November 2017, the EMA said data from the clinical trial in the primary progressive group indicate that patients in the early stage of disease benefit more and "more investigation is needed to better understand how beneficial Ocrevus might be in the more advanced stages of the disease." (Also see "All Systems Go as Roche MS Drug Ocrevus Secures EU Okay At Last" - Scrip, 12 Jan, 2018.)
Lilly’s Emgality (galcanezumab) and Novartis’s Aimovig (erenumab) were both approved for the prophylaxis of migraine in adults having at least four migraine days per month. The products will compete with each other within the new class of GCRP inhibitors; a third potential competitor, Teva's fremanezumab, was filed for approval in Europe at the beginning of 2018. Fremanezumab was approved in the US as Ajovyin September last year. While the data supporting efficacy and safety of these three products as preventives for episodic and chronic migraine are comparable, the drugs could be differentiated by developing them for secondary indications. (Also see "14 Approvals To Look Out For In Q3" - Scrip, 10 Jul, 2018.)
TiGenix NV/Takeda’s orphan therapy Alofisel (darvadstrocel) for complex perianal fistulae in Crohn’s disease became the tenth ATMP to gain an EU marketing authorization. A PharmaVitae company analyst said last year that the approval, “while not surprising, is a watershed moment for regenerative medicine as the first allogeneic stem cell therapy to be approved in Europe.”
Almirall SA’s Ilumetri (tildrakizumab) was approved for use in adults with moderate to severe plaque psoriasis who are candidates for systemic therapy, while Fasenra(benralizumab) is AstraZeneca’s new maintenance treatment for severe eosinophilic asthma.
Also OKd for marketing in 2018 were two vaccines: Sanofi’s Dengvaxiafor the prevention of dengue fever, and GlaxoSmithKline Biologicals SA’s Shingrix (recombinant varicella zoster vaccine) for the prevention of herpes zoster/post-herpetic neuralgia in adults 50 years and over.
Dengvaxia is the first vaccine for dengue to become available in the EU. The approved indication excludes the populations of the EU mainland and territories outside tropical areas, although the EMA noted at the time of the CHMP positive opinion that a number of EU territories, mainly overseas, were situated in endemic areas and could benefit from the vaccine. However, the vaccine has been hit by controversy over its alleged links with death in children in the Philippines. (Also see "Controversial Dengue Drug Among Six Products To Get EMA Thumbs Up" - Pink Sheet, 19 Oct, 2018.)
In 2018, the CHMP delivered a total of 84 positive recommendations on marketing authorization, including products containing 42 new active substances, compared with 35 NAS in 2017. (Also see "42 New Substances Among 84 EU Approval Recommendations In 2018" - Pink Sheet, 7 Jan, 2019.)
From the editors of Scrip Regulatory Affairs.
Pink Sheet: global policy and regulatory coverage
By Brenda Sandburg 24 Sep 2020
Governor Cuomo will establish two panels, one examining safety and efficacy and another considering distribution and pricing, to advise the...
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