2017 IN REVIEW

Drugs that made headlines in 2017 In 2017, cancer drugs once again dominated the news, with many of these medications making headlines for being the first of their kind to gain approval. Beyond cancer, drugs for inflammatory diseases also received attention, for both their successes and their failures.

Green light

Dupixent achieved a remission rate of 83% within three in the IDH2 gene. Idhifa works by blocking In March, the US Food and Drug months of treatment. the activity of an enzyme that promotes cell Administration (FDA) approved a drug growth. All participants in a 199-person for adults with a moderate-to-severe Radicava trial received Idhifa, and 19% of participants form of eczema. Dupixent () New Jersey–based Mitsubishi Tanabe experienced remission for roughly eight is being developed jointly by Regeneron Pharma America won approval from the months following at least six months of Pharmaceuticals and Sanofi, and is FDA for its amyotrophic lateral sclerosis treatment. One-third of the participants administered by injection. The dupilumab (ALS) drug Radicava (edaravone) in May. who previously needed blood or platelet antibody binds to the receptor for a The drug, which has been approved in Japan transfusions because of their AML no longer protein called IL-4, thereby inhibiting the since 2015, is administered as an injection required transfusions for at least one 56-day inflammation underlying eczema. Although and could help the approximately 12,000 cycle after receiving Idhifa. Dupixent provides a new option to those Americans, according to the CDC, who suffer who have not had relief from topical eczema from ALS. FDA officials approved Radicava Imfinzi () treatments such as creams, the drug comes at based on data from a trial of 137 participants The immunotherapy agent Imfinzi a hefty price of $37,000 a year. conducted in Japan. Those being treated with (durvalumab), when compared with placebo, Radicava demonstrated a 33% reduction in improved the overall length of time during Ocrevus the rate of decline in their physical function which disease did not worsen in patients with The FDA approved Ocrevus () when compared to those treated with locally advanced, unresectable stage 3 non- in March for severe and relapsing forms of placebo. The approval of Radicava is the first small-cell lung cancer (NSCLC). According multiple sclerosis, making it the first drug to of an ALS drug in the US in more than two to results from the Pacific trial, which is treat the severe form of the disease, known decades. evaluating Imfinzi, the 473 patients treated as primary progressive multiple sclerosis with the drug had a median progression- (PPMS). The US Centers for Disease Ilaris free survival time of almost 17 months, Control and Prevention (CDC) estimates Two new studies funded by Novartis found as compared to an average survival time that roughly 15% of the people with multiple signs that Ilaris (), a drug that of less than 6 months in the 236 placebo- sclerosis in the US have PPMS. In a phase is already being marketed by the company to treated patients (N. Engl. J. Med. http:// 3 trial evaluating Ocrevus in those with treat a form of systemic juvenile idiopathic dx.doi.org/10.1056/NEJMoa1709937, 2017). PPMS, the proportion of participants who arthritis, could also reduce the risk of heart Imfinzi is being developed by AstraZeneca, had not relapsed or experienced disease attack, stroke and even lung cancer in those which received breakthrough designation progression after 96 weeks of treatment was who have already had a heart attack and are for Imfinzi for the treatment of stage 3 82% greater than for participants who were at risk for another. For every 100 patients unresectable NSCLC from the FDA in July given another standard multiple sclerosis followed for a year, 4.5 in the placebo group of this year. treatment. Ocrevus is being produced by had a heart attack, stroke or died from a

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. All rights part Nature. of Springer Inc., America, Nature © 2017 Genentech. heart attack (N. Engl. J. Med. 377, 1119– Heplisav-B 1131, 2017). That figure for those treated An FDA advisory panel voted 12–1 in favor Kymriah with the optimal dose of Ilaris was around of approving the hepatitis B virus vaccine In August, Kymriah (tisagenlecleucel) became 3.9. In a second study, researchers found from Dynavax Technologies, Heplisav-B, in the first gene therapy approved in the US that the highest dose of Ilaris also seemed to July of this year. But in August the agency when the FDA granted approval for use of the reduce the incidence of lung cancer by 67% delayed its decision on whether to approve drug to treat a form of acute lymphoblastic and deaths by 77% (Lancet 390, 1833–1842, the vaccine, pending information from leukemia (ALL) in patients 25 years of age 2017). Dynavax about its plans for post-market or younger. Kymriah uses a patient’s own T studies. As far back as 2008, the FDA placed cells that have been genetically modified to Idhifa a clinical hold on trials testing the vaccine include a gene encoding a chimeric antigen Those who have acute myeloid leukemia because of an adverse autoimmune event receptor (CAR). The modified T cells are (AML) with isocitrate dehydrogenase-2 in a clinical trial. In 2013, the FDA rejected injected into the patient, at which point (IDH2) mutations have a new therapeutic Dynavax’s application, requesting more the CAR protein directs the T cells to find option in Idhifa (enasidenib), which received clinical trial data, and again rejected it in and kill cancerous cells that have the CD19 FDA approval in August. Idhifa is produced 2016, citing concerns over cardiac events antigen on their surface. In a clinical trial of by Celgene and is approved for use with the in a different trial. Finally, on 9 November, 63 patients with relapsed or refractory B cell companion diagnostic assay produced by the company announced that the FDA had ALL, Kymriah, which is made by Novartis, Abbott Laboratories that detects mutations approved Heplisav-B.

