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
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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
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.
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%.
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
Madrigal Pharma’s Resmetirom Approaching FDA Review for NASH
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%.
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.
Potential FDA Approvals: A Look Ahead for 2024
By: Rahul Jasuja, PhD
In 2023, we saw the FDA approve 55 drugs under the Center for Drug Evaluation and Research (CDER) and 17 under the Center for Biologics Evaluation and Research (CBER), one of the most prolific FDA drug approval years. Aside from this high number of approvals in 2023, the innovation in drug development was notable, marked by the approval of the first CRISPR-based gene therapy and the approval of the first beta amyloid antibody therapy for Alzheimer’s disease (see our note on 2023 drug approvals here).
Our evaluation of drug candidates lined up for potential FDA approvals in 2024 looks promising on both the innovation and market potential fronts. Here, we highlight select drug candidates that are expected to be approved in 2024 and that have significant innovation impact and revenue potential.
Key drug candidates slated for FDA review in 2024
Sotatercept (MK-7962) is being developed by Merck (NYSE: MRK) for pulmonary arterial hypertension (PAH). PAH is a rare and progressive blood vessel disease accompanied by increased arterial blood pressure and narrowing of the arteries in the lungs. Sotatercept is a first-in-class activin-signaling inhibitor with a novel mechanism of action that will add to the current treatment options for PAH. Based on approval in 2024, Visible Alpha consensus estimates project 2033 risk-adjusted revenues of $4.8 billion (consensus probability of success is at 89.4%).
Resmetirom (MGL-3196) is developed by Madrigal Pharmaceuticals (NASDAQ: MDGL) for nonalcoholic steatohepatitis (NASH) with liver fibrosis. NASH is an advanced form of nonalcoholic fatty liver disease (NAFLD). NAFLD is estimated to afflict more than 20% of adults globally, about 30% in the U.S. Of that NAFLD population, 20% may have NASH. The prevalence of NAFLD/NASH, along with type 2 diabetes and obesity, is rising worldwide. Resmetirom is a thyroid hormone receptor (THR)-β selective agonist that increases hepatic fatty acid β-oxidation and decreases the burden of lipotoxic lipids. Based on approval in 2024, Visible Alpha consensus estimates project 2033 risk-adjusted revenues of $3.6 billion (consensus probability of success is at 87.2% for the U.S./FDA).
Ensifentrine (RPL-554) is being developed by Verona Pharma (NASDAQ: VRNA) for chronic obstructive pulmonary disease (COPD). Ensifentrine is a first-in-class, inhaled, dual inhibitor of the phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) enzymes. The selective and dual inhibition combines bronchodilator and non-steroidal anti-inflammatory properties in one compound, differentiating it from other marketed COPD drugs. In addition, Ensifentrine activates the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), making it effective in reducing mucous viscosity and improving mucociliary clearance (currently in Phase 2 for cystic fibrosis). Based on approval in 2024, Visible Alpha consensus estimates project 2032 risk-adjusted revenues of $2.0 billion (consensus probability of success is at 95.0%).
Table 1: Select drug candidates with upcoming 2024 Prescription Drug User Fee Act (PDUFA) dates
Source: Visible Alpha consensus (January 30, 2024) *POS for Resmetirom and KarXT are for U.S./FDA approval **Reflects 2032 revenues for Ensifentrine
KarXT (xanomeline-trospium) is being developed by Karuna Therapeutics (NASDAQ: KRTX) for schizophrenia. KarXT is based on a novel mechanism of action in the treatment of schizophrenia. It is a muscarinic antipsychotic that acts as a dual M1/M4 muscarinic acetylcholine receptor agonist in the central nervous system and improves cognitive symptoms of schizophrenia. KarXT does not block dopamine receptors like currently approved schizophrenia therapies and presents as a new mechanism of action in the treatment of schizophrenia. It is also in development for psychosis related to Alzheimer’s disease. Based on approval in 2024, Visible Alpha consensus estimates project 2033 risk-adjusted revenues of $4.4 billion (consensus probability of success is at 88.9% for the U.S./FDA for schizophrenia).
