January 17, 2019; Silver Spring, MD; Notes – Draft

An FDA Advisory Committee voted 8-8 on Sanofi/Lexicon’s NDA for sotagliflozin in adult type 1 diabetes, casting a numerically neutral yet highly controversial vote on the potential first-ever oral adjunct for type 1. As we wrote an hour after the meeting concluded, we can’t remember the last time an Ad Comm was so contentious (or resulted in a tie) – see all of Sanofi/Lexicon’s slides here and FDA’s slides here.

During the morning, the FDA credibly raised concerning points about relative risk increases and real-world evidence from off-label SGLT-2 use in the broad type 1 diabetes patient population, while the OPH testimonies reinforced a very strong case for individual benefit. We believe that the diabetes community is increasingly challenged to reconcile optimal personal therapy with the urgent need to improve population outcomes, particularly given some of the risks that more underserved and vulnerable populations may have. Given that HCPs are overworked in both endocrinology and primary care (and increasingly cardiology), ordinarily we’d say that the population risk should be addressed first, followed by individual risk and benefit – in this particular case, given that we don’t think population risk can be determined only through RCTs, we suggest limited approval and risk assessment and management work “in the real world”. Importantly, there is a big opportunity with a major educational campaign to reduce DKA risk within type 1 diabetes broadly speaking – and as T1D Exchange data shows us, this risk remains significant today.

Ultimately, our biggest questions are about how FDA can help “square” what the population risk is and how it can be addressed so that individuals who are appropriate candidates for the drug can gain “real” access. While some may argue they can easily get SGLT-2s “off-label,” we worry for all those taking it off-label, particularly since it is clear that they are experiencing at least some DKA as a population (not surprisingly, since there is no standardized education – see dQ&A data, below). On balance, we imagine if the drug is approved, it actually will be harder to get if the education works right – and that it will be easier to prevent those who may not be as educated to get it since there will be standards on this. As such, we believe that the FDA will either approve sotagliflozin NDA (and MAA, in the EU) with a strict risk mitigation plan and registry or that it will be delayed while more work is attempted on risk mitigation. Ultimately, pending FDA views, we’d like sotagliflozin to be approved with a strict risk mitigation plan so that some “real-world” experience can be gained that will enable risk management to be assessed.

We are not sure about the risk mitigation plans for AZ’s sNDA/Type II Variation applications for Farxiga (dapagliflozin) in type 1 or Lilly/BI’s anticipated regulatory filings for Jardiance for type 1. Of course, the latter seems to be aggressively pursuing a lower dose as a fundamental aspect of risk mitigation; more intensive education is another route. From where we stand, there’s an enormous onus on the first company to market to “get it right.” In a perfect world, there would be substantial coordination of risk mitigation strategies between manufacturers: From a practical perspective, both patients and providers would benefit greatly from uniformity across the anticipated three drugs in type 1. We’re also eager for thorough validation of any given protocol: How can risk mitigation be made better than what was done in the trials, and how can that be proven? Would it be possible to test a more robust protocol against that used in phase 3 trials?

An opinion from EMA’s CHMP is expected by the end of the month for Sanofi/Lexicon’s sotagliflozin, and BI/Lilly’s Jardiance (empagliflozin) filing could come at any time. Sotagliflozin’s PDUFA date at FDA is technically March 22, 2019, but that’s also contingent on funding and could well be impacted by the US government shutdown.

See below for a deep dive on key themes and highlights from the day’s discussion, summaries of OPH speaker presentations, a breakdown of Committee votes and rationales, plus our take on the competitive implications of this vote and lingering questions.

Top Seven Highlights

1. DKA Dominates the Day: Uncertainty Over Risk-Management Protocol, Possibility of Reducing Real-World Risk; FDA Pushes Back on Hypoglycemia Claim

We’re not sure how DKA risk can be “officially” studied, given the “controlled” nature of clinical trials, which doesn’t match the conditions in which patients would have to manage this risk in the real world. Panelists seemed uncertain of whether risk could truly be “managed” in the real world, and there was great concern voiced over euglycemic DKA, particularly at the high dose (400mg). During the discussion question on DKA, panelists underscored the negative impact of DKA on individuals, the severity of the DKA in inTandem, the expectation that incidence will only be higher outside a clinical trial setting, and the fact that DKA still occurred in trials despite the availability of ketone monitoring supplies to all trial participants. Whether or not patients really understood their DKA education is a major question in our view; in fact, Dr. John Buse has noted that the DKA-related messaging that inTandem participants received was probably far from optimal. There were multiple calls for evidence supporting that risk mitigation protocols actually “work” before exporting any strategies to patients, as well as for more meaningful patient and provider education in addition to written materials and letters. Yet collecting information about what is “not” working would also be hard to get, given the design itself of such a trial may be fairly complicated.

Multiple “no” voters pointed to the eight-fold increased risk (95% CI: 3.2-19.9 with a NNH of 26 patient years; estimated HRs ranged from ~4 to 11 across subgroups) vs. placebo put forth in the morning’s presentations (albeit, from a small base), and FDA outlined the argument that, because sotagliflozin appears to be no different than any other SGLT-2 inhibitor, its Sentinel analysis (#2, just below) indicates substantial risk – above and beyond that seen in inTandem – would follow sotagliflozin to the market. It seems reasonable to assume that risk will be higher outside a clinical trial, though we also think it could be lower with appropriate education. It is very logical that FDA would like to see safety data and risk data – as noted, we’re not sure the data from a very controlled clinical trial will be generalizable. While Sanofi/Lexicon presented broad and multi-faceted plans to tackle patient and provider education (more on these just below), there was uncertainty as to whether these would actually work because there was not trial data – as noted numerous times, we’d like to see how these work in the real world. We do believe the sponsors would have benefitted from having more fleshed-out and robust responses ready for presentation though we know this is very hard to create. Ad Comm member Dr. Kashif Munir put it, disparagingly, on mass communication: “I receive letters all the time, and I throw them away.” Although some might say that Dr. Munir’s commentary is the reality of mass mailings to HCPs who are drowning in mail, we believe that at least Ad Comm members should have to show they are responsible enough to read important mail about patient risk.

Indeed, we had hoped the discussions would lead toward action to reduce DKA in the entire type 1 population. A few panelists alluded to the fact that increased awareness of DKA overall would benefit all type 1s. We were struck by Ms. Tina Roth’s (College Diabetes Network) OPH testimony, in which she stated using an SGLT-2 off-label has only made her feel safer by increasing her knowledge of ketosis and DKA risk. Sanofi/Lexicon made a strong attempt to show that the vast majority of DKA cases have recognizable triggers (these were said to be acute illness or insulin delivery interruption – others could be nausea or other factors.) Presumably, risk can be predicted to some degree (women, pump users, prior DKA) though it is unclear whether they would consider those populations as ones who should not use SGLTs as a result. Sanofi also presented data from a MarketScan analysis showing that DKA rates with SGLT-2s used off-label have gone down over time with visibility of the danger and also likely as fewer new people have gone on this drug (as noted above, see all of Sanofi’s slides here – the MarketScan analysis can be seen toward the end). Additionally, the companies pointed out that after the risk of euglycemic DKA was recognized and the trials’ risk management protocol amended, DKA rates in inTandem also fell – however, due to the small number of events, there was not statistically significant difference, as pointed out by one panelist. Ultimately it seemed Sanofi/Lexicon’s plans for risk management weren’t enough to sway many votes though we believe it was on the right track and would have benefited from more data.

