Visible Alpha GLP-1 Drug Monitor: The Emerging Pipeline
By: Rahul Jasuja, PhD
The Visible Alpha GLP-1 Drug Monitor tracks the current and projected growth of the GLP-1 (glucagon-like peptide-1) receptor agonist family of therapeutics marketed by publicly traded companies for type 2 diabetes, obesity or weight management, and other indications. The monitor evaluates both approved GLP-1 drugs and developing GLP-1 pathway-related drug candidates in the pipeline based on revenue potential while taking into account innovation and mechanism-of-action impact as well as clinical and regulatory risk. This update follows the first GLP-1 monitor published on March 26, 2024.
Figure 1: The Visible Alpha GLP-1 Drug Monitor
(Change from the previous GLP1 Monitor – Pfizer’s Danuglipiron, in Phase2, has been removed from pipeline drug candidates, to depict only lead Phase 3 drug candidates) Source: Visible Alpha BioPharma consensus (March 22, 2024); forecasts are in millions of U.S. dollars
Figure 2: Revisions to 2032 Estimates for Five Leading GLP-1 Drugs
Source: Visible Alpha consensus (July 19, 2023)
Key Takeaways
|
Competitive Landscape of Emerging GLP-1 Drug Candidates
The next wave of GLP-1-based drug candidates, currently in Phase 3, will be dominated by NVO and LLY, further consolidating their dominance (Table 2). These include NVO’s CagriSema (GLP-1 receptor agonist + amylin receptor agonist) and LLY’s orfoglipiron (oral GLP-1 receptor agonist) and retatrutide (GLP-1 receptor agonist + GIP receptor agonist + glucagon receptor agonist).
NVO and LLY to maintain dominance for now; could face challenges from developing pipeline
The top 5 leading GLP-1 drugs currently on the market are owned by Novo Nordisk (NYSE: NVO) and Eli Lilly (NYSE: LLY). Together, these two companies captured 98.1% of total GLP-1 drug revenues in 2023, amounting to $37.2 billion out of approximately $37.9 billion. Looking ahead to 2033, based on Visible Alpha consensus, NVO and LLY are expected to maintain their dominant position, accounting for 89.9% of all GLP-1 drug revenues. By 2033, the combined NVO and LLY GLP-1-based drug revenues are expected to reach $152.5 billion. Overall, GLP-1-based drugs are forecasted to generate $169.7 billion in revenue in 2033.
However, the projected 2033 dynamics could shift if any of the competing Phase 3 or Phase 2 drug candidates are approved and show superiority over the current GLP-1 portfolios of NVO and LLY, either on the market or in development pipelines. Other companies advancing next-generation drugs in Phase 3/Phase 2 stages, aside from NVO and LLY, include (Table 2 and Table 3):
- Zealand Pharma (CPH: ZEAL)
- Pfizer (NYSE: PFE)
- Amgen (NASDAQ: AMGN)
- Structure Therapeutics (NASDAQ: GPCR)
- Altimmune (NASDAQ: ALT)
- Viking Therapeutics (NASDAQ: VKTX)
- Merck (NYSE: MRK)
- Roche (SIX:ROG)/Genentech
- AstraZeneca (NASDAQ, LSE: AZN)
- Terns Pharma (NASDAQ: TERN)
Notably, the only Phase 3 candidate outside of LLY and NVO’s offerings is ZEAL and Boehringer Ingelheim’s (private) Survodutide.
Novel Mechanisms & Improved Drug Profiles in the Pipeline
While GLP-1 receptor agonism and dual GLP-1 and GIP receptor agonists continue to be successful, new combinatorial approaches are being developed. These engage additional metabolic pathways that could potentially generate improved glucose regulation, greater weight loss, increased durability of weight loss, and improved tolerability/safety.
These innovative yet related metabolic pathway approaches target novel biology and mechanisms distinct from GLP-1 receptor agonism (semaglutides – Ozempic, Wegovy, Rybelsus) and dual GLP-1 and GIP receptor agonists (tirzepatides – Mounjaro, Zepbound).
GLP-1 and GLP-1 pathway-related drug candidates with new mechanisms of action include:
- GLP-1 receptor agonist & amylin receptor agonist (cagrilintide) – CagriSema (NVO), amycretin (NVO)
- GLP-1 receptor agonist & glucagon receptor agonist – mazdutide /LY3305677 (LLY), pemvidutide/ALT-801 (ALT), survodutide/BI-456906 (Boehringer Ingelheim & ZEAL), efinopegdutide/MK-6024 (MRK),
- GLP-1 receptor agonists & insulin analog – Icosema/NN1535 (NVO)
- GLP-1 receptor agonist & glucagon receptor agonist & GIP receptor agonist – retatrutide (LLY), AZD9550 (AZN)
- GLP-1 receptor agonists & GIP receptor antagonist – AMG-133/maridebart + cafraglutide (AMGN)
- GLP-1 receptor agonists & dapagliflozin, a SGLT2 inhibitor – SemaDapa (NVO)
- GLP-1 receptor agonists & GLP-2 receptor agonists – dapiglutide (ZEAL)
- Amylin receptor agonist (no GLP-1) – petrelintide, (ZEAL), AZD6234 (AZN)
Besides mechanism of action, innovative approaches to improve drug profile include – oral versions of current injections or novel oral formulation drug candidates, long-acting and less frequently dosed drug candidates, but with efficacy that is comparable or better to the currently approved drugs. These include oral GLP-1 receptor agonists such as PF-06882961/danuglipron by Pfizer, which is a once-daily oral pill in Phase 2, or NVO’s NN9650 that is a GLP-1 receptor agonist that is a once monthly dual GLP1/GIP receptor agonists.
The novel mechanisms and new formulations (oral, long-acting) aim to differentiate from the competition by improving the drug profile via one metric or the other – efficacy, safety, tolerability, and/or clinical outcomes across the board or within distinct patient sub-populations.
Table 1: Approved GLP-1-based drugs:
Semaglutides (Ozempic, Rybelsus, Wegovy) are GLP-1 receptor agonists; tirzepatides (Mounjaro and Zepbound) are GLP-1 receptors, and GIP receptor agonists. Liraglutide, dulaglutide, and exenatide are first generation GLP-1 based drugs
Table 2: GLP-1-based drug candidates in Phase 3 studies – NVO and LLY dominate the Phase 3 pipeline:
Emerging GLP-1-based drug candidates with a novel mechanism of action or an improved drug profile (e.g., oral versus injectable) are designed to compete with the current market leaders, if approved.
Table 3: GLP-1-based pipeline of drug candidates in Phase 2 and Phase 1 studies:
Unlike the Phase 3 pipeline, the Phase 2 pipeline of drugs is not dominated by LLY and NVO. Note that petrelintide (ZEAL) and AZD6234 (AZN) are amylin receptor agonists that are not GLP-1 pathway-based. AMG-133 (AMGN) is a GIP receptor antagonist (not agonist). MASH is metabolic dysfunction-associated steatohepatitis – a similar disease to the prior term, NASH.
Notable Novel Mechanisms of Action of GLP-1 and GLP-1-related Pathways in Clinical Development
GIP receptor antagonism (not agonism): GIP receptor agonism as occurs in Mounjaro and Zepbound, works by regulating energy balance through cell-surface receptor signaling in the brain and adipose tissue and by enhancing lipid storage and acts on the central nervous system to lower food intake. A notable and differentiating mechanism of action in the developing pipeline includes Amgen’s AMG-133 which is a GLP-1 receptor agonist and GIP receptor antagonist. AMG-133 is a bispecific construct engineered by conjugating a monoclonal anti-human GIP receptor antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Pre-clinical and early clinical data has demonstrated that antagonizing GIP receptors (in combination with GLP-1 agonism) leads to improved weight loss and improvements in metabolic metrics.
Biased GLP-1 receptor agonism, the next generation of GLP-1 receptor agonists: Conventional GLP-1 receptor agonism involves full agonism by engaging multiple intracellular signaling pathways. In contrast, selective or biased agonism by engaging select intracellular signaling pathways results in distinct physiological pathways. Biased agonism of the GLP-1 receptor can enhance glucose regulatory efficacy by avoiding GLP-1 receptor desensitization and downregulation, by reduced β-arrestin pathway engagement and intracellular signaling. This effect can be achieved without disturbing the intracellular cAMP signaling pathway that leads to the multiple beneficial metabolic effects associated with GLP-1 receptor agonism. Companies developing biased GLP-1 receptor agonists include Structure Therapeutics (GSBR-1290 in Phase 2) and Roche/Genentech (RG6641/CT-868, RG6640/CT-388, RG6652/CT-996 in Phase 2 and Phase 1).
