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Dapagliflozina e câncer

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  • 1. N E W S & A N A LY S I S Diabetes field cautiously upbeat despite possible setback for leading SGLT2 inhibitor Concerns about cancer risks prompted a negative vote by an FDA advisory committee on the SGLT2 inhibitor dapagliflozin, but experts remain hopeful for the novel class of antidiabetic drugs.Dan Jones glucose levels directly by suppressing immediate question is whether the difference glucose reabsorption via kidney-expressed is just due to chance. John Wilding,Last month a US Food and Drug SGLT2. And although concerns about Head of the Department of Obesity andAdministration (FDA) advisory committee potential cardiovascular side effects have Endocrinology at the University of Liverpool,voted 9–6 against the approval of been a major issue for approved and UK — and an investigator for dapagliflozinBristol-Myers Squibb and AstraZeneca’s investigational diabetes drugs in recent and other SGLT2 inhibitors — raises anotherfirst-in-class dapagliflozin for type 2 diabetes. years in the wake of the problems with possibility. “I suspect what we’re seeing hereFor many of the panellists, safety concerns — GlaxoSmithKline’s Avandia (rosiglitazone), is a diagnosis bias,” he says. In the case ofmost notably a possible increased incidence SGLT2 inhibitors seem to promote weight bladder cancer, glucose in the urine increasesof bladder and breast cancer among patients loss and so might reduce cardiovascular the incidence of urinary tract infections,receiving the drug — precluded its approval. risks. They have therefore been seen as which could increase the likelihood thatBut while the negative vote threatens to providing a promising new therapeutic treated patients visit their urologists, havecast a shadow over the burgeoning class of avenue, both as a monotherapy and in their urine examined and are diagnosed withsodium-dependent glucose co-transporter 2 combination with other agents (Nature Rev. bladder cancer. This idea is supported by the(SGLT2) inhibitors, the jury is not yet out. Drug Discov. 9, 551–559; 2010). fact that six of the nine patients diagnosed First, the FDA is not due to rule on “This is a new class of agents that work with bladder cancer showed haematuriadapagliflozin until the end of October in a completely different way to any of the (blood in the urine), which is often a sign2011. Although the agency nearly always existing diabetes therapies,” says Bailey. of developing pathology, before startingfollows negative advisory committee “In principle they should be effective at any the trial. Similarly, the weight loss in therecommendations, it is not obliged to. In a stage in type 2 diabetes, because their effects treatment arms may have made lumps in thenotable case, the FDA conditionally approved are independent of the secretion and action breast easier to find, and therefore increasedRoche/Genentech’s Avastin (bevacizumab) of insulin, and they could also be used in type the rate at which breast cancer was diagnosedin 2008 for metastatic breast cancer despite 1 diabetes alongside insulin therapy, which is — an effect that has also been reporteda 5–4 vote against its approval from another why they’ve generated so much interest.” with weight-loss drugs, says Wilding.advisory committee. And as some experts “This is more likely to be early diagnosis ofhope that the nominally increased incidence Is the cancer risk real? pre-existing or developing cancer, rather thanof carcinogenicity with dapagliflozin could One of the key issues contributing to the drug causing cancer.”be an experimental artefact, if not a chance the negative vote for dapagliflozin was There are further reasons to doubtfinding, the drug may still have a chance of a concern over carcinogenicity. In particular, that dapagliflozin caused these cancers,first-cycle approval. panellists were swayed by a higher — but not says Bailey. “Half of the cases of bladder Clifford Bailey, professor of clinical statistically significant —number of bladder cancer were detected within 6–12 monthsscience at Aston University, UK, and an and breast cancers in the treatment arms of entering the trial, and were sufficientlyinvestigator on dapagliflozin clinical trials, compared with the placebo arms. Among advanced in most cases that they are highlyadds that the panel was presented with data the treatment arms of the 11 Phase III trials unlikely to have been caused by the drug,”that had only become available shortly before that comprised dapagliflozin’s submission he says. In addition, preclinical animalthe meeting, and more will be forthcoming. package, there were 9 cases of bladder cancer toxicology has not suggested a cancer risk.