• Sanofi/Lexicon’s proposed risk mitigation program seems a valuable start and includes both prescriber and patient education. Specifically, the sponsors plan to educate ~one million HCPs (endos, emergency room doctors, and nurse practitioners were all mentioned as targets) through product labelling and a communication letter sent within 60 days of approval. We’d rather see communication go prior to launch (which may be what they have in mind) and for it to span creative education channels. Under this program, patients would also receive a portable, in-product alert card containing the signs, symptoms, triggers, and management details of DKA as well as access to a medication guide and website distributed with each prescription fill; though it was not mentioned, we’d also love to see a required video for each patient and a quiz that would test education and retention (if it’s determined this is not needed, the requirement could be dropped over time). As for the content of the professional materials, Sanofi/Lexicon expressed plans to emphasize more specific patient selection, ketone monitoring and mitigation instructions (including use of sick day rules), and insulin dose guidance (see below). Notably, Sanofi/Lexicon labelled these measures as “additional beyond clinical trial activities,” and FDA was quick to point out a little bit wryly that certain clinical trial components, such as complementary ketone monitors, were not included in the sponsor’s proposal.

• Notably, as follow-up, Sanofi/Lexicon plan to report incidence rates of DKA yearly for four years after approval, conduct drug utilization studies to evaluate practice patterns and assess prevention, diagnosis, and treatment of DKA in real-world settings, and undertake prescriber surveys (and hopefully patient ones) to test effectiveness of communication.

• The FDA challenged the sponsors’ claim of a hypoglycemia benefit – although this was surprising, we were glad to hear FDA’s focus on hypoglycemia. Sanofi/Lexicon explained that, on the endpoint of number of symptomatic hypoglycemia events <55 mg/dl, sotagliflozin beat placebo: When pooling inTandem 1 and 2 data, the 200 mg dose was associated with a 22% relative risk reduction (RR=0.78, 95% CI: 0.68-0.88) and 400 mg with a 20% risk reduction (RR=0.80, 95% CI: 0.70-0.91) vs. placebo. This held for inTandem 3 (RR=0.76, 95% CI: 0.68-0.86). However, FDA offered a different interpretation of this data. The agency showed that this benefit was no longer seen when un-pooling the data from inTandem 1 and 2, and felt that the lack of a consistent trend on hypoglycemia measures across phase 3 was not compelling in favor of a hypoglycemia benefit – for example, there was no benefit in the proportion of patients with hypoglycemia <55 mg/dl. While even some of the tougher panelists acknowledged that it seemed a benefit, to some degree, existed, these analyses seemed to simply lack the powered needed to show one. However, it’s important to note that FDA’s analysis only includes up to 24 weeks on inTandem 1 and 2, although both of these studies extend to 52 weeks. Moreover, hypoglycemia was not intended to be an efficacy endpoint in these studies; rather, it was a safety endpoint. For our part, we feel confident that some degree of risk reduction does exist. While this can’t be proven at present, we believe that more hypoglycemia may exist when patients go on SGLTs, particularly with physicians who are not reducing insulin at all. Meanwhile, other protocols may have some standardized insulin reductions when going onto a SGLT may be too much and this may inadvertently result in DKA. Indeed, how much to lower total daily insulin dose when starting an SGLT regimen and whether to cut from basal or bolus insulin remains an open question (one that was hotly debated at ADA as well)

• On a final note, Dr. Mitra Rauschecker closed FDA’s presentation of sotagliflozin data: “To our knowledge, the sponsor does not intend to distribute ketone monitoring supplies.” In general, while we do not see this as the sponsor’s responsibility, we believe this could be useful; on the other hand, there is only so much we think the community can ask of the sponsors. Because access to ketone testing kits is a primary concern in bringing SGLTs to a wider audience, many have suggested that sponsors take the initiative to package BHB meters and strips with the pills. While some call this “an idea that has broad support among patients and providers, but which manufacturers have not really addressed,” it hasn’t been publicly raised and it would be fairly difficult for a pharmaceutical manufacturer to take on this responsibility. If we had a functional system, of course, this would already be determined. We’d also ask if diagnostic companies could all make sure this is at the top of their lists – and to get strips that are more cost-effective would also be very positive (Kelly recently bought a pack of 60 that were $597 at Walgreen’s – luckily Aetna insurance covered them all but surely all patients will not be as lucky). To be sure, cost is an issue for all players here, and while sending patients supplies outright with the drug could make this safer for patients, this will need some assessment since not all patients will need the same number of strips, etc. Ultimately, we’d love to see initiative from all manufacturers on ensuring access and availability but we would likely stop short at bundling them due to logistics.

2. FDA Provides Novel Insights on DKA Data and Risk, Contributing to Overall High Quality of Discussion

In general, though some panelists on the Advisory Committee with less familiarity with type 1 brought down the level of discussion, we were struck by what appeared to be a fairly high level of discussion through this Advisory Committee meeting overall – especially from the Advisory Committee itself as well as from FDA, which brought forth several novel insights in original analyses performed by the agency. This performance from the regulatory agency was also acknowledged by Ad Comm member Dr. Michael Blaha, who characterized the FDA’s presentations as “unusually helpful” at one point, drawing laughs from the packed room. Indeed, FDA contributed to the discussion on several points throughout the day:

• FDA challenged the use of Sanofi/Lexicon’s composite endpoint in inTandem3, both on terms of validity and the view that it masks the severity of DKA risk. The defined composite endpoint in this study was the proportion of subjects with an A1c <7% with no episodes of severe hypoglycemia or DKA. At first glance, this composite endpoint holds merit, as it appears to encompass the three pillars of clinically meaningful outcomes that an efficacious type 1 adjunct therapy must hold: (i) reduce A1c; (ii) do not increase hypoglycemia risk; and (iii) do not cause DKA. Sotagliflozin (400 mg only in this study) met significance on this composite endpoint with a high level of statistical significance (p<0.0001), supporting its efficacy on these terms. However, FDA presented an incisive analysis challenging the utility of this composite endpoint. In its briefing document, FDA noted that the composite endpoint uses a responder rate for glycemic efficacy (achieving or not achieving an A1c target) and puts equal weight on inherently unequal outcomes; e.g. lowering A1c from 7.5% to 6.9% vs. lowering from 9.5% to 6.9%. Moreover, FDA pointed out that DKA events in Study 312 were disproportionately clustered in patients with an A1c >7% – 22 events vs. 3 events in those with an A1c <7%; as a result, the composite endpoint may have been more easily met, seeing as fewer DKA events were likely to occur in patients around an A1c mark above 7%. As the first speaker in the Open Public Hearings, Mr. Sydney Wolf built on this criticism, deeming the composite endpoint a “meaningless way of measuring benefit/risk” because of these aforementioned shortcomings. While we think characterizing this endpoint as “meaningless” is not inappropriate – after all, getting patients to an A1c <7% surely isn’t without merit – we do understand its drawbacks in excluding DKA in the A1c cohort in which it is most common. Overall, the committee as a whole seemed less than satisfied with the endpoint. While one might question whether why FDA and Sanofi/Lexicon were not able to agree on a more appropriate endpoint before the initiation of the study, especially in light of DKA signals seen in earlier trials, we also point out that CGM data at this stage is not accepted by FDA and so “time in range” claims are not yet possible to include in the label (in other words, Sanofi/Lexicon were limited to A1c).

