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Medscape
02-06-2025
- Health
- Medscape
Skills Lab: Rethinking Surrogate Endpoints Approval
This transcript has been edited for clarity. Hello, everyone. This is Dr Bishal Gyawali, from Queens University, Kingston, Canada. Thank you for joining us in our Skills Lab video series. In the last lecture we discussed how progression-free survival (PFS) response rate and the surrogate endpoints are defined. We talked about the particularities with response rate and PFS, and in the adjuvant setting, with disease-free survival. Today we'll talk about surrogate endpoints and their role in regulatory approval. One question that people commonly ask is: What strength of surrogacy is required for drug approval? Are different strengths of surrogacy required for accelerated approval (or 'conditional' approval) vs regular approval (or 'full' approval)? We would expect that regular approval requires a higher bar of evidence as compared to accelerated approval. Unfortunately, there are no such published criteria, but based on the data we have seen, I think there are probably no unpublished criteria either. If we compare the response rates of drugs that have received accelerated approval vs regular approval, then we don't see much of a difference. Also, in one of these studies from 2002 to 2021, we saw that 30% of approvals were based on response rates from single-arm trials that received regular approval rather than next approval. You would believe that a response rate–based approval would usually be acceleratedor conditional approval so that the drug confirms clinical benefit in the future, but we found that in 30% of these cases, they received upfront, regular, full approval rather than accelerated approval. I call this upfront, premature, regular approval. If you look at the trends of the FDA approval, you'll notice in recent years that the number of approvals based onsurrogate endpoints is increasing, while simultaneously, the number of accelerated approvals is decreasing. At first, it does not make sense because accelerated approvals are supposed to be surrogate-based approvals. What this means is that nowadays we are approving more and more drugs on the basis of surrogate endpoints by giving them full or regular approval rather than accelerated approval, which I think is very concerning from a societal point of view. If we are giving upfront, regular approval, then we can never be sure that they confirm clinical benefit because they don't have a mandate to do such a confirmatory trial. Also, even if these drugs were to fail in subsequent trials, we can't withdraw them. Only accelerated approvals get withdrawn. I'll give you one example:the BOLERO-2 trial of everolimus in breast cancer. As you can see, the first graph is PFS, and there was a 6-month improvement in PFS, with a hazard ratio of 0.36, which led to the drug's approval. It was not accelerated approval; it was full approval. In just 2 years, the overall survival results were published. As you can see in the second graph, the overall survival was negative. Overall survival did not improve, but because it was a full approval, the drug was not withdrawn. I call this premature approval, and we should be asking why we are granting full approval based on surrogate data. One more example: Margetuximab in breast cancer was approved on the basis of PFS improvement. You can see how much PFS improvement there was. It was 5.8 vs 4.9 months, so it was just 0.9 months, or less than 1 month, of PFS improvement. This drug was given full approval, not accelerated approval like it was supposed to. You can look at the date. This drug was approved in December 2020, and just 9 months later, in September 2021, we received overall survival results from this trial. The drug failed to improve overall survival. If we had not given regular approval, then we would have withdrawn this drug, but because it was given premature full approval, the drug was not withdrawn. It took only 9 months to get overall survival data, so why did we not give accelerated approval? That is something we should be asking. We recently published a paper in JCO about why PFS should not be used as a primary endpoint for registration of anticancer drugs. We list several reasons why PFS fails to capture clinical benefit in these trials. I think we should at least agree that, if we're approving drugs based on surrogate endpoints, it should be accelerated or conditional approval and not full approval. The other common question is: If PFS did not lead to overall survival improvement, did it not improve quality of life? We tried to answer that question. First, of course, there is no reason for PFS to correlate with overall survival. As we discussed in the last lecture, nothing magical happens at 20% and not all progression events are the same. Some progression events are more symptomatic than others, therefore the quality-of-life effectis not always predictable. Quality-of-life impact is not only a function of how big the tumor is but also a function of drug toxicities. In recent years, we have seen that PFS has become the default primary endpoint. In the past decade or so, the frequency of trials using PFS at the primary endpoint has increased substantially and now exceeds the percentage of trials with overall survival as the primary endpoint. The strange thing about PFS is that we talk about correlation of PFS with overall survival and how we need to do correlation analysis to confirm that this is a valid surrogate as we saw with the case of bevacizumab in breast cancer, even after eight clinical trials were conducted, was PFS a good surrogate for overall survival in this setting? The answer was that we do not know. Maybe, maybe not. What I'm trying to say here is that, even after eight clinical trials of the same drug in the same setting, we are still unable to conclude definitively whether PFS is a goodsurrogate for overall survival. This means that it is far more expedient to just measure overall survival than to continue to do multiple trials and continue to guess whether PFS is a good surrogate for overall survival. Thank you very much. I'll see you in the next lecture, in which we will talk about physicians' and patients' understanding related to surrogate endpoints.