Lifileucel (LN-144) is being developed by Iovance Biotherapeutics (NASDAQ: IOVA) for advanced melanoma. Lifileucel is the first tumor-infiltrating lymphocyte (TIL) therapy to be reviewed by the FDA. TILs are immune cells that have recognized tumor antigen but are rendered ineffective or “exhausted” by the tumor. These TILs can be harvested from the patient, expanded, and rejuvenated ex-vivo and then infused back into the patient. TIL therapy is a novel approach in immunotherapy based on the pioneering work of tumor immunologist Steve Rosenberg at NIH. Based on approval in 2024, Visible Alpha consensus estimates project 2033 risk-adjusted revenues of $1.0 billion (consensus probability of success is at 87.0%).
Donanemab (LY3002813) is being developed by Eli Lilly (NYSE: LLY) for early Alzheimer’s disease. Donanemab is a beta-amyloid targeting antibody that follows in the footsteps of Leqembi (lecanemab), approved in 2023. Both Donanemab and Leqembi reduce amyloid plaques and slow disease progression. Based on approval in 2024, Visible Alpha consensus estimates project 2033 risk-adjusted revenues of $4.3 billion (consensus probability of success is at 90.7%). Our previous evaluation of Leqembi and donanemab can be viewed here.
Drug development themes and trends continuing in 2024
The following drug development trends will continue to interest investors and corporate business development through 2024 and beyond:
- Antibody Drug Conjugates (ADC)-based drugs will continue to drive investor and corporate interest with several acquisitions already completed in recent months. Even though we don’t see any FDA approvals upcoming for novel ADC drugs in 2024 (except for supplemental applications for indication extensions for already approved ADCs), ADC drug development remains an area of significant innovation and Big Pharma acquisitions. Notable was Pfizer’s (NYSE: PFE) acquisition of Seagen in 2023 and Johnson & Johnson’s (NYSE: JNJ) acquisition of Ambrx (NASDAQ: AMAM) in January 2024.
- Investors will be anxiously watching the performance of beta-amyloid antibodies for Alzheimer’s disease — Leqembi approved in 2023 and donenamab (PDUFA date in March 2024). Unlike currently marketed drugs, Leqembi and donanemab target the underlying cause of Alzheimer’s and have the potential to modify the course of the disease. Several next generation beta-amyloid targeting inhibitors for Alzheimer’s disease are in the pipeline.
- Investors will also keep an eye on the 2020 Nobel Prize winning technology, CRISPR-based gene therapy. Following the approval of the first CRISPR gene therapy, Casgevy, for sickle cell disease (SCD) in 2023, we expect novel CRISPR-based gene therapies to progress to the market in the near future. Casgevy for beta thalassemia was recently approved by the FDA on January 16th, 2024.
- The GLP-1 pathway space will continue to be prominent beyond just the blockbuster revenues for the two leaders, Novo Nordisk (NYSE: NVO) and Eli Lilly. Several GLP-1 mid-stage and late-stage clinical trials are ongoing in cardiometabolic indications other than obesity and type 2 diabetes. The developing pipeline for the next generation GLP-1 is long and other Big Pharma companies are vying to compete with the leaders. The frequent business development activity that occurred in 2023 is bound to continue in 2024. Big Pharma companies are seeking novel early-stage private and public GLP-1 and GLP-1-related pathway assets.
Drug development innovation continues at a robust pace as several first-in-class and groundbreaking therapies were approved by the FDA in 2023. Visible Alpha provides consensus revenue projections for novel therapeutic drugs approved in 2023 with the highest market potential and those with a major innovation impact. (See also our overview of 2022 FDA-approved drugs.)