“The panel understandably wanted to wait for out of 5,478 patients (0.16%) and 9 cases of “Dapagliflozin has been studied at up toa fuller picture,” says Bailey. If these data allay breast cancer out of 2,223 female patients 100 times the clinical dose in animals, andthe cancer concerns, then the tide may still (0.4%). By comparison, in the placebo arms over several years, and there’s no evidence ofturn for dapagliflozin. As yet, there does not of the trials there was 1 case of bladder cancer carcinogenesis or mutagenesis.”seem to be any clear evidence of a cancer risk out of 3,156 patients (0.03%) and 1 case of Once regulators have had a chancefrom trials of other SGLT2 inhibitors either breast cancer out of 1,053 female patients to review the entire data package for(TABLE 1), leaving many optimistic for the (0.09%). One case of liver toxicity was also dapagliflozin, the field may also gain moreoverall class as well. observed in the treatment arms. clarity on potential implications for other Whereas most current diabetes treatments Given the lack of statistical significance of agents in the class. John White, professoraddress insulin resistance and impaired the bladder and breast cancer observations of pharmacotherapy at Washington Stateinsulin secretion, SGLT2 inhibitors affect (P = 0.15 and P = 0.27, respectively), an University, USA, says that “more often ▶NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | SEPTEMBER 2011 | 645 © 2011 Macmillan Publishers Limited. All rights reserved
  • 2. N E W S & A N A LY S I Sthan not, side effects are class effects”. But agents remaining in development have aexceptions are common. For example, in the C-glycosidic linkage, which confers greaterdiabetes area, Roche recently discontinued This is more likely to be early stability to the molecules, says Wilding.development of its glucagon-like peptide From a structural perspective, one notable diagnosis of pre-existing or1 (GLP1) mimetic taspoglutide because of exception in the class is Isis Pharmaceuticals’hypersensitivity concerns, an effect that hasn’t developing cancer, rather than antisense molecule ISIS-SGLT2Rx, whichbeen seen with any of the other approved the drug causing cancer. reduces the expression of SGLT2. The agentor experimental GLP1 mimetics. Apparent is currently in Phase I trials, with resultsdifferences in the side-effect profile of expected later this year.dipeptidyl peptidase 4 inhibitors — another Another inhibitor, Lexicon Pharmaceuticals’popular class of antidiabetic drugs —have Pivotal trials from the other leading LX4211, differentiates itself from the pack byalso contributed to the approval of sitagliptin investigational SGLT2 inhibitor, Boehringer simultaneously targeting SGLT2 in the kidneyand saxagliptin in the United States versus a Ingelheim’s empagliflozin, could also provide and SGLT1 in the lumen of the GI tractdelay for alogliptin and a withdrawn approval results next year. (SGLT1 is also expressed in the kidney atsubmission for vildagliptin (although More clinical data will also shed light on lower levels). There has been some warinessvildagliptin has been approved in Europe). whether there are any meaningful differences in the field about targeting SGLT1 because Brian Zambrowicz, Vice President in the biological effects of the current SGLT2 of the potential for intolerable GI effects. “Ifand Chief Scientific Officer of Lexicon inhibitors in development. To date, Phase II you block SGLT1 to any great extent, you’rePharmaceuticals, argues, moreover, that as clinical data on dapagliflozin, canagliflozin, likely to end up with severe diarrhoea,”yet there is no evidence to suggest that these empagliflozin and Astellas Pharma’s ASP-1941 says Wilding. “Blocking a