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Yellow light

UCART123 Keytruda Fitusiran Paris-headquartered Cellectis faced a Merck faced both ups and downs this year with Alnylam and Sanofi’s collaborative study setback to its CAR-T program when the its anti-PD-1 drug Keytruda (). of the RNA interference drug fitusiran FDA placed a clinical hold in September On the positive side, the FDA approved Keytruda was halted after a patient died of a blood on two of its phase 1 trials evaluating the for use in patients with solid tumors—usually clot in a phase 2 trial. The drug is being company’s candidate therapy UCART123. colorectal, endometrial or gastrointestinal—with evaluated in patients with the A and B The two trials were testing UCART123 in a biomarker of high microsatellite instability or types of hemophilia and works by targeting AML and in blastic plasmacytoid dendritic deficiency for DNA mismatch repair. This marks defective RNA code with small interfering cell neoplasm (BPDCN), a rare and aggressive the first time the FDA has granted approval to RNA molecules, thereby suppressing the form of blood cancer. The clinical hold was a drug that will be administered based not on synthesis of a defective protein that fails to placed after a patient in the BPCDN trial tumor location but on the genetic qualities of the produce coagulation. The death of the study died after experiencing a lung infection tumor. In a disappointment, however, Keytruda participant led to Alnylam pausing other and cytokine release syndrome. A patient failed to improve the overall survival of clinical clinical trials of fitusiran. As Nature Medicine in the AML arm also experienced cytokine trial participants with head and neck cancers. went to press, Alnylam and the FDA had release syndrome, after which an advisory The drug is still being evaluated in two other agreed upon new safety measures when it committee recommended reducing the dose trials in individuals with head and neck cancers, came to dosing fitusiran, and the FDA was of UCART123. The FDA removed the clinical and so Keytruda’s ability to treat this type of considering removing the clinical hold on hold on Cellectis’ phase 1 trials on 6 November. cancer remains to be seen. the phase 2 trial.

Red light

Lampalizumab patients with metastatic NSCLC, with results drugs without the same safety issues are already Roche’s Genentech announced in September from those endpoints expected in the first half available commercially. that one of its two phase 3 trials to evaluate of 2018. lampalizumab had failed to meet its primary Baricitinib endpoint. Lampalizumab is a monoclonal Verubecestat In April of this year, Eli Lilly and Incyte failed antibody for the treatment of geographic Merck announced in February that it was to receive FDA approval for their rheumatoid atrophy, an advanced form of age-related suspending its Epoch study, which was arthritis drug baricitinib. The FDA cited macular degeneration. When compared evaluating verubecestat for treating mild-to- concerns that the clinical trial data presented to placebo, lampalizumab fared no better moderate Alzheimer’s disease. Verubecestat in the application were not sufficient to when it came to reducing the average size is an inhibitor of beta-site amyloid precursor determine the most appropriate dosages for of geographic atrophy lesions in patients, protein–cleaving enzyme 1 (BACE1) that the drug. In response, the two companies and the company stopped further treatment would have helped prevent the buildup of announced plans in August to resubmit an of study participants. On 10 November, amyloid-b and, according to some theories application with new efficacy data by January Genentech announced that its other phase 3 surrounding Alzheimer’s disease, stop 2018. Baricitinib works by inhibiting enzymes trial evaluating lampalizumab had also failed progression or prevent onset of the disease. in the Janus kinase (JAK) family, which are to meet its primary endpoint. As a result of The drug was being evaluated in two phase known to enhance cytokine signaling and, in the two trials’ results, Genentech announced 3 studies, but an external data-monitoring turn, inflammatory responses. that it would not be pursuing marketing committee said that there was “virtually no

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. All rights part Nature. of Springer Inc., America, Nature © 2017 approval for lampalizumab for the treatment chance of finding a positive clinical effect,” NSI-189 of geographic atrophy. adding to the string of phase 3 disappointments Maryland–based biopharmaceutical company in the Alzheimer’s disease field. Merck is Neuralstem announced in July that the lead Imfinzi, again evaluating the drug in another trial in those candidate in its pipeline, an antidepressant Despite success in the Pacific trial, with a very early form of Alzheimer’s disease, known as NSI-189, failed to meet its primary AstraZeneca’s Imfinzi (durvalumab) failed and results of that trial are expected in early endpoint of a statistically significant reduction to meet a primary endpoint when combined 2019. in depression symptoms. The company was with (anti-CTLA-4) in patients evaluating NSI-189 in a phase 2 trial of 220 with metastatic NSCLC in a trial known Plivensia patients with major depressive disorder as Mystic. Although not formally tested, a Janssen Biotech in Horsham, Pennsylvania, and measuring changes in scoring on the secondary endpoint evaluating Imfinzi on its announced in early August that the FDA did Montgomery–Åsberg Depression Rating own as a therapy to block disease progression not recommend approval of its rheumatoid Scale, a questionnaire used to determine the in study participants also would have failed arthritis drug Plivensia (). The drug severity of depression. Neuralstem is also when comparing the drug with the current is an antibody that works to block inflammation evaluating NSI-189 for the treatment of other standard of chemotherapy. The trial will caused by the cytokine IL-6. An FDA panel conditions, including diabetic neuropathy and continue to evaluate Imfinzi’s effect, both voted 12–1 against approving the drug, saying ischemic stroke. as a standalone therapy and in combination that its safety profile did not justify putting the with tremelimumab, on the overall survival of drug on the market, especially when two similar Shraddha Chakradha

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