CENTER FOR DRUG EVALUATION AND
`RESEARCH ’
`
`APPLICATION NUMBER:
`
`22-350
`
`. OFFICE DIRECTOR MEMO
`
`

`

`Summary Basis for Regulatory Action
`
`
`Ju_ly 31, 2009
`Curtis J. Rosebraugh, MD, MPH
`
`Director, Office of Dflg Evaluation 11
`
`Summary Review
`NDA 22-350
`
`
`NDA/BLA #
`Sun 4 #
`
`A licant Name
`Proprietary /'
`Established
`
`Bristol-M ers Suibb
`Onglyza
`saxagliptin
`
`
`
`Dosage Forms /
`Strength
`Proposed
`Indication s
`
`Tablets
`2.5 mg_and 5 mg
`As an adjunct to diet and exercise to improve glycemic control in adults
`with e 2 diabetes mellitus
`
`Introduction and Discussion
`
`This review will be a brief summary ofthe basis for the regulatory action regarding saxagliptin
`and the reader should refer to the reviews in the action package for a more detailed discussion.
`Saxagliptin is an inhibitor ofthe serine protease enzyme - dipeptidyl peptidase IV (DPP-4)
`which is responsible for the rapid degradation of the incretin hormones, glucagon-like peptide-
`1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are short-
`lived intestinal peptides released in response to food ingestion that have an inhibitory effect on
`glucagon (which would result on inhibiting hepatic glucose synthesis) and an enhancing effect
`on insulin secretion when serum glucose is elevated. DPP-4 inhibitors therefore enhance the
`effect of the incretins by increasing their circulating half-life. Of note is that incretins have
`minimal, if any, effect on insulin secretion when glucose is normal or low and therefore would
`likely have less hypoglycemia as compared to some of the other agents used to treat diabetes.
`
`The Agency has recently approved two agents that manifest their activity through the incretin
`pathway. The first is sitagliptin, a DPP-4 inhibitor like saxagliptin that is also administered
`orally, and the other is exenatide, a 34-amino acid GLP-l analogue that has agonistic activity
`at the GLP-1 receptor and is given by twice—daily subcutaneous injection.
`
`Over the last two to three years, concerns over the cardiovascular safety of certain diabetic
`drugs have led to debate regarding the adequacy of development programs to assure that these
`agents don’t increase the cardiovascular risk in diabetic populations, which already have a 2-4
`fold increase risk for cardiovascular events compared to matched non-diabetic populations.
`This issue was discussed at an Advisory Committee meeting in July of 2008, where the panel
`recommended that glycemic control agents for type 2 diabetes coming before the agency for
`approval should have pre-approval cardiovascular assessment screening, with further post—
`approval definitive testing to determine that increased cardiovascular risks associated with the
`medication are not noted. After much internal deliberation, we issued a final guidance
`
`

