Dordaviprone

The FDA has granted a third approval for WELIREG, authorizing its use as a treatment for patients with rare endocrine system tumors known as pheochromocytoma or paraganglioma (PPGL). This approval applies to individuals aged 12 and older with locally advanced, unresectable, or metastatic PPGL, making WELIREG the first oral therapy available for advanced cases of the disease. LAS VEGAS, May 28, 2025 /PRNewswire/ -- Pheochromocytomas and paragangliomas (PCPG) are highly vascular neuroendocrine tumors originating from chromaffin cells of the adrenal medulla or from neural crest-derived cells located outside the adrenal glands. These tumors are categorized based on their location, either in the adrenal medulla or in extra-adrenal paraganglia. They arise from sympathetic tissues found in the adrenal glands or along the abdomen, or from parasympathetic tissues in areas such as the head, neck, and thorax. Sympathetic tumors often secrete large quantities of catecholamines and are found in the adrenal medulla in about 80% of cases. The remaining 20% are extra-adrenal, typically located along the prevertebral and paravertebral sympathetic ganglia in the chest, abdomen, or pelvis. In 2024, there were 4,900 incident PCPG cases across the 7MM, with numbers expected to rise in the coming years. Although significant progress has been made in understanding these tumors, accurately predicting their malignancy remains challenging in the absence of detectable metastases. Surgical resection remains the primary treatment for most localized PCPGs when feasible. In cases of advanced or metastatic disease, management typically involves symptom control using medications such as alpha-blockers, beta-blockers, and inhibitors of catecholamine synthesis to avoid serious complications. When surgery is not viable, treatment options include systemic chemotherapy with Cyclophosphamide, Vincristine, and Dacarbazine (CVD), as well as radiolabeled MIBG therapy ( AZEDRA, which was approved in 2018 but discontinued in early 2024). However, the effectiveness of CVD in improving overall survival is unclear, as most patients eventually face disease progression and death. Learn more about the PCPG treatment @ New Treatment for Pheochromocytomas and Paragangliomas DEMSER (metyrosine) was authorized for use in the United States in 1979 to treat pheochromocytoma. This FDA-approved drug is indicated for preoperative preparation, treatment of patients who are not candidates for surgery, and long-term management of malignant pheochromocytoma. In January 2019, ONO gained approval in Japan to produce and sell DEMSER capsules aimed at controlling catecholamine excess in pheochromocytoma patients. Later, in July 2020, the US FDA approved the first generic version of DEMSER oral capsules, manufactured by Amneal Pharmaceuticals, marking the initial generic approval for DEMSER in the US. In May 2025, Merck announced that the FDA approved WELIREG, the company's oral inhibitor of hypoxia-inducible factor-2 alpha (HIF-2α), for treating adults and children aged 12 and older with locally advanced, inoperable, or metastatic pheochromocytoma or paraganglioma (PPGL). The approval was based on findings from the LITESPARK-015 clinical trial, a single-arm study in which the primary measure of efficacy was the objective response rate (ORR). The trial included 72 patients in a single group (Cohort A1) with measurable disease confirmed by blinded independent central review (BICR) per RECIST v1.1. All participants had a histopathological diagnosis of PPGL and either locally advanced or metastatic disease not suitable for surgical or curative treatment. Their blood pressure was adequately controlled (below 150/90 mm Hg for adults and below 135/85 mm Hg for adolescents) without recent changes in antihypertensive therapy. Patients with carcinomatous meningitis were excluded. Participants received WELIREG at 120 mg once daily until disease progression or the onset of unacceptable toxicity. The primary efficacy endpoint was ORR as assessed by BICR under RECIST v1.1 criteria. Secondary endpoints included duration of response and time to initial response. WELIREG's prescribing information includes a boxed warning noting that exposure during pregnancy may cause harm to the fetus. Healthcare providers are advised to confirm pregnancy status before starting treatment and to counsel patients on the importance of using effective non-hormonal contraception, as WELIREG can reduce the effectiveness of hormonal methods. Additionally, the drug may lead to severe anemia requiring blood transfusions and serious hypoxia, which could necessitate treatment discontinuation, supplemental oxygen, or hospitalization. Regular monitoring for anemia is recommended before and during therapy. Find out more on FDA-approved PCPG drugs @ Pheochromocytomas and Paragangliomas Treatment Options Ongoing clinical trials are assessing a range of targeted therapies aimed at improving treatment outcomes for PCPG. These include radionuclide therapies using SSTR2 agonists and antagonists, alpha-emitting agents, and SSTR2 analogs. Other approaches under investigation involve Dopamine Receptor D2 (DRD2) modulators and ClpP agonists. Each therapy employs distinct mechanisms of action, offering promising advantages and making them key candidates in the advancing