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Gene&Cell Therapy >> Novo clears Phase 3 hemophilia A trial, plans to submit application by year's end: Novo Nordisk said Monday that its investigational treatment met both primary endpoints in an open-label Phase 3a study in patients with hemophilia A, meaning patients had fewer bleeding episodes. Following the topline FRONTIER 2 data disclosure via a press release, the Danish drugmaker’s shares $NVO were up about 3.5%. Novo revealed only a few headline data points on the 26-week, 254-patient trial, but said it will release more data at “upcoming congresses and in publications” this year and in 2025. By the end of this year, Novo said it plans to submit the treatment known as Mim8 for its first regulatory approval. For patients who had no prior prophylaxis treatment, the once-weekly and once-monthly Mim8 showed nearly 100% reductions in treated bleeds, at 97% and 99%, respectively. Most patients experienced zero bleeds that needed treatment. In the once-weekly group, 86% had no treated bleeds. For the once-monthly cohort, 95% had zero treated bleeds. In patients with prior coagulation factor prophylaxis, Mim8 showed superior reductions of treated bleeds by 48% and 43% in the once-weekly and once-monthly groups, respectively, as compared to their prior prophylaxis. About two-thirds of patients on both dosing schedules experienced zero treated bleeds, Novo said. “Headline mim8 efficacy results near our ‘best’ case,” Jefferies analyst Peter Welford wrote in a note shortly after the data release, “with 86% (weekly) and 95% (monthly) of patients not on prior prophylaxis experiencing zero treated bleeds, compared to the high of 80% reported by Roche’s HAVEN-6 at its interim readout, or 56%-60% in HAVEN-3, albeit caveating for cross trial comparisons.” Analysts await a fuller dataset to see how competitive Mim8 could be with Roche’s Hemlibra and Sanofi’s Altuviiio. BioMarin also markets a treatment for the condition, with its gene therapy Roctavian approved last summer, but few patients have received it so far, and executives have floated the idea of a potential divestment. Martin Holst Lange “These data demonstrate the ability of Mim8 to prevent bleeding episodes effectively and safely in people with haemophilia A, regardless of their dosing frequency,” Martin Holst Lange, Novo’s executive vice president for development, said in a press release. “Given the differing needs of people living with haemophilia A, a convenient once-weekly or once-monthly dosing provides optionality and flexibility for people living with haemophilia A with or without inhibitors.” Other treatments could be on the way for the rare inherited bleeding disorder, in which patients have missing or defective clotting factor VIII. Pfizer’s antibody marstacimab is set for a fourth-quarter approval decision at the FDA. Novo is also developing another… #lucidquest #genetherapy #celltherapy

Viral vector-based gene therapy drug product (DP) development continues to grow in importance as these therapies demonstrate promising clinical results and gain regulatory approval for the treatment of genetic diseases, different types of cancers, and other indications. The progression of discovery and development of gene therapies is now leading to increased manufacturing capacity to support an increasing number of clinical trials. For more on this, click below. #genetherapy #drugdelivery #containerclosure

👏 Great news for Ultragenyx! 🤔 Or is it? Let me explain why I'm skeptical: The Good – Ultragenyx secured FDA’s acceptance of cerebral spinal fluid (CSF) heparan sulfate (HS) as the primary endpoint for its investigational gene therapy in the treatment of Sanfilippo syndrome. The pivotal study was underway when Ultragenyx in-licensed the product. It is thus a huge win for them as they avoid the need to run an additional study to seek approval in the US. The Bad – Payers show a limited willingness to reimburse gene therapies based on a surrogate endpoint. At least not without significant restrictions, such as impossible to fulfill prior authorization criteria. To date, Zolgensma in the treatment of Spinal Muscular Atrophy remains the only gene therapy that has reached blockbuster status. It is no coincidence that it was approved based on 2 patient- and physician-relevant co-primary endpoints: ability to sit autonomously and survival. The Ugly – Even with a clinically relevant endpoint, payers in Europe show no leniency vis-à-vis study designs. They expect comparative data in indications where non-GTx options are available. One of the latest victims of poor payer evidence planning is Roctavian in Hemophilia A, for which BioMarin opted for a single-arm open-label study despite the availability of proven options including emicizumab. Last year, Roctavian sales totaled $3.5mio out of a $150mio analysts' forecast. The company’s new CEO blames market access. The bottom line – It is 2024 and the majority of GTx in-licensing / out-licensing deals are still anchored on regulatory milestones. For biotech, racing to approval remains the fastest way to unlock venture capital money and milestone payments from big pharma. Clearly, in my honest and nonbiased opinion, it should be market access. A ray of light? Potentially. The demand for a proper integration of the payer’s viewpoint in due diligence is on the up, on both the sell- and buy-side. At Inbeeo we support payer due diligence on both ends of the table, providing our clients with fast and cost-effective estimates of achievable prices and access barriers PS. I'm mostly skeptical about everything. So maybe it is just me being me and this is just great news for Ultragenyx. The future will tell https://lnkd.in/eTZmsUCt