• An FDA Sentinel analysis (per the website, Sentinel “enhances the FDA’s ability to proactively monitor the safety of medical products after they have reached the market and complements the Agency’s existing Adverse Event Reporting System”) of off-label SGLT-2 use in type 1 predicts DKA rates higher than those seen in sotagliflozin’s phase 3 studies. While this may cast doubt on the feasibility of mitigating DKA in real-world settings, we’d point out this has not been tested at length and education to date on DKA (even in the trials) was not as strong as it could be. FDA’s Dr. Christian Hampp presented results from this analysis, which aimed to estimate (i) off-label usage of SGLT-2 inhibitors currently on the market (this was fascinating as it was far higher than we’d imagined); (ii) real-world rates of DKA in these situations; and (iii) compare real-world rates with DKA rates seen in sotagliflozin’s clinical studies – see his slides here. The analysis used administrative claims data from 17 Sentinel data partners, including CMS-Medicare, between March 2013 and June 2018 to identify new users of SGLT-2 inhibitors (as a side note, we can’t imagine CMS would be paying for off-label use – perhaps it was not identifying it). Type 1 diabetes patients were identified in various ways (we would love to see greater discussion of this) and DKA events were recognized based on inpatient/ED diagnosis. Interestingly, assuming the inputs were accurate (we are not sure of this), the analysis found that just under 1% of all SGLT-2 inhibitor users have type 1 diabetes; however, this rate of off-label usage looked considerably higher in younger patients (<25 years old), probably mainly because there are relatively fewer patients with type 2 diabetes in that age group (i.e., a smaller denominator). Rates of DKA hovered between four and eight events per 100 patient years for all available agents in the class in the US (Invokana, Farxiga, and Jardiance). Most importantly, standardizing these rates for age and sex and comparing to them to the sotagliflozin clinical program found that “DKA rates in the Sentinel analysis were significantly higher than expected based on the sotagliflozin clinical trial program.” Dr. Hampp pointed to a couple of reasons that may explain this phenomenon. First, he pointed to a lack of patient/HCP education with off-label usage that inflates DKA risk. This seems obvious, based on OPH testimony, particularly dQ&A data showing poor understanding by so many patients of even the basics of ketone monitoring. As well, the regimented design of clinical trials more than likely reduced DKA rates in that setting – though it would be nice to know about the education in the trial about the monitors themselves and how to use. The question, then, is how to formally bring an SGLT to market for type 1 diabetes and overcome this increased risk. Asked another way, in other words, what happens when someone uneducated in the finer points of diabetes management takes an SGLT inhibitor and:

  • Does not have a meter and has to use urine ketone strips – there still seems to be some debate over to what degree (if at all) this is a problem, particularly among certain patients;

  • Has a meter but doesn’t know how to use it – i.e., how to assess what is a baseline level and what are inappropriate levels;

  • Doesn’t have a blood ketone monitor and doesn’t know whether and how to use urine ketone strips (or whether they are “better” for his or her cohort);

  • Has a meter and has run out of strips and has no urine ketone strips (this seems fixable);

  • Has strips but not multiple strips for when approaching DKA and needs to test frequently (within a matter of hours);

  • Doesn’t understand the protocol of what to do when approaching or in DKA and blood glucose is normal (“take insulin” may be counter-intuitive to some, though followed by eating carbs should be reassuring – though if glucose is low, this may particularly hard to follow);

  • Can’t afford additional strips in months when more are used (we recently saw a receipt for 60 strips that cost nearly $600 – some months far more strips than others may be needed and for some low-risk patients, virtually no strips may be needed, and this may be hard to determine).

• The real-world data are certainly concerning and underscore the need to understand whether proper education, awareness, and other risk mitigation techniques can meaningfully reduce DKA rates outside of a clinical trial setting. Indeed, however, as we understand it, there is growing agreement that randomized controlled trials themselves may not be sufficient to understand DKA risk since it is hard to compare clinical practice to an RCT environment in which DKA risk would be so “controlled.”

3. Outcomes Beyond A1c: Modest A1c Reduction Leaves Some Members Searching for Validated Microvascular, Quality-of-Life Measures; Questions on Long-Term Benefit Linger

Outcomes beyond A1c were referenced throughout the day, evoking both strong support from patients and endocrinologists and challenges from FDA and some panelists. While there was criticism that specific outcomes could not be “proven,” the importance of reducing weight and hypoglycemia was very well-acknowledged by FDA, particularly hypoglycemia.

• Ultimately, we believe we will see more focus on PROs (patient reported outcomes) going forward – one FDA member even congratulated Sanofi/Lexicon for their presentation of quality-of-life and diabetes burden metrics – but we acknowledge they could use more standardization. Indeed, panelists seemed to be asking the broader diabetes ecosystem to develop “diabetes integrative metrics” (e.g., correlative measures between time-in-range and functionality or quality-of-life).

• On the other hand – and despite an early-morning presentation from Dr. Steve Edelman on the unmet clinical needs in type 1 diabetes and the value of outcomes beyond A1c – there was substantial confusion on the panel over the importance of non-A1c endpoints, both in terms of clinical validity and importance to patients.

• One panelist seemed unconvinced of a link between in-range glucose and improved PROs, suggesting that all he currently sees is “anecdotal.” Given recently published evidence (see Beck et al., Validation of Time in Range as an Outcome Measure for Diabetes Clinical Trials, Diabetes Care, August 2018) supporting outcomes beyond A1c, although more data would be nice and FDA acceptance is needed, we feel strongly about the strides that have been made. We know there were multiple thought leaders, including Drs. Edelman and Thomas Danne, in the room who could have helped the panelists on this issue, and it’s unfortunate that some of the panel may not have understood what the data in front of them meant for patients. This is the reality of uneducated or unprepared panel members. That said, we very much appreciated Dr. Low Wang’s comment to her fellow panelists, “I have plenty of patients struggle to get A1c down, it’s hypoglycemia that limits things. That doesn’t alleviate concerns about the drug, but the modest degree of A1c lowering doesn’t capture the whole thing,” and the patient/consumer advocates, particularly Ms. Anna McCollister-Slipp, did a strong job of voicing the importance of non-A1c endpoints like weight and time in zone. Of note, Dr. Satish Garg has said previously that losing weight is what keeps his type 1 patients excited about their off-label SGLT therapy, and what heightens their engagement in their own diabetes care.

• Many patients are convinced about the paramount importance of time-in-range. As shown below, a recent survey conducted by dQ&A and The diaTribe Foundation found that TIR was the #1 outcome having “a big impact on daily life” regardless of diabetes type or insulin use (see below). In our observation, the relatively modest A1c reduction of sotagliflozin (compared to most type 2 diabetes drugs) led many panelists to consider other significant benefits – in many ways, a win – though we wish the evolving relationship of glycemic variability and time-in-range with long-term complication risk would have been better characterized and recognized at the meeting.

• Notably, the non-significant reduction in hypoglycemia conferred by sotagliflozin in phase 2 and 3 trials primarily occurred during the day (see below). This is perhaps to be expected, given the postprandial effects of sotagliflozin (less severe post-meal spikes may lead to more stability) and the majority of insulin reduction due to sotagliflozin’s effect was in bolus insulin. That said, no analysis on hypoglycemia following meals was available. We wonder whether a hypoglycemia benefit is seen for current cohorts and not others – for example, for the patients trying to sort out how much insulin should be reduced who start with “no insulin reduction” – they will not likely seen a hypoglycemia benefit, for example, while patients who have “figured this out” will.

Both micro and macrovascular outcomes were also discussed at length, with significant focus placed on relating the modest A1c reduction with sotagliflozin to microvascular complications (see below). Dr. Edelman strongly commented after a clarifying question, “This is not only a quality of life issue: Data now suggests this may reduce complications. Improving time in range is why patients want this drug. They’ll seek it out, they will get it, so we need regulation and education. Let the patient have a say in the risk-benefit ratio.” It is certainly correct that multiple patients will seek out SGLT-2 inhibitors and use them even if sotagliflozin is not approved, and in the absence of education and ketone monitoring, we believe this constitutes a growing health risk.

