Novo Nordisk submits oral semaglutide to FDA, also requesting CV indications for Ozempic and oral semaglutide; Exclusive interview with NN's Chief Scientific Officer Mads Thomsen – March 20, 2019

Novo Nordisk just announced the submission of two NDAs for oral semaglutide, requesting FDA approval for (i) treatment of type 2 diabetes; and (ii) CV risk reduction in adults with type 2 diabetes. Additionally, an sNDA has been submitted requesting a CV indication for Ozempic. Filing of oral semaglutide in the EU is anticipated in 2Q19 and in Japan in 3Q19.

Very notably and as expected, a priority review voucher (PRV) was applied to the general type 2 approval NDA for oral semaglutide, so a decision is expected within six months. We don’t anticipate major regulatory hurdles, though an Advisory Committee is possible given this is the first oral GLP-1 agonist. As such, we expect oral semaglutide’s approval by September 2019.

Review of both requested CV indications will take 10 months, meaning decisions are expected by the end of January 2020; an Ad Comm could be more likely for these indications than for general approval. In a conversation today with our team, Novo Nordisk CSO Dr. Mads Thomsen confirmed the company is seeking indications for reducing risk of three-point MACE in people with type 2 and established CVD. As a reminder, SUSTAIN 6 for Ozempic enrolled 83% with existing CVD and the 26% risk reduction on MACE was driven by stroke and MI; PIONEER 6 for oral semaglutide enrolled 85% with existing CVD and the 21% MACE benefit was driven by CV death and stroke.

Cardiovascular (and Renal?) Indications

• Novo Nordisk has requested CV indications for both Ozempic and oral semaglutide but will still conduct the SOUL CVOT of oral semaglutide and the FLOW renal and CV outcomes trial of Ozempic. According to Dr. Thomsen, these studies are designed to support one another: Positive CV outcomes from SOUL will support a CV indication for both oral semaglutide and Ozempic, and positive renal outcomes from FLOW will support a renal indication for both, assuming the data are consistent. In many ways this is a win-win setup for Novo Nordisk: In the event that FDA rejects the NDA and/or sNDA for oral semaglutide and Ozempic’s CV indications, they’ll already have superiority-powered trials running; and if FDA approves those submissions, they’ll also have data coming down the pipeline that may support a first-ever renal indication(s) for a GLP-1 agonist. (For reference, on the company’s 4Q18 call, CSO Dr. Mads Thomsen mentioned that Novo Nordisk is focused on obtaining renal indications for both oral and injectable semaglutide and is in the midst of “bridging” primary endpoints to “crisscross between Ozempic and oral semaglutide for renal data too.”)

  • We hadn’t heard much emphasis on FLOW before our call with Dr. Thomsen, though it was mentioned in passing on the 4Q call: The study aims to enroll 3,120 people with type 2 diabetes and CKD (eGFR 25-75 ml/min/1.73 m²) for up to five years. Expected completion is August 2024, and the primary endpoint is a composite of persistent eGFR decline of ≥50%, reaching ESRD, and CV or renal death. Traditional MACE endpoints will also be measured. This is a highly-notable, first-ever renal outcomes trial among GLP-1s, and we’re thrilled by Novo Nordisk’s investment in renal disease. While the GLP-1 agonist class receives generally less attention than SGLT-2 inhibitors for its potential impact on kidney disease, the data for GLP-1s is certainly promising.

  • Dr. Thomsen explained that SOUL (originally the post-market CVOT for Ozempic, now for oral semaglutide) has been scaled to approximately the size of LEADER (~9,300 participants). However, the trial design will include an interim analysis that will enable early cessation of the study if the primary endpoint is met sooner, given anticipated greater efficacy with semaglutide compared to liraglutide. To our knowledge, SOUL has not been posted to clinicaltrials.gov.

• When Novo Nordisk announced PIONEER 6 CVOT results for oral semaglutide, the company explained it was evaluating the potential to use combined PIONEER 6 and SUSTAIN 6 (for Ozempic) data to obtain a CV indication for Ozempic specifically, in discussion with FDA – today’s submissions ostensibly mean those conversation with FDA went very well. As a reminder, PIONEER 6 – the shortest and smallest GLP-1 CVOT to date – found a non-significant 21% relative risk reduction on three-point MACE with oral semaglutide (no CI or p-value given), while SUSTAIN 6 identified a significant 26% RRR on the same endpoint (95% CI: 0.58-0.95). In 2Q18, the company made waves in announcing that FDA would allow one superiority-powered CVOT of oral semaglutide – plus a bridging study with Ozempic – to support CV indications for both formulations, canceling the original post-market SOUL CVOT for Ozempic. At that time, the company also explained that, if PIONEER 6 demonstrated a significant CV benefit, the company could actually go ahead and file for two CV indications based on the combination of data from both the PIONEER and SUSTAIN CVOTs. It seems that, despite the fact that oral semaglutide missed significance on three-point MACE in PIONEER 6, FDA has indicated a willingness to consider the combination of SUSTAIN and PIONEER data in support of both formulations’ CV efficacy – this would be a huge win for Novo Nordisk and patients alike.