Amylin receptor agonism: Approaches that target the amylin receptor are differentiated from GLP-1-based therapies. Amylin is co-secreted with insulin and assists in glucose control. It inhibits glucagon secretion, delays gastric emptying, and signals satiety, suppressing the intake of food. Amylin is released from the pancreas and induces feelings of satiety, in contrast, GLP-1 is secreted by the gut and primarily reduces appetite. Early data suggests that amylin may have a more tolerable safety profile, however, larger clinical trials are needed to confirm. Amylin analogs could capture a market population that does not tolerate GLP-1-based drugs. We are aware of two drug candidates that target amylin exclusively – petrelintide (ZEAL) and AZD6234 (AZN), both in Phase 1 studies for obesity/weight loss. In addition, amylin receptor agonists in combination with GLP-1 receptor agonists are in clinical studies – CagriSema (NVO) in Phase 3 for type 2 diabetes and obesity/weight loss, amycretin (NVO) in Phase 2 for obesity/weight loss and NN9487 (NVO) an oral GLP-1 plus amylin analog in Phase 1 studies for obesity/weight loss.
Glucagon receptor agonists: Glucagon is a peptide hormone secreted from the alpha cells of the pancreatic islets of Langerhans. Glucagon plays important roles in glucose, amino acid, and fat metabolism and may also regulate appetite and energy expenditure. Glucagon regulates liver lipid metabolism by stimulating lipolysis and fatty acid oxidation and inhibiting lipogenesis, thereby reducing liver storage of fat. The combination of a GLP-1 receptor agonist and a glucagon receptor agonist has utility in obesity/weight loss via GLP-1 receptor agonism and reduction in liver fat via glucagon receptor agonism for fatty liver disease or MASH (metabolic dysfunction-associated steatohepatitis). MASH is the new term for nonalcoholic steatohepatitis (NASH).
Next Generation GLP-1 Drug Candidates Nearing Approval: NVO’s Cagrisema Stands Out
Based on Visible Alpha consensus revenue projections, NVO’s Cagrisema, and LLY’s Retatrutide and Orfoglipiron are the leading candidates to compete with the currently marketed GLP-1 drugs in the near term. All three could potentially be on the market in 2025.
Cagrisema, in Phase 3 for type 2 diabetes and obesity/weight loss, has the highest market potential. CagriSema is a combination of a GLP-1 receptor agonist (semaglutide) plus an amylin receptor agonist (Cagrilintide). Based on Visible Alpha consensus, by the year 2035, CagriSema’s risk-adjusted revenues are expected to top $37.9 billion, which is significantly more than LLY’s Retatrutide and Orfoglipiron revenue estimates. Risk-adjusted revenues for Retatrutide and Orfoglipiron in 2035 are $9.3 billion and $14.6 billion, respectively.
Notably, Cagrisema risk-adjusted revenue projections are even more than the revenue projections for the currently approved blockbuster GLP-1 drugs – Ozempic, Wegovy, Mounjaro, or Zepbound.
Figure 3: Comparing the Phase 3 GLP-1-based drug candidates:
Of the next-generation GLP-1-based drug candidates, currently in Phase 3, NVO’s Cagrisema, if approved, could reach almost $38 billion in risk-adjusted revenues by 2035. In comparison, risk-adjusted revenues for LLY’s Retatrutide and Orfoglipiron are dramatically lower.
Source: Visible Alpha consensus (July 19, 2024)
Wegovy’s Cardiovascular Benefit Label Expansion Approved by the FDA
Wegovy is the first weight loss drug that is also approved to help prevent life-threatening cardiovascular events in adults with cardiovascular disease and either obesity or overweight (not diabetic). The FDA announced its decision in March 2024.
This will compel health insurance agencies currently not covering weight loss drugs to cover Wegovy if the patient is at risk of cardiovascular disease, which is often the case in obese/overweight patients. Medicare is prohibited by law to cover drugs for obesity/weight loss. However, the FDA’s extension of the Wegovy label to include cardiovascular benefits has changed Medicare’s view.
The FDA’s decision was based on a multicenter, double-blind, randomized, placebo-controlled, outcomes study (SELECT Trial) conducted by NVO and published in the New England Journal of Medicine in November 2023 (Lincoff et. al., 2023 NEJM. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes). The trial began in 2018 and enrolled 17,604 patients across 41 countries.
This is an advantage for Wegovy over its obesity/weight loss competitor Zepbound (LLY) since applicable Medicare patients can be reimbursed and avoid the steep cost (approximately $1,300 per month). Data suggests that the tirzepatides (Zepbound) may also offer cardiovascular in the obese non-diabetic population similar to semaglutides (Wegovy), however a completed study on cardiovascular risk-reduction has not been reported by LLY to date.
Effect of Wegovy in reducing cardiovascular risk is independent of weight loss & glucose control
At the recent American Diabetes Association meeting (June 21-24, 202) where data from the SELECT trial evaluating Wegovy’s cardiovascular benefits were presented, an area of much discussion was Wegovy’s beneficial effect on cardiovascular metrics independent of weight loss or glucose regulation. Reduction in inflammation is a factor in cardiovascular benefit. It is likely that along with glycemic, dyslipidemia, and blood pressure control, reduction in inflammation contributes significantly to cardiovascular benefit. Inflammation was measured by the high-sensitivity C-reactive protein (hs-CRP) test. This data confirmed that the semaglutide class (Wegovy) reduces inflammation, contributing to cardiovascular benefits independent of weight loss or glucose regulation. It remains to be seen if tirzepatides (Zepbound) will also have the same effect on inflammation and cardiovascular benefit as the semaglutides (Wegovy).
Conclusion
Next-generation GLP-1-based drug candidates with novel mechanisms of action are currently in Phase 3 trials and are projected to be approved in 2025. The next generation of drug candidates targeting GLP-1-related metabolic pathways in combination with GLP-1 receptor agonism harness complementary metabolic pathways that have the potential to improve glucose regulation, increase weight loss, and reduce cardiovascular risk with improved safety and tolerability. In addition, GLP-1 receptor agonist drug candidates with superior efficacy and an improved drug profile (biased agonism, long-acting or oral formulations) are also in development. The leading next-generation drug candidates in Phase 3, slated for approval in 2025, belong to either NVO or LLY, thus extending dominance over the competition. Based on Visible Alpha consensus, CagriSema (NVO) has the largest market potential of the next-generation GLP-1-based drug candidates currently in Phase 3.
The reduction in cardiovascular risk with GLP-1-based drugs for obesity (so far demonstrated with semaglutides) bodes well for further market expansion given medicare coverage and private insurance coverage of obesity/weight loss drugs.
As Big Pharma companies compete in the GLP-1 space, we anticipate partnering/acquisition transactions to continue to bolster Big Pharma pipelines with next-generation GLP-1 pathways and related drugs. Several biotechs with novel and promising GLP-1 and GLP-1 related pathway drug candidates in Phase 1 and 2 may be ripe for Big Pharma partnering/acquisition.
Novel Personalized Cancer Immunotherapy Approach Faces Challenges
By: Rahul Jasuja and Raunaq Sahil
Gritstone Bio (NASDAQ: GRTS) is developing a next-generation personalized therapeutic cancer vaccine based on its tumor-specific neoantigen platform (GRANITE). Neoantigens are tumor antigens unique to the patient and/or the tumor and are not expressed on normal cells. The GRANITE program has received the FDA’s Fast Track designation and is currently in Phase 2/3 trials as a maintenance therapy in patients with newly diagnosed metastatic microsatellite-stable colorectal cancer (MSS-CRC). Results from the Phase 2 portion of the Phase 2/3 GRANITE trial missed its primary endpoint measuring circulating tumor DNA (ctDNA). A secondary endpoint of progression-free survival had encouraging trends but was not statistically significant.
Analysts see increased risk following Phase 2 data
Visible Alpha consensus shows that following the Phase 2 GRANITE data release, analysts perceive heightened risk in the program, with the consensus probability of success (POS) for FDA approval dropping to 33.9% from the 65% POS expected in March. Based on Visible Alpha consensus, analysts expect GRANITE for colorectal cancer (CRC) to generate $29 million in risk-adjusted revenues in 2027 in the U.S. markets. By 2035, risk-adjusted revenues in the U.S. are projected to reach $509 million.
Phase 2 portion of Phase 2/3 GRANITE study misses primary endpoint
The Phase 2 portion of the Phase 2/3 study failed to meet its primary endpoint of a short-term molecular response defined as at least a 30% decline from baseline in circulating tumor DNA (ctDNA). The data showed that only 30% of patients who received GRANITE achieved this molecular response, compared to 42% in the control group.
