Nuvalent Announces Publication in Cancer Discovery Detailing Design and Characterization of ALK-selective inhibitor NVL-655
Nuvalent (Nasdaq: NUVL) has published a manuscript in Cancer Discovery detailing the design and characterization of NVL-655, their ALK-selective inhibitor for ALK-positive non-small cell lung cancer (NSCLC). The publication highlights:
1. NVL-655's activity against ALK single and compound resistance mutations
2. Its selectivity for ALK over TRK family, potentially reducing neurological adverse events
3. Preclinical studies demonstrating brain penetrance and intracranial activity
4. Three case studies from the ALKOVE-1 trial showing tumor responses without CNS effects
The ongoing global Phase 2 portion of the ALKOVE-1 trial is designed with registrational intent. Updated Phase 1 data will be presented at the ESMO Congress 2024 in Barcelona.
Nuvalent (Nasdaq: NUVL) ha pubblicato un manoscritto su Cancer Discovery che descrive il design e la caratterizzazione di NVL-655, il loro inibitore selettivo per ALK adatto per il tumore polmonare non a piccole cellule (NSCLC) positivo per ALK. La pubblicazione evidenzia:
1. L'attività di NVL-655 contro le mutazioni di resistenza singole e compound di ALK
2. La sua selettività per ALK rispetto alla famiglia TRK, potenzialmente riducendo eventi avversi neurologici
3. Studi preclinici che dimostrano la penetrazione cerebrale e l'attività intracranica
4. Tre casi studio dal trial ALKOVE-1 che mostrano risposte tumorali senza effetti sul sistema nervoso centrale
La fase 2 globale in corso del trial ALKOVE-1 è progettata con intento registrativo. I dati aggiornati della fase 1 saranno presentati al Congresso ESMO 2024 a Barcellona.
Nuvalent (Nasdaq: NUVL) ha publicado un manuscrito en Cancer Discovery que detalla el diseño y la caracterización de NVL-655, su inhibidor selectivo de ALK para cáncer de pulmón de células no pequeñas (NSCLC) positivo para ALK. La publicación destaca:
1. La actividad de NVL-655 contra las mutaciones de resistencia simples y compuestas de ALK
2. Su selectividad por ALK frente a la familia TRK, lo que podría reducir los eventos adversos neurológicos
3. Estudios preclínicos que demuestran la penetración en el cerebro y la actividad intracraneal
4. Tres estudios de caso del ensayo ALKOVE-1 que muestran respuestas tumorales sin efectos en el sistema nervioso central
La fase 2 global en curso del ensayo ALKOVE-1 está diseñada con intención de registro. Los datos actualizados de la fase 1 se presentarán en el Congreso ESMO 2024 en Barcelona.
누발렌트(NASDAQ: NUVL)가 암 발견(Cancer Discovery)에 NVL-655의 설계 및 특성에 관한 원고를 발표했습니다. 이 약물은 ALK 양성 비소세포 폐암(NSCLC)에 대한 ALK 선택적 억제제입니다. 이 발표에서는 다음과 같은 사항을 강조합니다:
1. ALK 단일 및 복합 저항성 변이에 대한 NVL-655의 활성이론
2. TRK 계열에 비해 ALK에 대한 선택성이 있어 신경계 부작용을 줄일 수 있음
3. 뇌 침투 및 두개내 활동을 입증하는 전임상 연구
4. CNS 효과 없이 종양 반응을 보이는 ALKOVE-1 시험의 세 가지 사례 연구
진행 중인 ALKOVE-1 시험의 글로벌 2상은 등록 의도로 설계되었습니다. 업데이트된 1상 데이터는 2024년 바르셀로나에서 열리는 ESMO Congress에서 발표될 예정입니다.
Nuvalent (Nasdaq: NUVL) a publié un manuscrit dans Cancer Discovery détaillant la conception et la caractérisation de NVL-655, leur inhibiteur sélectif ALK pour le cancer du poumon non à petites cellules (NSCLC) positif pour ALK. La publication met en lumière :
1. L'activité de NVL-655 contre les mutations de résistance simples et composites d'ALK
2. Sa sélectivité pour ALK par rapport à la famille TRK, ce qui pourrait réduire les événements indésirables neurologiques
3. Des études précliniques démontrant la pénétration cérébrale et l'activité intracrânienne
4. Trois études de cas de l'essai ALKOVE-1 montrant des réponses tumorales sans effets sur le système nerveux central
La phase 2 actuelle de l'essai ALKOVE-1 est conçue avec l'intention d'enregistrement. Les données mises à jour de la phase 1 seront présentées au Congrès ESMO 2024 à Barcelone.