`

`incorporating recommendations from the advisory committee. This guidance allows for a two-
`step, ‘step-wise’ assessment ofpotential cardiovascular risk during drug development. The
`first step, ‘step-one’, is to make a determination that the investigational agent has an upper
`bound of a two-sided 95 percent confidence interval for the estimated risk ratio of less than 1.8
`compared to a control group (with a point estimate near unity). Assuring that there is not an
`eighty percent increase in risk would allow marketing while a longer and larger outcome
`study, which would assure even less risk, is conducted. The boundary of 1.8 was chosen
`because a more conservative ‘goal-post’ to pre-approval testing would be too
`burdensome/prohibitive to drug develop, but this level of assurance (1.8) would be feasible
`and would provide some assurances while further testing was underway. The ‘step-two’
`testing would be accomplished by a larger outcome study that must demonstrate that the
`investigational agent has an upper bound of a two-sided 95 percent confidence interval for the
`estimated risk ratio of less than 1.3 compared to a control group in order for marketing to
`continue. Although one could question whether ruling out an 80% increase for initial
`marketing and ultimately ruling out a 30% increase is enough assurance, the reality is that
`these goals are what is practical to actual test in a randomized trial and the practicality of the
`situation was instrumental in dictating the risk ratios described above. It should also be noted
`that these risk ratios should be viewed in the context ofthe necessity that the point estimate is
`near unity.
`
`These principles incorporate recommendations from the advisory committee. The details of
`this approach are outlined in the guidancel, but of relevance is that at the time of issuance of
`the guidance, three NDA’s were in review. We concluded that recommendations should apply
`to all ongoing programs including those with applications pending with the agency at the time
`of guidance issuance. Although not totally in alignment with the guidance, two of the three
`seemed to, in spirit, fulfill ‘step-one’ which would allow for marketing while awaiting the
`results of a ‘step-two’ definitive study. These two applications, one being this one, were
`presented at an Advisory Committee meeting (April 1 and 2, 2009), where the majority of the
`panel members concurred that ‘step-one’ had been fulfilled for saxagliptin that would allow
`marketing from a cardiovascular evaluation standpoint. Please see reviews of Drs. Parks, Joffe
`and Lowy for further details.
`
`As another point for consideration, there has been concern with the DPP-4 inhibitors in regard
`to their potential adverse event profile based on their promiscuity toward other DPP enzymes,
`in particular DPP-8/9. During phase 3 development of a different DPP—4 agent, it was noted
`that monkeys developed dose and duration dependent cutaneous lesions that ranged from some
`flaking and blistering to frank ulceration and necrosis requiring euthanasia of the animals.
`Therefore, 13-week monkey studies (the most sensitive species) have been required of all
`DPP-4 agents in development. Sitagliptin, the currently marketed agent, did not cause these
`lesions in monkeys, and it was felt that this was because it was highly selective for DPP—4 with
`little activity for other DPP enzymes. Saxagliptin is also fairly selective for DPP—4, but it has
`been noted to cause these lesions. However, this happens only at doses 20-fold (mild) to 60-
`fold (necrotizing) above clinical exposure, so a large safety margin exists.
`
`
`
`’ Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes,
`December 2008, Clinical/Medical.
`
`