Yahoo
08-05-2025
- Business
- Yahoo
VRTX Stock Down as Q1 Sales of New Drugs Miss Expectations
Vertex Pharmaceuticals Incorporated's VRTX first-quarter results were weak as it missed estimates for both earnings and sales. The company's total revenues of $2.77 billion rose 3% year over year, driven by higher sales of its triple combination cystic fibrosis (CF) therapy Trikafta/Kaftrio and an early contribution from the U.S. launch of Alyftrekt. Trikafta sales rose 9% in the quarter. While sales rose 9% in the United States, in outside U.S. markets, sales decreased 5%, hurt by the availability of an illegal copy of Trikafta in Russia, where Vertex is experiencing a violation of its intellectual property rights. Vertex raised the low end of its total revenue guidance by $100 million from $11.75-$12 billion to $11.85-$12 billion. Though Vertex revenues come mostly from its CF franchise, investor focus on the first-quarter call was on the performance of its newer drugs, which were approved in the past year. Vertex gained approval for two new products, its novel non-opioid pain medicine Journavx (suzetrigine) and its fifth CF medicine, Alyftrek, in the last few months. Vertex and partner CRISPR Therapeutics' CRSP one-shot gene therapy, Casgevy, was approved for two blood disorders, sickle cell disease and transfusion-dependent beta-thalassemia, in multiple regions in late 2023/early 2024. However, sales from its new drugs, Casgevy, Alyftrek and Journavx, fell short of investor expectations, which, coupled with the disappointing first-quarter results, led VRTX stock to decline 10% on Tuesday. Year to date, shares of Vertex have risen 11.8% against the industry's decrease of 2.2%. Image Source: Zacks Investment Research Let's dig deeper to understand how these new products performed in the first quarter and the company's outlook for the same through the rest of the year. Alyftrek (vanza triple), a next-in-class triple combination regimen for treating people with CF aged six years and older, was approved in the United States in December 2024 and in the United Kingdom in April 2025. Vertex's regulatory application for vanza triple is also under review in the EU and some other countries. In April, the European Medical Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) gave a positive opinion recommending approval of Alyftrek. Vertex expects Alyftrek's approval in Europe in the second half of 2025. This new once-a-day oral combination medicine has the potential for enhanced patient benefit over Trikafta and to become a new standard-of-care treatment in CF. It can potentially treat CF patients who have discontinued Trikafta or other Vertex CF medicines. It can improve dosing (once daily), lower the royalty burden and extend patent protection. The drug generated sales of $53.9 million in its first quarter of launch. Vertex said it is seeing a steady uptake from all patient groups who are eligible for treatment with Alyftrek, including new patients and patients looking to switch from Trikafta. However, the switch from Trikafta to Alyftrek was slower than expected. Alyftrek's sales fell short of most analysts' expectations. Journavx (suzetrigine), Vertex's non-opioid NaV1.8 pain signal inhibitor, was approved for the treatment of moderate-to-severe acute pain in January 2025. Vertex said Journavx's contribution to total revenues was 'insignificant' in the first quarter as the drug was launched in mid-March. However, many analysts believe that the Journavx launch progress has been slower than expected. Journavx sales are expected to pick up in the second half of the year as the product's uptake accelerates through patient assistance and supply/stocking initiatives in the first half. Vertex and partner CRISPR's one-shot gene therapy, Casgevy, contributed $14.2 million in sales in the first quarter compared with $8 million in the previous quarter. However, Casgevy sales also fell short of expectations of some analysts. The company now has more than 65 activated authorized treatment centers or ATCs in all regions where the therapy is approved. More than 90 patients have initiated cell collection. Vertex is also making rapid progress for the drug's access and reimbursement. Vertex expects Casgevy revenues to ramp up as the year progresses, as more patients are treated in geographies where the drug has secured regulatory approval and reimbursement. Vertex leads the global development and commercialization of Casgevy under the terms of the 2021 agreement with support from CRISPR Therapeutics. Vertex is rapidly advancing its diverse late-stage pipeline with four programs in pivotal development, including povetacicept added from last year's Alpine Immune Sciences acquisition. Vertex believes povetacicept has a 'pipeline in a product' potential. The other three candidates in pivotal development are suzetrigine in diabetic peripheral neuropathy, semelocell in type I diabetes and inaxaplin in APOL1-mediated kidney disease. Three of these phase III programs are on track to complete enrollment this year, setting the stage for several potential regulatory filings next year and potential new drug approvals in a couple of years. However, on the call, Vertex said it is temporarily pausing the multiple ascending dose portion of the phase I/II study of its mRNA therapeutic, VX-522, which it is developing in partnership with Moderna MRNA due to tolerability issues. In partnership with Moderna, Vertex is developing VX-522 for approximately 5,000 people with CF who do not make the CFTR protein and who cannot benefit from its CFTR modulators. A single ascending dose portion of a phase I/II clinical study on VX-522 is complete. Vertex currently carries a Zacks Rank #3 (Hold). You can see the complete list of today's Zacks #1 Rank (Strong Buy) stocks here. Vertex Pharmaceuticals Incorporated price-consensus-chart | Vertex Pharmaceuticals Incorporated Quote Want the latest recommendations from Zacks Investment Research? Today, you can download 7 Best Stocks for the Next 30 Days. Click to get this free report Vertex Pharmaceuticals Incorporated (VRTX) : Free Stock Analysis Report Moderna, Inc. (MRNA) : Free Stock Analysis Report CRISPR Therapeutics AG (CRSP) : Free Stock Analysis Report This article originally published on Zacks Investment Research ( Zacks Investment Research Error in retrieving data Sign in to access your portfolio Error in retrieving data Error in retrieving data Error in retrieving data Error in retrieving data
