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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
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

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

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
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:

  1. 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.
  2. Agnello F et al; Novel and Emerging LDL-C Lowering Strategies: A New Era of Dyslipidemia Management. Journal of Clinical Medicine. 2024, 13, 1251.
  3. 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.
  4. 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.
  5. Dayoub EJ et al; Adoption of PCSK9 Inhibitors Among Patients With Atherosclerotic Disease. Journal of the American Heart Association. 2021,10 (9).

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
Figure 1 Phase 2a Venture study with dual GLP 1GIP 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
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

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.

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
Wegovy vs placebo

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

Wegovy


Reference:

  1. 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.

Vertex Vanza

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

Eli Lilly Donanemab revenue revisions

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

Eli Lilly Donanemab revenue projections

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.

BIIB

References

  1. 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
  2. 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

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
GLP 1 Drug Monitor 2024 03 22

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
2032 Revisions Chart

Source: Visible Alpha BioPharma consensus (March 22, 2024); estimates are in millions of U.S. dollars

 

Key Takeaways

  • The GLP-1 receptor agonists and related class of drugs are projected to reach over $164 billion in combined revenue by 2032, based on Visible Alpha consensus, ramping up from $37.9 billion in 2023. These are record-breaking revenues for any drug class in the history of drug development.
  • Over the past few years, analysts have frequently revised revenue estimates higher as scientific, clinical, and regulatory data have demonstrated efficacy and safety with the new generation of GLP-1 drugs for type 2 diabetes, obesity/weight management, and related cardiometabolic diseases. In particular, the efficacy for obesity and weight loss (with generally manageable tolerability), coupled with cardiovascular benefits, is a big driver of market acceptance and revenue growth.
  • Novo Nordisk (NYSE: NVO) and Eli Lilly (NYSE: LLY) are the dominant companies by far, currently accounting for 99% of GLP-1 receptor agonist drug revenues. While analysts project continued domination by NVO and LLY in the years ahead, innovation in the developing pipeline could change the competitive landscape.

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
GLP 1 Approved Table 2024 03 22

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
GLP 1 Phase 3 Table 2024 03 22

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
GLP 1 Phase 2 1 Table 2024 03 22

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)
NVO LLY Dominance 2024 03 22

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
Mounjaro Revisions 2024 03 22

Source: Visible Alpha BioPharma consensus (March 22, 2024); forecasts are in U.S. dollars

Figure 5: Upward revisions for Ozempic (Novo Nordisk) revenue
Ozempic Revisions 2024 03 22

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

According to Visible Alpha consensus, Takeda Pharmaceutical’s (TSE: 4502) dengue vaccine Qdenga (TAK-003) is expected to generate ¥13 billion in revenue in 2024, and is anticipated to grow at a strong double-digit pace until 2032. Visible Alpha consensus revenue estimates show peak global sales of ¥171 billion for Qdenga by 2033. Sales are projected to dip starting in 2034 as Qdenga’s patent is set to expire on September 17, 2035.

Qdenga

The rise of Qdenga is timely, as two of Takeda’s leading drugs, Vyanase for attention deficit hyperactivity disorder (ADHD) and Azilva for hypertension, lost patent exclusivity in 2023, opening the door for generic competition.

About dengue fever and Qdenga

Dengue fever is caused by the dengue virus that is spread via the bite of an infected mosquito. According to the Centers for Disease Control and Prevention (CDC), a population of around 4 billion (half the world’s population) live in areas at risk for dengue virus infection. Each year, about 40,000 individuals die from serious dengue infection. An estimated 400 million get infected and about 100 million become ill from infection with dengue virus.

The Qdenga vaccine is based on a live-attenuated dengue serotype 2 virus that provides a genetic backbone for the four known dengue virus serotypes. It is designed to protect against all of the dengue virus serotypes. Qdenga aims to improve upon Sanofi’s Dengvaxia, the world’s first dengue virus vaccine. Following safety concerns, Dengvaxia’s use has been restricted to children aged 6 to 16 with evidence of prior dengue infection, specifically in endemic regions.