`

`Another concern is that there are now postmarketing reports of pancreatitis in association with
`Byetta and Januvia that call into question if drugs working through the incretin system may
`have adverse effects on the pancreas. This is actively under review, but needs to be considered
`for any evaluation, and perhaps, labeling for saxagliptin.
`
`Finally, a non-clinical finding for saxagliptin that will require further exploration was
`unexpected teratorgenicity in a rat embryofetal development study during co-administration of
`saxagliptin/metformin in a fixed dose tablet. This finding has been thoroughly reviewed and
`discussed by the division and upper pharmacology/toxicology management, all of which
`concur that this would not prohibit marketing, but should be more thoroughly explored as part
`of a post-marketing requirement to inform labeling and perhaps our concepts of What is needed
`for other combination tablets. I will discuss this issue more below.
`
`' The Division and I agree that saxagliptin may be approved for marketing as long as
`appropriate labeling can be agreed upon.
`
`Efficacy
`
`Efficacy has been thoroughly discussed in Ms. Mele’s and Drs. Lowy and Joffe’s reviews. I
`agree with their conclusions and Iwill not repeat the specifics here. The following table from
`Dr. Joffe’s review (Page 13) demonstrates the efficacy results for the randomized trials.
`
`
`T
`
`able 2. HbAlc % results for the base 2 and 3 clinical trials intent-to—treat Houlation
`Change from Difference in adjusted
`.
`.
`Baseline
`
`baseline
`mean change
`N mean :l: SE1
`p-value
`
`Ad'. mean t SE2
`95% CI
`.
`
`
`
`Stud CV181008 dose-ran in —— 12-weeks for cohort 1; 6 weeks for cohort 2
`
`Saxa 2.5 mg (cohort l)
`55
`~05 (-O.8, -0.l)
`<0.01
`
`
`
`
`
`Saxa 5 mg (cohort l)
`<0.001
`47
`-0.6 (—l .0, -0.3)
`
`
`
`
`
`
`
`Saxa 10 mg (cohort 1)
`63
`-0.5 (—0.9, -0.2)
`<0.001
`
`
`
`
`
`-0.5 (~0.8, -0.l)
`<0.01
`Saxa 20 mg (cohort l)
`54
`
`
`
`
`
`-0.5 (-O.9, ~02)
`<0.01
`Saxa 40 mg (cohort l)
`52
`
`
`
`
`
`Placebo (cohort l)
`67
`
`
`Saxa 100 mg (cohort 2)
`44
`
`-0.7 (-1.0,—0.5)
`Not provided
`
`
`Placebo (cohort 2)
`41
`
`
`Stud CV181011 monothera
`
`
`Saxa 2.5 mg
`
`~0.6 (—0.9, 43.3)
`
`Saxa 5 mg
`-0.6 (-0.9, -O.4)
`
`
`
`
`95
`-O.7 (-1.0, -0.4)
`Saxa 10 mg
`
`
`
`
`Placebo
`92
`
`
` Stud CV181038 monothera.
`
`
`67
`
`Saxa 2.5 mg (AM)
`
`
`—0.5 (—0.7, -02)
`Saxa 2.5 mg—>5 mg (AM)
`69
`-O.4 (-0.7, ~0.1)
`
`
`
`
`Saxa 5 mg (AM)
`69
`~04 (-0.7, -O.1)
`
`
`
`
`Saxa 5 mg (PM)
`70
`-O.4 (-0.6, -0.1)
`
`
`
`
`Placebo
`68
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`'
`
`Stud CV181013 add-on to thiazolidinedione
`Saxa 2.5 mg
`192
`8.2:t0.l
`—0.7:e0.1
`-0.4 (—0.6, —0.2)
`<0.001
`Saxa 5 mg
`183
`8.4:1:0.1
`-0.9i0.1
`-0.6 (-0.8, -0.4)
`<0.001
`Placebo
`180
`8.2:h0.1
`-0.3:I:0.1
`
`Stud CV181014 add-on to metformin
`
`
`
`
`
`
`Saxa 2.5 mg
`186
`8.13:0.1
`-0.7 (-0.9, —0.5)
`
`Saxa 5 mg
`-0.8 (—1.0, -0.6)
`8.1:t0.1
`186
`
`
`Saxa 10 mg
`
`
`8.0i0.1
`-0.7 (-0.9, -0.5)
`180
`Placebo
`175
`8.1:E0.1
`
`tud CV181'040 add-on to sulfon lurea
`
`
`Saxa 2.5 mg
`246
`8.4:h0.1
`-0.5i0.1
`-0.6 (-0.8, -0.5)
`<0.001
`Saxa 5 mg
`250
`8.5:t0.1
`-0.7d:0.1
`-0.7 (-0.9, -0.6)
`<0.001
`Placebo + gl buride
`264
`8.43:0.1
`+0.1i0.l
`Stud CV181039 initial combination with metformin
`
` 306
`Saxa 5 mg + met
`315
`Saxa 10 mg + met
`317
`Saxa 10 mg
`Met
`313
` :tSD for -008 and -011;
`:|:SD for -011; SE=standard error; CI=conf1dence interval
`
`
`
`The table above demonstrates that the sponsor has conducted multiple monotherapy and
`combination studies that do demonstrate that saxagliptin has a modest but clinically important
`hypoglycemic effect as measured by change in HbAlc. I agree with Dr. Joffe’s conclusions
`that there is little difference between the 2.5 mg and 5 mg dose, but there is enough evidence
`based on the totality of the data (presented in the other reviews) to suggest that the 5 mg dose
`may provide additional efficacy for some patients not adequately responding to the 2.5 mg
`dose, while not increasing clinical important safety issues.
`
`I do note that the amount of DPP-4 inhibition at 24-hours with the 2.5 mg dose is 37% while
`that with the 5 mg dOSe is 65%. This is interesting because it was original theorized by other
`sponsors that these agents would need to have 80% inhibition at 24-hours to be clinically
`effective. However, we now have saxagliptin and alogliptin which have had less inhibition
`than 80% at 24-hours, but seem to have a plateau in their clinical dose response well below the
`80% DPP—4 inhibition level.
`
`Safety
`
`The available safety data and conclusions are outlined in Drs. Lowy, Joffe and Parks reviews
`and I agree with there conclusions and would refer the reader to their excellent reviews for an
`overview of the safety issues.
`I will only comment on selected issues.
`
`In regards to the cardiovascular safety evaluation, the filing of this application predated
`Agency guidance. As such, this program did not have pre-specified definitions or prospective
`adjudication of major cardiovascular endpoints and any evaluation was retrospective in nature.
`Therefore the cardiovascular event data were evaluated in many different ways. I believe the
`
`