Gritstone attributed these results to a misunderstanding of how ctDNA would change after treatment – ctDNA decreased for longer than expected on chemotherapy in both arms, resulting in similar molecular response in the short term. The longer-term evaluation shows the expected correlation between ctDNA with clinical benefit and favors GRANITE patients. Progression-free survival (PFS) trends were encouraging but not statistically significant. Gritstone reported hazard rates (HR) of 0.82 for the overall population and 0.52 for a subgroup of high-risk patients with increased risk of disease progression – the vast majority of this group have liver metastases. The data was more mature in the high-risk group and the clinical effect of GRANITE was pronounced in this high-risk group.
Longer-term PFS data is expected in 3Q 2024. The company chose to use ctDNA, an untested measure, due to concerns that immunotherapies can sometimes cause tumors to enlarge temporarily as they infiltrate the cancer (pseudo-progression).
About Gritstone’s personalized neoantigen vaccine approach
A salient feature of a neoantigen vaccine approach is the potential to induce a potent cytotoxic CD8+ T cell-driven anti-tumor immune response that is personalized to the patient’s unique tumor antigens (neoantigens). Tumor antigen heterogeneity within tumors and from patient to patient is a major challenge in cancer immunotherapy, and the GRANITE personalized neoantigen approach has the potential to address this unmet need.
Neoantigens are peptides found exclusively within cancer cells and absent in normal cells. A neoantigen-based therapeutic cancer vaccine approach that activates neoantigen-specific CD8 + T cells would complement checkpoint inhibitors (for example, Merck’s Keytruda or Bristol-Myers Squibb’s Opdivo) that are effective in activating pre-existing CD8+ T cells targeted against a distinct repertoire of tumor antigens that are immunogenic. This approach increases the repertoire of cytotoxic CD8+ T cells that may lead to a more potent and broad immune response.
Eli Lilly’s Donanemab Gets Positive FDA Advisory Committee Review
By: Rahul Jasuja, PhD
The FDA Advisory Committee evaluating Eli Lilly’s (NYSE: LLY) donanemab for Alzheimer’s disease unanimously recommended approval in patients with early Alzheimer’s disease with mild cognitive impairment and mild dementia. The FDA usually heeds the advice of its Advisory Committee but is not obligated to.
Donanemab Could Be on the Market Later in 2024
Donanemab is an amyloid β targeting antibody that follows in the footsteps of Biogen’s (NASDAQ: BIIB) & Eisai’s (TSE: 4523), Leqembi (lecanemab). Leqembi was the first amyloid β targeting antibody approved in July 2023. Visible Alpha consensus revenue estimates show donanemab reaching $4.6 billion in risk-adjusted revenues by 2033. The current Visible Alpha consensus probability of approval (POS) for donanemab is at 91.9%, however, the POS will likely increase as analysts update their models given the recent positive Advisory Committee review.
Donanemab FDA Advisory Committee Meeting
FDA’s Peripheral and Central Nervous System Drugs Advisory Committee met to discuss donanemab efficacy and safety on June 10, 2024. Donanemab was expected to be approved by the end of 2023, however regulatory delays related to safety evaluation prolonged the timeline. It is no surprise that the majority of the Advisory Committee meeting discussion was focused on the safety of donanemab, followed by evaluation of Tau protein levels in patients enrolled and the duration of donanemab treatment.
The Advisory Committee was voting on two questions:
- Does the available data show that donanemab is effective for the treatment of Alzheimer’s disease in the population enrolled in the clinical trials with mild cognitive impairment and mild dementia?
- Do the benefits outweigh the risks of donanemab in the treatment of Alzheimer’s disease in the population enrolled in the clinical trials with mild cognitive impairment and mild dementia?
On both voting questions, the Advisory Committee voted unanimously (11 to 0) in favor of efficacy and in favor of benefits outweighing risks.
The other notable areas of discussion at the Advisory Committee meeting included:
- Analysts believe that the FDA will likely approve donanemab with a broad label for early-stage Alzheimer’s disease, with close monitoring required for certain high-risk patient subgroups
- Even though the donanemab Phase 3 Trial (TRAILBLAZER-ALZ 2) stratified patients based on the levels of Tau protein (a predictive biomarker for Alzheimer’s disease progression), the Advisory Committee did not recommend Tau PET imaging for screening of patients for donanemab use. Tau protein PET imaging would have restricted the use of donanemab given the limited access to Tau PET imaging available to patients.
- Donanemab will likely be approved with a standard boxed warning for amyloid β targeting therapies – similar to Leqembi.
- The Advisory Committee was in agreement with the LLY approach to donanemab dosing, i.e. treating until amyloid β clearance as measured by an amyloid β PET scan. Therefore, dosing with donanemab will be stopped when the patient shows a negative amyloid PET scan.
Merck’s Oral Drug Candidate Could Change the Hypercholesterolemia Landscape
By: Rahul Jasuja, PhD
Merck’s (NYSE: MRK) MK-0616 is an oral PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor drug candidate currently in Phase 3 studies for hypercholesterolemia. This drug could be the first oral PCSK9 inhibitor that makes it to market, which could significantly change the landscape for hypercholesterolemia treatment.
PCSK9 inhibition is an effective therapeutic tool, usually as an add-on to statins, in the control of hypercholesterolemia that is not controlled by statins alone. Currently approved PCSK9 inhibitors are administered by injection (antibodies or siRNA-based drugs). The prospect of an oral PCSK9 inhibitor may have the potential to expand the current PCSK9 inhibitor market.
Currently marketed PCSK9 inhibitors have fallen short of initial market expectations
PCSK9 inhibitors were projected to be blockbuster drugs when first approved. The currently approved PCSK9 inhibitors are Amgen’s (NASDAQ: AMGN) Repatha, Sanofi (NASDAQ: SNY) and Regeneron’s (NASDAQ: REGN) Praluent, and Alnylam (NASDAQ: ALNY) and Novartis’ (NYSE: NVS) Leqvio. Repatha and Praluent are monoclonal antibodies, and Leqvio is RNA-interference based. All three are subcutaneous injections. The clinical experience with PCSK9 inhibitors had shown effective LDL-cholesterol lowering across most patient subgroups, along with safety. In patients with atherosclerotic cardiovascular disease (ASCVD) where more aggressive LDL-cholesterol reduction is required, PCSK9 inhibitors in combination with statins may be the most effective in reaching treatment goals of lowering LDL-cholesterol.
Figure 1: PCSK9 inhibitors on the market
Adapted from Agnello et al; J. Clin. Med. 2024, 13, 125. Repatha (MRK) and Praluent (SNY & REGN) are monoclonal antibodies against PCSK9. Leqvio (ALNY and NVS) is RNA interference/siRNA targeted against PCSK9 mRNA. All three approved PCSK9 inhibitors are injections.
However, market acceptance has been less than expected since the approval of Repatha and Praluent in 2015, and then Leqvio in 2020. This lower-than-expected market success of PCSK9 inhibitors can be attributed to the high cost, a complex insurance approval process, and the fact that the approved PCSK9 inhibitors have all been injections. Importantly, patients are reluctant to self-inject or choose injections as an add-on to statins for a condition that does not have symptoms. Patient compliance was also a factor — patients on statins often did not comply with monthly injections after the first few injections. Compared to Repatha and Praluent monthly injections, Leqvio has the advantage of twice-yearly injections after the first year.
In 2018-19 the cost of Repatha and Praluent was reduced significantly by about 60%, bringing the cost down to approximately $5,800 for annual therapy. The cost of Leqvio is $9,700 for the first year and then $6,700 for subsequent years.
Analysts project improved prospects for Repatha & Leqvio
Visible Alpha consensus shows increasing estimated revenues in the coming years for Repatha and Leqvio, potentially as a result of a reduction in cost that is far more acceptable for insurance. Praluent revenue projections are modest. For example, in 2023, Repatha revenues were $1.7 billion — based on Visible Alpha consensus, Repatha revenues in 2024 are estimated at $2.6 billion, and reach $3.1 billion in 2028. Leqvio revenues in 2023 were $396 million and are estimated at $808 million in 2024, reaching $3.3 billion in 2029. Leqvio is a siRNA-based injection that requires a less frequent dosing schedule compared to the monoclonal antibodies, Repatha and Praluent. Efficacy in LDL-cholesterol reduction is generally considered similar between the monoclonal antibody-based PCSK9 inhibitors (Repatha/Praluent) and siRNA based Leqvio. However, unlike for Repatha and Praluent, it should be noted that there is no cardiovascular outcomes study with Leqvio showing reduction in risk of atherosclerotic cardiovascular disease (ASCVD).
Figure 2: Consensus revenue projections for currently approved PCSK9 inhibitors
MK-0616 could be the first approved oral PCSK9 inhibitor
The development of an oral PCSK9 inhibitor is a significant achievement since PCSK9 interaction with the LDL-receptor does not easily cater to small molecule drug inhibition. Merck’s MK-0616 is an oral macrocyclic peptide that has demonstrated efficacy and safety in Phase 2b studies.