Additionally, we’ve heard that patients are actively seeking out SGLT-2 inhibitors hoping for cardio- and renal-protection, sometimes more so than the short-term benefits (even though this has not yet been established in type 1!). By the sponsors’ assessment, the reduction in A1c translates to a roughly 20% risk reduction in retinopathy, neuropathy, and renal disease based on data from the DCCT (see below). However, FDA’s new diabetes lead at CDER, the highly-respected Dr. Lisa Yanoff, pointed out that the DCCT compared intensive glucose control vs. 1980’s standard of care, meaning that the data can’t necessarily be extrapolated to current clinical practice or a study comparing adjunctive sotagliflozin use vs. insulin alone. As a whole, the committee seemed hesitant to accept a long-term benefit on complications (understandable given the lack of evidence and novelty in type 1), or at least uncertain of how to think about one – Dr. de Lemos called any conclusions on this front a “leap of faith,” which we felt was going too far. There was near equal interest in a potential CV benefit. With sotagliflozin, A1c reduction often comes in concert with other favorable CV risk factor improvements in weight and blood pressure – both of which were seen in the clinical development program for sotagliflozin and may well tip then needle further toward CV benefit in the real-world, according to Sanofi representatives. Consideration must also be given to the limited current understanding of how SGLT-2 inhibitors provide CV benefit in type 2 diabetes, where CV risk reduction appears to occur far above and beyond improvements in BP and weight.

• An interesting comment from Dr. Ken Burman reinforced our thinking: He pointed out that insulin optimization in the inTandem program very likely limited the A1c lowering sotagliflozin gave. By this logic, he says, patients in the real-world, “clinical circumstance” would likely see greater A1c reductions than the ~0.4% seen in the trials, in the absence of the intensive, committee-monitored insulin titration that was included in the study’s protocol. And while the studies were designed that way for a reason – to show the true benefit of sotagliflozin on top of well-titrated insulin – the real-world scenario certainly deserves consideration. Given substantial concern over what some felt were unimpressive A1c benefits, we would have appreciated further discussion of this comment, which could have a big impact on how we think about the potential microvascular benefit of sotagliflozin. More importantly, we would’ve appreciated even slightly more focus on the “time in range” data that did exist, even though this is not established as an accepted endpoint by FDA.

• As might be expected, there was not a single case of heart failure in the phase 2 or 3 programs investigating sotagliflozin, so the proven HF benefit of the SGLT-2 inhibitor class could not be assessed with data currently available for sotagliflozin.

4. Patient Agency, Empowerment, and Individualization Emerges as Key Component of Conversation; Day-to-Day Improvements in Functionality, Productivity Underscored

17 patients, providers, and advocates spoke in favor of approval during OPH, emphasizing that patients should have access to therapies that can improve their daily life. In committee discussion, patient responsibility emerged as an interesting piece of the conversation. Dramatically different positions were adopted on this topic, with physicians and researchers taking a more conservative stance. Patient and consumer representatives on the panel underscored the transformative effects of time-in-range and weight improvements, ultimately advocating for more agency and choice to be given to the patient. We believe that there was increased support for sotagliflozin as the day continued, due in no small part to comments from the OPH:

• “I’m the parent of two children with diabetes who are now adults. Thinking about weight control – I have a daughter (also a healthcare provider) who struggles to control her weight – and [sotagliflozin] would be a huge win for her. [It gives her] the glycemic control she needs. But what I’d like to say about this is that … it’s a step in the right direction. I know the clinicians and the physicians here all make decisions for the patient all the time, but – patients need this desperately.” – Ms. Susan Lellock (Patient Representative)

• “I think we need to be careful not to hold the sponsor accountable for the fact that we don’t, as a diabetes community, have particularly good outcomes measures. I don’t think A1c necessarily reflects the experience of patients on a day-to-day basis, so any drug that limits glycemic variability is welcome and needed and the risks can be weighed on an individual basis with physicians. I take two additional drugs in addition to insulin: pramlintide and Victoza. Neither of them have had a material impact on my A1c, but both of them have had significant impact on glycemic variability, quality-of-life, and functionality. These are very critical issues for which we currently have a very limited set of tools in our toolbox – that’s something that needs to be considered. The fact that sotagliflozin can do this alongside weight loss, lowering blood pressure, and potentially renal protection is incredibly significant. I say this as someone with retinopathy and microvascular complications. It’s not that those aren’t important but other things are important too, such as functionality, being able to work, being able to go to the gym and do social activities. So I think we need to think about this in the greater context of living with diabetes, day-to-day risk, functionality, and the fact that this is a chronic disease that is lifelong.” – Ms. Anna McCollister-Slipp (Consumer Representative)
  

The inherent empowerment in giving people with type 1 diabetes another therapeutic choice beyond insulin was cited as a major upside to sotagliflozin – and one that should not be ignored, in our opinion. That said, we hear that many of those who have sought out or been prescribed SGLTs off-label may be more engaged in their diabetes management, as well as more privileged (see Dr. Anne Peters’ OPH below), meaning that the population risk for DKA may be much higher than the individual risk put forth by patient and consumer representatives on the panel and in the OPH.

• Some panelists were not convinced by patient testimony. Specifically, Dr. Cecilia Low Wang cited the OPH stories as “compelling,” but ultimately ineffective in alleviating DKA concerns (we understand why she says this and in fact her comment crystallized this for us), and Dr. de Lemos struggled to connect “anecdotal” evidence of day-to-day benefit based on time-in-range to hard patient outcomes (see our Outcomes Beyond A1c highlight above for more. Said Tufts' Dr. Marvin Konstam, “We need to see in a quantitative way that this drug actually improves patient lives.” Added UT Southwestern’s Dr. de Lemos, “I’m not seeing quantified what I’ve heard in testimonies.” This boils down to a gap in the data – one that we hope will be filled soon.

5. Questions of Dose: Patient/Consumer Reps Advocate for Patient Choice, Specialists Opt for 200 mg Only or Regimented Titration

Lexicon management has previously stated that they’d try to “make the case for [the higher 400 mg] dose,” and the question of dose grew increasingly important as the day wore on. Many panelists expressed substantial reservation over whether the apparent increased DKA risk at 400 mg justified what some saw as marginal increases in weight loss and time-in-range, while others defended the importance of having an up-titration option given heterogeneity in how any given patient might respond to sotagliflozin. We had not seen before (or at least as vivid) the DKA difference in the two doses and we understand why the lower dose might be preferred, even just at the start. During his presentation of efficacy results, Lexicon CMO Dr. Pablo Lapuerta argued that the 400 mg dose should be considered for those who still need better glycemic control after taking 200 mg, and there was some support on the panel for this dose – we like the idea of everyone starting at the lowest dose. Notably, Dr. Yanovski, though he eventually voted “no,” likened the dosing scheme to that of drugs like warfarin – most patients won’t need a higher dose, but some do see substantial benefit from more aggressive dosing (this seemed a bit generalized). Additionally, Ms. McCollister-Slipp characterized the additional weight loss benefit as very compelling for many patients, and it was pointed out that sotagliflozin efficacy was dependent on body weight, with higher doses needed for those at higher body weights to achieve the same level of glucose excretion seen at lower weights. However, many panelists felt that the increased DKA risk the higher dose presented was not justified by the margin of improvement in efficacy. To this end, four distinct stances on dose came out during the approval vote: (i) Don’t approve either dose; (ii) approve only the 200 mg dose because the DKA risk with 400 mg outweighed marginal benefit; (iii) approve both, and require all patients to start on the 200 mg dose and assess efficacy, safety, and ability to monitor DKA risk before up-titrating; or (iv) approve both doses with no titration scheme. No particular consensus was reached on which of the three approval stances was most favorable, with patient and consumer reps advocating for patient choice between both doses and endocrinologists and other specialists opting for the more conservative single dose approval or purposeful titration. Overall, ~one-quarter of the panel seemed to advocate for both doses to be approved in some form or another, another quarter supported only the 200 mg dose, and the other half the panel did not comment due to their “no” vote though we believe some would have advocated for the lowest dose at a minimum if risk mitigation interventions were standardized and successful.

