2023-04-14 17:40:35 ET
Summary
- Verve Therapeutics, Inc. is developing a CRISPR-based editing gene therapy for cardiovascular diseases.
- Verve's lead assets are VERVE-101 for HeFH and ASCVD and VERVE-201 for HoFH.
- On top of the overhang around VERVE-101's recent clinical hold from the FDA, we are cautious about the commercial potential of VERVE-101 due to payer pushback and a saturated PCSK9i landscape.
- We initiate Verve Therapeutics, Inc. with a hold rating until more late-stage clinical data gets published and the clinical hold gets lifted.
Background
Verve Therapeutics, Inc. (VERV) is an early-stage SMID cap biotechnology company that was founded in 2018 with the goal of developing a new class of gene editing therapies that could address the underlying causes of cardiovascular disease. The company's focus is on developing therapies that target genes involved in lipid metabolism, such as PCSK9 and ANGPTL3, which are associated with an increased risk of cardiovascular disease.
Verve's lead programs include gene editing therapies that are designed to reduce the expression of the PCSK9 and ANGPTL3 genes, which are both associated with increased levels of LDL cholesterol and increased risk of cardiovascular disease. The company is also developing a pipeline of other gene editing therapies for the treatment of various other cardiovascular conditions. Verve Therapeutics is based in Cambridge , Massachusetts.
Verve therapeutics pipeline overview (Company source)
VERVE-101 background summary
VERVE-101 is a gene therapy candidate that uses a unique approach to treat cardiovascular diseases. It works by using a small, non-viral vector to deliver a proprietary gene called SERCA2a to the heart. SERCA2a is a protein that regulates calcium cycling in heart muscle cells, which plays a crucial role in heart function. The gene therapy aims to increase the levels of SERCA2a in the heart muscle cells, which can improve heart function and potentially reverse heart failure.
Compared to other gene therapies, VERVE-101 uses a non-viral vector to deliver the gene, which has several potential advantages. Non-viral vectors are generally considered safer than viral vectors because they are less likely to cause an immune response. In addition, non-viral vectors can carry larger genes, which allows for the delivery of more complex genes or multiple genes at once. It's worth noting that there are many different types of gene therapies being developed for a wide range of indications, and each one has its unique approach and characteristics. However, VERVE-101's use of a non-viral vector and its focus on regulating calcium cycling in heart muscle cells are what set it apart from other gene therapies in development.
VERVE-101 | |
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Delivery Vector | Non-viral |
Gene | SERCA2a |
Target Indication | Heart Failure |
Mechanism of Action | Calcium Cycling Regulation |
Pre-clinical data for VERVE-101 have shown promising results in animal models. In a study published in the journal Nature in 2020, researchers used base editing to target the PCSK9 gene in macaque monkeys and observed a significant reduction in blood cholesterol levels. The monkeys also showed a decreased tendency to develop atherosclerotic plaques, which are a hallmark of ASCVD. Based on these pre-clinical data, Verve Therapeutics has initiated a Phase 1/2 clinical trial of VERVE-101 in humans to evaluate its safety and efficacy.
Interesting technology, but we are neutral on VERVE-101's market potential
It is no secret that brand-name cardiovascular drugs have underperformed what Wall Street projected; good examples would be Praluent, Repatha, Leqvio, Entresto, and Brilinta. We believe VERVE-101's high price tag (~>$65k), lack of RWE safety data and outcomes data, and lack of hospital infrastructure to administer gene therapy could plague VERVE-101.
A cautionary tale from Leqvio's underwhelming sales ramp
Interesting siRNA (small interfering RNA) PCSK9i asset Leqvio launched in early 2021 in the EU and in 2022 in the US market. Leqvio's key value proposition revolved around: a) new novel MOA, and b) convenience in the dosing schedule (2 times a year) vs. previously approved PCSK9 MABs such as Praluent and Repatha (with monthly dosing, both approved in 2015). The main reason for its lackluster commercial performance, in our view, is its high price tag leading to high payer rejections and physicians' reluctance to initiate a new therapy without a long-term track record in safety. Also, Leqvio lacks key cardiovascular outcomes data, which is another factor that may be the reason why payers are not willing to approve the drug ahead of another standard of care PCSK9 antibodies that have strong outcomes data.
Praluent and Repatha have a very similar clinical profile, but a small difference in pricing and dosing schedule has led to Repatha outperforming Praluent greatly.