PCPG therapeutic landscape. Radionuclide therapy works by delivering radiolabeled peptides to tumor cells via specific receptor targeting. Current clinical guidelines suggest that radioligand therapy may serve as a suitable first-line treatment for patients with slowly to moderately progressive metastatic PCPG, provided the tumor demonstrates uptake of the relevant radioisotope. Several prominent institutions, including the National Cancer Institute (NCI), M.D. Anderson Cancer Center, Gustave Roussy Cancer Campus, and Columbia University are actively conducting clinical studies in this area. Discover which therapies are expected to grab major PCPG market share @ Pheochromocytomas and Paragangliomas Market Report Some of the drugs in the pipeline include ONC201 (Jazz Pharmaceuticals/Chimerix), [212Pb]VMT-α-NET (Perspective Therapeutics), and LUTATHERA (Lutetium [177Lu] oxodotreotide/dotatate) (Novartis), among others. ONC201, also known as dordaviprone, is a first-in-class small-molecule imipridone that specifically targets the G-protein-coupled receptor DRD2 and the mitochondrial protease ClpP. It was investigated in a Phase II, open-label, investigator-initiated trial at the Cleveland Clinic, involving 30 patients with rare neuroendocrine tumors. Interim results demonstrated a 50% overall response rate (ORR) in paraganglioma cases with dopamine-secreting tumors located outside the brain. These findings, based on investigator assessments, were presented at the 2021 ASCO Annual Meeting and later published in Clinical Cancer Research in 2022. [212Pb] VMT-α-NET is a Targeted Alpha Therapy (TAT) radiopharmaceutical in clinical development for diagnosing and treating SSTR2-positive neuroendocrine tumors, a challenging and uncommon cancer type. Perspective Therapeutics is conducting a multicenter, open-label Phase I/IIa dose-escalation and expansion trial (NCT05636618) in patients with unresectable or metastatic SSTR2-expressing tumors who have not previously received peptide receptor radionuclide therapy. The FDA has granted Fast Track Designation (FTD) for this program based on encouraging preclinical data, regardless of patients' prior treatment history. As of February 2025, 30 patients have been enrolled in Cohort 2, with regulatory alignment pending for Cohort 3. In April 2025, Perspective Therapeutics announced that data from both the [212Pb] VMT-α-NET and [212Pb] VMT01 programs had been accepted for presentation at the upcoming ASCO Annual Meeting, scheduled for May 30–June 3, 2025, in Chicago, Illinois. Details for regular abstracts are expected to be released on May 22, 2025, at 5:00 PM EDT. Discover more about drugs for PCPG in development @ Pheochromocytomas and Paragangliomas Clinical Trials The anticipated launch of these emerging therapies for PCPG are poised to transform the market landscape in the coming years. As these cutting-edge therapies continue to mature and gain regulatory approval, they are expected to reshape the PCPG market landscape, offering new standards of care and unlocking opportunities for medical innovation and economic growth. DelveInsight estimates that the market size for PCPG is expected to grow from USD 310 million in the 7MM in 2024 at a significant CAGR by 2034. Increasing awareness and improved detection rates are contributing to a rising patient pool. Additionally, ongoing research and development of novel treatment options, including precision medicine approaches, are fueling market expansion. The growing prevalence of these rare neuroendocrine tumors, coupled with supportive healthcare infrastructure, further boosts market opportunities worldwide. DelveInsight's latest published market report, titled as Pheochromocytomas and Paragangliomas Market Insight, Epidemiology, and Market Forecast – 2034 , will help you to discover which market leader is going to capture the largest market share. The report provides comprehensive insights into the PCPG country-specific treatment guidelines, patient pool analysis, and epidemiology forecast to help understand the key opportunities and assess the market's underlying potential. The PCPG market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Incident Cases of PCPG Occurrence or Absence of mutation in PCPG Age-specific Cases of PCPG Stage-specific Cases of PCPG The report provides an edge while developing business strategies by understanding trends shaping and driving the 7MM PCPG market. Highlights include: 10-year Forecast 7MM Analysis Epidemiology-based Market Forecasting Historical and Forecasted Market Analysis upto 2034 Emerging Drug Market Uptake Peak Sales Analysis Key Cross Competition Analysis Industry Expert's Opinion Access and Reimbursement Download this PCPG market report to assess the epidemiology forecasts, understand the patient journeys, know KOLs' opinions about the upcoming treatment paradigms, and determine the factors contributing to the shift in the PCPG market. Also, stay abreast of the mitigating factors to improve your market position in the PCPG therapeutic space. 