small amount ofcancers are linked to SGLT2 inhibition. “Of provide little information. “From the data I’ve SGLT1 in the gut might help a little bit, butthe 50 or so humans known to lack functional seen, there’s not much difference between it probably isn’t something that is consideredcopies of the genes encoding SGLT2, no them in terms of efficacy profiles,” says desirable.”similar problems have been reported,” he Wilding. “Different studies have revealed Lexicon’s Zambrowicz is aware of thesesays. “In addition, we’ve created hundreds of slightly different side-effect profiles, but there’s concerns, but thinks they’re unfounded.SGLT2-knockout animals, and they do not nothing that makes me think, ‘Goodness me, “The dogma in the industry is that youappear to suffer a higher incidence of these this drug is very different’. ” don’t want to inhibit SGLT1 because you’llcancers.” Overall, says Zambrowicz, “there’s This is in contrast to pharmacokinetic have GI effects, but we have not observedno evidence that these supposed effects are differences between earlier and more recent these in animal pharmacology studies ormechanism-based”. SGLT2 inhibitors. “All of the SGLT2 inhibitors in Phase IIa trials,” he says. On the efficacy that are currently in development are stable side, Zambrowicz says that LX4211 producesThe SGLT2 inhibitor pipeline molecules with a long half-life,” says Wilding. rapid and robust drops in fasting plasmaGiven the outstanding questions, there is Getting to this point has been a learning glucose levels, improvements in postprandialclearly a need for more data. Thankfully, the experience based on the failure of earlier glycaemic control and reductions in levelsnext batch of clinical results is coming soon. SGLT2 inhibitors, such as GlaxoSmithKline’s of haemoglobin A1c (HbA1c), a measureJohnson & Johnson is currently running sergliflozin and remogliflozin, which showed of the ability to control glucose levels in theglobal Phase III trials of its SGLT2 inhibitor unfavourable pharmacokinetics and were long term. The HbA1c reductions achievedcanagliflozin. These trials are planned to discontinued in Phase II development. Both in the clinic with LX4211 after 4 weeks mayenrol 10,000 patients in total — twice as of these agents contained an O-glycosidic also be comparable to those achieved with themany as in dapagliflozin’s combined Phase III linkage that made them susceptible to SGLT2-specific inhibitors after 12 weekstrials. Results are expected in the first half of hydrolysis by β-glucosidase enzymes in (Ann Med. 15 Apr 2011 [epub ahead ofnext year. “I think that the canagliflozin data the gastrointestinal (GI) tract, reducing print]). LX4211 entered Phase IIb trials in Julywill really clarify things,” says Zambrowicz. their half-life. By contrast, most of the this year, and top-line results are expected in the first half of next year. Table 1 | The SGLT2 pipeline As these and other trials start to provide results, sponsors and regulators will be Name Lead company Phase paying close attention to any potential Dapagliflozin Bristol-Myers Squibb NDA carcinogenicity signals. Yet, says White, Empagliflozin (BI 10773) Boehringer Ingelheim III there are some simple steps that sponsors Canagliflozin Johnson & Johnson III who haven’t committed to Phase III trials yet could take, if the FDA rules that further data Ipragliflozin (ASP1941) Astellas Pharma IIb will be needed to address concerns about LX4211* Lexicon Pharmaceuticals IIb this potential risk. With regard to bladder BI 44847 Boehringer Ingelheim II cancer, they may want to consider excluding Tofogliflozin (CSG452) Chugai Pharmaceutical II patients who have unexplained haematuria at the beginning of the study, and monitor PF-04971729 Pfizer II urine analysis more closely during the study. TS-071 Taisho Pharmaceutical II “They should perhaps also ensure that female ISIS-SGLT2Rx Isis Pharmaceuticals I patients receive a mammogram before, *LX4211 is a dual sodium-dependent glucose co-transporter 1 (SGLT1) and SGLT2 inhibitor. NDA, new during and after the trial to address the breast drug application. cancer concerns,” says White.646 | SEPTEMBER 2011 | VOLUME 10 www.nature.com/reviews/drugdisc © 2011 Macmillan Publishers Limited. All rights reserved