6. Dr. Steve Edelman Opens with the Unmet Clinical Need in T1d; Shares T1D Exchange Registry Data on A1c, Severe Hypo, and Overweight/Obesity

UCSD’s Dr. Steve Edelman took the podium immediately following Dr. Belder’s introduction to speak to the unmet medical need for adjunctive therapies in type 1 diabetes to improve clinical and emotional wellbeing. Beginning with the observation that only one non-insulin medication has been approved for type 1 diabetes since insulin was discovered ~a century ago, Dr. Edelman noted that the current therapeutic armamentarium is limited: With insulin comes risk of hypoglycemia, weight gain (which is associated with hypertension and premature CV disease), and unpredictable swings of blood glucose. Not surprisingly, type 1 outcomes are sorely lacking. Even in the T1d Exchange Registry – a consortium of the very best clinics in the US – only 21% are below the A1c target of 7% (Beck et al. 2012); 4.5%-12.9% of patients reported a severe hypo in the past three months (higher incidence with age; T1d Exchange, 2018); and many are overweight and obese (33%-69% depending on age group; T1D Exchange, 2018). This last point on excess weight resonates with a recent concerning publication showing that rates of overweight and obesity in type 1 diabetes equals those of the general population, and has detrimental effects: Dr. Edelman explained that there’s a 3x higher prevalence of hypertension in type 1, a 10x greater risk of CVD, and a 4x greater risk of hospitalization for heart failure; CVD is the leading cause of death in type 1. As a clinician and 48-year type 1 vet, Dr. Edelman concluded: “We care deeply about reducing glycemic variability and increasing time-in-range. We worry about increased risk of heart disease, and struggling with weight as we get older is a real concern. As a physician living with type 1 diabetes myself, I can tell you there’s a tremendous amount of physical burden affecting patients and their loved ones. There is a need for adjunctive therapies to help people have overall better glycemic control and quality of life.”

7. Amidst Otherwise High-Quality Discussion, Lack of Diabetes Understanding Amongst Panelists Seeps Through

Although the overall level of discussion at this Ad Comm was certainly passionate and of general high-quality, we were nonetheless struck by several comments made by panelists reflecting a poor understanding of diabetes. As noted above, serious confusion persisted throughout the day over outcome beyond-A1c (particularly time-in-range) and their clinical meaningfulness. Evidence continues to build supporting not only on the importance that patients place on these measures, but also on the impact they have on long term complications, and we would have loved to see this acknowledged and understood during discussion. Additionally, one panelist asked whether DKA risk is generally higher in type 1 or type 2 diabetes patients. This lack of understanding is concerning, especially considering that DKA risk was the most important discussion topic of the day. Another particularly concerning question from a panelist asked how many SGLT-2 inhibitors have been taken off the market to date. Zero drugs in the class have been removed from the market – though Invokana does have a black box warning for amputations –  and it seems strange to us that panelists unfamiliar with the class at baseline can strongly sway the fate of a new drug. To be fair, not every panelist is necessarily a diabetologist – and this diversity is surely beneficial in bringing unique perspectives to these panels. However, we sincerely hope that future Ad Comms work to better educate panelists who may not have experience in diabetes on the most essential background facts pertinent to the day’s discussion.

Open Public Hearing

Of the 19 talks in the Open Public Hearing, 17 were firmly in favor of approval. Speakers included Drs. Anne Peters, Satish Garg, Will Cefalu (ADA), Sanjoy Dutta (JDRF), Charles Alexander, Daniel DeSalvo (as read by diaTribe’s Ms. Emily Fitts), Jen Sherr (as read by DiabetesSisters’ Ms. Anna Norton), and representatives from Close Concerns, The diaTribe Foundation, and dQ&A. Read some highlights below. You’ll quickly notice a recurring formula: There is an unmet need in type 1 diabetes; sotagliflozin and the SGLT class can make a big difference; and the DKA risk is serious but manageable. This same sequence seemed to be played on loop all day, though the OPH speakers tended to place more emphasis on the first two variables, while the Committee was more focused on the risk. In hindsight, we think the DKA risk was still mostly discussed in terms of individual risk – not DKA “population” risk, which having now seen the presentations, we agree is an area that is very important to come to consensus on.

• A number of type 1s who have used SGLT inhibitors in studies or off-label made the trek to FDA to tell the committee about the benefits of sotagliflozin. As Dr. Blaha later noted, we only heard from people with positive experiences – not one mentioned having a DKA episode – but these talks were still extremely powerful and persuasive. We’ve included some of the most impactful quotes in the following sub-bullets.

  • “Prior to the study, my daily insulin dose was 31 units, with a basal dose of 14 units per day. In the last month of the study, my total daily dose was down to 21.8 units, and my basal rate was 10 units per day…Before I started, my average blood glucose was 164 mg/dl and standard deviation 78 mg/dl. At the end of the study, my average blood glucose was 143 mg/dl with a standard deviation of 53 mg/dl…I went from 180 to 160 pounds.”

  • “As you are well aware, diabetes shortens a lifespan. I want to do everything possible to live as long as possible; after all, I have many grandkids. With the help of this drug, I see reductions in blood glucose fluctuations, better control, and potential for a lifespan closer to normal.”

  • People without diabetes may consider that treatment protocol for ketones is a burden – I remind all of you that I administer a potentially life-threatening med every day. I also inspect the bottoms of my feet, count carbs, keep glucose tabs around, rotate my insulin pump sites, calibrate my CGM, check OTC and prescription medications that may interfere with my CGM or alter my blood glucose, monitor skin reactions, wear clothes with pockets, avoid pump tubing getting caught on drawers with knobs... Honestly, I don’t think testing ketones is an undue burden.”

  • “Insulin is the gremlin on my shoulder that has been there for 42 years and wants to be fed. This drug, finally one focusing on the day-to-day struggles…As a type 1, having good numbers and A1cs is a constant battle. I’m failing more often than not, and this brought me physical and psychological success.”

  • “I think of [using SGLT inhibitors] like bowling with bumpers. Kids try so hard to get the ball down the lane – bumpers help. It’s still not a straight shot, and you don’t get every pin down every time, but it’s still much better.” – Ms. Tina Roth (CEO, College Diabetes Network)

  • “Ups and downs feel like the days following sleepless nights: You’re tired, so you pound coffee, then you crash, then you have more caffeine, then you crash – that’s what it feels like…On this drug, I felt wonderful. I miss it every day, I’m praying it’s approved. It’s not a cure, but it’s a step in the right direction.”

  • For me, safety was the most significant thing. After being a type 1 for 37 years, I had three ambulance rides, drowned in a swimming pool and my wife had to save me in front of my kids, I crashed my car on the freeway, had daily highs and lows well below 70. Once I started the study, they went away…I didn’t change anything else I was doing.”

  • “When I leave today on the plane, I’m going to put my seatbelt on, we’ll go through some turbulence, and it’ll take care of me. Now, if I put my head on the seat and wrapped the belt around my head, then maybe we’ll get a different outcome. And if I wear mine but the person next to me doesn’t, then we’ll get a different outcome. Should I not be able to wear mine because the person next to me is not doing it properly?”

