Memorandum

Lilly 2022 Investor Community Meeting – Lilly doubles down on GLP-1, with new phase 3 trials of tirzepatide in overweight/ obesity, sleep apnea, and new CKD trial; huge weight loss potential of “Triple G”; oral GLP-1 candidate – December 15, 2021

Executive Highlights

  • This morning, Lilly hosted an investor community meeting with significant emphasis on tirzepatide, including the announcement of three upcoming trials: phase 3 SURMOUNT-MMO, phase 3 SURMOUNT-OSA, and phase 2 mechanism of action TREASURE-CKD. Given tirzepatide’s success in the SURPASS program (with additional read-outs announced at EASD 2021), we are thrilled to see the initiation of further phase 3 studies and can’t wait to follow along for updates.
  • Lilly highlighted obesity care as the number one emerging trend in biopharmaceutical innovation, stating “obesity is a treatable disease; and by reversing it we can dramatically improve population health outcomes.” We were glad to hear this so clearly stated and look forward to hearing more about obesity outcomes, which we suspect will be one key to unlocking policy change, especially reimbursement. Big picture, it sounds like many stakeholders will be pleased to see the company’s firm commitment to improving this public health issue, which continues to gain traction following the approval of Novo Nordisk’s Wegovy (semaglutide 2.4 mg) for chronic weight management in June 2021 and where the absence of treatments (even now) continues to be a massive barrier. [1]  
  • For 2022, Lilly expects $28.0 to $28.3 billion in revenue, up from $27.2 to $27.6 billion in 3Q21. Per the press release, this reflects an additional $2.1 billion in revenue from COVID-19 antibodies as well as channel impact of the updated 2022 NRDL formulary in China.
  • We’ll be studying history over vacation – the last major investor meeting was in 2018 and it’s instructive to see how the company continues to transform.

Lilly hosted an investor community meeting this morning (see press release, webcast, R&D overview presentation, and diabetes presentation), in the company’s first major R&D meeting since December 2018. Below, you’ll find seven highlights from the call, covering tirzepatide, weekly basal insulin, and oral GLP-1s. We’ll be back with more on Lilly’s 2022 financial guidance and the Analyst Q&A.

Top Eight Highlights

1. Lilly highlights commitment to obesity care; management believes the company is well-positioned to be a leader in this space

Lilly kicked off the entire investor community meeting by highlighting three emerging trends in biopharmaceutical innovation and highlighted obesity care as the number one trend. Specifically, noting that obesity is a treatable disease and that they are investing “heavily” in this area. This is a major shift from the last investor meeting in 2018 where obesity was mentioned only in reference to high-dose dulaglutide, or Trulicity. In fact, at that time, Lilly seemed fairly clear that it was working on diabetes, singularly, rather than obesity or prevention. Our coverage noted: “Lilly has previously shown a laser focus on type 1 and type 2 diabetes rather than obesity, and this seems to persist for the time being …” This year, in contrast, management spent a significant portion of the presentation highlighting the alarming increase in obesity noting that “current patient outcomes are not acceptable” and the role they hope to play in addressing this issue – most notably with the highly anticipated dual GIP/GLP-1 dual receptor agonist tirzepatide. They emphasized their expanded focus that includes obesity and diabetes together with the goal of disrupting disease progression earlier in the disease cadence to reduce complications. Management focused on the public health implications of obesity, noting that despite more than 100 million people in the US living with obesity, only about 3% are treated with pharmacological interventions. Dr. Daniel Skovronsky (CSO, CMO) noted that we are at a turning point where obesity is started to be treated as a reversible disease that can lead to substantial reductions in morbidity and mortality from cardiovascular disease, type 2 diabetes, liver disease, and other complications. He believes that this will be a major change in public health and that Lilly is well positioned to be a leader in this space.

