Cover story. Austedo Ingrezza Brineura Alunbrig Rydapt Tymlos Imfinzi Radicava Kevzara Baxdela Bevyxxa

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1 Cover story Downloaded via on March 9, 2019 at 14:34:33 (UTC). See for options on how to legitimately share published articles. Trulance Parsabiv Emflaza Siliq Xermelo Kisqali Xadago Bavencio Symproic Zejula Dupixent crevus DA approvals hit a 20-year high in 2017, with cancer and rare-disease drugs dominating the list of new medicines Austedo Ingrezza Brineura Alunbrig Rydapt Tymlos Imfinzi Radicava Kevzara Baxdela Bevyxxa LISA M. JARVIS, C&E CICAG Tremfya erlynx Vosevi Idhifa Mavyret Besponsa Vabomere Benznidazole Aliqopa Solosec Verzenio Calquence Vyzulta Prevymis asenra Mepsevii emlibra zempic Xepi Rhopressa Macrilen Steglatro Giapreza 26

2 CREDIT: WILL LUDWIG/C&E/SUTTERSTCK In brief The pharmacopoeia grew nicely in 2017, with DA drug approvals hitting a 20-year peak. Although some new drugs were retreads of older ones, several important breakthroughs for science and for patients arrived last year. Cancer and rare-disease drugs dominated the new drug list, thanks in part to DA s efforts to clear the path for truly innovative treatments. Read on for more about the 46 additions to the medicine cabinet. After a dip in 2016, 2017 brought a two-decade peak in drug approvals. The U.S. ood & Drug Administration gave its green light to 46 new molecular entities, the highest number since Cancer treatments and drugs for rare diseases continued to command a hefty portion of approvals, and many benefited from an agency that seems motivated to streamline development for truly innovative medicines. Early on in 2017, it was clear the year would bring a bountiful crop of new medicines. By mid-june, DA had given its nod to as many new molecules as were approved in all of The prior year s meager output meant many big companies were in need of a rebound in productivity. And indeed, for some, 2017 was a salve. AstraZeneca, for example, had no approvals in It now has three new products in its portfolio: two cancer treatments and an asthma drug. Pfizer, which in 2016 had a lone approval that came only through a midyear acquisition, also scored three new products last year. owever, it must share rights to two of them: the cancer immunotherapy Bavencio, which came to Pfizer in 2014 through a multi-billion-dollar deal with Germany s Merck KGaA, and the diabetes treatment Steglatro, an internally developed drug that in 2013 Pfizer chose to codevelop with U.S.- based Merck & Co. or others, the drought persisted. Although Bristol-Myers Squibb continued to expand the types of cancer that are treated with its existing immuno-oncology drugs, 2017 was the company s second year in a row without a new product approval. The drug industry s record-breaking productivity does come with caveats. Although DA said 33% of the products it approved belonged to new classes of compounds, most drug industry watchers would consider several of them to be older drugs. or example, DA s list of firstin-class drugs includes Emflaza, a decades-old corticosteroid approved for the first time in the U.S. to treat Duchenne muscular dystrophy. A handful of other treatments either are similarly old drugs just now reaching the U.S. market or work against older protein targets now associated with new diseases. Cancer treatments continued to dominate the list, representing over a quarter of all new molecules approved last year. owever, many of the new oncology drugs are not especially unique and work by the same mechanism of action as already marketed drugs. The approval list included two more CDK4/6 inhibitors, two more PD-L1 inhibitors, and more compounds that block the proteins PARP, BTK, and ALK. The new cancer treatments were the primary beneficiaries of DA s effort to speed development of potentially important new drugs. f the 12 oncology products approved, nine had breakthrough therapy designation (BTD), a status introduced in DA has previously described BTD as triggering an all-handson-deck approach at the agency to ensure efficient and well-designed clinical programs for drugs that are novel or address an underserved disease. The program has been growing quickly. verall, 17 drugs approved in 2017 had BTD status. In 2015, which previously held the recent record for new drug approvals, just 10 products had the special status. Beyond cancer, anti-infectives and drugs for rare diseases were the other beneficiaries of breakthrough status. According to the Tufts Center for the Study of Drug Development, BTD is significantly shortening drug development timelines. The average time from Investigational ew Drug Application asking DA to begin clinical trials to approval letter was 65 months for the 17 BTD drugs approved in 2015 and 2016, compared with 110 months for drugs approved without the status. The cost of cancer Despite ongoing scrutiny over health care costs, new oncology treatments continue to carry high price tags. DRUG AME Idhifa Imfinzi Rydapt Calquence Alunbrig Bavencio Aliqopa Kisqali Verzenio erlynx Zejula WLESALE ACQUISITI CST $24,872/month $15,000/month $14,990/28 days $14,259/month $14,250/month $13,000/month $12,726/month $10,950/28 days (600 mg dose) $10,948/month $10,500/month $9,833/month for 200 mg/ day (recommended 300 mg/day dose) Sources: Companies, insurers JAUARY 22, 2018 CE.ACS.RG C&E 27