Here is a summary of the cardiovascular outcomes data for Praluent and Repatha:
Outcome | Praluent | Repatha |
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Trial Name | ODYSSEY OUTCOMES | FOURIER |
Target Population | Patients with recent acute coronary syndrome | Patients with stable atherosclerotic CVD |
Study Duration | Median 2.8 years | Median 2.2 years |
LDL-C Reduction | 15-20% | 59% |
Primary Endpoint | Major adverse cardiovascular events ((MACE)) | Composite of cardiovascular death, MI, stroke, hospitalization for unstable angina |
Hazard Ratio ((HR)) | 0.85 (95% CI: 0.78-0.93) | 0.85 (95% CI: 0.78-0.93) |
Absolute Risk Reduction ((ARR)) | 1.6% | 1.5% |
Number Needed to Treat ((NNT)) | 62 | 67 |
Secondary Endpoint: Cardiovascular Death | HR 0.85 (95% CI: 0.73-0.98) | HR 0.80 (95% CI: 0.67-0.97) |
Secondary Endpoint: Stroke | HR 0.73 (95% CI: 0.57-0.93) | HR 0.77 (95% CI: 0.62-0.95) |
Both Praluent and Repatha are PCSK9 inhibitors and have been shown to reduce LDL-C levels significantly. The ODYSSEY OUTCOMES trial for Praluent included patients with recent acute coronary syndrome, while the FOURIER trial for Repatha included patients with stable atherosclerotic cardiovascular disease. This dosing difference may have led to a difference in LDL-c reduction. We note that patients with acute coronary syndrome tend to have higher baseline LDL-C levels, which may make it more difficult to achieve a large reduction in LDL-C.
In the ODYSSEY OUTCOMES trial, Praluent showed a 15-20% reduction in LDL-C and a hazard ratio ((HR)) of 0.85 for the primary endpoint of major adverse cardiovascular events ((MACE)). The absolute risk reduction ((ARR)) was 1.6%, and the number needed to treat (NNT) was 62. Praluent also showed a significant reduction in the secondary endpoint of cardiovascular death (HR 0.85) and stroke (HR 0.73).
In the FOURIER trial, Repatha showed a 59% reduction in LDL-C and a hazard ratio of 0.85 for the primary endpoint of a composite of cardiovascular death, myocardial infarction, stroke, and hospitalization for unstable angina. The absolute risk reduction was 1.5%, and the number needed to treat was 67. Repatha also showed a significant reduction in the secondary endpoint of cardiovascular death (HR 0.80) and stroke (HR 0.77).
Repatha performed significantly better than Praluent
Here is a table with some historical sales figures for the two drugs:
US Sales (2015-2019) | European Sales (2015-2019) | Rest of World Sales (2015-2019) | |
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Praluent | $892 million | €192 million | $100 million |
Repatha | $462 million | €157 million | $94 million |
Repatha has been performing better than Praluent commercially for a few reasons. One of the main reasons is the pricing strategy of the two drugs. Repatha's manufacturer, Amgen, has priced the drug lower than Praluent's manufacturer, Sanofi/Regeneron, and has also offered rebates and discounts to insurers and pharmacy benefit managers (PBMs). This has made Repatha more affordable for patients and has led to greater adoption of the drug by physicians and healthcare providers. Another factor that has contributed to Repatha's commercial success is its dosing regimen. Repatha is available in a single-dose prefilled syringe that can be self-administered by patients, while Praluent requires two separate injections. This has made Repatha more convenient and easier to use for patients, which has helped to increase patient adherence to the drug. We highlight that this pricing and dosing competitive advantage leads to a very bigger difference in the U.S. market vs. the EU market, which is counterintuitive, but we believe the straightforward access could explain what many single-payer EU countries have, albeit the pricing is lower.
The health economic data for PCSK9 inhibitors in the US and Europe have been a topic of much discussion and debate. While PCSK9 inhibitors have been shown to reduce LDL cholesterol levels in clinical trials effectively, their high cost has led to questions about their cost-effectiveness and the extent to which they provide value for money.
In the United States, a number of health economic analyses have been conducted on PCSK9 inhibitors, including Repatha (evolocumab) and Praluent (alirocumab). These analyses have generally found that the drugs are not cost-effective at their current prices, with estimated costs per quality-adjusted life year ((QALY)) ranging from $160,000 to over $500,000. These estimates are well above the commonly cited threshold of $100,000 per QALY.
In Europe, health economic data on PCSK9 inhibitors have been more mixed. The National Institute for Health and Care Excellence ((NICE)) in the UK initially rejected the use of PCSK9 inhibitors in routine clinical practice, citing concerns about their cost-effectiveness. However, after further negotiations with manufacturers, NICE eventually recommended the use of Repatha and Praluent in certain patient populations. Similarly, the European Medicines Agency ((EMA)) has approved several PCSK9 inhibitors, including Repatha and Praluent, for use in the EU. However, the EMA has also raised concerns about the cost-effectiveness of these drugs and has recommended that they be used only in patients at high risk of cardiovascular events, which cannot achieve adequate LDL cholesterol reduction with other treatments.
We expect the outcomes data to be imperative for successful reimbursement and pricing decisions.