Our picks for the two potentially most lucrative and innovative therapeutic drug development approvals in 2023 are Leqembi and Casgevy. We chose Leqembi for overcoming the scientific, clinical, and regulatory challenges in developing the first beta amyloid inhibitor for Alzheimer’s disease, a disease with complex and poorly understood biology as well as for the potential for blockbuster annual revenues of almost $10 billion by 2033. We picked Casgevy primarily for the innovation behind CRISPR gene-editing technology that marks a milestone in drug development history. Casgevy’s revenue potential is also impressive — over $4 billion in 2033.
Standouts in the class of 2023: Leqembi for Alzheimer’s and the first CRISPR gene-editing therapy
The 2023 FDA therapeutic drug approval list reflects continued innovation in drug development. In our view, the approval of the first beta amyloid targeting antibody for Alzheimer’s disease, Leqembi (lecanemab), marks a major milestone after decades of research and development hiccups in attempting to develop a beta amyloid inhibitor. Leqembi was developed by Eisai (TSE: 4523) and Biogen (NASDAQ: BIIB), and was approved in July 2023 as the first disease-modifying therapy that targets the underlying cause of Alzheimer’s disease (see also our previous article on Leqembi). With the approval of Leqembi, we expect a long pipeline of improved beta amyloid pathway inhibitors in clinical development. According to Visible Alpha consensus, analysts project revenues of $9.8 billion for Leqembi in 2033.
The invention of the first gene-editing CRISPR technology (“genetic scissors”) was awarded the Nobel Prize in chemistry in 2020, less than a decade after the discovery of all the various molecular components of the system (CRISPR/Cas9). Casgevy (Exa-cel), the first CRISPR-based gene-editing therapy for sickle cell disease (SCD), was approved by the FDA in December 2023. The rapid pace of innovation and drug development within a short timespan is remarkable. The approval of the first CRISPR-based therapeutic opens the floodgates to many more CRISPR-based therapeutics targeting a broad repertoire of gene-editing targets for several indications. According to Visible Alpha consensus, analysts project 2033 revenues of $4.1 billion for Casgevy.
Comparing market potential with GLP-1 drugs approved in prior years
While Leqembi and Casgevy are potentially blockbuster drugs by most historical standards, they are dwarfed when compared to the market potential of the GLP-1 based drugs approved in prior years. Last year, we projected Eli Lilly’s Mounjaro, approved in 2022 for type 2 diabetes, at around $20B in estimated consensus revenues for 2030. Mounjaro has since been granted expanded FDA approval for obesity in 2023, marketed under the brand name Zepbound. Currently, Visible Alpha consensus revenue projections for 2033 for Mounjaro and Zepbound combined are at a staggering $45 billion ($22 billion for Mounjaro for type 2 diabetes plus $23 billion for Zepbound for obesity). Novo Nordisk’s competing GLP-1 franchise, which includes Ozempic (approved in 2017 for type 2 diabetes), Wegovy (approved in 2021 for obesity), and Rybelsus (approved in 2019 as an oral drug for type 2 diabetes), are projected to reach a combined $38 billion in revenue by 2033.
Checkpoint inhibitors also have large market potential
Another drug with massive market potential is Keytruda, the checkpoint inhibitor targeting the PD-1/PD-L1 pathway for oncology that was first approved by the FDA in 2014 for advanced melanoma. Keytruda is FDA approved for 16 different cancers today. Visible Alpha consensus revenue estimates project peak revenues in 2027 of $34.4 billion.
Other notable drugs approved in 2023 with significant market potential
There are several other drugs approved in 2023 that are noteworthy in their own right in overcoming an innovation challenge or in addressing an unmet medical need for patients:
- Bimzelx (bimekizumab), developed by UCB, is projected to reach $3.4 billion in revenue by 2033. Bimzelx, a monoclonal antibody against IL-17A and IL-17F, is approved for moderate-to-severe plaque psoriasis. While there are other approved IL-17A inhibitors, Bimzelx is the first that targets both IL-17A and IL-17F. Both IL-17A and IL-17F contribute to inflammatory signals in autoimmune disease.
