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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 and
Administration (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 dapagliflozin
Bristol-Myers Squibb and AstraZeneca’s                investigational diabetes drugs in recent                   and other SGLT2 inhibitors — raises another
first-in-class dapagliflozin for type 2 diabetes.     years in the wake of the problems with                     possibility. “I suspect what we’re seeing here
For many of the panellists, safety concerns —         GlaxoSmithKline’s Avandia (rosiglitazone),                 is a diagnosis bias,” he says. In the case of
most notably a possible increased incidence           SGLT2 inhibitors seem to promote weight                    bladder cancer, glucose in the urine increases
of 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 that
But while the negative vote threatens to              providing a promising new therapeutic                      treated patients visit their urologists, have
cast a shadow over the burgeoning class of            avenue, both as a monotherapy and in                       their urine examined and are diagnosed with
sodium-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 haematuria
dapagliflozin until the end of October                in a completely different way to any of the                (blood in the urine), which is often a sign
2011. Although the agency nearly always               existing diabetes therapies,” says Bailey.                 of developing pathology, before starting
follows negative advisory committee                   “In principle they should be effective at any              the trial. Similarly, the weight loss in the
recommendations, it is not obliged to. In a           stage in type 2 diabetes, because their effects            treatment arms may have made lumps in the
notable case, the FDA conditionally approved          are independent of the secretion and action                breast easier to find, and therefore increased
Roche/Genentech’s Avastin (bevacizumab)               of insulin, and they could also be used in type            the rate at which breast cancer was diagnosed
in 2008 for metastatic breast cancer despite          1 diabetes alongside insulin therapy, which is             — an effect that has also been reported
a 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 of
hope that the nominally increased incidence           Is the cancer risk real?                                   pre-existing or developing cancer, rather than
of 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 doubt
finding, 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 months
science at Aston University, UK, and an               and breast cancers in the treatment arms                   of entering the trial, and were sufficiently
investigator on dapagliflozin clinical trials,        compared with the placebo arms. Among                      advanced in most cases that they are highly
adds 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 animal
the 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 to
a fuller picture,” says Bailey. If these data allay   breast cancer out of 2,223 female patients                 100 times the clinical dose in animals, and
the cancer concerns, then the tide may still          (0.4%). By comparison, in the placebo arms                 over several years, and there’s no evidence of
turn 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 chance
from 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 more
overall 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, professor
address insulin resistance and impaired               the bladder and breast cancer observations                 of pharmacotherapy at Washington State
insulin 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
N E W S & A N A LY S I S

than not, side effects are class effects”. But                                                                  agents remaining in development have a
exceptions are common. For example, in the                                                                      C-glycosidic linkage, which confers greater
diabetes 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 or
1 (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, which
been seen with any of the other approved              the drug causing cancer.                                  reduces the expression of SGLT2. The agent
or experimental GLP1 mimetics. Apparent                                                                         is currently in Phase I trials, with results
differences 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 by
also contributed to the approval of sitagliptin      investigational SGLT2 inhibitor, Boehringer                simultaneously targeting SGLT2 in the kidney
and saxagliptin in the United States versus a        Ingelheim’s empagliflozin, could also provide              and SGLT1 in the lumen of the GI tract
delay for alogliptin and a withdrawn approval        results next year.                                         (SGLT1 is also expressed in the kidney at
submission for vildagliptin (although                    More clinical data will also shed light on             lower levels). There has been some wariness
vildagliptin 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. “If
and Chief Scientific Officer of Lexicon              inhibitors in development. To date, Phase II               you block SGLT1 to any great extent, you’re
Pharmaceuticals, 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 of
cancers are linked to SGLT2 inhibition. “Of          provide little information. “From the data I’ve            SGLT1 in the gut might help a little bit, but
the 50 or so humans known to lack functional         seen, there’s not much difference between                  it probably isn’t something that is considered
copies 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 these
says. “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 you
appear to suffer a higher incidence of these         this drug is very different’. ”                            don’t want to inhibit SGLT1 because you’ll
cancers.” Overall, says Zambrowicz, “there’s             This is in contrast to pharmacokinetic                 have GI effects, but we have not observed
no evidence that these supposed effects are          differences between earlier and more recent                these in animal pharmacology studies or
mechanism-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 produces
The SGLT2 inhibitor pipeline                         molecules with a long half-life,” says Wilding.            rapid and robust drops in fasting plasma
Given the outstanding questions, there is            Getting to this point has been a learning                  glucose levels, improvements in postprandial
clearly a need for more data. Thankfully, the        experience based on the failure of earlier                 glycaemic control and reductions in levels
next batch of clinical results is coming soon.       SGLT2 inhibitors, such as GlaxoSmithKline’s                of haemoglobin A1c (HbA1c), a measure
Johnson & Johnson is currently running               sergliflozin and remogliflozin, which showed               of the ability to control glucose levels in the
global Phase III trials of its SGLT2 inhibitor       unfavourable pharmacokinetics and were                     long term. The HbA1c reductions achieved
canagliflozin. These trials are planned to           discontinued in Phase II development. Both                 in the clinic with LX4211 after 4 weeks may
enrol 10,000 patients in total — twice as            of these agents contained an O-glycosidic                  also be comparable to those achieved with the
many as in dapagliflozin’s combined Phase III        linkage that made them susceptible to                      SGLT2-specific inhibitors after 12 weeks
trials. Results are expected in the first half of    hydrolysis by β-glucosidase enzymes in                     (Ann Med. 15 Apr 2011 [epub ahead of
next year. “I think that the canagliflozin data      the gastrointestinal (GI) tract, reducing                  print]). LX4211 entered Phase IIb trials in July
will 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