  • Particularly before seeing the full PIONEER 6 data, it’s difficult to tell how FDA may be thinking about the situation. But we note that PIONEER 6 identified ~50% reductions in both CV death and all-cause death, and the magnitude of those improvements is hard to ignore.

  • All of this occurs against a backdrop of changing CVOT dynamics: FDA hosted an Advisory Committee in October 2018 to revisit the original 2008 CVOT draft guidance. Moreover, we’ve perceived growing flexibility from FDA on CV indications for diabetes drugs – read our thoughts on the broad CV indication for J&J’s SGLT-2 inhibitor Invokana here.

Oral Semaglutide: Class and Commercial Implications

• The biggest questions surrounding oral semaglutide are (i) the patient population to whom the therapy will be targeted; and (ii) how will Novo Nordisk price the first-ever oral GLP-1 agonist? Many anticipate oral semaglutide will compete with other oral agents more so than injectable GLP-1 agonists. Overall, Novo Nordisk has been relatively quiet on commercial strategy and explicitly avoided discussing pricing. Back at the company’s 2017 Capital Markets Day, management outlined the expectation that oral semaglutide would absorb some market share from daily GLP-1 agonists (most prominently, its own Victoza). But more importantly, they also emphasized that oral semaglutide would primarily compete with DPP-4 and SGLT-2 inhibitors for its own share of second-line prescriptions –citing that these comprise 17% of US total prescriptions vs. 6% for GLP-1s, at that time. Head-to-head data vs. both Merck’s Januvia and Lilly/BI’s Jardiance work in its favor as far as clinical positioning goes, and it makes sense that Novo Nordisk would want to avoid cannibalizing its injectable GLP-1 business from Ozempic and Victoza as much as possible. Dr. Thomsen indicated to us today that this is still a strategy Novo Nordisk intends to pursue. Doubtless, we would love to see more patients starting on GLP-1s earlier, and oral semaglutide makes that far more of a reality. On balance, however, management has also commented that they expect it will take more time to build access and coverage for oral semaglutide than it did for Ozempic, so we shouldn’t necessarily expect such rapid uptake of the oral version.

  • Pricing strategy is more uncertain, and it’s not clear whether formularies will consider oral semaglutide within the GLP-1 agonist category or a category of its own. Pricing decisions stand to meaningfully impact not only Novo Nordisk’s negotiations with PBMs/payers for coverage, but also prescribing practices, patient affordability, and even rebates and realized price for Novo Nordisk. Dr. Thomsen emphasized to us that, in his mind, oral semaglutide is a GLP-1 agonist scientifically equivalent to injectable GLP-1s, but also acknowledged that he wasn’t sure how US PBMs and payers would see things. Will Novo Nordisk price the tablets on par with its existing GLP-1 agonist offerings, or will they reduce injected list price to better fit in with existing oral options? And how will this impact dynamics within the injectable GLP-1 agonist segment?

• The ten-study phase 3 PIONEER program (n=9,543) started reading out in February 2018 and completed with PIONEER 6 in November; see a full table of these studies and their results here. By and large, PIONEER has supported efficacy and tolerability of oral semaglutide; the combination of glucose-lowering and weight loss efficacy with a remarkable safety profile (especially on hypoglycemia) is unparalleled among oral agents, and even offers improvements over some existing injectable GLP-1 agonists. Excitement in the field for the first-ever oral GLP-1 agonist is undeniably high, and opportunities for earlier treatment intensification with GLP-1 agonist through oral dosing are tremendously important.

Oral vs. Injectable Medication: Market Research

• Oral GLP-1 has major potential to expand the highly efficacious class to more people. Doubtless, aversion to injectables has historically been a barrier to better glycemic control for some who could certainly benefit from GLP-1 or insulin therapy. Market research and patient insights firm dQ&A asked about preferred administration method of type 2 diabetes therapies (n=3,499) in 2Q16. Their findings are consistent with this conclusion.

  • dQ&A respondents who were taking only oral therapies strongly preferred to stay on orals. In the survey, preference for a daily oral medication (such as oral semaglutide) was highest among those taking only orals, relative to those on other therapies – 34% ranked it as their #1 choice of administration method. Preference for a weekly injection (such as Ozempic) was lowest in this group – only 2% ranked it as their #1 choice.

  • Those not taking any medications were similarly in favor of orals. Only 4% of this group ranked a weekly injection as their ideal administration method vs. 25% for a daily oral medication. 