An outcomes-based agreement for the gene therapy Hemgenix (etranacogene dezaparvovec) has been signed in Denmark. CSL Behring negotiated the deal for the haemophilia B therapy with Amgros. Denmark thus becomes the first Scandinavian country to approve the drug for routine use. Under the terms of the agreement, hospitals will pay for Hemgenix as long as it is effective, suggesting that the OBA is linked to instalment payments. The first patients are expected to receive treatment in autumn 2024.   The Danish Medicines Council (DMC) had discussed the drug in November 2023 but decided not to recommend it for reimbursement on account of the uncertainty regarding long-term safety and duration of effect, as well as the price of DKK 21.5 million (€2.9 million). It called on CSL Behring to come back with a better offer, which the company has now done.   Birgitte Klindt Poulsen, the Vice Chairman of the DMC, said: “The new gene therapies have great potential and may be able to cure patients in some cases, but they are also often extremely expensive, and there is great uncertainty about long-term effects and side effects. That's why it's great that we've now entered into an agreement for Hemgenix, where payment depends on whether the effect lasts. We would very much like to see more agreements like this, so that together we can overcome the challenges of uncertain effect and high prices for some of the new advanced therapies.”   At the end of 2023, Amgros and the DMC published guidelines on 13 types of managed entry agreement (MEA) (tinyurl.com/ycysc655). The document observes that payment-by-results (PbR) agreements can be among the most challenging MEAs. The guide recommends short time horizons to facilitate administration in hospitals. It notes that “softer outcomes targets can be problematic—disagreements can arise as to whether an outcomes target has been achieved or not.” It is possible to retrieve data from registers or through manual data collection. However, “data collection can be very complex and must be described in great detail in the agreement. In addition, it must be clearly stated in the agreement, who bears the risk of various pitfalls, as well as how costs for development of the data model and data collection are financed.”   Instalment payments can present similar challenges to PbR in terms of disagreements over softer outcomes targets. The guide notes that, “in general, neither the regions nor Amgros have challenges with liquidity. Therefore, an instalment payment model is not interesting as a stand-alone agreement model. Amgros takes the view that the instalment payment model must be linked to the collection of outcomes data.” #Denmark #managedentry #Hemgenix #genetherapies #OBA

Gene&Cell Therapy >> Q&A: FDA's Peter Marks ready to encourage more accelerated approvals for rare diseases: FDA biologics center director Peter Marks said the agency plans to encourage sponsors to use the accelerated approval pathway, particularly for rare disease treatments, as the agency also moves ahead with an Operation Warp Speed-like pilot for rare diseases later this year. In an expansive interview with Endpoints News, Marks said he expects to see more accelerated approval applications in the rare disease gene therapy space as well as potentially in cell therapies. Marks said the rare disease Operation Warp Speed effort, which he announced in February, will “start small” to make sure the agency can work closely with the first round of participants. Marks spoke with Endpoints on Aug. 15. This interview has been substantially edited for length and clarity. Lia DeGroot: I wanted to start with a question about the Office of Therapeutic Products. You’ve brought on Nicole Verdun to lead that office and are staffing up. How are things going? Peter Marks: It’s great to have her on board because that stability will help us get to our hiring goals. People like to know who their bosses are going to be. We’re making reasonable progress toward getting our reviewer positions filled, including physicians and CMC reviewers. It’s a little early to tell how far we’re going to get by the end of the year. I’d always love if we had more people wanting to come work at the agency. DeGroot: A few months ago, there was a bit of a backlog with cell and gene therapy applications. Is there still? Marks: There’s probably a slight backlog still. We’re still trying to do better with the timeliness of the feedback that we’re giving. We’re trying to make sure we get through the backlog and then cut down the time it’s taking to give people things like interact meetings and some of the more helpful meetings that we don’t have quite the same statutory timelines on as type A, B, C meetings. That’s what staffing up helps with. There is something that is still a valid concern, which is that we’re doing more written responses than industry would like. We’re doing that simply because of bandwidth. DeGroot: I wanted to switch gears a little bit to accelerated approvals. FDA is now working with some more authorities around requiring confirmatory trials to have started before decisions. Any progress on implementing that? Marks: Yeah, although it’s a work in progress, we are very actively working on making sure sponsors understand that we are serious about wanting good evidence, as required by the FDORA, that we be able to have compelling evidence that these clinical trials are either underway, enrolling or completed before we actually take our regulatory action, or at least enrollment is completed. Some of this that we’re doing right now is… #lucidquest #genetherapy #celltherapy

