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Pictured: Novartis sign at its office in Germany/iStock, TBE The European Commission has formally revoked its conditional marketing authorization for Novartis’ sickle cell disease therapy Adakveo (crizanlizumab), the Swiss pharma company announced Friday. The decision comes after the Committee on Medicinal Products for Human Use (CHMP) recommended in May 2023 to pull the approval following a review of additional Phase III data. The EC’s decision is legally binding, forcing Novartis to withdraw Adakveo from all 27 territories covered by the Commission, including Germany, Sweden and Spain, as well as Iceland, Norway and Liechtenstein, which are part of the European Economic Area. Patients in these territories should discuss alternative treatment options with their doctors and healthcare providers, Novartis said in its announcement. Adakveo is a humanized IgG2 monoclonal antibody that works by binding to the cell adhesion molecule P-selectin, which is found on the surface of platelets and blood vessel endothelium, while disrupting its interaction with its corresponding ligands. In turn, this mechanism of action allows Adakveo to prevent vaso-occlusion in sickle cell disease (SCD). The FDA approved Adakveo in November 2019 as a treatment to lower the frequency of vaso-occlusive crises in SCD patients aged 16 years and above. Nearly a year later, in October 2020, the European Medicines Agency signed off on a conditional approval for the SCD therapeutic and its conversion to standard authorization was contingent on further evidence to validate the efficacy and safety of the product. Novartis ran the Phase III STAND trial to support Adakveo’s full approval in the EU, but in January of this year the company reported that the late-stage study was unable to replicate previous efficacy findings. A preliminary analysis of STAND showed that Adakveo was unable to significantly distinguish itself from placebo in terms of lowering the annualized rates of vaso-occlusive events in SCD patients. The CHMP flagged this and launched its own review of Adakveo, confirming in May 2023 that Novartis’ treatment “did not reduce the number of painful crises leading to a healthcare visit” as compared with placebo. The European regulator also looked at past studies of Adakveo, a managed access program and real-world performance data, noting that these studies “had several limitations, such as the lack of a comparator, and could not be used to show the effect of Adakveo or counterbalance the negative results of the STAND study.” Despite the lack of significant evidence of therapeutic benefit, Novartis pointed out that STAND did not document new safety concerns with Adakveo, and its adverse event pro consistent with what had been established in prior trials. Still, the CHMP noted that STAND “showed a higher rate of severe and serious treatment-related side effects,” therefore concluding that Adakveo’s benefits do not outweigh its risks. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Novartis will withdraw its sickle cell disease drug Adakveo from the European market after authorities there formally revoked the treatments authorization.The decision from the European Commission on Thursday followed a May recommendation by a committee advising the European Medicines Agency to pull Adakveos conditional clearance. The regulatory reversal was due to results from a late-stage clinical trial that compared the treatment to placebo, and found no significant difference between the two in lowering rates of the pain crises that many with sickle cell experience.In an emailed statement, Novartis said that patients currently on Adakveo should discuss alternative treatment options with their physician. The company did not answer a question from BioPharma Dive on how long the withdrawal process will take.No new safety concerns were identified with the medicine, Novartis noted.The European Commissions decision is legally binding and covers all 27 EU countries, along with Iceland, Norway, Liechtenstein and Northern Ireland. (Northern Ireland is following EU centralized procedures until January 2025.)An antibody drug, Adakveo was approved in Europe in late 2020 to prevent vaso-occlusive crises, which are a typical symptom of severe sickle cell. The drug binds to a substance called P-selectin thats found on the surface of blood vessel cells. Blocking P-selectin is thought to prevent the clogging up of blood vessels during pain crises.The drug is also approved in the U.S., and Novartis said it is discussing the recent negative study findings with the Food and Drug Administration.Globally, some 11,800 people with sickle cell have received Adakveo, according to the company. Over the first six months of the year, Novartis reported just over $100 million in sales.In the U.S., it arrived on market alongside a drug from Global Blood Therapeutics thats now owned by Pfizer. While the treatments were welcomed as important new options, theyve gone relatively little used, according to reporting by Stat. Both are expensive, and neither are considered cures for sickle cell, which is caused by red blood cells deforming into crescents that stick and snag in blood vessels.Theyve also arrived as potent genetic medicines for the disease near market. Later this year, two gene-corrective treatmentsthat are seen as potentially curative could win FDA approval. '

Syros' only revenue from the first quarter of 2023 was $3 million that came from the sickle cell collaboration with Pfizer. Pfizer is walking away from a sickle cell disease licensing deal with Syros Pharmaceuticals that it inherited from its takeover of Global Blood Therapeutics last year. At tail-end of 2019, GBT agreed to pay Syros $20 million upfront and bankroll at least three years of research funding up to $40 million to discover, develop and commercialize new therapies for sickle cell disease and beta thalassemia. The plan was for Syros to use its gene control platform to identify potential drugs that could induce fetal hemoglobin, with GBT having first choice to pick up the worldwide license to take any resulting candidates through development and on to market.   With Pfizer’s acquisition of GBT in 2022, the Big Pharma not only inherited an existing pipeline of exciting sickle cell drugs—it also became the partner in Syros’ research collaboration. But in a July 21 SEC filing, Syros said that it was informed by Pfizer on July 18 that it would be ending the partnership, effective in October. The biotech will now “seek to identify a new out-licensing partner for its sickle cell disease program,” it said in the filing. In addition to losing a high-profile partner, the end of the agreement also means that Syros must wave goodbye to the $315 million in potential development and sales-based milestone payments that were included as part of the GBT agreement. Syros ended March with $166 million in cash and equivalents. Syros' $3 million in revenue from the first quarter of this year came from the collaboration with Pfizer. The biotech’s most advanced asset is tamibarotene, a selective retinoic acid receptor alpha agonist in a phase 3 trial for higher-risk myelodysplastic syndrome as well as a phase 2 study for acute myeloid leukemia. There’s also SY-2101, an oral formulation of arsenic trioxide in phase 1 for acute promyelocytic leukemia. Meanwhile, Pfizer still has a portfolio of three sickle cell assets acquired from GBT. One of these, Oxbryta, was approved by the FDA in 2019, while inclacumab, a monoclonal antibody targeting a protein called P-selectin, is undergoing a phase 3 trial. A third, a HbS polymerization inhibitor called GBT021601, is in phase 2 development.