- Arexvy, developed by GSK with 2033 consensus revenue estimates at $3.1 billion, and Abrysvo, developed by Pfizer with 2033 consensus revenue estimates at $2.3 billion, are pioneering RSV vaccines approved for adults over 60 years of age. Abrysvo is also approved for pregnant women at risk for transmitting RSV to their infants. The RSV vaccine is poised to have a major impact globally — there are over 33 million RSV infections worldwide and over 100,000 deaths annually.
- Elevidys (delandistrogene moxeparvovec-rokl), developed by Roche, Sarepta, and Chugai, is projected to reach revenue of $2.7 billion in 2033. Elevidys is the first gene therapy approved for patients aged 4 through 5 years with Duchenne Muscular Dystrophy (DMD) with a confirmed mutation in the DMD gene. The gene therapy corrects for a mutation in the dystrophin gene that regulates muscle cell cytoskeleton and muscle cell membrane interaction with the extracellular matrix. The mutation results in loss of muscle function (muscular dystrophy) affecting walking, breathing, cardiovascular health and even learning disabilities. Elevidys is a one-time treatment that will alter the course of a disease with acute unmet needs.
- Truqap (capivasertib), developed by AstraZeneca with 2033 consensus revenue estimates at $926 million in 2033, is the first AKT inhibitor approved in combination with estrogen receptor antagonist fulvestrant for hormone-receptor-positive, HER2-negative metastatic breast cancer that is biomarker positive.
- Vowst (fecal microbiota spores, live, in a capsule form), developed by Seres Therapeutics, has consensus revenue estimates of $334 million by 2033. Vowst is approved to prevent the recurrence of Clostridioides difficile infection. The drug is derived from human fecal matter sourced from qualified donors. The repertoire of healthy natural microbiota in Vowst competes with Clostridioides difficile and restores the gut’s natural resistance to infection with Clostridioides difficile.
Below, we’ve selected 16 therapeutic drugs with a high market potential and notable innovation, and provide consensus revenue estimates for the year 2033 (Table 1).
Table 1: Consensus revenue estimates for therapeutic drugs approved in 2023 with robust market potential and notable innovation
* Projected revenue for Beyfortus is for 2032 (not 2033), and utilizes ConsensusExMinExMax
A Breakdown of the CDER and CBER 2023 Approvals
There are two branches that approve drugs under the FDA — Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). CDER approves new molecular entities (NMEs, or small molecule drugs) under a New Drug Application (NDA), or as new therapeutic biological products (large molecule drugs that include antibody-based therapeutics, enzymes, peptides) under a Biologic License Application (BLA). The CBER branch regulates vaccines, blood products, cell therapies (including CAR-T cells), gene therapies, and CRISPR/gene-editing therapies.
- There was a substantial increase in 2023 approvals compared to 2022. In 2023, the CDER branch approved 53 novel therapeutic drugs (see Table 2). We exclude Posluma, the prostate cancer diagnostic agent, and Paxlovid, the COVID anti-viral, since it had already been granted Emergency Use Authorization (EUA) during the pandemic in 2021 (including Posluma & Paxlovid, the 2023 CDER approvals are 55). The 53 novel therapeutic drugs approved is a significant increase over the 37 drugs approved by CDER in 2022. The 2023 rate of drug approval is in keeping with prior years — 2022 was an anomaly (see Figure 1), with COVID being a major factor. Notably, 2023 had the second highest number of drugs approved by CDER, behind the 59 drugs approved in 2018.
- CBER approved 16 novel drugs in 2023 — we count the RSV vaccine Abrysvo, approved for pregnant women and for adults above the age of 60, as one approval (CBER lists it separately). In comparison, in 2022, CBER approved 14 novel drugs.