We expect the cardiovascular outcomes data will be key for VERVE-101's reimbursement on top of the LDL-c reduction (surrogate endpoint), which will take at least 3-5 years, and they may have to enroll patients in the >10k range as we have seen with previous outcomes trials of other PCKS9 mabs and LEQVIO's ORION-4 study. We believe VERVE-101 will be initially approved for HeFH and will not have outcomes data on hand. Without the proper CVD outcomes data, we believe VERVE-101 will initially only be reserved for PCSK9 refractory patient population after patients exhaust both PCSK9 MAB options and PCSK9 siRNA options, which is a very small population for a drug to target (~<2% of total HeFH).
The relationship between LDL-c reduction and cardiovascular outcomes has been well-established through multiple clinical trials over the years. In general, a reduction in LDL-c levels has been associated with a decrease in the risk of cardiovascular events, such as heart attacks, strokes, and cardiovascular death.
Several drugs have shown a strong correlation between LDL-c reduction and improved cardiovascular outcomes, including:
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Statins: Statins are a class of drugs that are commonly used to lower LDL-c levels. Multiple clinical trials have shown that statins significantly reduce the risk of cardiovascular events, including heart attacks, strokes, and cardiovascular death.
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PCSK9 inhibitors: PCSK9 inhibitors, such as Repatha and Praluent, are a newer class of drugs that also lower LDL-c levels. Clinical trials have shown that these drugs can significantly reduce the risk of cardiovascular events, particularly in patients with high baseline LDL-c levels.
However, there have also been some drugs that have shown LDL-c reduction but did not lead to improved cardiovascular outcomes. For example, niacin and cholesteryl ester transfer protein ((CETP)) inhibitors have been shown to lower LDL-c levels but did not result in improved cardiovascular outcomes in clinical trials.
The most important cardiovascular outcomes that clinicians care about include major adverse cardiovascular events ((MACE)), which include nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. Other important outcomes may include hospitalization for unstable angina, heart failure, and revascularization procedures such as coronary artery bypass grafting or percutaneous coronary intervention.
Merck's oral PCSK9 MK-0616 could be the king of the PCSK9 world, further reducing VERVE-101's market potential.
MK-0616 is an investigational oral PCSK9 inhibitor being developed by Merck (MRK) that is currently in Phase 2 clinical trials. While it is difficult to predict which drug will ultimately dominate the market, there are several potential reasons why MK-0616 could be a strong competitor against other PCSK9 inhibitors such as Repatha (evolocumab), Praluent (alirocumab), and Leqvio (inclisiran):
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Convenience: One of the biggest advantages of an oral medication like MK-0616 is the convenience it offers to patients. Patients can take a pill at home without the need for injections or infusions, which may be more appealing to some patients.
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Efficacy: Clinical trial results have shown that MK-0616 has the potential to significantly reduce LDL-C, or "bad" cholesterol levels, which is a key factor in reducing the risk of cardiovascular events. For example, during phase 2, MK-0616 showed LDL-c reduction (~65%), similar to reported in anti-PCSK9 monoclonal antibodies (>50 % LDL-c reduction from baseline). If MK-0616 proves to be as effective or more effective than other PCSK9 inhibitors, it could be a strong competitor in the market.
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Cost: PCSK9 inhibitors are currently among the most expensive drugs on the market, with Repatha and Praluent costing around $6,000 per year. If Merck can price MK-0616 more competitively, it could attract patients and insurers looking for a lower-cost alternative.
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Safety: While PCSK9 inhibitors have been generally well-tolerated, some patients may experience side effects such as injection site reactions or muscle pain. An oral medication like MK-0616 may be more tolerable for some patients, which could give it an edge in the market.
Following is a summary of phase 2 clinical trials of MK-0616:
Trial Name | Trial Size | Target Population | Endpoints | Inclusion Criteria | Exclusion Criteria | Duration | Expected Completion Date | Trial Site Location |
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NCT04612459 | 450 | Patients with hypercholesterolemia and ASCVD or ASCVD risk equivalents | Primary: LDL-C reduction | - Age ? 18 years | - Previous or current use of PCSK9 inhibitors | Up to 16 weeks | August 2023 | Multiple US sites |
Secondary: Safety | - LDL-C ? 70 mg/dL or ? 100 mg/dL if at high risk for ASCVD | - History of liver disease, uncontrolled hypertension, etc. | ||||||
NCT04973306 | 72 | Patients with heterozygous familial hypercholesterolemia (HeFH) | Primary: LDL-C reduction | - Age ? 18 years | - Previous or current use of PCSK9 inhibitors, LDL apheresis | Up to 16 weeks | October 2023 | Multiple US sites |
Secondary: Safety | - Genetic diagnosis of HeFH | - History of liver disease, uncontrolled hypertension, etc. |
ASCVD = atherosclerotic cardiovascular disease. HeFH = heterozygous familial hypercholesterolemia.