  • Those taking an injectable (insulin, GLP-1 agonist, or both) also preferred orals over injectables, though there was less of a difference compared to the oral only and no medication groups. Among those taking insulin only, 17% ranked a daily oral medication as their #1 choice vs. 12% for a weekly injection. Among those taking GLP-1s only, 14% ranked daily orals as #1 vs. 12% for weekly injectables, and among those taking both insulin and a GLP-1, 15% ranked daily orals as #1 vs. 10% for weekly injections.

• Of course, these results don’t take into account differences between oral vs. injectable therapies (e.g., atherosclerotic vs. heart failure/renal benefit). However, they do suggest the potential for higher interest in an oral GLP-1, particularly amongst those not already on an injectable. This research also corroborates Novo Nordisk’s long-term commercial strategy for its trio of GLP-1 agonists, with oral semaglutide competing with SGLT-2 and DPP-4 inhibitors for second-line prescriptions, and injectable GLP-1 initiated slightly later in disease development but still considered before insulin (slide 10). 

• dQ&A’s survey compared implantable therapy, weekly oral medication, daily oral medication, weekly injection, and daily injection – write Richard Wood for more information on dQ&A and this dataset.

Interview with Novo Nordisk CSO Dr. Mads Thomsen

CC: Thank you so much for taking the time to speak to us, Dr. Thomsen, and congratulations on these submissions. What these potential approvals and indications will enable for patient health is incredible.

Dr. Thomsen: Thank you.

Q: What specific CV indication(s) is Novo Nordisk seeking and for what populations? 

Dr. Thomsen: The CV indications are as you might expect – to reduce the risk of MACE events (CV death, non-fatal MI, non-fatal stroke) in people with established CV disease and type 2 diabetes. Exactly how the wording will end up is a matter of debate if and when we achieve the indications for Ozempic and oral semaglutide.

Data from the SUSTAIN and PIONEER programmes strongly indicate that the systemic effects of semaglutide are independent of route of administration. It is therefore relevant to assess all of the evidence generated for semaglutide and not only the evidence generated for oral semaglutide. Accordingly, data from SUSTAIN 6 have been included in the oral semaglutide NDA for CV risk reduction and vice versa. FDA has approved 10-month reviewal periods, to be completed in parallel, for the two CV indications.

Q: Will you conduct another CVOT of semaglutide in type 2 diabetes, and does that depend on whether these CV indications are approved? 

Dr. Thomsen: At this point, we are proceeding with the SOUL trial for oral semaglutide, which is predominantly a CVOT scaled to be the same size as LEADER. However, because the efficacy level of semaglutide might be higher than what we have seen with other GLP-1s, we’ve built in an interim analysis which makes it possible to stop early on. For example, with a 20% MACE reduction early, maybe you don’t need 1,200 or 1,300 MACE events as was the case for the LEADER trial. It is important that FDA has allowed us to bridge CV outcomes, so that trials of the same molecule can support each other assuming they have similar levels of exposure regardless of the route of administration.

Q: On your 4Q18 call, you mentioned serious interest in pursuing renal indications – can you elaborate on what’s needed for that?

Dr. Thomsen: FLOW – the chronic kidney disease trial that we are doing for Ozempic^® starting in mid-2019 – will suffice to seek  a diabetic nephropathy indication for Ozempic^® for CKD; in other words, it is the pivotal trial for CKD with diabetes for Ozempic^®.

The SOUL CVOT for oral semaglutide has secondary confirmatory endpoints related to renal disease. Provided that good results are achieved, the SOUL trial provides the basis for seeking an indication for oral semaglutide in CKD, with FLOW enabling the bridging of the indication and label from Ozempic^® onto oral semaglutide.

Q: We’ve heard chatter that superiority on PIONEER 6 was missed by only one or two events – what is your take on the data? 

Dr. Thomsen: We are very much looking forward to presenting the PIONEER 6 findings at ADA in June. It’s important to keep in mind that PIONEER 6 had less than 140 MACE events. While significance was not met on the MACE endpoint despite having a hazard ratio of 0.79, oral semaglutide reduced all-cause mortality by 49% and CV mortality by 51%, with both being statistically significant. That is highly unusual in such a small and brief trial where the exposure was only slightly above one year on average.

Q: Given the heterogeneity of patients and outcomes Novo Nordisk is trying to prevent, how do you think about segmentation – which patients need which therapies?

Dr. Thomsen: As a company, we support the ADA and EASD treatment guidelines, which recognize that both GLP-1 agonists and SGLT-2 inhibitors, which have very different mechanisms, are efficacious on CV risk, weight, renal risk, hypoglycemia and so on. These two classes are quite different, but we support the way that the guidelines are formulated because they encourage the early use of these two classes which can save a lot of lives going forward if treating physicians adhere to the guidelines. We are working on all types of patient segmentation going forward. We have a huge database from some of these trials going on such as the SELECT trial to find which patients are most in need of some of these agents.