- CDER approvals in 2023 based on modality included: 29 small-molecule drugs (not including a diagnostic agent small molecule), 12 antibody-based drugs (these include bispecifics and ADCs), 8 proteins/peptides/fusion proteins, and 4 DNA/RNA-based drugs.
- CBER approvals in 2023 based on modality included: 5 vaccines, 2 autologous cell therapy gene therapies (including CRISPR), 2 allogeneic cell therapies, 3 viral vector-based gene therapies, 1 fecal microbiota, 1 enzyme replacement therapy, 1 fusion protein, and 1 natural plasma derived protein.
- The highest number of drugs approved in 2023 were for oncology (17), followed by neurology (6), infectious diseases (5), metabolic disorders (5), and ophthalmology (3).
- Based on the FDA regulatory pathway of approval (some drugs may fall under more than one regulatory pathway): 9 Accelerated Approvals, 8 Orphan Drug designations, 16 Fast-Track designations, 24 Priority Reviews, and 9 Breakthrough Therapy designations.
See Tables 2 and 3 for descriptions, including modality, indication, and mechanism of action for CDER and CBER approvals in 2023.
Figure 1: Historical view of yearly FDA approvals since 1994
New molecular entities (NMEs) and biologics license applications (BLAs) approved by the FDA’s Center for Drug Evaluation and Research (CDER) branch since 1994. Note that CBER approvals are not depicted here. The 55 drug approvals in 2023 were significantly higher than the 37 drugs approved by CDER in the previous year.
References
- Novel Drug Approvals for 2023 (CDER). https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2023
- 2023 Biological Approvals (CBER). https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/2023-biological-approvals
- FDA Approves Many New Drugs in 2023 that Will Benefit Patients and Consumers. Patrizia Cavazzoni, M.D., Director, Center for Drug Research and Evaluation. https://www.fda.gov/news-events/fda-voices/fda-approves-many-new-drugs-2023-will-benefit-patients-and-consumers
- Mullard A; 2023 FDA approvals. Nature Reviews Drug Discovery, 2024 Jan 2. https://pubmed.ncbi.nlm.nih.gov/38168801/
Key Takeaways
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TL1A (TNF-like ligand 1A) is a high-value target that has gained significant interest of late. This target has implications across several auto-immune inflammatory diseases, including ulcerative colitis and Crohn’s disease.
In June 2023, Merck & Co. (NYSE: MRK) acquired Prometheus Biosciences for $10.8 billion, driven by the promise of its TL1A antibody, PRA-023.
In October 2023, Roche (SIX: ROG) agreed to acquire rights to RVT-3101, Roivant Sciences’ (NASDAQ: ROIV) TL1A-targeting antibody, for $7.1 billion upfront and $150 million in upcoming milestone payments. RVT-3101 is held under Telavant Holdings, a Roivant and Pfizer (NYSE: PFE) joint venture. Roivant owns 75% of the joint venture and Pfizer owns 25%.
Analysts’ projections for RVT-3101 revenue
Visible Alpha consensus estimates project peak global revenues of nearly $2.5 billion in 2032 (not adjusted for risk). Risk-adjusted consensus revenue projections for 2032 are nearly $1.6 billion. Analysts apply a probability of success of 61.7% for RVT-3101. Currently, RVT-3101 has completed Phase 2 studies and is ready to begin Phase 3 clinical trials for ulcerative colitis. For Crohn’s disease, RVT-3101 is currently in Phase 2.
Figure 1: Consensus revenue projections for Roivant’s RVT-3101
About TL1A
TL1A is secreted from antigen-presenting cells upon stimulation and plays a central role in activating innate and adaptive immune pathways by binding to TNFRSF25 (or death receptor 3 (DR3)) on T cells. Under disease conditions, loss of regulation of TL1A-TNFRSF25 signaling leads to proinflammatory effects including excessive T cell activation. This inflammatory pathology is implicated in inflammatory bowel disease that collectively includes Crohn’s disease and ulcerative colitis. The potential for blocking TL1A across numerous other auto-immune inflammatory diseases is also promising.