Nuvalent (Nasdaq: NUVL) hat ein Manuskript in Cancer Discovery veröffentlicht, das das Design und die Charakterisierung von NVL-655, ihrem ALK-selektiven Inhibitor für ALK-positives nicht-kleinzelliges Lungenkarzinom (NSCLC), beschreibt. Die Veröffentlichung hebt hervor:
1. Die Wirksamkeit von NVL-655 gegen ALK-einzelne und kombinierte Resistenzmutationen
2. Seine Selektivität für ALK im Vergleich zur TRK-Familie, was potenziell neurologische Nebenwirkungen reduzieren könnte
3. Präklinische Studien, die die Gehirnpenetration und die intrakranielle Aktivität demonstrieren
4. Drei Fallstudien aus der ALKOVE-1-Studie, die Tumorantworten ohne ZNS-Effekte zeigen
Der laufende globale Teil der Phase 2 der ALKOVE-1-Studie ist mit der Absicht der Registrierung konzipiert. Aktualisierte Phase-1-Daten werden auf dem ESMO-Kongress 2024 in Barcelona präsentiert.
- Publication in prestigious Cancer Discovery journal, enhancing scientific credibility
- NVL-655 shows activity against ALK resistance mutations, including the common G1202R mutation
- Preclinical studies demonstrate brain penetrance and intracranial activity of NVL-655
- Preliminary clinical data from ALKOVE-1 trial shows tumor responses without CNS side effects
- Ongoing Phase 2 trial designed with registrational intent, potentially expediting drug approval process
- None.
Insights
This publication in Cancer Discovery presents significant preclinical and early clinical data for Nuvalent's NVL-655, an ALK-selective inhibitor. The compound shows promise in addressing key limitations of current ALK tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC).
Key highlights include:
- Efficacy against ALK single and compound resistance mutations, including the common G1202R mutation
- Improved selectivity for ALK over TRK, potentially reducing neurological side effects
- Promising brain penetrance and intracranial activity
- Early clinical case studies showing tumor responses in patients with brain metastases or G1202R mutations
These findings suggest NVL-655 could potentially become a best-in-class treatment for ALK-positive NSCLC, particularly for patients with resistant mutations or brain metastases. The ongoing ALKOVE-1 Phase 1/2 trial will be important in confirming these early results.
As an oncologist, I find the potential of NVL-655 particularly exciting. Current ALK TKIs, while effective, often face challenges with drug resistance and CNS toxicity. NVL-655's design principles address these issues head-on.
The reported case studies are especially intriguing. Patients with brain metastases and those harboring the G1202R mutation - both challenging scenarios - showed responses without significant CNS side effects. This could be a game-changer for patients who've exhausted other ALK TKI options.
However, it's important to temper enthusiasm with caution. While promising, these are early results. The Phase 2 ALKOVE-1 trial will provide more robust data on efficacy and safety. If confirmed, NVL-655 could significantly improve outcomes for ALK-positive NSCLC patients, particularly those with options.
This publication represents a significant milestone for Nuvalent (NASDAQ: NUVL), potentially boosting investor confidence in their drug development pipeline. Key financial implications include:
- Market potential: ALK-positive NSCLC represents a substantial market, with current therapies facing limitations. If NVL-655 proves superior, it could capture a significant market share.
- Competitive advantage: The drug's design addressing multiple challenges (resistance, brain penetrance, selectivity) could provide a strong competitive edge.
- Pipeline validation: Success with NVL-655 would validate Nuvalent's approach to targeted therapies, potentially increasing confidence in their entire pipeline.
- Future partnerships: Positive data could attract potential partnerships or licensing deals, providing additional revenue streams.
While promising, investors should note that full clinical trial results and potential FDA approval are still pending. The upcoming ESMO presentation on September 14, 2024, may provide additional data to further assess NVL-655's potential market impact.
Publication provides comprehensive assessment of NVL-655's preclinical activity and includes preliminary clinical case studies
The manuscript, entitled "NVL-655 is a selective and brain-penetrant inhibitor of diverse ALK mutant oncoproteins, including lorlatinib-resistant compound mutations," is published online and can be accessed here: https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-24-0231/748436/NVL-655-Is-a-Selective-and-Brain-Penetrant
"Currently available ALK tyrosine kinase inhibitors (TKIs) are important treatment options for patients with ALK-driven lung cancer. However, limitations including treatment-emergent drug resistance, off-target neurological adverse events, and inadequate control of brain metastases, support the need for continued development in this disease," said senior author Alexander Drilon, MD, Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, and investigator in the ALKOVE-1 trial. "As detailed in this publication, preclinical characterization and preliminary clinical data provide a compelling rationale for the ongoing clinical investigation of NVL-655 and evaluation of its potential to address the limitations of available ALK TKIs for patients with ALK-positive NSCLC."