Phase 2b clinical trial data with MK-0616
Merck conducted a Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of MK-0616 in patients with hypercholesterolemia. A total of 381 patients were enrolled. The doses of MK-0616 used were 6, 12, 18, or 30 mg administered once daily, or placebo. The reduction in LDL-cholesterol from baseline to 8 weeks vs placebo was 41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). All doses of MK-0616 were statistically significant. MK-0616 was well tolerated as adverse events were comparable between treatment arms and placebo. A reduction of LDL-cholesterol from baseline of 60.9% in the highest dose (30 mg) is impressive.
Comprehensive Phase 3 clinical program initiated with MK-0616
Merck has initiated a comprehensive Phase 3 program that also includes a cardiovascular outcomes study, besides a lipid-lowering study and a supportive study in different hypercholesterolemia subgroups. A total of 17,000 patients will be enrolled across the three trials:
- A Study of MK-0616 (Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids (NCT05952856 https://classic.clinicaltrials.gov/ct2/show/NCT05952856)
- A Study of MK-0616 (Oral PCSK9 Inhibitor) in Adults With Heterozygous Familial Hypercholesterolemia (MK-0616-017) CORALreef HeFH (NCT05952869 https://classic.clinicaltrials.gov/ct2/show/NCT05952869)
- MK-0616 (Oral PCSK9 Inhibitor) Cardiovascular Outcomes Study (MK-0616-015) CORALreef Outcomes (NCT06008756 https://classic.clinicaltrials.gov/ct2/show/NCT06008756)
MK-0616 revenue potential
According to Visible Alpha consensus, analysts project that MK-0616 will be on the market in 2026 and reach an estimated $4.8 billion in revenues by 2035. Risk-adjusted revenues in 2035 are an estimated $2.9 billion. Visible Alpha consensus probability of success for MK-0616 approval is 67.4%. If approved, MK-0616 will be the first oral PCSK9 inhibitor on the market. An oral PCSK9 inhibitor is expected to have advantages over the currently marketed PCSK9 inhibitors that are all injections.
Figure 3: Consensus revenue projections for Merck’s MK-0616
AstraZeneca’s oral PCSK9 inhibitor follows in the footsteps of MK-0616
AstraZeneca (NASDAQ: AZN) is developing an oral small molecule PCSK9 inhibitor, AZD0780. Phase 1 studies have been completed. A statistically significant reduction of 52% in LDL-cholesterol levels was observed when AZD0780 was added to statin treatment (78% reduction from baseline) in treatment-naive participants with hypercholesterolemia. The company has initiated Phase 2 studies with AZD0780.
Besides the oral PCSK9 inhibitors in development, other approaches targeting PCSK9 include gene silencing, DNA base editing, and vaccine therapies. These are in earlier stages of development and are not discussed in this report.
About PCSK9 and hypercholesterolemia
PCSK9 is involved in cholesterol homeostasis and is related to the concentration of cholesterol in the cell. Elevated levels of circulating PCSK9 are associated with increased low-density lipoprotein cholesterol (LDL-cholesterol) and worse cardiovascular outcomes.
PCSK9, an enzyme (serine protease) encoded by the PCSK9 gene, is predominantly produced in the liver. PCSK9 binds to the LDL-receptor on the surface of hepatocytes, leading to the degradation of the LDL-receptor and subsequently to higher plasma LDL-cholesterol levels. When PCSK9 is inhibited and not attached to the LDL-receptor, the LDL-receptor is recycled back to the cell surface and can reduce serum LDL-cholesterol (see Figure 4, below). PCSK9 inhibitors are usually given as an add-on to statin treatment.
Figure 4: Mechanism of action of PCSK9 inhibitors
Source: Fitzgerald & Kiernan; 2018; Expert Review of Cardiovascular Therapy, 16:8, 567-578. PCSK9 regulates LDL-receptors (LDL-R) and its inhibition increases LDL-R recycling to the cell surface of hepatocytes and subsequent lowering of LDL-cholesterol (LDL-C) concentration in serum.
References:
- Chapman & Packard; Realizing the Potential of PCSK9 Inhibition: A Novel Oral Macrocyclic Peptide on the Horizon; Journal of the American College of Cardiology. 2023, 81 (16) 1565–1568.
- Agnello F et al; Novel and Emerging LDL-C Lowering Strategies: A New Era of Dyslipidemia Management. Journal of Clinical Medicine. 2024, 13, 1251.
- Ballantyne MC et al; Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616; Journal of the American College of Cardiology. 2023, 81:16, 1553-1564.
- Gerald Fitzgerald & Tom Kiernan; PCSK9 inhibitors and LDL reduction: pharmacology, clinical implications, and future perspectives. Expert Review of Cardiovascular Therapy. 2018, 16:8, 567-578.
- Dayoub EJ et al; Adoption of PCSK9 Inhibitors Among Patients With Atherosclerotic Disease. Journal of the American Heart Association. 2021,10 (9).
Viking Therapeutics’ Weight-Loss Drug Shows Promise in Phase 2a Obesity Study
By: Rahul Jasuja, PhD
Among the next generation of GLP-1 based therapies currently in clinical development, Viking Therapeutics’ (NASDAQ: VKTX) VK2735, a dual GLP-1 and GIP agonist, is one of the most attractive weight-loss drug candidates based on recent Phase 2a trial data (Venture study) in obese patients. Viking is planning for VK2735 Phase 2b trials, and investors are paying close attention to any potential Big Pharma partnership or acquisition before Phase 3 trials. (See also our latest Visible Alpha GLP-1 Monitor for more on this family of drugs.)
Phase 2a obesity trial with VK2735
The Phase 2a study with VK2735 was a 13-week trial in obese patients with body mass index (BMI) ≥30, or ≥27 for patients with comorbidities. The study was a randomized, placebo-controlled study enrolling 176 patients. The primary endpoint of the study was percent change in body weight at 13-weeks versus placebo. The study arms included placebo, 2.5mg, 5mg, 10mg and 15mg VK2735 dose groups.
At the end of 13 weeks, the reduction in body weight was: 1.7% (placebo), 9.1% (2.5mg), 10.9% (5mg), 12.9% (10mg) and 14.7% (15mg). As depicted in Figure 1, the placebo-adjusted reduction in weight was 7.4% (2.5mg), 9.2% (5mg), 11.3% (10mg), and 13.1% (15mg). By any standard, these are impressive weight reductions within a 13-week timeline. At the end of the 13 weeks, there was no plateau observed, suggesting that weight loss would potentially continue with dosing. The study also achieved a significant secondary endpoint, demonstrating that 88% of patients experienced ≥10% weight loss.
Figure 1: Phase 2a Venture study with dual GLP-1/GIP agonist, VK2735, in obese patients
Source: VKTX presentation (May 2024). The Phase 2a showed as much as a 13.1% placebo adjusted reduction in body weight in the 15 mg dose group. The effect of VK2735 was dose dependent.
Treatment-emergent adverse events (TEAEs) that resulted in patients discontinuing the study were modest – no discontinuations in the placebo, 2.5mg, 5mg, or 10mg dose. There was only one patient discontinuation in the highest 15mg dose.
How does VK2735 compare with the competition?
While Phase 2a data with VK2735 is only available for 13 weeks, it appears promising, and longer-term data could lead to an even greater reduction in weight. As noted above, there was no plateau observed at 13 weeks, which implies that weight reduction may potentially continue with longer-term treatment. Figure 2 compares published data on GLP-1 based marketed drugs and drugs in clinical development with VK2735 Phase 2a 13-week data. Weight loss of 13.1% with VK2735 in 13 weeks is impressive. For a rough comparison, weight loss at 12 weeks with Eli Lilly’s (NYSE: LLY) tirzepatide (Zepbound) was 8%, as pointed out in the VKTX presentation (Figure 2, orange dotted line). Longer-term data with VK2735 is required for conclusive determination of comparative efficacy.
Figure 2: VK2735 13-week weight loss compared with published data for other GLP-1 based drugs on the market or in development
Source: VKTX presentation (May 2024). Novo Nordisk’s (NYSE: NVO) CagriSema (GLP-1 agonist + amylin receptor agonist) is in Phase 3 trials; NVO’s Semaglutide, Wegovy (GLP-1 agonist) is on the market; NVO’s Cagrilintide (amylin receptor agonist) is in Phase 2; Altimmune’s (NASDAQ: ALT) Pemvidutide (GLP-1/glucagon dual receptor agonist) has completed Phase 2 studies; LLY’s Retatrutide, also termed Triple-G (GLP-1, GIP, & glucagon receptors agonist) is in Phase 3 trials; and LLY’s Tirzepatide, Zepbound (GLP-1/GIP dual receptor agonist), is on the market.