Lilly beams up Verve gene therapy programs for $600M from deal-hungry Beam Beam Therapeutics is selling opt-in rights to Verve’s gene therapy programs aimed at cardiovascular disease to Eli Lilly for up to $600 million, a third of which is upfront cash. The deal, disclosed Tuesday, gives Lilly rights to opt in to Verve’s programs aimed at PCSK9, ANGPTL3 and another undisclosed target. The PCSK9 program, VERVE-101, recently had an FDA hold lifted, allowing enrollment to begin in the U.S. for additional parts of an ongoing phase 1 trial. In exchange, Lilly is coughing up $200 million in upfront cash in addition to a $50 million equity investment. The deal puts $350 million on the table should the programs reach certain milestones. https://lnkd.in/gxJaVV-a

LucidQuest Strategic Insights (lqventures.com) >>> Gene&Cell Therapy >> Marks: FDA open to using single-arm studies for accelerated approval of rare disease gene therapies: Peter Marks, the FDA official who oversees gene therapies, is again advocating for the use of accelerated approvals for gene therapies that treat rare diseases. Marks, who is the director of the FDA’s Center for Biologics Evaluation and Research, said Monday during a webinar organized by the NYU Grossman School of Medicine that the FDA is “trying to be patient-focused.” Under Marks, the FDA has appeared more flexible with accelerated approvals and the kinds of trials and results needed to bring rare disease therapies to market. “We’ll use our accelerated approval provisions to lean in and try to get things across the finish line,” he said. He discussed the use of single-arm studies for potential accelerated approvals, noting that randomized controlled trials, which are considered the gold standard study in drug development, may not always be feasible for very rare diseases that only affect a few hundred patients in the US. But even in cases where there are enough patients, a randomized controlled trial may not always be needed. He pointed to Zolgensma, a gene therapy marketed by Novartis for spinal muscular atrophy, that the FDA fully approved based on single-arm studies that showed striking results compared to the natural history of the debilitating muscle disease. “Some of this flexibility is increasingly being shown,” Suyash Prasad said about the FDA’s approach to biomarker data. Prasad previously was chief medical officer for Audentes — which was acquired by Astellas — and Taysha Gene Therapies, and now consults for gene therapy companies. He pointed to the case of Grace Science, a biotech company co-founded by Nobel laureate Carolyn Bertozzi that’s developing a gene therapy for a very rare disease known as NGLY1 deficiency. Earlier this month, Grace Science received FDA clearance to begin a single-arm Phase I/II/III study that features both clinical and biomarker endpoints. Marks said that gene therapies are particularly “well-tailored” to accelerated approval because they often are attempting to replace or knock down a protein, which can be measured and used as a biomarker. Protein expression levels in the blood can be measured fairly easily and can be used as surrogate endpoints in the accelerated approval process. He also reiterated his concerns around reimbursement for gene therapies, which are among the most expensive treatments in the US. “For us, it’s very important that we have enough evidence initially through a biomarker that we can get an insurance company to reimburse for these products, because this is a major issue, right?” he said. “If these products can’t get paid for, they’re not going to get to patients, and we’ve seen that… #lucidquest #genetherapy #celltherapy

REGENXBIO Inc.’s investigational gene therapy shows promise in Hunter syndrome Patients receiving RGX-121 demonstrated an 86% median reduction in D2S6, which Regenxbio said is “approaching normal levels”. The rare genetic disease is estimated to affect one in every 100,000 to 170,000 births Regenxbio has shared positive results from a pivotal study of its investigational gene therapy in boys aged up to five years with mucopolysaccharidosis type 2 (MPS 2), a rare genetic disease estimated to affect one in every 100,000 to 170,000 births. The company said the results will support a regulatory submission to the US Food and Drug Administration (FDA) this year under the accelerated approval pathway. Also known as Hunter syndrome, MPS 2 occurs when a child’s body does not properly digest certain sugar molecules. When these molecules accumulate over time, they can cause cell, tissue and organ dysfunction, including in the central nervous system (CNS). There is currently no treatment to address fatal neuronopathic CNS disease in MPS 2. Results from the pivotal section of the phase 1/2/3 CAMPSIITE trial, presented at this year’s WORLDSymposium, showed that MPS 2 patients treated with Regenxbio’s one-time gene therapy, RGX-121, achieved decreased levels of D2S6, a key biomarker of brain disease activity, below maximum attenuated disease levels 16 weeks after administration. Patients receiving RGX-121 demonstrated an 86% median reduction in D2S6, which Regenxbio said is “approaching normal levels”. The results were consistent with data from the dose-finding phase of the study, the company said, in which the majority of patients are "exceeding expectations" in neurodevelopmental function compared to natural history data up to four years. The new long-term follow-up of those treated with RGX-121 in the dose-finding phase also showed there was a high rate of patients who were allowed to discontinue or remain naïve to standard-of-care intravenous enzyme replacement therapy. https://lnkd.in/eBSmxd6B