2. Management announces two phase 3 trials in patients with obesity that are expected to initiate in 2022

Management announced two new phase 3 studies investigating tirzepatide in patients with obesity that are expected to initiate in 2022. The first trial, SURMOUNT-MMO, will specifically assess the effect of tirzepatide on morbidity and mortality in patients with diabetes. In this discussion, Dr. Jeff Emmick (VP, Diabetes Product Development) discussed the many comorbidities associated with obesity and noted they hope to leverage weight loss conferred by tirzepatide to pursue clinically meaningful outcomes. Notably, more than 4 million deaths and 120 million disability-adjusted life years are related to high BMI. Cardiovascular disease accounts for 68% of those deaths, while obesity-related cancer accounts for approximately 10% of deaths and chronic kidney disease accounts for around 8%. Importantly, though, significant weight loss, such as that conferred by tirzepatide, leads to improvements in a host of comorbidities, including 65% resolution of dyslipidemia, 73% resolution of type 2 diabetes, 44%-74% reduction in cardiovascular disease, and a 30%-40% reduction in mortality. Obesity is also a risk factor for obstructive sleep apnea, a disorder characterized by narrowing of the upper airway that impairs breathing during sleep. Between 60% and 90% of patients with sleep apnea have overweight or obesity, and despite it being a modifiable CVD risk factor, it is largely underdiagnosed. Notably, the current standard of care, positive airway pressure, has not been shown to improve non-sleep related sleep apnea outcomes, such as MI, stroke, diabetes, and depression. Thus, Lilly management announced a phase 3 trial of tirzepatide in patients with obesity and sleep apnea called SURMOUNT-OSA, which is also expected in initiate in 2022. Management suspects that in addition to improving obesity, tirzepatide may also improve upper airway dysfunction and respiratory control instability. As of December 15th, neither of these trials have been listed on clinicaltrials.gov, but we are looking forward to learning more about potential trial design, enrollment size, completion date, and more in the coming quarters.

  • Recall that the first of the SURMOUNT trials are expected to be readout in 2022. The SURMOUNT program includes four trials investigating tirzepatide in adults with obesity and overweight with and without type 2 diabetes. SURMOUNT 1 began in 2020 and is expected to reach primary completion in April 2022, while the other three trials (SURMOUNT 2, SURMOUNT 3, and SURMOUNT 4) were initiated this year and expected to complete in 2023. In Lilly’s 3Q21 financial update and again on today’s call, management was quite bullish on the potential of tirzepatide in obesity and stated that they anticipate FDA submission and approval in 2024, assuming all ongoing SURMOUNT trials produce positive results. If approved, tirzepatide would join Novo Nordisk’s GLP-1 agonists Saxenda (liraglutide) and Wegovy (semaglutide) as new incretin-based weight loss pharmacological options.

3. Phase 2 GIP/GLP-1/glucagon triple agonist is expected to confer “bariatric surgery like weight loss”

Management also expressed optimism with the “Triple G” agonist LY3437943 – the GIP/GLP-1/Glucagon receptor agonist is a single peptide derived from a GIP backbone with triple-agonist activity for the GIP, GLP-1, and glucagon receptors. The goal of the incretin is to maintain the benefits of tirzepatide with the additional benefits of glucagon receptor activation to achieve differentiated weight loss and other metabolic health benefits. During Q&A, when asked how this compares to Novo Nordisk’s amylin analog cagrilintide+ semaglutide combination, management noted the benefits of delivering all three moieties in one molecular backbone. This delivery method “simplifies the development paradigm” and is less challenging than co-formulating the cagrilintide and semaglutide. Recall that the phase 1 trial, presented at EASD 2021, showed that the Triple G agonist conferred found dose-dependent weight loss that was sustained over the 43 days of the study in healthy participants (n=45). Participants also had reduced appetite, as indicated by an increased visual analog scale (VAS) score, which is a measure of hunger, fullness, satiety, and prospective food intake, where greater scores indicate lower appetite. Additionally, a phase 1 proof-of-concept trial in patients with type 2 diabetes found that patients reduced body weight by 8.57 kg over a 12-week trial. Preclinical data has found that LY3437943 reduced body weight through decreased food intake and increased energy expenditure and was associated with an impressive 80% loss of fat mass. The phase 2 trial with the Triple G agonist in patients with type 2 diabetes was started in May 2021 and is expected to complete in 2H22.