Favorable pharmacokinetic data from Phase 1 study
Phase 1 single ascending dose studies showed that VK2735 has a favorable pharmacokinetic profile. Pharmacokinetic studies showed a T1/2 of 170 to 250 hours, making weekly (or even longer) dosing possible, and a Tmax of 75-90 hours indicates a slow onset of drug exposure that lends to the safety and efficacy of VK2735.
VK2735 consensus revenue projections
VK2735 is expected to be on the market in 2028. Visible Alpha consensus revenue projections (risk-adjusted) estimate VK2735 will reach $3.6 billion within 5 years of market approval in 2033. By the year 2040, VK2735 tops almost $10.5 billion in projected risk-adjusted revenues. Based on Visible Alpha consensus, the likelihood of VK2735 approval is 74.2%.
Figure 3: VK2735 risk-adjusted consensus revenue projections
Based on efficacy and safety data available to date in Phase 2a studies, VK2735 has the potential to become a lucrative asset in the obesity/weight management market. Viking plans to conduct a Phase 2b study in a larger patient population with 24-36 weeks dosing. This longer-term study within a larger patient population will add to the rigor of VK2735 data. In addition to subcutaneous VK2735, Viking is also developing an oral VK2735, currently in Phase 1 trials. Early data with oral VK2735 appears promising.
Major Clinical Data Unveiled for Novo Nordisk (NVO) Obesity Drug Wegovy
By: Rahul Jasuja, PhD
Clinical researchers across the globe, including from Novo Nordisk (NYSE: NVO), recently published a long-term study evaluating the company’s obesity drug, Wegovy (a semaglutide), in patients that had pre-existing cardiovascular disease and were overweight or obese, but were not diabetic. The results of this trial validate the safety, efficacy, and durability of Wegovy in obesity/weight management and cardiovascular benefit. Wegovy may be the first weight-loss drug that has such impressive and durable cardiovascular benefits. (See also our Visible Alpha GLP-1 Monitor for more on this family of drugs.)
This trial was termed “Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity,” or the SELECT trial. It enrolled 17,604 patients across 41 countries treated with Wegovy or placebo (control) that were evaluated over four years. The SELECT trial marks the longest clinical trial that evaluates the effects of a semaglutide (once-weekly Wegovy injection) versus placebo on weight loss, safety, and durability in a geographically and racially diverse population that is overweight or obese, but not diabetic.
Summary of SELECT trial results
The primary endpoint of the study was the time to first occurrence of a composite endpoint consisting of: cardiovascular (CV) death, non-fatal myocardial infarction, or non-fatal stroke within a 59-month time frame. Secondary endpoints included several measures within a 59-month timeframe related to cardiovascular metrics (including cardiovascular death and all causes of death) and several endpoints related to blood pressure, blood metabolism chemistry, and change in body weight and waist circumference measured at baseline and at 2 years. Body Mass Index (BMI) was used to measure weight loss over the four years of the study. BMI is a measure of body fat based on height and weight.
The results of the SELECT trial can be summarized as follows for 2.4 mg Wegovy administration every week over 208 weeks (almost 48 months or four years) versus placebo:
- Mean reduction in weight of 10.2% in the Wegovy arm versus 1.5% in the placebo arm
- Waist circumference reduction of 7.7 cm in the Wegovy arm versus 1.3 cm in the placebo arm
- Waist-to-height ratio reduction of 6.9% in the Wegovy arm versus 1.0% in the placebo arm
- P < 0.0001 for all the above comparisons of Wegovy-treated versus placebo-treated arm
- Weight loss was sustained over the four years while on Wegovy
The individuals in the trial were grouped in four categories based on BMI (<30, 30 to <35, 35 to <40, and ≥40 kg/m2). Each of the BMI categories had lower rates of serious adverse events in the Wegovy-treated arm versus placebo arm, pointing to the safety and tolerability of Wegovy. Notably, the difference in the rate of serious adverse events between the Wegovy-treated and placebo arm was most pronounced in the highest BMI group – the more obese individuals had increased serious adverse events in the placebo arm compared to the Wegovy arm. This demonstrates the significant efficacy and safety benefit of Wegovy treatment compared to placebo.
Figure 1: Wegovy vs. placebo for weight loss
Source: Ryan et al; Nature Medicine. May 13, 2024. Categorical weight loss from baseline at week 104 for Wegovy and placebo in the SELECT trial. Data is from the in-trial period. Bars depict the proportion (%) of patients receiving Wegovy or placebo who achieved ≥5%, ≥10%, ≥15%, ≥20%, and ≥25% weight loss.
The results of this trial, especially on cardiovascular safety metrics, are likely to expand the market potential of Wegovy and the other major semaglutide in Novo Nordisk’s portfolio, Ozempic. Ozempic is approved for type 2 diabetes, not for obesity/weight management. Note that in March 2024 the FDA expanded Wegovy approval for cardiovascular benefit in addition to Wegovy’s initial approval for obesity/weight management.
According to Visible Alpha consensus, analysts’ revenue projections estimate Wegovy will reach $9 billion in 2024 and top $22.5 billion in 2030.
Figure 2: Novo Nordisk’s Wegovy consensus revenue projections
Reference:
- Ryan et al; Nature Medicine; Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. May 13, 2024
Vertex Pharmaceuticals (NASDAQ: VRTX) has a leading position in the cystic fibrosis (CF) market, driven by Trikafta. Positive Phase 3 data for the company’s pipeline drug, vanza, was reported in February this year, and it’s likely to follow in the footsteps of Trikafta, which was approved in 2019.
Vertex conducted two Phase 3 studies with vanza (vanzacaftor/tezacaftor/deutivacaftor) that met their primary and key secondary endpoints in treating CF patients, demonstrating non-inferiority to Trikafta in enhancing lung function (measured as percent predicted forced expiratory volume in 1 second (ppFEV1)). Vanza demonstrated superiority over Trikafta in reducing sweat chloride (SwCl) levels, a secondary endpoint in the trial. Based on these results, Vertex intends to file for approval in the U.S. and Europe by mid-2024 for patients with CF ages 6 years and older. Vertex also plans to use its FDA priority review voucher, which guarantees an expedited six-month review process in the U.S.
Vanza and Trikafta are both triple-combination CFTR (cystic fibrosis transmembrane conductance regulator) protein modulators. Vanza is a next-generation CFTR modulator administered once daily, while Trikafta is administered twice daily.
Vanza may not have a clear market advantage over Trikafta
A once-daily administration with vanza versus a twice-daily administration with Trikafta may not necessarily equate to greater market penetration of vanza in CF patients. This is reflected in analysts’ consensus revenue projections for Trikafta and vanza. Based on the Phase 3 trials, vanza shows equal efficacy (non-inferiority) to Trikafta in improving lung function. Vanza did show improvement over Trikafta in a measure of sweat chloride levels; however, the measure of sweat chloride levels may not lead to improvement in lung function, and sweat chloride measures are not used routinely in clinical practice. Furthermore, there is currently no long-term clinical efficacy data for vanza.
The bar set by Trikafta is high, showing effective therapeutic benefits in lung function, pulmonary exacerbations, and durability. For a subset of patients that experience side effects with Trikafta (rash, liver enzyme dysregulation, CNS issues), vanza could potentially be a preferred alternative, though full safety data for vanza has yet to be released. The positive clinical experience with Trikafta since market approval in 2019 is another barrier for clinicians to switch patients to vanza without good reason. At this stage, it is unclear if the dosing convenience of once-daily versus twice-daily compels clinicians to make the switch from Trikafta to vanza in CF patients that are well-controlled with Trikafta.
According to Visible Alpha consensus, vanza is estimated to generate $1.3 billion in risk-adjusted revenue in 2025, assuming FDA approval by the end of 2024 or early 2025. Vanza is projected to generate $7.8 billion in risk-adjusted revenues in its peak sales year of 2033. Visible Alpha consensus pegs the probability of success (POS) for vanza approval by the FDA for treating patients with CF at 90%. Vertex’s CF sales are currently driven by Trikafta, Kalydeco (ivacaftor), Orkambi (lumacaftor/ivacaftor), and Symdeko (tezacaftor/ivacaftor).
About Cystic Fibrosis and Vanza
Cystic fibrosis (CF) is a progressive, multi-organ disease caused by dysfunction or mutation of the CFTR gene. Patients with CF have a mutated protein that impacts an ion channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The channel transports negatively charged chloride ions into and out of cells and controls water flow into tissues, required for generation and flow of mucus that lubricates the lining of airways and the digestive tract, among other organs. Symptoms can vary, ranging from few or no symptoms to severe or even life-threatening complications. The most serious and common complications of CF are lung-related, including frequent pulmonary or respiratory exacerbations, typically caused by serious lung infections.