🌟 Big News in Gene Therapy! PTC Therapeutics' Upstaza Receives FDA Priority Review for AADC Deficiency 🌟 PTC Therapeutics, Inc. has reached a major milestone in the quest to treat aromatic L-amino acid decarboxylase (AADC) deficiency. The FDA has granted priority review to Upstaza, PTC Therapeutics, Inc.'s gene therapy candidate designed to address this rare and devastating genetic disorder. AADC deficiency typically manifests early in life, leading to severe disability and suffering. Upstaza offers hope as a one-time gene replacement therapy for patients aged 18 months and older with confirmed severe AADC deficiency. By delivering a functioning human DDC gene directly into the brain using a recombinant adeno-associated virus serotype 2 (AAV2), Upstaza aims to correct the underlying genetic defect and restore dopamine production crucial for neurological function. The BLA acceptance marks a significant step forward, with a target regulatory action date set for November 13, 2024. PTC Therapeutics, Inc. CEO Matthew Klein, MD, MS, FACS expressed excitement about bringing this transformative therapy to patients in the United States. Clinical trials and compassionate use programs have validated Upstaza's safety and efficacy, showing transformative neurological improvements. While common side effects include initial insomnia, irritability, and dyskinesia, the therapy's potential impact is profound. Administering Upstaza requires a stereotactic surgical procedure conducted by qualified neurosurgeons at specialized centers, ensuring precise delivery of the gene therapy. This news underscores PTC Therapeutics, Inc. commitment to advancing innovative treatments for rare diseases and offers hope to patients and families affected by AADC deficiency. Stay tuned for further updates as we await the FDA's decision. Discover more about this here: https://lnkd.in/eF4ATVXj For the latest in healthcare innovation, follow World Pharmaceutical Frontiers. 🧬💡 #PTCTherapeutics #Upstaza #GeneTherapy #RareDisease #WorldPharmaceuticalFrontiers 🌍

How are HTA bodies responding to the assessment challenges posed by cell and gene therapies?   Cell and gene therapies are different than other drugs, because they are mostly used for rare conditions, are potentially transformative in terms of health gains and have a potential for long-term "cure" - though usually associated with large uncertainty. Most HTA bodies do not have a separate approach to review these drugs.   In a recent paper, Drummond et al., reviewed HTA reports for 9 cell and gene products across Canada, Spain, UK, US (ICER), Scotland, Italy, Germany and France to determine what elements of evidence were being considered and challenges being encountered.   HTA Bodies Positively Reacted to:  ✔ Treatment for a rare disease or serious condition ✔ Lack of alternative therapies ✔ Evidence indicating substantial health gains ✔ When alternative payment models could be agreed on   HTA Bodies Negatively Reacted to:  ➖ Unvalidated surrogate endpoints ➖ Single arm trials without an adequately matched alternative therapy ➖ Inadequate reporting of adverse consequences and risks ➖ Short length of follow-up in clinical trials ➖ Extrapolating to long-term outcomes ➖ Uncertainty around the economic estimates   There was a variation amongst HTA bodies around what elements of evidence were considered. Nonetheless, the authors made suggestions for addressing assessment challenges posed by these therapies: 💡 Use structured approaches to validate surrogate endpoints and justify adoption based on prognostic value 💡 Design post-launch evidence generation programs (ad hoc studies, registries, administrative databases etc.) to validate surrogate endpoints and produce RWE +/- linked to outcomes based managed entry agreements 💡 Agree on criteria for when single arm trials can be deemed acceptable and have guidelines for assembling a matching comparator cohort 💡 Mixture cure models are becoming more common - conduct extensive scenario and sensitivity analyses for the presence and length of cure fraction 💡 Consider a broader societal view in the economic model or explicitly mention impact on caregivers/family in the clinical discussion (very relevant for severe conditions or those that afflict kids) 💡 Consider adding "insurance value" as a modifier (value placed by people on future therapies for serious conditions - even if they don't need them)   The authors concluded that jurisdictions conducting HTAs of cell and gene therapies can consider whether these suggestions could be incorporated within their existing approaches. Let me know what you thought of this post in the comments section!