• USC’s Dr. Anne Peters explained that she has two Los Angeles practices: One in Beverly hills (affluent), and one on the east side (not so affluent). At her Beverly Hills clinic, she was an early adopter of SGLTs in type 1, and the worked – patients got better, lowered BGs, reduced glycemic variability, and lost weight. She was impressed, but then the first sign of a DKA signal caused her to halt the prescriptions. “I decided it wasn’t worth the risk, but my patients begged me to stay on them because they felt so much better. She wrote a protocol that has worked ever since, and she feels like she can use these drugs safely and effectively. However, one big caveat: “If you asked me, do I ever use these in my east LA patients with type 1 diabetes? No. Sadly, they lack access to healthcare, frequently go into DKA, and can’t do ketone testing.” Still, she advocated for approval and widespread education on their safe use. We don’t believe Dr. Peters has ever published her protocol, but we’d sure love for the world to see it!

• Mr. Sydney Wolf opposed approval, taking issue with the “meaningless” composite primary outcome (A1c <7.0% + no severe hypoglycemia + no DKA). On the benefit side, he noted that giving equal weight to different magnitude A1c reductions was problematic – i.e., the vascular benefit of a 2% A1c drop that brings the final value under 7% is certainly greater than the vascular benefit of a 0.2% A1c drop that brings the final value under 7%. Secondly, he was the first to describe the 8x risk of DKA in the treatment arm as the “elephant in the room.” He posed to the Committee: “Would you prescribe this drug for a patient?”

• JDRF’s Dr. Sanjoy Dutta and ADA’s Dr. Will Cefalu both spoke generally about the unmet needs in type 1 diabetes, the benefits of SGLT inhibitors (including outcomes beyond A1c), as well as what they view to be the manageable risk of DKA. Citing T1D Exchange Registry data, Dr. Dutta explained that type 1s face significant challenges with glucose control and complications, and there is therefore a need for innovative, safe, and effective therapies (of which sotagliflozin could be one, as it positively impacts A1c, hypoglycemia, hyperglycemia, and time-in-range). Dr. Cefalu referred to the recently-published 2019 ADA Standards of Care, which states that intensive insulin therapy is the only effective option for type 1 diabetes, yet hypoglycemia and weight gain can be barriers to intensive insulin use – “thus huge unmet need and we have a great interest in adjunctive therapies.” He noted that if benefits seen in type 2 diabetes – cardio- and renal-protection – as well as those in type 1 RCTs (A1c, variability, blood pressure, and hypoglycemia) translate to clinical practice, it would be a significant advance to improve care for all people with type 1 diabetes. Both then turned to DKA risk, with Dr. Dutta concluding that “with appropriate risk management, therapies from this class will positively affect the lives of type 1s” and Dr. Cefalu agreeing that “increased risk can be mitigated through increased awareness and specific education of patients and providers.”

• Barbara Davis Center’s Dr. Satish Garg brought some new framing to the conversation over sotagliflozin. Given that patients feel judged by their A1c, T1D Exchange numbers are going in the wrong number, and people prefer to not raise their insulin doses for a host of reasons, he posited that the goal of an adjunctive therapy should be to provide a stable glucose profile, confer weight loss, and without an increase in hypoglycemia. He also addressed earlier confusion regarding the value of seemingly small dips in A1c: “Keep in mind that improvement of 0.4% of an A1c beyond 7.5% is huge for patients with type 1 diabetes. I’ve been in practice nearly four decades, and every 0.1% after 7.5% is huge.” Finally, he noted that, while there is an increased risk for DKA with sotagliflozin in RCTs, the background rate of DKA is already high (4%-5%) in the most recent T1D Exchange data: “I personally think we have an opportunity to reduce the overall risk of DKA by educating patients and providers, following STICH, and creating an interactive app.”

• Dr. Charlie Alexander reviewed some of the top-level principles included in the recent Diabetes Care consensus paper focused on DKA risk mitigation with SGLT inhibitors in type 1 diabetes. This paper represents consensus guidelines developed by 20+ thought leaders after an ATTD meeting in June 2018 to discuss the topic. Following the meeting, 24 participants completed an online survey to better understand areas of consensus and areas of disagreement including appropriate cut-points for DKA diagnosis, patient selection, and patient management. To briefly summarize, the paper includes the following sections:

  • Background on putative mechanism of DKA in regard to SGLT use in type 1 patients, along with DKA diagnosis

  • Approaches to DKA prevention, including patient selection, insulin dose adjustments, initiation and dosing of SGLT inhibitors, ketone monitoring, and clinician/patient selection.  

  • Research questions in the area that still must be addressed

Despite the consensus reflected in this paper, it’s important to note that a tremendous amount is still unknown and must be researched further. For example, the notion of insulin reductions once starting on an SGLT inhibitor remains unclear – although the consensus paper recommends a “cautious” reduction in insulin, Dr. Anne Peters’ personal protocol does not involve any such insulin reductions.

• Notably, Lexicon has frequently cited the upcoming publication of these consensus guidelines as a point in favor of coalescing agreement amongst the academic community on how to best mitigate DKA risk – nevertheless, the real-world effectiveness of these measures still need to be documented. The paper will soon be available online at Diabetes Care.

• Pediatric endocrinologists Drs. Daniel DeSalvo and Jen Sherr couldn’t make the meeting, but sent in comments that were read aloud about their personal use of SGLTs to help manage their own and their patients’ type 1 diabetes. Both were cited as invaluable in reinforcing support for this therapy. Read Dr. DeSalvo’s remarks here and Dr. Sherr’s here.

• Dr. Helena Rodbard (Endocrine and Metabolic Consultants) pulled from her >40 years of experience as an endocrinologist, during which she has conducted >100 clinical trials, including several RCTs with sotagliflozin in type 1) to offer a resounding message in support of approval. “Benefits my patients obtained: improved A1c, less glycemic variability, more time-in-range, increased sense of general wellbeing, and improved treatment satisfaction. Also, modest reduction in insulin dose. Added bonus, weight loss. No DKA, no severe hypoglycemia. In my opinion, sotagliflozin in type 1 far outweighs the potential risk. The DKA risk can be mitigated.”

• Remarks and slides from Kelly Close of The diaTribe Foundation focused on a sentiment analysis from real-world patient accounts using SGLT inhibitors off-label in type 1 (see slides); Ann Carracher and Brian Levine of Close Concerns framed the risk-benefit of SGLT inhibitors in type 1 diabetes; (see remarks, slides), and Erik Shoger of dQ&A discussed the current state of ketone testing in type 1s (remarks, slides).

• Remarks and slides from Kelly Close of The diaTribe Foundation focused on a sentiment analysis from real-world patient accounts using SGLT inhibitors off-label in type 1 (see slides); Ann Carracher and Brian Levine of Close Concerns framed the risk-benefit of SGLT inhibitors in type 1 diabetes; (see remarks, slides), and Erik Shoger of dQ&A discussed the current state of ketone testing in type 1s (remarks, slides).

  • The centerpiece of Ms. Close’s OPH speech was a series of qualitative analyses from an open call to type 1s who are already using SGLT inhibitors to share their subjective experiences. The comments were derived from a one-question survey disseminated through the various communications channels of diabetes organizations: The diaTribe Foundation, Diabetes Sisters, T1D Exchange, College Diabetes Network, Tidepool, Beyond Type 1, and Children with Diabetes. At the time of the meeting – ~three weeks after the survey was originally posted – there were 179 stories from people who had experience using this therapy off-label or in a clinical trial. (There were an additional 30+ responses from people who either had an opinion on the matter despite having never taken an SGLT inhibitor or misunderstood the prompt.) In addition to scoring the responses for their overall sentiment (positive, mixed, negative, or neutral), The diaTribe Foundation pulled out and quantified common thematic elements. While this data is by no means intended to be representative, that quantity and diversity of responses effectively demonstrated that (i) people are passionate about this issue and (ii) heterogeneity reigns supreme in the lived experience of type 1 diabetes. Here are some of the main takeaways:

    • Overall sentiment: 62% of respondents who had previously used SGLT inhibitors were positive on the use of this class in type 1 diabetes; 14% were negative; 21% were mixed, 3% were neutral.