Qdenga not yet FDA-approved

First approved for use in Indonesia in 2022, Qdenga is currently approved in the U.K., Brazil, Argentina, Indonesia, Thailand, and Malaysia. Qdenga was approved in Europe in 2023. Approval by the FDA in the U.S. encountered obstacles. In November 2023, the FDA initiated a priority review for Qdenga, a process that typically takes less than six months, as opposed to the standard 10-month review. However, Takeda voluntarily withdrew its U.S. application because the FDA required additional data that Takeda had not captured in the Phase 3 trial. Takeda has not re-initiated the application with the FDA.

Reviewed by Rahul Jasuja, PhD

Vertex Pharmaceuticals (NASDAQ: VRTX) is expected to generate $21.1 million in revenue from its non-opioid pain treatment VX-548 in 2024. The company is currently preparing a new drug application (NDA) for VX-548, which has been granted both breakthrough therapy and fast track designations. This application is set to be submitted to the FDA by mid-2024. According to Visible Alpha consensus, analysts project risk-adjusted revenue of $1.3 billion by 2028 and $3.3 billion by 2034. Analysts estimate the likelihood of success for VX-548 at 75%.

VX 548

About VX-548

VX-548’s mechanism does not hold addictive potential, thereby achieving opioid-like efficacy without the abuse potential of that class of effective, but problematic, drugs. In January, Vertex announced successful results from three Phase 3 studies of VX-548, showing significant pain reduction for both surgical and non-surgical patients. However, it failed to meet the secondary goal in two trials of reducing pain when compared to a combination of the opioid drug hydrocodone and acetaminophen, the basis for popular pain medications like Tylenol. Vertex is also pursuing a broad label for VX-548 in peripheral neuropathic pain, with positive Phase 2 results in painful diabetic peripheral neuropathy reported and plans to advance pivotal development in this area.

Prior to VX-548, Vertex discontinued development of three other non-opioid drugs—VX-128, VX-150, and VX-961—due to unsuccessful Phase 1 and 2 trials. This makes VX-548’s Phase 3 results a significant win for Vertex.

Potential advantages of VX-548

Selective inhibition of voltage-gated sodium channel NaV1.8 with VX-548 for acute pain is a novel approach. Most approved pain drugs either act on the opioid-receptor system, or are non-steroidal anti-inflammatory drugs (NSAIDs), or are non-selective sodium-channel inhibitors (for example, lidocaine). Opioid use is limited by safety concerns and the potential for misuse and addiction, and NSAIDS and non-selective sodium-channel inhibitors have safety and efficacy limitations. Selective inhibition of voltage-gated sodium channel NaV1.8 is an important addition in the armory of pain drugs.

Reviewed by Rahul Jasuja, PhD

The FDA is slated to review Madrigal Pharmaceuticals’ (NASDAQ: MDGL) Resmetirom for patients with nonalcoholic steatohepatitis (NASH) with fibrosis — the FDA’s Prescription Drug User Fee Act (PDUFA) date is set for March 14, 2024. NASH is a dangerously progressive liver disease with no approved pharmacological agent. If Resmetirom is approved, it will be the first FDA-approved drug for NASH. Several NASH drug candidates have failed in clinical trials or in regulatory review, and a long pipeline of NASH drug candidates are in clinical trials.

Resmetirom projections

Based on Visible Alpha consensus, Resmetirom is projected to generate over $4.1 billion in risk -adjusted revenues in its peak sales year in 2031. Visible Alpha consensus pegs the probability of success (POS) for Resmetirom approval by the FDA in NASH patients with liver fibrosis at 86.3%.

Resmetirom

NASH and NAFLD

According to the American Liver Foundation, NASH, now also called metabolic dysfunction-associated steatohepatitis (MASH), is a form of nonalcoholic fatty liver disease (NAFLD) in which patients have inflammation of the liver and liver damage, in addition to excess fat accumulation in the liver. Patients with NASH have significant liver fibrosis leading to compromised liver function. Ultimately, NASH may progress to cirrhosis and/or liver cancer. At that stage, the liver may be permanently damaged and the only option is liver transplantation.

Resmetirom’s mechanism of action

Resmetirom has a novel mechanism of action — it is an oral thyroid hormone receptor beta-selective agonist. In NASH, the beta thyroid hormone receptor function is impaired, leading to reduction in mitochondrial function as well as reduction in β-oxidation of fatty acids that progresses to fibrosis (Harrison et al; New England Journal of Medicine 390;6, February 8, 2024). Resmetirom was a topic of discussion in our recent publication: Potential FDA Approvals: A Look Ahead for 2024.