3 Bountiful year Cancer and rare-disease drugs scored the most approvals in 2017, and small molecules continued to be an important drug modality. DRUG AME ACTIVE IGREDIET APPLICAT MDE ACTI IDICATI Trulance Plecanatide Synergy Guanylate cyclase-c agonist Chronic idiopathic constipation Parsabiv Etelcalcetide Amgen Calcium-sensing receptor Secondary hyperparathyroidism in chronic kidney modulator disease Emflaza Deflazacort Marathon Corticosteroid prodrug Duchenne muscular dystrophy Siliq Brodalumab Valeant IL-17RA antagonist Psoriasis Xermelo Telotristat ethyl Lexicon Tryptophan hydroxylase inhibitor Carcinoid syndrome diarrhea 1 Kisqali Ribociclib ovartis CDK4/6 inhibitor R-positive/ER2-negative advanced or metastatic breast cancer 2 Xadago Safinamide ewron Monoamine oxidase B inhibitor Parkinson's disease Bavencio Avelumab Merck KGaA/Pfizer PD-L1 inhibitor Merkel cell carcinoma Symproic aldemedine Purdue Pharma Mu opioid receptor antagonist pioid-induced constipation 3 Zejula iraparib Tesaro PARP inhibitor Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer Dupixent Dupilumab Sanofi/Regeneron IL-4 and IL-13 inhibitor Eczema crevus crelizumab Roche CD20 binder Multiple sclerosis 4 Austedo Deutetrabenazine Teva Pharmaceutical Vesicular monoamine transporter 2 inhibitor untington's disease-associated chorea Ingrezza Valbenazine eurocrine Biosciences Vesicular monoamine transporter 2 inhibitor Tardive dyskinesia Brineura Cerliponase alfa BioMarin Pharmaceutical Enzyme replacement therapy Batten disease 5 Alunbrig Brigatinib Takeda Pharmaceutical ALK inhibitor ALK-positive non-small cell lung cancer 6 Rydapt Midostaurin ovartis Multikinase inhibitor, including LT3 and KIT LT3-positive acute myeloid leukemia Tymlos Abaloparatide Radius ealth Parathyroid hormone-related protein steoporosis Imfinzi Durvalumab AstraZeneca PD-L1 inhibitor Urothelial carcinoma Radicava Edaravone Mitsubishi Tanabe Unknown Amyotrophic lateral sclerosis Kevzara Sarilumab Sanofi/Regeneron IL-6R inhibitor Rheumatoid arthritis Baxdela Delafloxacin Melinta Therapeutics luoroquinolone Skin infections Bevyxxa Betrixaban Portola actor Xa inhibitor Venous thromboembolism ote: Drugs appear in order of approval during Source: DA 1 Kisqali (ribociclib) (C 3 ) C 2 Xadago (safinamide) S 2 3 Zejula (niraparib) + 2 S 2 3 C C 3 7 Idhifa (enasidenib) C 3 2Cl 8 Aliqopa (copanlisib) Solosec (secnidazole) 28

4 KEY: Small molecule Peptide Antibody Enzyme Antibody-drug conjugate DA breakthrough status Accelerated approval Priority review voucher earned DRUG AME ACTIVE IGREDIET APPLICAT MDE ACTI IDICATI Tremfya Guselkumab Johnson & Johnson IL-23 inhibitor Psoriasis erlynx eratinib maleate Puma Biotechnology EGR, ER2, and ER4 inhibitor ER2-positive breast cancer Vosevi Sofosbuvir, velpatasvir, S5B polymerase, S5B, and Gilead Sciences and voxilaprevir S3/4A protease inhibitors epatitis C 7 Idhifa Enasidenib Celgene ID2 inhibitor ID2-positive acute myeloid leukemia Mavyret Glecaprevir and S3/4A protease and S5A AbbVie pibrentasvir inhibitors epatitis C Besponsa Inotuzumab CD22-binding antibody and Pfizer ozogamicin cytotoxic antibiotic Acute lymphoblastic leukemia Vabomere Meropenem and vaborbactam The Medicines Co. Carbapenem antibacterial and non-β-lactam β-lactamase inhibitor Complicated urinary tract infections Benznidazole Benznidazole Chemo Research itroimidazole antimicrobial Chagas disease 8 Aliqopa Copanlisib Bayer Pan-PI3K inhibitor ollicular lymphoma 9 Solosec Secnidazole Symbiomix Therapeutics itroimidazole antimicrobial Bacterial vaginosis 10 Verzenio Abemaciclib Eli Lilly & Co. CDK4/6 inhibitor Breast cancer 11 Calquence Acalabrutinib AstraZeneca BTK inhibitor Mantle cell lymphoma 12 Vyzulta Latanoprostene bunod Metabolizes into two pressurelowering moieties Valeant ophthalmic solution Glaucoma/ocular hypertension 13 Prevymis Letermovir Merck & Co. Cytomegalovirus DA terminase Infection prevention after bone marrow complex inhibitor transplant asenra Benralizumab AstraZeneca IL-5R α receptor binder Severe asthma Mepsevii Vestronidase alfa Ultragenyx Pharmaceutical Enzyme replacement therapy MPS VII (Sly syndrome) emlibra Emicizumab Roche actor IX and X binder emophilia A zempic Semaglutide ovo ordisk GLP-1 receptor agonist Type 2 diabetes Xepi zenoxacin Medimetriks onfluorinated quinolone antibiotic Impetigo Rhopressa etarsudil ophthalmic solution Aerie ρ-kinase inhibitor Glaucoma/ocular hypertension Macrilen Macimorelin acetate Aeterna Zentaris Ghrelin mimetic Adult growth hormone deficiency 14 Steglatro Ertugliflozin Merck & Co./Pfizer SGLT2 inhibitor Type 2 diabetes Giapreza Angiotensin II La Jolla Pharmaceutical Synthetic human angiotensin II ypotension in sepsis or critical illness CD 3 CD 3 3 C 4 Austedo (deutetrabenazine) 10 Verzenio (abemaciclib) 3 C 5 Alunbrig (brigatinib) 2 3 C Cl P C3 11 Calquence (acalabrutinib) C 3 C 3 6 Rydapt (midostaurin) JAUARY 22, 2018 CE.ACS.RG C&E 29