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Dapagliflozina e câncer

  • 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 and Administration (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 dapagliflozin Bristol-Myers Squibb and AstraZeneca’s investigational diabetes drugs in recent and other SGLT2 inhibitors — raises another first-in-class dapagliflozin for type 2 diabetes. years in the wake of the problems with possibility. “I suspect what we’re seeing here For many of the panellists, safety concerns — GlaxoSmithKline’s Avandia (rosiglitazone), is a diagnosis bias,” he says. In the case of most notably a possible increased incidence SGLT2 inhibitors seem to promote weight bladder cancer, glucose in the urine increases of 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 that But while the negative vote threatens to providing a promising new therapeutic treated patients visit their urologists, have cast a shadow over the burgeoning class of avenue, both as a monotherapy and in their urine examined and are diagnosed with sodium-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 haematuria dapagliflozin until the end of October in a completely different way to any of the (blood in the urine), which is often a sign 2011. Although the agency nearly always existing diabetes therapies,” says Bailey. of developing pathology, before starting follows negative advisory committee “In principle they should be effective at any the trial. Similarly, the weight loss in the recommendations, it is not obliged to. In a stage in type 2 diabetes, because their effects treatment arms may have made lumps in the notable case, the FDA conditionally approved are independent of the secretion and action breast easier to find, and therefore increased Roche/Genentech’s Avastin (bevacizumab) of insulin, and they could also be used in type the rate at which breast cancer was diagnosed in 2008 for metastatic breast cancer despite 1 diabetes alongside insulin therapy, which is — an effect that has also been reported a 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 of hope that the nominally increased incidence Is the cancer risk real? pre-existing or developing cancer, rather than of 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 doubt finding, 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 months science at Aston University, UK, and an and breast cancers in the treatment arms of entering the trial, and were sufficiently investigator on dapagliflozin clinical trials, compared with the placebo arms. Among advanced in most cases that they are highly adds 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 animal the 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 to a fuller picture,” says Bailey. If these data allay breast cancer out of 2,223 female patients 100 times the clinical dose in animals, and the cancer concerns, then the tide may still (0.4%). By comparison, in the placebo arms over several years, and there’s no evidence of turn 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 chance from 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 more overall 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, professor address insulin resistance and impaired the bladder and breast cancer observations of pharmacotherapy at Washington State insulin 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 S than not, side effects are class effects”. But agents remaining in development have a exceptions are common. For example, in the C-glycosidic linkage, which confers greater diabetes 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 or 1 (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, which been seen with any of the other approved the drug causing cancer. reduces the expression of SGLT2. The agent or experimental GLP1 mimetics. Apparent is currently in Phase I trials, with results differences 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 by also contributed to the approval of sitagliptin investigational SGLT2 inhibitor, Boehringer simultaneously targeting SGLT2 in the kidney and saxagliptin in the United States versus a Ingelheim’s empagliflozin, could also provide and SGLT1 in the lumen of the GI tract delay for alogliptin and a withdrawn approval results next year. (SGLT1 is also expressed in the kidney at submission for vildagliptin (although More clinical data will also shed light on lower levels). There has been some wariness vildagliptin 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. “If and Chief Scientific Officer of Lexicon inhibitors in development. To date, Phase II you block SGLT1 to any great extent, you’re Pharmaceuticals, 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 of cancers are linked to SGLT2 inhibition. “Of provide little information. “From the data I’ve SGLT1 in the gut might help a little bit, but the 50 or so humans known to lack functional seen, there’s not much difference between it probably isn’t something that is considered copies 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 these says. “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 you appear to suffer a higher incidence of these this drug is very different’. ” don’t want to inhibit SGLT1 because you’ll cancers.” Overall, says Zambrowicz, “there’s This is in contrast to pharmacokinetic have GI effects, but we have not observed no evidence that these supposed effects are differences between earlier and more recent these in animal pharmacology studies or mechanism-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 produces The SGLT2 inhibitor pipeline molecules with a long half-life,” says Wilding. rapid and robust drops in fasting plasma Given the outstanding questions, there is Getting to this point has been a learning glucose levels, improvements in postprandial clearly a need for more data. Thankfully, the experience based on the failure of earlier glycaemic control and reductions in levels next batch of clinical results is coming soon. SGLT2 inhibitors, such as GlaxoSmithKline’s of haemoglobin A1c (HbA1c), a measure Johnson & Johnson is currently running sergliflozin and remogliflozin, which showed of the ability to control glucose levels in the global Phase III trials of its SGLT2 inhibitor unfavourable pharmacokinetics and were long term. The HbA1c reductions achieved canagliflozin. These trials are planned to discontinued in Phase II development. Both in the clinic with LX4211 after 4 weeks may enrol 10,000 patients in total — twice as of these agents contained an O-glycosidic also be comparable to those achieved with the many as in dapagliflozin’s combined Phase III linkage that made them susceptible to SGLT2-specific inhibitors after 12 weeks trials. Results are expected in the first half of hydrolysis by β-glucosidase enzymes in (Ann Med. 15 Apr 2011 [epub ahead of next year. “I think that the canagliflozin data the gastrointestinal (GI) tract, reducing print]). LX4211 entered Phase IIb trials in July will 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