4. Phase 1 trial with oxyntomodulin analog (GLP-1/glucagon receptor agonist) produces differentiated weight loss

Data from the 16-week proof of concept trial suggests that the oxyntomodulin (dual GLP-1/glucagon agonist) also confers substantial weight loss. A phase 1 16-week proof-of-concept study in patients with type 2 diabetes found that over a period of 12 weeks, oxyntomodulin conferred 8 kilograms of weight loss with this molecule and after 16 weeks, patients had lost an average of 11 kilogram. Notably, this was accompanied by substantial glucose lowering, similar to that seen with tirzepatide. Oxyntomodulin is a single peptide derived from a glucagon backbone with dual agonist activity for GLP-1 and glucagon receptors. Similar to the triple agonist, the goal of oxyntomodulin is to add glucagon receptor activation to achieve differentiated weight loss and other metabolic health benefits in patients with obesity. This compound was first announced at the community investor meeting in 2016, and in today’s call, management noted the possibility of combining it with a long-acting GIP molecule to achieve more weight loss, glucose control, and additional metabolic benefits. They plan to progress oxyntomodulin through the pipeline in parallel with the triple agonist with the hopes of eventually selecting the best available molecule for patients.

  • Notably, OPKO Health is also developing an oxyntomodulin (GLP-1/glucagon) compound and announced positive topline results from a phase 2 trial with the agent in 2019. In September 2021, OPKO Health announced they had partnered with China-based LeaderMed Health Group to develop, manufacture, and commercialize the candidate in a move suggesting they are not moving forward with development and approval in the US for the time being.

5. Once-weekly basal insulin candidate advances to phase 3; five studies launching in 2022

We received exciting news today regarding Lilly’s once-weekly basal insulin candidate as the company announced plans to launch five global phase 3 studies in 2022. Collectively known as the QWINT program, these studies will primarily focus on insulin naïve individuals with type 2 diabetes; however, one study will compare glycemic outcomes in people with type 1 diabetes who use the once-weekly basal insulin to those who use insulin degludec. Lilly was highly encouraged by the candidate’s performance in phase 2 studies, prompting the development of an extensive phase 3 program.

  • Dr. Ruth Gimeno (Vice President, Diabetes Research and Clinical Investigation, Lilly) shared results from phase 2 studies, exuding optimism regarding the insulin’s efficacy and safety. She shared data demonstrating the weekly insulin had much lower peak-to-trough ratios than insulin glargine and insulin icodec, speculating this may improve individuals’ glycemic control and reduce hypoglycemia risk. Furthermore, results indicated the once-weekly insulin was non-inferior to daily insulin degludec in glycemic control (A1c reduction) after 26 weeks in both those with type 1 and type 2 diabetes. Hypoglycemia risk in once-weekly basal insulin users was comparable to insulin degludec users, and intriguingly, those with type 2 diabetes who previously used basal insulin demonstrated lower rates of hypoglycemia compared to those using insulin degludec. Dr. Gimeno stated these were “outstanding” results, especially for a weekly insulin, expressing hope the reduction in dosing burden could greatly benefit those who struggle with managing daily injections.
  • Although no specific timelines regarding initiation, recruitment, or data collection were announced, Lilly did reveal the general populations each study will compare. Two studies will analyze the weekly basal insulin’s efficacy in insulin naïve individuals with type 2 diabetes; QWINT-1 will compare its performance to insulin glargine in this population, while QWINT-2 will compare it to insulin degludec. QWINT-3 will compare the candidate’s efficacy in previous basal insulin users with type 2 diabetes to insulin degludec users, and QWINT-4 will compare its performance to insulin glargine in people with type 2 diabetes who take multiple daily injections. Only QWINT-5 will enroll those with type 1 diabetes, which will compare the once-weekly basal insulin’s performance to that of insulin degludec. We look forward to hearing more details about these studies, including enrollment criteria, timelines, and endpoints, next year.