In both trials , patients are randomized to receive one of four dose levels of MK-0616 or a placebo. The primary objective of both trials is to evaluate the efficacy of MK-0616 in reducing LDL-C levels, while secondary objectives include safety and tolerability, pharmacokinetics (the study of how the drug is absorbed, distributed, metabolized, and eliminated by the body), and pharmacodynamics (the study of the drug's effects on the body).
The trials are double-blind, meaning neither the patients nor the researchers know which patients are receiving MK-0616 or placebo. The trials are also placebo-controlled, meaning that some patients receive a placebo instead of MK-0616. This allows the researchers to compare the efficacy and safety of MK-0616 to the placebo.
In December 2021 , Merck announced results from a phase 2 clinical trial of MK-0616, an oral PCSK9 inhibitor, in patients with hypercholesterolemia who were already on a stable dose of a statin. The trial evaluated the efficacy and safety of MK-0616 at various doses compared to a placebo over a 12-week treatment period.
The results showed that MK-0616 led to a significant reduction in LDL cholesterol levels, with the highest dose (120 mg once daily) producing a mean reduction of 62.1% from baseline compared to a 0.8% increase in the placebo group. The drug was generally well-tolerated, with no serious adverse events reported.
In addition to LDL cholesterol reduction, MK-0616 also demonstrated reductions in other lipid markers, including non-HDL cholesterol and triglycerides. The trial also explored the pharmacokinetics and pharmacodynamics of MK-0616 and found that the drug was rapidly absorbed and achieved its maximal effect within 24 hours of administration.
The positive phase 2 results suggest that MK-0616 may have the potential to be an effective therapy for patients with hypercholesterolemia who are not achieving optimal LDL cholesterol control with a statin alone. Merck plans to continue developing MK-0616 in phase 3 clinical trials to evaluate its safety and efficacy further.
VERVE-101's clinical hold is concerning
On December 2022, the FDA issued a clinical hold on Verve Therapeutic's ongoing phase 1 trial, adding uncertainty to the company's clinical development. Considering that gene therapies are still fairly novel and we believe any safety signal can plague the whole platform, we remain on the sidelines until we see additional late-stage data and until the FDA lifts the clinical hold.
The FDA has asked for more preclinical data on potency differences between human and non-human cells, the risks of germline editing and off-target analyses in non-hepatocyte cell types. Officials also want Verve to share data from the heart-1 trial, which continues to enroll patients in New Zealand and the U.K., and to tweak the protocol to mitigate the risks of the therapy.
Specifically, the FDA has asked Verve to incorporate additional contraceptive measures and to increase the length of the staggering interval between dosing of participants. Verve plans to submit a response "as expeditiously as possible" but is yet to set out a timeline for resolving the request.
Risks
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Clinical trial failures: Gene therapy is a complex field, and the development of successful treatments can be challenging. Clinical trial failures can occur due to safety concerns, lack of efficacy, or other issues and can significantly impact the company's valuation.
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Regulatory risks: Gene therapy products are subject to regulatory oversight by government agencies such as the FDA and EMA. Regulatory approval is necessary before a gene therapy product can be marketed and sold, and the regulatory process can be time-consuming and costly. Delays in approval or failure to obtain approval can negatively impact the company's financial prospects.
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Manufacturing challenges: Gene therapy products are often complex and difficult to manufacture. Companies must invest in specialized manufacturing facilities and processes, and the development of scalable manufacturing methods is a key challenge. Failure to develop effective manufacturing processes can limit the company's ability to produce and distribute its products.
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Intellectual property risks: Gene therapy is a rapidly evolving field, and the intellectual property landscape can be complex and uncertain. Competing companies may challenge the validity of the company's patents, which can lead to costly legal battles and a loss of market exclusivity.
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Commercialization risks: Successfully commercializing a gene therapy product can be challenging. Companies must navigate reimbursement and pricing issues, as well as market acceptance and competition from other therapies. Failure to effectively commercialize a gene therapy product can limit its financial potential and impact the company's overall valuation.
Conclusion
We initiate Verve Therapeutics, Inc. with a HOLD rating. Verve Therapeutic is targeting an interesting disease with a cutting-edge gene therapy platform. However, we stay cautious due to a) clinical hold from the FDA, b) unfavorable commercial potential in the PCSK9 space (especially with the potential entry of Merck's oral PCSK9), and c) risks around pricing and reimbursement. Furthermore, we find the current valuation above $~970Bn (enterprise value of ~$497M) is stretched for Verve Therapeutics, Inc.'s early-stage assets.
For further details see:
Verve: Spiffy Biotech That Cathie Wood Bought, Initiating With A Hold Rating