Emerging Drugs Show Promise in Targeting Difficult-to-Treat Cancers
By: Rahul Jasuja, PhD
Key Takeaways
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Cancers harboring KRAS mutations have historically been a challenge to treat. After almost four decades of research, two KRAS mutation-targeting therapies that have already been granted conditional (accelerated) approval by the FDA for non-small cell lung cancer, are undergoing the process towards full approval – Amgen’s (NASDAQ: AMGN) Lumakras and Mirati Therapeutics’ (NASDAQ: MRTX) Krazati.
Visible Alpha consensus revenue projections show Krazati at approximately $2.2 billion and Lumakras at approximately $1.3 billion in 2032 global revenues. Based on clinical trial data and recent FDA Advisory Committee views, analysts are wary of Lumakras given the recent regulatory concerns (discussed below), and view Krazati as the potentially superior KRAS inhibitor.
Figure 1: Revenue projections for Amgen’s Lumakras and Mirati Therapeutics’ Krazati
Conditional approvals of Lumakras and Krazati
Amgen’s KRAS inhibitor, Lumakras (sotorasib), was granted conditional approval for non-small cell lung cancer in May 2021, and Mirati Therapeutics’ Krazati (adagrasib) was granted conditional approval for non-small cell lung cancer in December 2022. Lumakras has also received conditional approval by the European Medicines Agency. Krazati was refused conditional approval by the European Medicines Agency, but Mirati Therapeutics will request re-examination.
Confirmatory trials for full approval of Lumakras and Krazati
Amgen has completed Phase 3 confirmatory trials for Lumakras and submitted the application for full approval to the FDA. On October 5, 2023, the FDA Advisory Committee meeting briefing document revealed the negative views of the Advisory Committee on the trial data supporting full approval of Lumakras for non-small cell lung cancer. Several of the points raised by the Advisory committee related to bias in the two arms of the clinical trial. The FDA has not made a decision yet, but it is likely that additional trials may be required in order for Lumakras to be fully approved for non-small cell lung cancer. Analysts have reduced the revenue potential for Lumakras given the regulatory concerns. Lumakras clinical trial data in other tumors such as colorectal cancer or in combination studies may be more positive.
The Krazati Phase 3 confirmatory trials are yet to be reviewed by the FDA. Krazati, in combination (with PD-1) or as a monotherapy, has a better safety profile and efficacy than Lumakras.
Bristol-Myers Squibb to acquire Mirati Therapeutics – driven partly by Krazati potential
On October 9, 2023, Bristol-Myers Squibb (NYSE: BMY) and Mirati Therapeutics entered into an agreement under which BMY will acquire MRTX for $58 per share, valued at $4.8 billion, plus a Contingent Value Right (CVR) potentially worth an additional $1 billion. The transaction is expected to close in the first half of 2024. Both BMY’s and MRTX’s boards have agreed to the terms of the transaction.
Even though the KRAS space faces regulatory challenges, Bristol-Myers Squibb clearly believes that the Krazati confirmatory Phase 3 data will be the basis for full approval in non-small cell lung cancer. The issues with Lumakras that the FDA Advisory Committee raised are specific to Lumakras, and not for KRAS in general. Mirati Therapeutics also has additional promising oncology targets in its pipeline.
About KRAS
KRAS is the most frequently mutated oncogene in cancer. KRAS, a member of the RAS family, is a key regulator of signaling pathways that orchestrate cell proliferation, differentiation, and survival. Mutations in the RAS pathway can drive uncontrolled tumor growth. Effective RAS pathway inhibitor drugs have been elusive for decades – the structural biology and chemistry of RAS has made it a challenge to design effective inhibitors. Both Lumakras and Krazati are selective inhibitors of tumors that specifically harbor a KRAS G12C mutation (i.e. where the mutation results in a glycine to a cysteine substitution) that drives tumor growth.
