Visible Alpha Health Care

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)

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.

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.

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.

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