Vanza is a triple combination CFTR modulator comprising two “correctors” (vanzacaftor and tezacaftor), that increase the amount of CFTR protein on the cell surface, and one “potentiator” (deutivacaftor) that increases the probability of opening the chloride ion channel. The effect of increased CFTR protein expression (i.e., increase in chloride ion channels) and increased chloride ion transport across the cell membrane provides therapeutic benefit in CF patients. Vanza was investigated in patients with the most common CF mutation in CFTR, F508del.
Reviewed by Rahul Jasuja, PhD
Eli Lilly’s (NYSE: LLY) donanemab treatment for Alzheimer’s disease has been subject to extended regulatory delays. Analysts and investors had expected that the FDA would approve donanemab in Q1 2024. In early March, however, the FDA announced that it would convene an Advisory Committee meeting to further evaluate the donanemab approval application. While it is not uncommon to convene an Advisory Committee meeting, it is unusual to convene it so late in the process.
The FDA communicated to Eli Lilly that the Advisory Committee meeting will further evaluate the safety and efficacy of donanemab in the Phase 3 trial. In particular, the FDA needs to understand the implications of the unique Phase 3 trial design that included limited-duration dosing, which allowed completion of treatment based on measure of amyloid plaque. In addition, the trial was also unique in using tau protein levels as an inclusion criterion.
Donanemab’s regulatory history
The company had announced the completion of Phase 3 trials (TRAILBLAZER-ALZ 2 study) and subsequent submission of the donanemab Biologics License Application (BLA) in July 2023. It was expected that donanemab would be approved by the end of 2023. In November 2023, however, the FDA requested additional data from Eli Lilly, pushing approval to Q1 2024. Currently, with FDA plans for an Advisory Committee meeting, donanemab approval has been pushed further to Q2 2024.
Prior to completion of the Phase 3 trial in July 2023, the FDA had declined in January 2023 to grant donanemab Accelerated Approval. The FDA was likely seeking more clarity on safety and efficacy after completion of the larger Phase 3 trial.
Revisions to donanemab revenue projections
Given the regulatory delays and stiff competition from Biogen’s (NASDAQ: BIIB) and Eisai’s (TSE: 4523) Leqembi, which was approved for early-stage Alzheimer’s disease in the summer of 2023, Visible Alpha consensus shows analysts have revised donanemab revenue projections downward. (See also our previous article on Novel Therapies for Treating Alzheimer’s Disease.)
Figure 1: Revisions to donanemab revenue projections
Based on Visible Alpha consensus estimates, donanemab is expected to reach risk-adjusted peak sales of $5.4 billion in 2032. Furthermore, the likelihood of approval is pegged at 91.7%, implying that analysts continue to believe that donanemab will likely be approved by the FDA, even though there is additional regulatory scrutiny.
Figure 2: Donanemab revenue projections
Biogen Strengthens Neurological Disease Portfolio with Reata Acquisition
By: Dilip Kaklotar
In September 2023, Biogen (NASDAQ: BIIB) completed the acquisition of Reata Pharmaceuticals for $172.50 per share in cash, amounting to an acquisition value of about $7.3 billion. Reata Pharmaceuticals specializes in developing therapies that regulate cellular metabolism and inflammation in severe neurologic diseases. This acquisition strengthens Biogen’s neurological disease portfolio. Biogen’s acquisition was driven by Reata’s lead asset, Skyclarys (omaveloxolone), for Friedreich’s ataxia (FA) currently on the market. Skyclarys was approved in the U.S. in May 2023 and in the EU in Feb 2024.
In 2023, Skyclarys generated $56 million in revenues. According to Visible Alpha consensus, Skyclarys is expected to generate $371 million in revenues in 2024 and reach peak sales of $2.2 billion by 2036.
About Friedreich’s ataxia (FA) and Skyclarys
FA is a rare, genetic disease that causes progressive damage to the nervous system, affecting approximately 5,000 patients in the U.S. FA occurs when mutations in the frataxin gene (FXN) cause mitochondrial iron accumulation leading to impaired nerve cell function. This condition damages the nervous system, resulting in muscle weakness, imbalance, and worsening of sensory deficits over time. Frequently, cardiomyopathy may also be observed. Symptoms typically start in childhood but can also begin in adulthood.
Skyclarys is the first and only FDA-approved treatment for FA (see our recent report on 2023 FDA Drug Approvals). Skyclarys activates the nuclear factor-erythroid 2-related factor 2 (NRF2) pathway, a pathway suppressed in patients with FA as a result of a mutated frataxin protein.
References
- Lynch DR, et al., Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol. 2021 Feb;89(2):212-225. doi: 10.1002/ana.25934
- NIH National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia#toc-what-is-friedreich-ataxia-
Reviewed by Rahul Jasuja, PhD
Visible Alpha GLP-1 Drug Monitor: Blockbusters & Up-and-Comers
By: Rahul Jasuja, PhD
The Visible Alpha GLP-1 Drug Monitor reflects the current and projected growth of the GLP-1 (glucagon-like peptide-1) receptor agonist family of therapeutics marketed by publicly traded companies for type 2 diabetes, obesity/weight management, and other indications. The monitor evaluates both approved GLP-1 drugs and developing GLP-1 drug candidates in the pipeline based on revenue potential, and takes into account innovation and mechanism-of-action impact as well as clinical and regulatory risk.
Figure 1: The Visible Alpha GLP-1 Drug Monitor
Source: Visible Alpha BioPharma consensus (March 22, 2024); forecasts are in millions of U.S. dollars
The GLP-1 drug monitor provides investors with a reference point to measure the growth performance of marketed drugs and the growth potential of the emerging pipeline based on Visible Alpha BioPharma consensus revenue projections. By monitoring marketed GLP-1 receptor agonists and the emerging pipeline, investors may better understand innovation trends, potential generic competition, and the interplay between marketed GLP-1 drugs and the GLP-1 pipeline. A grasp of these metrics paints an informed view of the future growth and direction of the rapidly growing GLP-1 drug development space.
Figure 2: Revisions to 2032 estimates for five leading GLP-1 drugs
Source: Visible Alpha BioPharma consensus (March 22, 2024); estimates are in millions of U.S. dollars
Key Takeaways
|
Unprecedented impact of GLP-1 drug class on obesity/weight management, related cardiometabolic diseases
The success of the GLP-1 receptor agonist class of drugs is unprecedented. The first of the first-generation GLP-1 receptor agonist drugs was approved in 2005 for type 2 diabetes (Byetta, an exenatide). The first GLP-1 receptor agonist for obesity/weight management was approved in 2014 (Saxenda, a liraglutide).
It was the development of the second generation of GLP-1 receptor agonists with an improved drug profile that led to the current successes – especially for obesity/weight management and cardiovascular benefits. Second-generation GLP-1 receptor agonists include the semaglutides (Ozempic, Wegovy, Rybelsus) and the tirzepatides (Mounjaro and Zepbound). Undoubtedly, the medical benefits of the second-generation GLP-1 drugs in addressing type 2 diabetes, in addition to obesity/weight management and cardiovascular health, has changed the practice of medicine in the treatment of cardiometabolic and metabolic disorders. Beyond the utility in medicine, the impact of second-generation GLP-1 drugs on society, driven largely by an effective weight-loss function, has lifestyle, consumer behavior, and cosmetic ramifications.
There have been barely a few instances in the history of drug development in which a drug class has had such a monumental paradigm-shifting impact on medicine and society as the GLP-1 receptor agonists drugs. Penicillin and insulin, both discovered in the 1920s, saved millions of lives and had a dramatic effect on society in alleviating sickness and death. In modern times, checkpoint inhibitors for immuno-oncology (Keytruda and Opdivo) have made a significant impact in cancer treatment and in generating lucrative revenues – projected to reach an estimated $46 billion in 2027 for Keytruda and Opdivo combined, based on Visible Alpha consensus. The anti-TNF class of drugs (Enbrel, Humira, etc.) are also worth mentioning. However, none of these drug classes compares to the revenue potential of the GLP-1 drugs.
Landscape for GLP-1-related therapeutics
Marketed GLP-1 receptor agonists: The market is dominated by Novo Nordisk’s (NYSE: NVO) and Eli Lilly’s (NYSE: LLY) portfolio of GLP-1 receptor agonists. Ozempic, Rybelsus (oral version of Ozempic for type 2 diabetes), and Wegovy (approved for obesity/weight management, twice the dose of Ozempic), are marketed by NVO and belong to the semaglutide class of GLP-1 receptor agonists. Mounjaro (type 2 diabetes) and Zepbound (same as Mounjaro but branded differently for obesity/weight management) are marketed by LLY and belong to the tirzepatide class of GLP-1 receptor agonists.