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For Roche, adding Zepzelca as a combination partner could help shore up Tecentriq in first-line ES-SCLC in its competition with AstraZeneca’s Imfinzi. Roche’s plan to bolster Tecentriq’s position in small cell lung cancer with Jazz Pharmaceuticals’ Zepzelca has paid off. But the pair’s success leaves room for improvement for future contenders.Adding Zepzelca on top of Tecentriq as maintenance treatment of first-line extensive-stage small cell lung cancer (ES-SCLC) significantly reduced patients’ risk of death by 27% compared with Tecentriq alone, according to data from the phase 3 IMforte trial.Patients who received the combo lived a median 13.2 months, versus 10.6 for those who got Tecentriq alone. The results will be presented at the 2025 American Society of Clinical Oncology annual meeting.Besides hitting its overall survival goal, IMforte also showed that by taking Zepzelca, patients had a 46% lower risk of cancer progression or death. The median progression-free survival time was 5.4 months for the combo versus 2.1 months in the Tecentriq-alone arm.For Roche, adding Zepzelca as a combination partner could help shore up Tecentriq in first-line ES-SCLC in its competition with AstraZeneca’s Imfinzi. For Jazz, the phase 3 win could move Zepzelca from the post-chemo setting to first-line treatment and maybe also turn the drug’s accelerated approval into a full nod.But as ASCO Chief Medical Officer Julie Gralow, M.D., remarked during a press briefing, there’s still room for improvement.“While this is a next step, progression-free survival is still quite low in both arms, and we need to work on additional ways of advancing this even further,” she said. And a better therapy is desired not just on the efficacy side. The addition of Zepzelca during the maintenance phase more than doubled the rate of treatment-related adverse events to 83.5%, compared with 40% in the control group. The rate of grade 3 or 4 adverse events was also notably higher, at 25.6% for the combo, versus 5.8% for Tecentriq alone. But most adverse events were manageable, which is “one of the reasons that Zepzelca was a really good choice for a maintenance regimen,” Jazz’s R&D head, Rob Iannone, M.D., said in an interview with Fierce Pharma.Adverse events led 6.2% of patients in the experimental arm to discontinue treatment, versus 3.3% in the control arm. Iannone described the rate as “very low.” The Zepzelca arm also saw marginally more frequent treatment-related deaths, at 0.8% versus 0.4%, respectively.For existing first-line ES-SCLC regimens involving Tecentriq or Imfinzi, patients receive chemotherapies only during the induction phase because continued dosing in the maintenance phase turned out to be detrimental due to toxicities, Iannone noted.But once that chemo is taken off, there’s a notable worsening of progression curves. That’s why Jazz and Roche figured patients still need another active therapy that’s better tolerated than traditional chemo that can be given as maintenance treatment, Iannone explained.However, as Gralow pointed out, Zepzelca, as a DNA transcription inhibitor, is still a type of chemotherapy, albeit a safer one.More novel agents are emerging. The DLL3 drug class, led by Amgen’s bispecific Imdelltra, has attracted much enthusiasm—including recently from Roche—for its potential in SCLC. Last year, Amgen launched the phase 3 DeLLphi-305 trial adding Imdelltra to Imfinzi as first-line maintenance treatment of ES-SCLC, with an estimated primary completion date in July 2027.Imdelltra’s future looks promising after Amgen recently reported a positive readout in a phase 3 trial in second-line SCLC. It marked the first overall survival win for a T-cell engager in a solid tumor.  At least for now, Zepzelca is the first one to have a positive phase 3 readout in this disease setting, and Iannone argued that the results are practice-changing and serve as a new paradigm for future drugs in the space. Jazz has submitted the IMforte results to the FDA, which has yet to set a target decision date, according to Iannone.IMforte is one of two phase 3 trials that the FDA has agreed could potentially confirm Zepzelca’s clinical benefit after a lower dose of the drug failed to move the needle against chemo in second-line SCLC in the phase 3 Atlantis study. IMforte was sponsored by Roche.The other phase 3 trial that the FDA said could give Zepzelca a traditional approval, Lagoon, finished enrollment in December and could read out topline data in the first quarter of 2026, according to PharmaMar. The three-arm trial evaluates Zepzelca either as monotherapy or in combination with irinotecan against the physician’s choice of topotecan or irinotecan.Jazz in-licensed U.S. rights to Zepzelca from PharmaMar in 2019 by paying $200 million upfront and committing up to $800 million in potential milestones.Jazz has a good track record in licensing cancer drugs. The company’s HER2-targeted bispecific Ziihera, licensed from Zymeworks, recently won FDA approval in HER2-positive biliary tract cancer and is moving toward gastric cancer and breast cancer.After CEO Bruce Cozadd highlighted the company’s continued interest in dealmaking, Jazz agreed to buy Chimerix for $935 million to get hold of dordaviprone, a near-approval small molecule being evaluated by the FDA in recurrent H3 K27M-mutant diffuse glioma.As to Jazz’s future business development plan in oncology, Iannone said: “We are agnostic to modality, again, focused on drugs that will make a meaningful difference for patients, where Jazz really has the capability to develop and commercialize.”