Q: How is training for new doctors changing to make sure they are following the guidelines?

Dr. Thomsen: At the moment, I believe it is not changing enough. However, we can make sure that the specialists are informed because the endocrinologists are the ones who are educating GPs and others at the local level about developments in diabetes. I think we have to accept that training is not changing enough today, but we will make sure that the specialist base that we cover has insights about the most recent publications and guidelines going forward. And it should come from all sides – not just providers but also patients. This is the first time where we are changing the dialog with patients to say that it’s about your heart, your kidneys, your life.

Q: Is earlier intensification of GLP-1 therapy the primary goal with oral semaglutide?

Dr. Thomsen: Yes, the injection barrier is a real thing in the real world. We want to position oral semaglutide as the world’s first biological treatment in a tablet for people with type 2 diabetes, and if accepted, people immediately after metformin have the ability to get the efficacy of a GLP-1 in a tablet. It also provides the opportunity to start and stay on a drug that is noninvasive. As seen in our PIONEER clinical trial programme, up to 80% of people taking oral semaglutide achieved well controlled blood sugar levels below the A_1C target of <7%.

Q: How do you perceive the current relationship between GLP-1 agonists and SGLT-2 inhibitors or other oral diabetes medications? How will that dynamic shift assuming oral semaglutide is approved?

Dr. Thomsen: In my view, there is no fight between GLP-1s and SGLT-2s. In PIONEER 2,  oral semaglutide demonstrated a statistically significant and superior improvement in A1c compared to empagliflozin. However, they have unique CV profiles – GLP-1s are recommended for atherosclerotic disease in people with type 2 diabetes and SGLT-2s are recommended for heart failure in people with type 2 diabetes. In this manner, they can complement each other, which is what we are investigating in SUSTAIN 8 and 9 – trials in which the classes are compared or administered concomitantly.

Q: Now that the PIONEER program is complete, can you share any thoughts on what treatment category and pricing you’re targeting?

Dr. Thomsen: In terms of treatment category for oral semaglutide, the target is any person with type 2 diabetes currently on metformin. From there, patients could intensify with basal insulin or high-dose Ozempic^®, which, if approved, could  be available by that time. Price-wise, we will not comment until the drug is approved.

Q: How long do you think it will be until GLP-1s or SGLT-2s are more prescribed than SUs?

Dr. Thomsen: Among people with insurance or those that can access the therapy, not long. It is of course better to use a generic SU at low cost than no drug at all. We are cognizant of the fact that SGLT-2s and GLP-1s are not available to everybody. With generic competition, I expect these drugs will become a lot cheaper and will displace even the low-cost SUs. In my humble opinion, SUs are the least attractive drug class out there.

Q: We understand that formularies for GLP-1 are not very exclusive. Will oral semaglutide be categorized as a GLP-1 on formularies or will it be given a new category?

Dr. Thomsen: Oral semaglutide is a GLP-1 in a tablet. We have not yet had the detailed discussions with payers. We will know much more by the end of the year.

Q: On the patient populations for SOUL and FLOW, what composition of primary vs secondary prevention do you expect to enroll?

Dr. Thomsen: These trials are not investigating primary prevention because we are hoping for trial readouts that do not come many years into the future. In the FLOW trial, we are enrolling people with established CKD; in the SOUL trial, it is people with established CV disease or at high risk for CV disease. Personally, I am curious about the primary prevention cohort – for example, in REWIND – will it in its own right achieve statistical significance. In my view, you need quite a long study and many events to achieve statistical significance in a primary prevention cohort, and that’s not where we are heading with these trials. Of course, we have the SELECT trial investigating people who don’t have diabetes which is enrolling as we speak.

CC: Thank you so much again, Dr. Thomsen – we truly appreciate your time and detail, as always.

Close Concerns’ Questions

• How supportive is FDA of these potential CV indications? How is the agency’s thinking around CVOTs and CV indications evolving?

• How will FDA consider the heterogeneity among components of the primary three-point MACE endpoint in both PIONEER 6 and SUSTAIN 6?

• Will there be an Advisory Committee meeting for either oral semaglutide’s approval or either CV indication?

• Before SOUL and FLOW complete, how might the diabetes community come to view SUSTAIN 6 and PIONEER 6, given neither were actually powered for superiority? Will this reflect positively on semaglutide’s efficacy, or will it provoke questions around the reliability of the data?

• How will oral semaglutide be priced and what categories will the company aim to “compete” in?

• As Novo Nordisk’s portfolio expands, how will it think about targeting different therapy classes to different patients most effectively?

--by Ann Carracher, Peter Rentzepis, and Kelly Close