6. Lilly highlights potential of oral GLP-1 LY3502970 as an alternative to injectable GLP-1 therapy for type 2 diabetes and obesity

During today’s call, management highlighted Lilly’s commitment to small molecule oral incretins to expand the reach of the GLP-1 mechanism for patients with diabetes and obesity, particularly those who may be hesitant to take an injection. As we learned in Lilly’s 3Q21 update, the company’s oral GLP-1 non-peptidic agonist (NPA) candidate LY3502970 has progressed into phase 2 studies in type 2 diabetes and overweight/obesity. This follows encouraging results from a 12-week proof-of-concept study in type 2 diabetes, which demonstrated the potential of LY3502970 to match high-dose subcutaneous GLP-1s. Specifically, the proof-of-concept study found A1c lowering of up to 1.77% points, a mean weight loss of approximately 5 kg, and safety and tolerability consistent with the GLP-1 class. Notably, phase 1 data supports once-daily dosing with no food or water restrictions, making the oral GLP-1 easier to use than oral GLP-1 Rybelsus, which must be taken at least 30 minutes before eating or drinking in the morning. Overall, management touted LY3502970’s benefits as a “convenient, easy-to-use oral incretin,” emphasizing that it may be a good option for people with moderate obesity and comorbidities such as diabetes, impaired liver health, and CVD, who could benefit from weight loss but may be hesitant to begin injection therapy. Given the wealth of evidence documenting strong weight loss and cardiovascular improvements with GLP-1s, we are glad to see Lilly expanding the scope of its development program in a patient-focused manner and remain excited about the availability of additional oral GLP-1s. 

7. “The next frontier”: Glucose-sensing insulin candidate remains in preclinical stage

Lilly’s glucose-sensing insulin candidate received minor attention in today’s briefing. In July 2021, Lilly acquired Protomer Technologies to accelerate its development of a glucose-responsive insulin (GRI), which the company believes could significantly reduce or eliminate the hypoglycemia risk associated with exogenous insulin use. Dr. Ruth Gimeno shared data from an in vitro study in which the insulin’s activity increased tenfold in the presence of high glucose concentrations compared to low glucose concentrations. The promising glucose responsiveness reaffirmed Dr. Gimeno’s belief that an effective GRI can “greatly simplify” and transform insulin therapy. Hailed by Lilly management as “the next frontier” in insulin therapy, several GRI molecules are in preclinical development, and according to the presentation slides, “multiple” molecules have “in vitro and in vivo profiles consistent with glucose responsiveness in the relevant physiological range.” No timeline was provided regarding how quickly the GRI may move into clinical trials; nevertheless, we are excited to see how Lilly and Protomer’s GRI progresses because this technology has the potential to be life-changing for people with diabetes. Novo Nordisk remains Lilly’s strongest competitor in the GRI field as a phase 1 clinical trial examining their GRI candidate NN1845 completed in June 2021, which was safe and well-tolerated and demonstrated “proof-of-principle” properties. A new multiple dose phase 1 study was recently posted online and opened recruitment in early December 2021.

8. Deep phase 1 cardiovascular pipeline seeks to address unmet need in ASCVD and heart failure

Management reviewed Lilly’s cardiovascular pipeline, which includes several phase 1 trials to address unmet needs in ASCVD and heart failure. In ASCVD, Lilly is targeting atherogenic remnant lipoprotein particles with its ANGPTL3 siRNA candidate LY3561774, developed in collaboration with Dicerna to silence mRNA with specific liver targeting. A phase 1 trial found that LY3561774 reduced atherogenic particles and significantly lowered triglycerides, and Lilly plans to initiate a phase 2 study in 1H2022. Lilly is also targeting Lp(a) with its oral Lp(a) disrupter program and Lp(a) siRNA. In heart failure, Lilly aims to harness the potential of NRG4 agonist to stimulate cardiac repair and contractile function improvement as well as the potential of pregnancy hormone Relaxin to increase cardiac output and renal blood flow. Overall, management highlighted their commitment to addressing the high residual risk in heart failure, noting the limited long-term impacts of current therapies despite a high mortality rate of 50% within five years of diagnosis. We note that this commentary echoed a presentation by Dr. Javed Butler at HiD 2021 and applaud Lilly for continuing to dig deeper into tough aspects of CVD.