`

`most pertinent aspect of this is that, no matter how the data is ‘sliced and diced’, the criteria of
`being less than the 1.8 goal-post was met with a point estimate near unity (bearing in mind all
`the caveats inherent in any type of unplanned, retrospective analysis on an endpoint that-was
`not originally identified as something of interest and where only a small number of events
`occurred). This does give us some reassurance that saxagliptin will not have a negative
`cardiovascular impact and while not a perfect analysis, does fulfill the spirit of our guidance
`and the Advisory Committee voting reflected this view point as well.
`I believe that due to this
`being an unplanned analysis, retrospective in nature, and with limited events, labeling should
`not include this analysis and should only have the standard labeling that we use for diabetic
`agents noting no conclusive evidence of cardiovascular benefit with any anti—diabetic drug. I
`believe to do otherwise would be misleading, would misrepresent our degree of comfort with
`the data, and Would create an unfair playing field for other agents.
`
`Hypersensitivity was noted in subjects exposed to saxagliptin (using a collection of 65
`preferred terms related to anaphylactic reaction, angioedema, hypersensitivity, edema and
`urticaria) 2.4% (50 events/2043 subjects) compared to 0.6% (5 events/799 subjects) receiving
`placebo. However, these rates were similar when a saxagliptin] metformin group (0.9%:9
`events/978 subjects) was compared to metformin alone (O.9%-3 events/328 subjects). For the
`term ‘hypersensitivity’ there were 18 events (18/2043, 0.9%) compared to none for placebo. I
`reviewed the case summaries supplied by the sponsor and all of these were minor, most
`associated with seasonal rhinitis, and did not cause interruption of therapy. It is difficult to
`interpret these results since there are small numbers involved, but there are reports of
`hypersensitivity/maphylaxis/angioedema/Stevens—Johnson syndrome with Januvia that has
`resulted in labeling changes, so this will need to close monitoring.
`
`As noted by Dr. Joffe, there appears to be minor dose-dependent reductions in lymphocyte
`counts without evidence of clinical repercussions. I agree with him that this could be further
`evaluated in the outcome study.
`
`Dr. Joffe also notes that the incidence of fracture is 1.0 per 100 patient—years for saxagliptin
`(n=35/3021 subjects) compared to 0.6 per 100 patient-years for comparator (n=7/1127
`subjects). The sponsor has been asked to clarify how many of these fractures were the result
`of major trauma and this is pending at this time, but as with the lymphocyte findings, this can
`also be an analysis incorporated into the outcome study.
`
`Saxagliptin and comparator groups had similar incidence of ALT >3x and >5x elevations, but
`had four cases >10x ULN (Sax group included all doses, N=3376; Comparator n=1232). Two
`of these cases had viral hepatitis. The other cases did not demonstrate Hy’s Law criteria and
`there was approximately a 3:1 randomization for saxagliptin compared to placebo. As such, I
`do not believe that a liver signal has been demonstrated, but this can continue to be evaluated
`in the outcome study. The review team, to further evaluate for hepatic toxicity, requested
`additional cases of severe transaminitis that have occurred since the 120-day safety update.
`This search revealed one case that fulfilled criteria for Hy’s law. However, upon unblinding
`this case it was revealed that the subject was taking a comparator medication (glipizide).
`
`