The semaglutide and tirzepatide classes are the second-generation GLP-1 receptor agonists with significant market potential projections (Table 1). The first-generation GLP-1 agonists, liraglutide (Victoza and Saxenda), dulaglutide (Trulicity), and exenatide (Byetta and Bydureon) were only modestly successful and declined significantly in projected market share from 2024 through 2033 (Table 1). The first generation of GLP-1 receptor agonist drugs had a relatively inferior drug profile, lacking in safety/tolerability, frequency of dosing, blood glucose regulation for type 2 diabetes, extent of weight loss, and overall effect on cardiovascular and cardiometabolic function.
Based on Visible Alpha consensus, the five leading GLP-1-based drugs (Ozempic, Rybelsus, Wegovy, Mounjaro, and Zepbound) combined, ramp up from $44 billion in projected revenues in 2024 to almost $99 billion in projected revenues in 2033 (Table 1).
Table 1: Approved GLP-1 receptor agonists drugs; semaglutides (Ozempic, Rybelsus, Wegovy) are GLP-1 receptor agonists; tirzepatides (Mounjaro and Zepbound) are agonists of GLP-1 receptors and GIP receptors
Source: Visible Alpha BioPharma consensus (March 22, 2024); forecasts are in U.S. dollars
GLP-1 and related biology drug candidates in Phase 3 development: As depicted in Table 2, GLP-1 receptor agonists and related biology drug candidates with a novel mechanism of action that are in Phase 3 could compete with the current market leaders, if approved, and change the future competitive landscape We classify these as third-generation GLP-1 drugs that aim to improve over the semaglutides and tirzepatides.
- Cagrisema (cagrilintide plus semaglutide) is being developed by NVO. Within the Phase 3 pipeline, Cagrisema is the most promising based on Visible Alpha consensus revenue projections and the novel mechanism of action leading to potentially improved efficacy. This is especially the case for weight loss, though it is yet to be confirmed in ongoing Phase 3 trials (https://pubmed.ncbi.nlm.nih.gov/37364590/). Cagrisema combines a GLP-1 agonist (semaglutide) with an amylin analog. In addition to the effects of GLP-1 receptor agonism, the amylin analog induces weight loss and blood glucose control. Cagrisema is projected to garner revenues of $23.7B in 2033 (peak not reached), based on Visible Alpha consensus. Analysts see considerable risk in Cagrisema’s regulatory approval, with the consensus probability of success at 65%. If approved, Cagrisema will be the first GLP-1 receptor agonist plus amylin analog to make it to market.
- Orforglipron (LY3502970, OWL833) is an oral GLP-1 receptor agonist being developed by LLY for weight loss and type 2 diabetes. Orforglipron is an oral, non-peptide GLP-1 receptor agonist. According to Visible Alpha consensus, analysts project 2033 revenues of $9.3B and a probability of success at 81.7%.
- Retatrutide (LY-3437943) targets 3 pathways that modulate cardiometabolic function: a GLP-1 receptor agonist, a glucagon receptor agonist, and a glucose-dependent insulinotropic polypeptide (GIP) agonist. Retatrutide is in Phase 3 studies for obesity/weight management, type 2 diabetes, and cardiovascular benefits. Notably, in a Phase 2 study retatrutide demonstrated a 17.5% reduction in mean weight at 24 weeks (primary endpoint) and a 24.2% reduction in mean weight at 48 weeks (secondary endpoint). According to Visible Alpha consensus, analysts project 2033 revenues of $7.6B and a probability of success at 76.0%.
Table 2: GLP-1 receptor agonist-based drug candidates in Phase 3 studies; emerging GLP-1 receptor agonist-based drug candidates with a novel mechanism of action or an improved drug profile (e.g., oral versus injectable) are designed to compete with the current market leaders, if approved
Source: Visible Alpha BioPharma consensus (March 22, 2024); forecasts are in U.S. dollars
GLP-1 and related biology drug candidates in Phase 2 and earlier development: The Phase 2 and earlier pipeline of GLP-1 and related drug candidates is long, with drug candidates having novel mechanisms of action. Notable is a GLP-1 fusion protein in development as an agonist. Amgen’s AMG-133 is a GLP-1 receptor agonist and a GIP antagonist (not a GIP agonist) – Amgen believes that GLP-1 receptor agonism combined with GIP antagonism leads to more effective weight loss.
Late last year, Pfizer halted twice-daily dosing of its oral obesity drug candidate danuglipron (PF-06882961) due to safety and tolerability. Pfizer will continue to develop oral danuglipron at a modified once-daily dose. It is yet to be determined if the modified lower dose can compete on efficacy.
Table 3: Earlier-stage GLP-1 receptor agonist-based pipeline of drug candidates in Phase 2 studies and earlier
Source: Visible Alpha BioPharma consensus (March 22, 2024)
NVO and LLY overwhelmingly dominate the GLP-1 receptor agonist market
NVO and LLY accounted for 98% of the total revenues derived from the global GLP-1 markets in 2023. NVO markets Ozempic, Rybelsus, Wegovy, Saxenda, and Victoza, generating $24.9 billion in 2023 GLP-1 drug revenues. LLY markets Mounjaro, Zepbound, and Trulicity, generating $12.4 billion in GLP-1 drug revenues in 2023. Total GLP-1 revenues in 2023 were $37.9 billion of which $37.3 billion were accounted for by NVO and LLY.
Based on Visible Alpha consensus, NVO and LLY will continue to dominate, accounting for 91% of all GLP-1 revenues in 2033. In 2033, NVO’s and LLY’s GLP-1 pipelines are expected to generate $74.1 billion and $73.7 billion, respectively.
NVO and LLY have promising drug candidates in the pipeline that follow their current lead-marketed drugs, which should sustain their market dominance. However, other competing pipeline programs with novel mechanisms of action may turn out to be superior in efficacy, safety, or patient convenience, and could change the dynamics of the NVO/LLY dominance.
Figure 3: GLP-1 domination by Novo Nordisk (NYSE: NVO) and Eli Lilly (NYSE: LLY)
Source: Visible Alpha BioPharma consensus (March 22, 2024); forecasts are in U.S. dollars
Factors underlying the impressive revenue projections for the GLP-1 agonist drug class
Though the GLP-1 receptor agonist drug class has been around since 2005, the increased interest and lucrative revenue projections are a more recent phenomenon. Several underlying scientific, clinical, and market factors over the last few years played a role in bolstering the utility and market potential of GLP-1 receptor agonists for type 2 diabetes and obesity/weight management, as listed below.
Second-generation GLP-1 receptor agonists have an improved drug profile: With the advent of the second-generation GLP-1 receptor agonists — semaglutide and tirzepatide — improved efficacy, safety, and tolerability were observed for type 2 diabetes and obesity/weight management over the older GLP-1 receptor agonists — liraglutide, dulaglutide, and exenatide.
Improved dosage and delivery: Less-frequent dosing, from daily to weekly, has driven broader patient compliance and increased market share. For example, once-daily Victoza (liraglutide) has been steadily replaced by once-weekly Ozempic (semaglutide). Rybelsus, an oral semaglutide, is now approved, which provides the patient with more options. Table 1 depicts the improvement in dosing frequency since the first GLP-1 drug was approved in 2005.
Innovation in pharmacotherapy of obesity: A crucial development in the last few years has been the innovation in obesity/weight management drug development, leading to relatively safe and dramatically more effective drugs. For years, drugs for obesity were plagued with the lack of meaningful efficacy and a challenging safety profile, especially related to cardiovascular risks.
Impressive efficacy in weight reduction: Second-generation GLP-1 receptor agonists in the semaglutide class improve efficacy over liraglutides, and the most advanced second-generation GLP-1 receptor agonist class — tirzepatides — improves efficacy over semaglutides (example below).
- Wegovy improves over Saxenda: Individuals who received Wegovy lost an average of 14.9% of their initial weight on Wegovy versus 2.4% for placebo. Wegovy is a semaglutide that improves over Saxenda, a liraglutide that had demonstrated an average loss of 5.2% of initial body weight compared to individuals who received a placebo (Wilding et al; NEJM, 2021) (Lingvay et al; Lancet 2022).
- Zepbound (Mounjaro) improves over Wegovy: Individuals who received the highest 15mg dose of Zepbound lost an average of 20.9% of their initial weight versus 3.1% in the placebo arm. Those on the 10mg dose of Zepbound lost 19.5% of their initial weight versus 3.1% on placebo (LLY press release, April 28, 2022).