Analyst Q&A

On tirzepatide

Q: Do you expect obesity or diabetes to be the larger indication for tirzepatide and why?

Mr. Mike Mason (President, Lilly Diabetes): That's a good question. I think, obviously if you look at the patient need, we're here and focused on stopping the progression of both of these diseases, and they are very linked. Obesity causes diabetes, and we need to make sure that the progression of diabetes is halted by getting weight under control. Diabetes is a more established treatment area today. We still have work to do in order to build the momentum in obesity with access and physician prescriptions. I think you'll see over the short run, that diabetes will dominate the forecast and the revenue. But long-term, we have a strong conviction that it's really important for society to get obesity and the progression of obesity under control, so we are very committed to make that happen.

Q: A question on development timelines, is there an opportunity to accelerate development of some of these programs? Can we think about there being faster pathways than, for instance, what we're seeing with tirzepatide as obesity gets better understood? Or is this just big programs are going to take time and there's not a whole lot you can do about it.

Mr. Jeff Emmick (VP, Diabetes Product Development): We’re always looking to shorten development timelines wherever possible. I think you saw that with tirzepatide, we did not do a Phase 2 program. We went directly to Phase 3 and gained alignment from the agency to do that, despite the fact that we had not studied that population. But we also need to understand the dose response and titration. If it's a compound that requires titration, then that's a place where having Phase 2 data is extremely helpful, it's not something you want to do in Phase 3. And then we're always looking to the cut the obvious places, enrollment. The enrollment in our diabetes program, and I can actually tell you that our SURMOUNT-2, SURMOUNT-3, SURMOUNT-4 studies are now fully enrolled. All of them, despite COVID, enrolled well ahead of our projected timelines.

So I think the other piece is, if you've got an exciting asset and investigators are excited, you can really move with speed and we've seen that with tirzepatide. We moved very quickly from when we announced SURPASS-4, which was one of our last studies to complete, to submission this year. So we're always looking to shave time off there. But we do look for innovative ways to structure our programs, whether it's a Phase 2/Phase 3 adaptive program, whether it's going directly to Phase 3 as we've done. Again now we're going to do that with sleep apnea. So we look across multiple spectrums and the challenge is always to move faster.

Mr. Mason: And you also see an increased conviction on obesity. I think that should be coming clear today. And so you'll see that as a primary indication, as one of the first indications that we launch and not the two-year delay potential you see between diabetes and obesity with tirzepatide.

Q: Slide 13 suggests Lilly thinks that tirzepatide will beat Wegovy by two-fold in terms of weight loss. Is that a correct interpretation of that schematic? And if that's the case, and given the strong data so far with tirzepatide in diabetes, has Lilly reconsidered not filing tirzepatide in obesity just on SURMOUNT-1? Kind of makes no sense to me that you wouldn't at least try?

Ms. Ruth Gimeno (VP, Diabetes Research and Clinical Investigation): I'll take the science question first. You have to be a little bit careful. We went back and forth about different studies, about which data we picked because you actually have to titrate tirzepatide up to its maximum efficiency and also via titrating our incretins in those studies. So, I wouldn't infer from this particular comparison that this is going to end up at a twofold difference. I think we are quite confident this is going to be more potent than tirzepatide. And I think we are very confident that you'll see more weight loss in an obese population than in a diabetes population, but I wouldn't want to put a number on it at this point in time

Mr. Emmick: Yeah, we don't put a specific number. I think I've referenced this before, but if we look at other incretins in patients with and without diabetes and some of our own modeling, you see 1.4 to 1.6-fold increase in weight loss in patients who don't have type 2 diabetes. So ultimately, that's why we're looking forward to SURMOUNT-1 that'll answer the story for dual agonists but we do expect robust weight loss. Mike I don't know if you want to touch on the strategy from a regulatory perspective?

Mr. Mason: Obviously, we're excited about the SURMOUNT-1 data, I think we're all looking forward to that. We agree to the FDA on our SURMOUNT-4 study clinical trials that would be required for submissions. And I think our best estimate is going to take all four trials in order to get the indication.