The manuscript details the design principles underlying the activity of NVL-655 against ALK single and compound resistance mutations, including the most commonly occurring resistance mutation, ALK G1202R. Additionally, it outlines a molecular rationale for the selectivity of NVL-655 for ALK over the structurally related tropomyosin receptor kinase (TRK) family, whose inhibition has been associated with neurological adverse events that can be dose limiting. Preclinical characterization of the activity and selectivity of NVL-655 is presented, including in vivo xenograft studies, preclinical assessments of brain penetrance and intracranial activity, and a comparison of eight ALK TKIs across multiple biochemical and cellular assays.
The manuscript further documents three case studies from the ALKOVE-1 trial of patients with ALK fusion-positive lung cancers who had received a range of ALK TKIs, including lorlatinib, and presented with brain metastases or with tumors that harbored ALK G1202R. NVL-655 elicited tumor responses in these patients without accompanying CNS effects attributed to off-target TRK inhibition. These findings support the potential for NVL-655 as a future treatment for these patient populations that may also enhance tolerability through improved selectivity for ALK.
"With this publication in Cancer Discovery, we are pleased to have now also elucidated our focused approach for ALK-positive NSCLC. Along with our parallel lead program for ROS1-positive NSCLC, these selective inhibitors form the foundation for our pipeline of precisely targeted therapies which aim to deliver potential best-in-class activity against recalcitrant targets through solving for multiple, and at times competing, challenges in structure-based drug design," said Joshua Horan, Ph.D., Vice President, Chemistry at Nuvalent. "We are grateful to our collaborators for their contributions to this manuscript and to the continued advancement of NVL-655."
Enrollment is ongoing in the global Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, designed with registrational intent. Updated data from the Phase 1 portion of the trial will be presented at the European Society for Medical Oncology (ESMO) Congress 2024 in
About NVL-655
NVL-655 is a novel brain-penetrant ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with single or compound treatment-emergent ALK mutations such as G1202R. In addition, NVL-655 is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy. NVL-655 has received breakthrough therapy designation for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who have been previously treated with two or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC. NVL-655 is currently being evaluated in the Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, a first-in-human study of NVL-655 in patients with advanced ALK-positive NSCLC and other solid tumors (NCT05384626).
About Nuvalent
Nuvalent, Inc. (Nasdaq: NUVL) is a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for patients with cancer, designed to overcome the limitations of existing therapies for clinically proven kinase targets. Leveraging deep expertise in chemistry and structure-based drug design, we develop innovative small molecules that have the potential to overcome resistance, minimize adverse events, address brain metastases, and drive more durable responses. Nuvalent is advancing a robust pipeline with investigational candidates for ROS1-positive, ALK-positive, and HER2-altered non-small cell lung cancer, and multiple discovery-stage research programs.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding Nuvalent's strategy, business plans, and focus; the expected timing of data announcements; the clinical development program for NVL-655; the potential clinical effect of NVL-655; the design and enrollment of the ALKOVE-1 trial, including its intended pivotal registration-directed design; the potential of Nuvalent's pipeline programs, including NVL-655; Nuvalent's research and development programs for the treatment of cancer; and risks and uncertainties associated with drug development. The words "may," "might," "could," "would," "should," "expect," "plan," "anticipate," "aim," "goal," "intend," "believe," "expect," "estimate," "seek," "predict," "future," "project," "potential," "continue," "target" or the negative of these terms and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. You should not place undue reliance on these statements or the scientific data presented.
Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties, and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation: risks that Nuvalent may not fully enroll the ALKOVE-1 trial or that enrollment will take longer than expected; unexpected concerns that may arise from additional data, analysis, or results obtained during preclinical studies or clinical trials; the risk that results of earlier clinical trials may not be predictive of the results of later-stage clinical trials; the risk that data from our clinical trials may not be sufficient to support registration and that Nuvalent may be required to conduct one or more additional studies or trials prior to seeking registration of our product candidates; the occurrence of adverse safety events; risks that the FDA may not approve our potential products on the timelines we expect, or at all; risks of unexpected costs, delays, or other unexpected hurdles; the direct or indirect impact of public health emergencies or global geopolitical circumstances on the timing and anticipated timing and results of Nuvalent's clinical trials, strategy, and future operations, including the ALKOVE-1 trial; the timing and outcome of Nuvalent's planned interactions with regulatory authorities; risks related to obtaining, maintaining, and protecting Nuvalent's intellectual property. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in Nuvalent's Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2024, as well as any prior and subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Nuvalent's views only as of today and should not be relied upon as representing its views as of any subsequent date. Nuvalent explicitly disclaims any obligation to update any forward-looking statements.
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FAQ
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