First CRISPR-based Gene Therapy for Sickle Cell Disease On Track for FDA Approval
By: Visible Alpha Research & Innovation Lab
Key Takeaways
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Two groundbreaking gene therapy treatments for sickle cell disease (SCD), offering potential cures, are on track for FDA approval with the expectation that both could be approved by December 2023. In April 2023, CRISPR Therapeutics (NASDAQ: CRSP) and Vertex Pharmaceuticals (NASDAQ: VRTX) submitted a Biologics License Application (BLA) for exa-cel (exagamglogene autotemcel), formerly known as CTX001. Exa-cel is intended to treat severe SCD and transfusion-dependent beta-thalassemia (TDT).
In the same month, Bluebird Bio (NASDAQ: BLUE) submitted a BLA for lovo-cel (lovotibeglogene autotemcel) for SCD patients 12 years and older with a history of vaso-occlusive events. Both submissions received FDA Priority Review status for SCD, indicating a regulatory decision within 6 months.
Exa-cel and lovo-cel
Exa-cel is a CRISPR-based gene editing approach to gene therapy, while lovo-cel is a lentivirus-based gene therapy. Exa-cel will be the first CRISPR-based therapy to be reviewed by the FDA — a major milestone for CRISPR gene editing, which was awarded the Nobel Prize in 2022. Both exa-cel and lovo-cel are potential one-time therapies that provide a functional cure for SCD by modifying the patient’s hematopoietic stem cells. Gene therapy approaches are particularly beneficial for those without a suitable bone marrow donor.
Current treatment options for SCD
Patients with SCD have limited treatment options and hematopoietic stem cell transplant (HSCT) is the only curative treatment for SCD that can restore red blood cell and hemoglobin function. HSCT is invasive, requires a suitable donor and is associated with immune rejection risk.
Other than HSCT, currently approved treatments for SCD address symptom management and prevention of complications. Pfizer’s (NYSE: PFE) Oxbryta is an oral medication for SCD approved in the U.S. and the EU that increases hemoglobin by inhibiting red blood cell sickling, improving red blood cell function, and reducing whole blood viscosity.
Novartis’s (NYSE: NVS) Adakveo is a P-selectin antibody that reduces the frequency of vaso-occlusive events and prevents SCD-related pain. Adakveo was approved in the U.S. in November 2019 and was granted conditional approval in the EU in October 2020. However, the EU revoked its authorization in August 2023 following an unsuccessful Phase 3 trial.
Shift toward gene therapy
With the expected approval of gene therapy treatments this year, analysts expect a growing shift toward gene therapy as an effective treatment option for SCD. According to Visible Alpha consensus, Exa-cel (CRISPR and Vertex) for SCD is expected to generate $2.34 billion in risk-adjusted revenue by 2030. Analysts peg the probability of success for exa-cel at 77.8%. Bluebird Bio’s lovo-cel is expected to generate $520 million by 2030, with a probability of success of 78.3%.
Other gene therapy drugs in clinical trials for SCD include BEAM Therapeutics’ (NASDAQ: BEAM) BEAM-101 and BEAM-102, as well as Editas Medicine’s (NASDAQ: EDIT) EDIT-301. BEAM-101 is currently in Phase 2 trials, BEAM-102 is in the preclinical stage, and EDIT-301 is in Phase 1.
Figure 1: Gene therapy revenue projections for sickle cell disease (SCD)
By: Aarti Surendran
Reviewed By: Rahul Jasuja, PhD
Eli Lilly’s Obesity Drug Surge; Plug Power’s Hydrogen Ecosystem; OPAL’s Renewable Natural Gas Focus
By: Visible Alpha Research & Innovation Lab
In our weekly round-up of the top charts and market-moving analyst insights: Eli Lilly’s (NYSE: LLY) Mounjaro is poised for a surge in sales with expected approval for obesity; Plug Power (NASDAQ: PLUG) is expected to see rising revenues fueled by its hydrogen ecosystem; OPAL Fuels’ (NASDAQ: OPAL) strategic focus on renewable natural gas is set to boost future revenue.