Q: Thinking about the obesity and expansion indications you talked about – sleep apnea and some of the kidney diseases – do you think this is an umbrella indication for obesity that will only help you expand into obesity, or do you see these as separate indications that may have separate revenue stream in addition to what you have in obesity?

Mr. Mason: I think the answer is both. First of all, there's big unmet needs in sleep apnea, in cardiovascular and chronic kidney disease. I think there is a real value proposition that tirzepatide can offer for those patients. Also, when you take a look at the broader obesity market of the 111 million adult Americans that live with obesity, only about 25 million of those have access. So as we talk to payers and clinicians, what's important is we've got a tremendous molecule that can provide higher weight loss than what's on the market today. And I think we owe it to clinicians and to payers to show, what are those subpopulations within the broader obesity population where the value proposition is high. And so our goal, overall, is to make sure that we provide segments that tirzepatide offers greater value for. And to increase that overall percent of people that have access for obesity agents from 25 million to much higher than that. So that we can really disrupt this progressive disease and improve outcomes.

Mr. Emmick: I just might add from a regulatory perspective, we were seeking with the Base SURMOUNT program, the chronic weight management indication. And we see these as new indications and line extensions, the latter under that primary indication. Much like the CV risk reduction line extension is for diabetes. I think Mike makes the point that showing the outcomes is really critical.

Mr. Mason: You look at sleep apnea for example. About 50 million Americans live with obesity, sleep apnea. When you look at those that have moderate to severe, that's about 20 million Americans, and of those about 8 million are diagnosed. Sleep apnea is a well-recognized treatment by payers, including Medicaid and Medicare and commercial, and so it has better access and a general chronic weight management. So it gives us the opportunity to again help people living with sleep apnea, as well as increase access for those that have obesity overall and sleep apnea.

Q: Just wanted to follow up on some of the next-generation incretins you mentioned. So tirzepatide as the successor to Trulicity was pretty straightforward and easy to understand, but as we think about these next-generation assets, it raises some portfolio questions. So should we think about sort of like a portfolio approach, where you’re going to be picking winners across that group or is there really an underlying view that there can be greater personalization of therapy based on patient characteristics? Thank you.

Ms. Gimeno: So as we think about the next-generation incretins, I think for example glucagon pharmacology we know brings something unique. It probably brings an increase in energy expenditure, potentially greater durability of weight loss. Glucagon itself has unique actions on the liver that really could translate into a broader NASH benefit. So we view the obesity population as a very heterogeneous population, and there may be space for multiple medications that are really tailored to the unique comorbidities or complications in this patient population.

Mr. Mason: I'd also say, as markets are immature, that customer segmentation doesn't get high, patient segmentation doesn't high. You’re just trying to get something there to the marketplace that works. But as markets become more mature, that's when you start getting a much more segmented approach. Some that prefer oral versus injectables and others that maybe need more weight loss than what tirzepatide can offer. So I think what you'll see over time as any market matures, you'll get definite segments in there and we'll have a good portfolio to meet many segment needs.

Ms. Gimeno: Yes, and there's definitely a need for additional weight loss beyond where tirzepatide can play.

On Triple G

Q: My main question is the application of glucagon and what you are seeing in that context. A couple other programs are out there. So just wanted to get a better understanding of how you’re thinking about the benefits of agonizing glucagon and then the risks that could be associated with it. Are there concerns around safety that we need to think about carefully? But then also, what could the potential benefits be, particularly on adipose and direct adiposity? Thanks.

Ms. Gimeno: I think, glucagon is one example where, as Dan mentioned, we initially saw really nice weight loss with glucagon plus GLP-1, even better weight loss with GGG, and this seems to be playing out in our clinical data so far. So we're excited from an efficacy perspective. In terms of safety, with any glucagon-containing molecule, it's really important to get the ratio between the glucagon and the GLP-1 correct. If you have too little GLP-1 activity, you'll have basically an increasing glucose that is mediated by glucagon. Glucagon is a catabolic hormone, if you don't counteract it, you could end up with catabolic actions. So, getting that ratio right is important.