5 2017 new drug approvals by the numbers 46 ew molecular entities approved in Approved in % Small molecules approved ew molecular entities approved Source: DA Cancer drugs approved in Approved in % Drugs with breakthrough therapy status $702,000 Annual price of treatment with BioMarin s Brineura Sources: DA, companies Peak ew drug approvals were the highest in 21 years I would say that s pretty good confirmation that this is another DA program that seems to be working, says Christopher-Paul Milne, director of research at the Tufts center. What has to come next is expansion into other therapeutic areas of need. That shortened development time, which in theory should mean lower R&D costs for companies focused on oncology, is not translating into lower prices. All 12 oncology drugs approved last year featured six-figure annual wholesale acquisition costs, the company s list price before any rebates or discounts. Although the biotech industry has been energized by the potential for new technologies and therapeutic modalities to tackle difficult-to-treat diseases, small molecules continue to dominate DA s docket. Conventional, chemically synthesized drugs represented almost two-thirds of the new molecular entities approved last year. Still, compared with a decade ago, the new drug list last year featured a wider range of modalities, including peptides, enzyme replacement therapies for rare diseases, and an antibody-drug conjugate. Industry insiders will notice that the tally of 46 does not include the two new therapeutic modalities that garnered the biggest headlines in Missing are ovartis s Kymriah and Gilead Sciences Yescarta, both chimeric antigen receptor (CAR) T-cell therapies, a new class of drugs made by reengineering a person s own T cells to seek and destroy cancer cells. Also absent is Spark Therapeutics Luxturna, the first-ever approved gene therapy for a genetic condition. Luxturna treats a rare form of blindness. C&E has long tracked DA s actions on new molecular entities, and these cellular treatments the approval of which the agency called historic fall outside that category. verall, DA gave the green light to a combined 56 new molecular entities and biologic therapies. Similarly, the list does not capture another groundbreaking approval that arrived in In May, DA green-lighted Merck & Co. s cancer immunotherapy Keytruda for use in anyone harboring a specific genetic profile. Keytruda had already been on the market for three years for a variety of cancer types. But last year the agency gave the drug its first tissue agnostic approval, meaning that a genetic mutation rather than the location of the cancer lung or colon, for example guides use of the treatment. Soon after coming on as DA commissioner on May 9, Scott Gottlieb signaled his intention to ease the path for other tissue-agnostic 12 Vyzulta (latanoprostene bunod ophthalmic solution) I would say that s pretty good confirmation that this is another DA program that seems to be working. Christopher-Paul Milne, director of research, Tufts Center for the Study of Drug Development, speaking about DA s breakthrough therapy designation C 3 13 Prevymis (letermovir) Cl 14 Steglatro (ertugliflozin) drugs, and he quickly acted: In December, the agency released draft guidance to clarify the clinical development for such treatments. When drugs successfully target these molecular mistakes to reverse the effects of different diseases, we need a development pathway that C 3 C 3 allows the new drug to pursue approval in each of these novel settings on the basis of the molecular marker that the drug targets, Gottlieb said when the draft guidance was released. Even as the breadth of modalities and clinical pathways expands, the agency said that every drug in 2017 was approved within the review time frame required by law; many applications actually got the nod before the deadline. Looking ahead, the agency appears determined to continue partnering with companies to make the development process for innovative drugs even more efficient. 2 30