Third-generation GLP-1 drugs currently in clinical development (e.g., Cagrisema) are designed to improve over the semaglutides and tirzepatides by harnessing related mechanistic pathways that synergize or are additive to the foundational GLP-1 receptor agonism pathway. Early data shows promise in improving weight reduction metrics and cardiovascular benefits.
Obesity management as a primary treatment goal for type 2 diabetes: Obesity and type 2 diabetes share pathophysiological mechanisms that lead to overlapping metabolic complications. GLP-1/GIP biology regulates insulin and glucagon via the pancreas (addressing glucose control in type 2 diabetes), the gastrointestinal tract, and the CNS, which leads to satiety, or reduced appetite, and weight loss. Obesity and diabetes are interlinked – the term “diabesity” is used to describe obesity and type 2 diabetes, which go hand in hand. Lingvay et al. (Lancet, 2022), pointed out that: “Weight loss is known to reverse the underlying metabolic abnormalities of type 2 diabetes and, as such, improve glucose control; loss of 15% or more of body weight can have a disease-modifying effect in people with type 2 diabetes, an outcome that is not attainable by any other glucose-lowering intervention.”
Conceptual change in treating type 2 diabetes beyond glucose control: Treatment of type 2 diabetes has undergone a conceptual change over the last few years, with treatment objectives shifting to include a cardio-centric goal in addition to the long-held gluco-centric goal of regulating blood sugar. This has changed the landscape for treatment of patients with type 2 diabetes. Professional societies (diabetes, endocrinology, and cardiology) have responded to this paradigm shift by advocating for the use of GLP-1 agonists for type 2 diabetes, further driving GLP-1 receptor agonist revenues.
Reduced risk of cardiovascular disease with GLP-1 agonists: Results from cardiovascular outcome studies have demonstrated that GLP-1 receptor agonist therapy leads to a robust and consistent reduction in atherothrombotic events, particularly in patients with established atherosclerotic cardiovascular disease. This is an important metric since type 2 diabetes and obese patients are at increased risk for cardiovascular disease. Most recently (March 8, 2024), Wegovy (a semaglutide), was approved by the FDA for reducing the risk of cardiovascular complications in individuals with obesity and heart disease. Mounjaro/Zepbound, belonging to the tirzepatide class, have also shown cardiovascular benefits in clinical trials, but are not yet FDA approved for reduction in risk of cardiovascular disease.
2022 guidelines on type 2 diabetes by the American Association of Clinical Endocrinology and the American Diabetes Association: Guidelines include recommendations for the use of GLP-1 receptor agonist-based drugs for type 2 diabetes. The positive benefits of GLP-1 receptor agonists in reducing risks of cardiovascular disease, renal disease, liver fibrosis, and obesity, in addition to glycemic control, were important criteria for the recommendation.
Strong market demand for Wegovy, Mounjaro (Zepbound), and Ozempic (off-label) for weight loss: The high demand for Wegovy soon after its FDA approval led to its short supply, which was helped by a contract manufacturer delay and significant off-label use (likely for cosmetic weight loss). Subsequently, given the shortage of Wegovy, many were prescribed the other semaglutide, Ozempic, off-label for weight loss (Wegovy is the same active ingredient as Ozempic, formulated at a higher dose for obesity). This resulted in a short supply of Ozempic for type 2 diabetes patients – the patients in actual medical need versus those using Ozempic for obesity or weight loss for cosmetic needs or less urgent medical needs. This high demand for Ozempic resulted in a dramatic increase in Ozempic sales for NVO starting in late 2021. Both Wegovy and Ozempic are marketed by NVO. LLY also encountered manufacturing supply challenges for Mounjaro in 2023 due to high demand.
Third-generation GLP-1 biology-related pipeline drugs begin to emerge, amplifying GLP-1 market potential: In 2023, positive Phase 2 data on third-generation GLP-1 biology-related drug candidates Cagrisema, orforglipron, and retatrutide (described above) generated significant interest. These drug candidates improved on weight loss efficacy and showed cardiovascular benefit – Phase 2 data was presented at high-impact medical meetings (American Heart Association and American Diabetes Association meetings, 2023). The novel mechanisms behind emerging Cagrisema, orforglipron, and retatrutide were underestimated and an unknown quantity until the Phase 2 data. The positive data and potential to improve over the currently marketed GLP-1 drugs further bolstered analyst and investor confidence. The Visible Alpha GLP-1 Monitor shows dramatic increases in analyst revenue projections from last year since Cagrisema, orforglipron, and retatrutide were relatively unknown and rightly underestimated by analysts until the presentation of Phase 2 data.
Upward revisions
As scientific, clinical, and regulatory events have unraveled, along with company announcements and quarterly updates, analysts have revised revenue estimates higher for the second-generation (semaglutide & tirzepatide) GLP-1 receptor agonist drugs. Depicted in the revision charts below are analysts’ multiple revisions to revenue estimates for Ozempic and Mounjaro. This positive sentiment for Ozempic, Mounjaro, and other second-generation GLP-1 agonists has been buoyed by the many encouraging scientific, clinical, regulatory, and market factors discussed above. Clearly, the unprecedented and unanticipated utility in obesity/weight management, coupled with cardiovascular benefits, has been the driving force.
Figure 4: Upward revisions for Mounjaro (Eli Lilly) revenue
Source: Visible Alpha BioPharma consensus (March 22, 2024); forecasts are in U.S. dollars
Figure 5: Upward revisions for Ozempic (Novo Nordisk) revenue
Source: Visible Alpha BioPharma consensus (March 22, 2024); forecasts are in U.S. dollars
The bottom line
GLP-1 receptor agonist-based drugs have changed the treatment paradigm for cardiometabolic disease, especially obesity. While the obesity/weight management attribute of the GLP-1 receptor agonist class of drugs attracts the most attention, the efficacy in type 2 diabetes, related metabolic disease, and cardiovascular benefits may be of equal or greater medical significance. Given that the tolerability and safety of second-generation GLP-1 drugs and beyond are generally acceptable, we expect revenue potential for the GLP-1 class of drugs to be massive, as seen in Visible Alpha consensus estimates.
The second-generation GLP-1 receptor agonists (semaglutides and tirzepatides), marketed by NVO and LLY respectively, categorically dominate the GLP-1 markets. Both NVO and LLY have plans to protect their dominance with promising candidates in the pipeline. However, several innovative GLP-1-related drug candidates and combinations in development by competing Big Pharma and biotechs could potentially displace the current leaders and change the landscape. Investors may also want to keep a close watch on the third-generation of GLP-1-based drugs in Phase 3 trials: Cagrisema (NVO), orforglipron (LLY), and retatrutide (LLY). These emerging drug candidates in development aim to improve on the marketed second-generation GLP-1 drugs and could shake the competitive landscape.
In 2024 and beyond, we expect healthy revenue growth for GLP-1 drugs marketed by NVO and LLY. In addition, we expect more clinical data for GLP-1 drugs with respect to related cardiometabolic diseases – reduction in risk of cardiovascular events (heart attack and stroke), non-alcoholic steatohepatitis (NASH), chronic kidney disease, and sleep apnea.
References:
1. Ussher & Drucker; Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nature Reviews Cardiology. Volume 20 (7) 463-474; July 2023
2. Jastreboff et al; Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine, Volume 389, 514-526, August 2023
3. Sheahan et al; An overview of GLP-1 agonists and recent cardiovascular outcomes trials. Postgraduate Medical Journal; Volume 96, Issue 1133, March 2020
4. Sharma et al; Recent updates on GLP-1 agonists: Current advancements & challenges. Biomedicine & Pharmacotherapy; Volume 108, December 2018
5. Jastreboff & Kushner; New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics. Annual Review of Medicine; Vol. 74:125-139, January 2023
6. Nauck et al; GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Molecular Metabolism; Volume 46, April 2021
7. Shaefer et al; User’s guide to mechanism of action and clinical use of GLP-1 receptor agonists. Postgraduate Medicine; Volume 127 (8), September 2015
8. Marx et al; GLP-1 Receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 Diabetes. Circulation; 146:1882–1894; December 2022
9. Lingvay et al; Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation. Lancet 22;399 (10322); January 2022
10. Wilding et al; Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine; 384; March 2021
11. Fisman & Tenenbaum; The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect. Cardiovascular Diabetology: Vol 20; 225 November 2021
12. Georgeo-Martinez et al; Clinical recommendations to manage gastrointestinal adverse events in patients treated with GLP-1 receptor agonists: a multidisciplinary expert consensus. Journal of Clinical. Medicine.12(1), 145; January 2023
13. Eli Lilly news release April 28, 2022: https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-delivered-225-weight-loss-adults-obesity-or
14. Novo Nordisk press release March 8, 2024: https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=167030