One of the reasons we actually tested our glucagon-containing molecules in type 2 diabetes – it tells you whether we have too little or too much glucagon activity. A molecule such as cotadutide probably has too little glucagon, it's not as efficacious. Other molecules may have too much glucagon activity and those you wouldn't expect to see a lot of glucose lowering in type 2 diabetes. So, we feel pretty good about our molecules, but it's obviously something we need to watch as we move forward.

Q: On timelines with Triple G and oxyntomodulin, is it an either-or decision? Will you wait until that second asset is through Phase 2 before you move to Phase 3, or will you keep pushing forward and make a decision later in the development program? Thanks.

Ms. Gimeno: I think it's a little bit too early to tell how excellent the oxyntomodulin versus GGG will play out. And certainly if we have great data with one of them, we wouldn't wait for the other one. I think that's not the right thing to do for patients.

Q: I have a question on the comparison between the strategy you’re taking mid-stage through pipeline versus the other powerhouse, Novo Nordisk. They have picked as their lead next-generation molecule the amylin combination with GLP-1, while you picked Triple G. I strongly suggest you synthesize their molecules and compare them to yours in preclinical models, I am sure you will not share all of it with us. Can you share with us how you think about the pharmacological properties of their choice of the next-wave product versus yours? And I know you have a preclinical program.

Ms. Gimeno: Yes, it's very different biology. So, we think that glucagon brings a different type of pharmacology to it. Anytime you have all the components of a molecule in one molecular entity, it greatly simplifies your development paradigm. So, this is one of the attractions of GGG.

I think it's actually been quite challenging to make good amylin-targeted molecules. Amylin is a protein that likes to fibrillate. You see some of these challenges still in Novo’s molecule – they have injection site reactions in 5% to 6% of patients, they have very high level of anti-drug antibodies. And they obviously have challenges about co-formulating with semaglutide, which leads them into a dual chamber device.

So, as we looked at this, we carefully designed our molecules. Our preclinical molecules are isolated peptides intended for once weekly delivery. We were very careful to try to make them as low immunogenicity as possible. The molecules are in principle combinable with our next-generation incretins.

What we decided to do is really look at two molecules that are either a very selective amylin molecule, so this allows us to maximize amylin pharmacology, and then the DACCRA is interesting because it brings calcitonin. I think we have some more calcitonin activity compared to Novo, and we think this brings some additional interesting pharmacology. From a preclinical perspective, we see insulin sensitization, obviously calcitonin has beneficial effects on bones. So we'll be interested to see what these molecules look like. We've taken a different path from Novo and I think that's good for patients – we don't want to do the same thing.

On glucose-sensing insulin

Q: A question on your glucose sensing insulin. It’s intriguing technology in very early days, but perhaps you could offer some comments on the safety in terms of how it could cause waking in hypoglycemia, as well as at the dosing frequency? And finally, how your technology platform may differ from any competitors who had the same type of asset in their pipeline.

Ms. Gimeno: I think it's still early days. Obviously I think the Holy Grail is we'd like to have an insulin that is so exquisite in terms of glucose control that we could dose it independent of any considerations in terms of insulin. We could dose it potentially once weekly. I think there's going to be multiple steps to get there. At this point, technologically or technically it's a very different challenge. So I think we actually need to bring these molecules in the clinic. We need to see what they can do and then we can see how they're best going to be utilized. I think it's definitely going to be simpler for patients. They won't have to worry about exactly predicting how much they eat, when they eat. We could see it as a prandial insulin, we could see it as a basal insulin. There's multiple ways to move forward in that space.

 

--by Andrew Goyette, April Hopcroft, Claire Holleman, and Kelly Close

 

[1] We also note it’s not simple – while some have expressed hope that Lilly’s commitment to obesity will inspire other smaller companies to do the same, we also know that small companies working in areas that ultimately will require large trials is a major barrier. As well, of course, people with obesity will do best with a holistic approach – given that therapy is foundation to T2D, we hope there will be movement to recognizing how much better people with obesity can do on therapy (in this case we’ve seen it for T2D), given tirzepatide’s remarkable, positive weight loss side effect profile when given in populations where patients are often overweight or have obesity.