`

`As mentioned above, drugs that work through the incretin system may have adverse effects on
`the pancreas, and this is actively being explored by the agency. As noted in Dr. Joffe’s review
`there were very few events and those that occurred were similar between saxagliptin—treated
`and comparator~treated subjects. However, for the other two drugs we are concerned about
`(Januvia and Byetta), there did not appear to be a pre-clinical or clinical signal in their
`application, yet we have post-marketing reports that are concerning. Therefore, this will need
`to be carefully monitored.
`
`9
`
`Regarding the teratorgenicity finding mentioned above, two fetus rats from a single dam and
`litter were noted to have neural tube malformations (craniorachischisis) in the treatment group
`of saxagliptin/metformin combination at 114x and 4x the clinical dose respectively.
`Craniorachischisis is apparently a rather rare finding in control rats and is therefore a cause of
`concern. There were not any such findings in a group receiving a lower saxagliptin but
`-
`identical metformin dose (21x and 4x clinical dose). The sponsor put forth what they felt was
`a plausible mechanism that related to reduced folate and homocysteine levels due to metformin
`use,‘but since the exposure to metformin did not change between the two groups, and
`saxagliptin does not have any effect on metformin levels or metabolism, we felt this
`explanation was inadequate. It should also be noted that these findings have not been
`demonstrated with metformin given as a single agent or with saxagliptin given as a single
`agent (saxagliptin given at doses greater than 1500x clinical exposure).
`
`These findings were discussed with the Reproductive and Developmental Toxicological
`Subcommittee (RDTS) as well as with the Director and Associate Director of
`Pharmacology/Toxicology where it was decided that the findings may be drug related and
`would require further exploration. However, it was also felt that since these findings had not
`been demonstrated with either drug given as monotherapy increased likelihood that these
`findings were spurious and that, combined with a several-fold safety margin, would allow
`marketing of saxagliptin while further investigation was being done post-approval. As such,
`the phannacology/toxicology review staff members are recommending two required non-
`clinical postmarketing studies to further explore this finding. Until these studies are completed
`and reviewed, labeling should advise of these findings of co—administration of metformin and
`saxagliptin in animals to inform clinicians who may be taking care of women that are pregnant
`or are planning on becoming pregnant.
`
`Advisory Committee Meeting
`
`An advisory committee meeting was held on April 1, 2009 to discuss the cardiovascular safety
`data included in this application. Regarding whether the sponsor had provided evidence to
`rule out an unacceptable excess of cardiovascular risk, 10 panel members voted yes and 2
`panel member voted no. All panel members voted that an appropriate outcome trial should be
`conducted post—marketing.
`
`Conclusions and Recommendations
`
`Saxagliptin has demonstrated efficacy for the 2.5 mg and 5 mg doses in reduction of HbAlc
`levels. This application does have adequate cardiovascular evaluation data to allow initial
`
`

`

`marketing, but will require a formal outcome study. There are other clinical concerns as noted
`above (decreased lymphocyte counts, fractures, skin reactions and hepatotoxicity), but for
`some of these they didn’t occur more often than in placebo/comparator treated subjects or for
`those that did occur more frequently the concern would not be serious enough to rise to the
`level of not allowing marketing. However, the planned outcome trial will allow an excellent
`opportunity to collect further data to define these concerns.
`I recommend approval of this
`application.
`
`

`

`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`CURTIS J ROSEBRAUGH
`07/31/2009
`
`