    • Reported benefits: 53% current/former users reported less glycemic variability/smoother BGs, 28% reported weight loss or stabilization, 23% reported using less insulin, and 22% reported lower A1c. It’s important to keep in mind that the survey did not directly ask about any of these benefits; they came up naturally in patients’ open-ended responses.

    • DKA incidence: There were 20 total incidents of DKA, spread across 17 individuals (9.5% of the total) – one person had three events, and another had two. This is not surprisingly a greater rate than seen in trials, likely due to DKA mitigation protocols in trials and something that could be coined “The Yelp Effect” – people are more likely to respond to this sort of survey if they feel very strongly about the product/service in question.

    • Side effects: 50 people (28%) reported other side effects such as UTI, yeast infection or dizziness.

    • People were more likely to stop their medication because of dehydration, UTI, or yeast infection than they were due to DKA. 76% reported stopping therapy due to a side effect, while 60% of people who experienced DKA stopped therapy.

    • Of those who reported duration, average time on therapy was 1.8 years. There was a broad range, from a matter of days to 5+ years.

    • The five respondents who identified as healthcare providers were all pro-SGLT in type 1.

    • Five people wrote that they had a better experiences on SGLT-2 inhibitors after switching from one brand to another. There were no obvious signs of one drug causing more problems than others. We’d note these responses are subject to bias, changes in physiology/environment, and dose considerations, but it again underscores the heterogeneity of experience among type 1s.

The Vote

Many panelists who voted “no” seemed very close to “yes,” (reminiscent of the recent CVOT Ad Comm), which we view as very encouraging in the long run as we absolutely believe sotagliflozin deserves approval and a broad market for type 1. While a few panelists were not convinced of the benefit SGLTs offer type 1s, many “no” voters were looking for more concrete and evidence-based risk management strategies – presumably, with those, they would vote yes. Notably, all three practicing cardiologists on the committee voted “no” while endocrinologist votes were split 3-2, yes-no (the cardiologists took a similarly conservative stance in the CVOT Ad Comm).

Summary of Committee Votes

Commentary from Voting Members

Yes

• Dr. Daniel Budnitz (CDC, Atlanta, GA) voted yes to allow those patients who find the risk-benefit profile of sotagliflozin favorable to take the drug. That said, prior to approval, he believes a significant REMS strategy mimicking the setting of the inTandem program must be implemented – including education (patient and provider), engineering (educational materials, ketone monitoring provided for patients), and enforcement. Post-approval, prospective studies on other risk management protocols should be assessed to improve the REMS program. Dr. Budnitz supported approval of both doses, with all patients starting on the 200 mg dose.

• Dr. Rebecca Brown (NIDDK, Bethesda, MD) echoed Dr. Budnitz on nearly all fronts, adding that she was compelled by minute-to-minute reductions in glycemic variability but remained hesitant on DKA safety in the broader type 1 diabetes population. Ultimately, she felt, the benefit outweighed the risk but only for those who can safely mitigate DKA and can be identified through a REMS program.

• Dr. Susan Ellenberg (University of Pennsylvania, Philadelphia, PA) drew comparisons to other approved drugs with serious risk such as clozapine, wondering if there could be a REMS program that requires patients to demonstrate that they test for ketones. She abstained from giving dosing recommendations.

• Patient representative Susan Lellock (Punxsutawney, Pennsylvania) resolutely stated that both doses should be approved, and ketone monitoring should go “in conjunction with prescription.” To this end, HCPs should be able to refuse or remove the drug if ketone testing is not assured.

• Consumer representative Anna McCollister-Slipp (VitalCrowd, Washington, DC) asserted that patients need to be trusted to work through the risk-benefit profile of sotagliflozin, noting that people with type 1 diabetes already live in a world of risk where the unmet need for type 1 therapies beyond insulin is too high. That said, she called for sponsors to take DKA and genital infection risk seriously – asking for true education beyond “photocopied sheets of paper.” To this end, she suggested testing how well patients and providers retain information.

• Chairperson Dr. Peter Wilson (Emory University School of Medicine, Atlanta, GA) cited current off-label use as an opportunity to direct “a concerted education effort efficiently and safely.” He agreed with Dr. Yanovski (below) that whether the REMS should be implemented and tested before or during approval is perhaps the toughest part of the process, acknowledging that he would like to see a program capable of reducing DKA risk beyond that seen in the clinical trials. He also expressed doubt in the quality of urinary ketone testing relative to blood and supported only the 200 mg dose being approved.

• Dr. Kenneth Burman (Georgetown University, Washington, DC) was frank in his assessment: the benefits of sotagliflozin outweigh possible side-effects. As he sees it, the improvements in A1c, weight, glucose variability, and blood pressure overpower the “very real” risk of DKA, though he supports the need for a REMS program and ketone monitoring despite no benefit being shown with the latter. On the label, he asked for a comment on heightened risk of DKA in younger patients and those who have already had it. He supported only the 200 mg dose.

• Dr. Kashif Munir (University of Maryland School of Medicine, Baltimore, Maryland) was the only committee member to extoll the 0.3%-0.4% reduction with sotagliflozin, calling it “pretty good for a baseline A1c of 7.5%” and “consistent with previous studies.” Even with a REMS program, he thinks DKA risk will always be present, thereby elevating the importance of surveying both patients and providers to assess mitigation strategies. He also stressed that DKA is most of the time very treatable and believes that should be communicated in any REMS program. Intriguingly, he wondered whether Sanofi/Lexicon might partner with a device company to include a ketone monitor with each patient’s first prescription. Despite tangible benefits on weight loss, blood pressure, and time-in-range with 400 mg, he supported only the 200 mg dose on account of heightened DKA risk.

No

• Dr. Jack Yanovski (NIH, Bethesda, MD) voted no but conceded that he very nearly voted yes. Dr. Yanovski stressed that it’s very clear there is a desperate need for additional approaches to type 1 diabetes but felt that sotagliflozin is “not ready for prime time.” He explained that additional studies are needed before a release to the wider public and that potential a REMS strategy needs to be tested for efficacy before approval. Overall, Dr. Yanovski was persuaded by the perception that the degree of benefit for sotagliflozin was small enough to not override the very real risk of DKA.

• Dr. Abigail Shoben (The Ohio State University, Columbus, OH) voted no because she was uncertain of how true of a clinical benefit there would be with sotagliflozin against a very real DKA risk. She would like to see documentation and proof that patient ketone monitoring would reduce DKA risk and cited evidence from elsewhere in public health, commenting that provider education efforts have not made a meaningful dent in the opioid crisis.

• Dr. Connie Newman (NYU, New York, NY) voted no because of the “serious” risk of DKA. She recommended further study in a diverse population, including people of different socioeconomic and education levels to see if risk mitigation strategies are broadly effective or not. If feasible, she would also like to see an outcomes study with sotagliflozin for microvascular and macrovascular complications.

• Dr. Marvin Konstam (Tufts Medical Center, Boston, MA) voted no, saying that although he thinks this drug is “approvable,” he has not yet seen enough evidence to actually approve it. He remarked that although there are specific sub-populations for whom the benefit/risk ratio is clearly favorable, the data so far has not been presented in such a way to emphasize this point. Dr. Konstam underscored that “we need to see in a quantitative way that this drug is actually improving patient lives” before it can be approved.