Eli Lilly’s Mounjaro Set for Revenue Surge with Expected Obesity Approval
According to Visible Alpha consensus, Eli Lilly’s (NYSE: LLY) Mounjaro is expected to generate revenue of $4.61 billion in 2023 and more than double in 2024, reaching a total of $9.51 billion. Looking ahead to 2030, consensus estimates suggest that Mounjaro’s revenue for type 2 diabetes (T2D) and obesity is projected to reach as high as $42 billion.
Mounjaro was approved in May 2022 for T2D, but has not yet been approved for obesity. In October 2022, Eli Lilly secured FDA fast-track designation for the possible approval of Mounjaro for obesity. FDA approval for obesity is expected by the end of 2023. Risk-adjusted revenue projections for Mounjaro are nearly as high as projections that are not adjusted for risk, as the probability of success for FDA approval for obesity is 97.33%, according to Visible Alpha consensus.
Mounjaro (tirzepatide) is a dual agonist targeting the GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) receptor pathways. Agonism of GLP-1 and GIP receptors leads to an increase in insulin secretion, improvement of insulin sensitivity, reduction in glucagon levels, decreased food intake, and slowing of gastric emptying. The net effect is glucose control for T2D, and weight loss for obesity.
Plug Power to See Rising Revenues Fueled By Hydrogen Ecosystem
According to Visible Alpha consensus, hydrogen fuel cell company Plug Power (NASDAQ: PLUG) is expected to see revenues jump across all of its segments in the forecast period, boosted by the company’s investments in building a hydrogen ecosystem. Plug Power has ambitious plans to build a vertically integrated ecosystem with the aim of becoming a one-stop shop for the hydrogen economy.
Analysts expect the company’s three main revenue segments — product, services, and fuel delivered to customers — to see annual revenue growth in 2023 of 85%, 17%, and 38%, respectively. Between 2023-2030, total product revenue is projected to grow at a CAGR of 32%, services at 27%, and fuel delivered to customers at 60%.
Within products, the company’s largest revenue-generating segment, revenue from electrolyzers is projected to reach $210 million (+639% YoY) in 2023, hydrogen infrastructure sites revenue to $266 million (+88% YoY), and cell system/forklift units/gendrive units revenue to $298 million (+43% YoY). The company’s total revenue is projected to be $1.2 billion in 2023, and analysts expect the company to become profitable by 2024, generating an estimated gross profit of $228 million.
OPAL Fuels’ Strategic Focus on Renewable Natural Gas to Boost Future Revenue
OPAL Fuels (NASDAQ: OPAL), which specializes in the production and distribution of renewable natural gas (RNG) and renewable electricity, has recently made a strategic shift, placing a stronger emphasis on RNG generation. With the RNG transition, analysts anticipate robust revenue growth for the company in the coming years. According to Visible Alpha consensus, OPAL Fuels is expected to boost its RNG production volume from an estimated 3.0 million MMBtu in 2023 to a projected 9.7 million MMBtu by 2025, growing at a CAGR of 82%.
Total revenue for the company is estimated to grow by 15% year over year in 2023, partially offset by an expected 7% decline in RNG revenue. This decline is primarily due to the company selling fewer units of RNG fuel in the first half of 2023, deferring environmental credit sales amid lower market prices, as the market awaited new clean fuel standards from the U.S. Environmental Protection Agency (EPA). In 2024, however, analysts expect RNG revenues to pick up, growing 100% year over year to $236 million, while total revenue is projected to grow by 56% to $421 million.