• Dr. Michael Blaha (Johns Hopkins, Baltimore, MD) voted no on the basis of not seeing clear evidence that the benefits outweigh the risks with sotagliflozin. The eight-fold relative increased risk of DKA was too much for Dr. Blaha to overlook, especially given the potentially fatal consequences of the complication. He explained that although he enjoyed the perspective given from many trial participants during the OPH, it’s important to keep in mind that the panel did not get the chance to hear from individuals who may have experienced DKA during the trial and whose experiences would have been considerably more negative.

• Dr. Celia Low Wang (University of Colorado, Aurora, CO) voted no because of an unfavorable benefit/risk ratio. Although Dr. Low Wang desperately wants more therapeutic options for her type 1 patients, she believes that the current data is insufficient to support approval. She noted that K-M curves presented by FDA showing that DKA risk doesn’t change over time “really struck me…this could be three or more decades of doing ketone monitoring.” Moreover, Dr. Low Wang was dismayed that there is no data to support the notion that risk mitigation of DKA will actually be effective. As a result, she hopes more data is collected to show that DKA risk can be decreased, or that an increase in clinical efficacy can be achieved to properly offset this risk.

• Dr. James de Lemos (UT Southwestern Medical Center, Dallas, TX) voted no because sotagliflozin was not demonstrated to be safe: “when a drug is not safe, the bar goes up,” and sotagliflozin did not meet this higher bar, in his mind. Dr. de Lemos remarked that “it doesn’t make a lot of sense to me to make a drug force type 1 diabetes patients into ketosis and have them lower their insulin doses.” Moreover, he did not see anything in the data presented to suggest that the DKA risk is in any way modifiable, and he remains “very concerned” that this signal cannot be overcome.

• Dr. Martha Nason (NIH, Bethesda, MD) voted no, explaining the risk/benefit ratio as not favorable enough. Dr. Nason communicated her fear that real-world DKA rates will be significantly higher than those seen in clinical trials, and that these rates cannot be effectively controlled with ketone monitoring or other methods. Dr. Nason would like to see further trials with more specific patient selection criteria, along with better algorithms to help providers pick the right patients to take sotagliflozin.

Competitive Implications

While we can’t say how FDA will proceed following this vote, there are multiple paths forward, including approval with further trials or data being developed separately, or a CRL or rejection. Below, we postulate about what each would mean for Sanofi/Lexicon, AZ (Farxiga for type 1 currently under review at FDA and EMA), and Lilly/BI (Jardiance submission to FDA, and likely EMA, expected roughly but not definitively in 2019). We also find it interesting to consider the potential advantage of being first-to-market with a type 1 indication: More often than not, this is considered a commercial advantage, but given the multiple unknowns surrounding this issue, it’s unclear to us whether hitting the market in type 1 first will truly be an advantage for any of Sanofi/Lexicon, Lilly/BI, or AZ. Another key question is how willing payers will be to cover SGLTs for type 1. Some have expressed substantial hesitation that any coverage will come given the potential cost of DKA hospitalizations, but we’re interested to see how payers will think about the goal for DKA event minimization and if they’ll try to influence where and how DKA is managed (i.e., in the hospital vs. at home, and how that might shift over time).

• FDA issues a CRL: In this case, we’d anticipate FDA requesting additional studies of sotagliflozin, quite possibly including some evidence-based demonstration of the companies’ risk mitigation strategy. Of course, CRL contents are confidential, but we would expect some indication from Lexicon, especially, of what it would take to resubmit. It is also possible that FDA issue a CRL requesting that the sponsors resubmit with a REMS protocol (to our understanding, resubmission would be required to be approved with REMS), though we’ve also heard chatter that FDA is trying/prefers to avoid REMS whenever possible (that is hearsay). In any circumstance, a CRL would mean a >one year holdup to sotagliflozin’s timeline – the candidate could even end up approved for type 2 diabetes first, maybe even leading to resubmission in the form of an sNDA. Given Sanofi and Lexicon’s fierce commitment to bringing the candidate to market for type 1 – and how integral this indication has been to its corporate strategy – we imagine management is willing to go many extra miles to make sotagliflozin for type 1 happen. Ultimately, Sanofi/Lexicon’s early filing in type 1 could end up a short-term commercial setback (though, they could later benefit from being second or third to market in type 1), and we’ll be curious to see how Lilly/BI handle their filing.

• FDA approves sotagliflozin: Approval (technically) would be great news not only for Sanofi and Lexicon, but also for AZ and Lilly/BI as long as there were no major disasters. That said, we find it very unlikely that outright approval is granted given the split vote today and meaningful concern from the committee over the potential for indiscriminate access to SGLTs to cause substantial harm – we agree. It’s also difficult to postulate what restrictions FDA might land on, but we don’t necessarily think FDA needs new data in order to consider the possibility of a black box warning for DKA for type 1, indication cautions based on insulin delivery method (pump vs. MDI), and other post-market requirements for study or support from Sanofi/Lexicon. Launch anytime soon is inappropriate in light of questions to be asked – though whether much of this could be done in parallel is a question. Proceeding with deliberate caution will be critical in rolling out SGLTs, and it’s hard to tell how far the sponsors have progressed on the logistics and specifics of the resource-based protocol they outlined. From where we stand, bringing sotagliflozin to market will need to be very carefully done: Many candidates for the drug are already happily taking SGLT-2s off label, and without substantially better reimbursement/access for sotagliflozin (certainly not a given although likely for some), we imagine Sanofi/ Lexicon could struggle to “steal” those patients away from their off-label use. On the other hand, some may prefer to take a drug actually indicated for type 1 diabetes, and this novel indication will likely help Sanofi/Lexicon attract new patients to the therapy. The companies will also be faced with pioneering and putting into place a risk reduction strategy, and being the first to do such may present unique challenges. All in all, however, we’ve been enthused by the companies’ willingness to take on these tasks, and Sanofi certainly has the experience in diabetes to make such a drug successful.

Close Concerns’ Questions

• Will FDA ask the company to work on risk parallel with approval or ask them to resubmit with a REMS program and issue a Complete Response Letter?

• How will this vote impact AZ’s sNDA for Farxiga in type 1 diabetes? Will FDA hold another Ad Comm, and will Farxiga have an easier path forward given it’s not a new drug and may have a different and more explicit connection?

• What decision will EMA’s CHMP issue on sotagliflozin given different physician workflow issues? A CHMP opinion is expected by the end of the month. How will this vote impact that decision in particular?

• When will Lilly and BI submit Jardiance to FDA and EMA? The companies haven’t offered a definite timeline (Lilly 2019 Financial Guidance stated both submission and an FDA decision as “potential” 2019 milestones). Presumably, this vote would encourage this submission – to what extent is that true?

• Will manufacturers seek to validate a DKA risk mitigation protocol? How can this be done ethically so that no patient experiences?

• Could collaboration between manufacturers on the risk mitigation emerge? This would certainly be favorable and simpler for patients and providers.

• How can SGLTs in type 1 drive forward (and benefit from!) outcomes beyond A1c, patient reported outcomes, and other quality of life/wellness measures?

• What opportunity is there for demonstrating long-term benefit of SGLTs in type 1, through any combination of cardioprotection, nephroprotection, and microvascular risk reduction? Is there a chance to investigate the impact of decreasing glucose variability, even in the absence of substantial A1c reduction?

• With better long-acting insulin analogs and the emerging device technology (closed loop AID – automated insulin delivery – systems), will there be less need moving forward for adjunctive therapy with SGLT inhibitors, especially given the DKA risk? Or will it be perceived that such systems work more on hypoglycemia avoidance than hyperglycemia avoidance?  

• Will FDA run out of funding before it can make a decision on sotagliflozin?

-- by Ann Carracher, Martin Kurian, Brian Levine, Peter Rentzepis, Charles Alexander, and Kelly Close