Ryvu Therapeutics Presents Preclinical Data on RVU120 and Synthetic Lethality Programs at the 2024 AACR Annual Meeting

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10 Apr, 2024

  • Ryvu PRMT5 inhibitors show potential best-in-class profiles, including a strong antiproliferative effect on MTAP-deleted cell lines and a good safety window versus MTAP WT cells.
  • Ryvu’s WRN inhibitor program has demonstrated target engagement and selective potency with a synthetic lethal effect; in vivo efficacy studies exhibited pronounced tumor growth inhibition in an MSI-H colorectal cancer xenograft model.
  • Ryvu’s proprietary ONCO Prime discovery platform, which recently received a PLN 26 million (approx. USD 6.6 million) grant from the Polish Agency for Enterprise Development, has identified novel drug targets in KRAS-mutant patient-derived cells (PDCs) with therapeutic potential in colorectal cancer; the ONCO Prime platform has broad potential across multiple tumor types.
  • RVU120 shows efficacy both as a monotherapy and synergistically in combination with ruxolitinib in preclinical models of myeloproliferative neoplasms, including myelofibrosis and polycythemia vera.
  • MEN1703 (SEL24), presented by partner Menarini Group, shows cytotoxic activity in myelofibrosis cell lines as a monotherapy and synergistically in combination with ruxolitinib.

KRAKOW, Poland, April 10, 2024 /PRNewswire/ — Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, presents preclinical data from its synthetic lethality pipeline, RVU120, and MEN1703 (SEL24) at the 2024 AACR Annual Meeting, April 5-10 in San Diego, California.

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Dr. Guo Develops Test Promising Answers for Cancer Patients

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Cancer researcher, Belinda Guo, knows that one of the biggest issues for people with myeloproliferative neoplasms (a group of rare blood cancers), is not knowing if the cancer will progress.

Dr Belinda Guo and her team at the University of Western Australia’s Translational Cancer Pathology Laboratory have invented a new blood-based test that detects specific changes in the blood of patients diagnosed with myelofibrosis.

With funding from Cancer Council WA, they are now working with clinicians to assess the blood of individuals who have undergone a bone marrow transplant to see if the transplant has worked.

We sat down with Belinda to hear more about her research project. Read the full interview below.

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Dr Raajit Rampal Discusses Disease Modification and Emerging Therapies in Polycythemia Vera

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Laura Joszt, MA

Achieving a disease-modifying therapy for polycythemia vera might require adjusting the end points in a study needed for a drug to be approved, said Raajit Rampal, MD, PhD, hematologic oncologist, associate attending physician, Memorial Sloan Kettering Cancer Center.

Transcript

Currently, there are no disease-modifying treatments in polycythemia vera, but it is being explored. What might such a therapy look like?

If we talk about disease modification, the first question is, what do you mean by disease modification? I think, what we would want is for our patients to live the longest and fullest life, free of the symptoms or burdens of their disease. To me, that is the sort of working definition of disease modification. From there, one can try to come up with biological definitions of things like depleting the stem cell, which are important things. But keeping this on a patient level, what we want for our patients [is a life free of disease burden]. How do we think about therapies that address those issues?

Part of it is a regulatory conundrum in the sense that studies have to meet certain end points for drugs to get approved, but the way we study the drugs is relative to the definitions of the end points that make the drugs successful. In many cases, [the end point is asking] are you controlling the hematocrit adequately? That’s one of the major things in polycythemia vera. But in order to really try to get at the question of disease modification, we’ve got to think about changing the end points of our studies to reflect that.

What are the things that are going to best correlate with the idea that you aren’t keeping patients free of the catastrophic consequences of their disease, like blood clots, like [disease] turning into leukemia or myelofibrosis? Are you controlling the patient’s symptoms to an adequate degree? Those are the things that I think are fundamental. But we’ve got to change the end points of our studies to really get at that.

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Follow-Up Needs for Blood Cancer Survivors May Determine Best Type of Provider

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Laura Joszt, MA

For patients with blood cancers, follow-up care consisting of management of psychosocial consequences, promotion of a healthy lifestyle, and disease prevention may be better addressed by primary care physicians (PCPs) than oncologists, according to a study published in Cancer Medicine.

The study, conducted in Germany, found most survivors of blood cancers were receiving care at a university hospital and a minority were actually being care for by community oncologists or PCPs. The researchers evaluated follow-up care received by survivors from the University Hospital of Essen using a questionnaire.

“Given the favorable prognosis of many types of blood cancer, there is a wealth of information about long-term treatment side effects, secondary diseases, and quality of life. How and by whom follow-up care is delivered, however, remains largely unexplored,” the authors noted.

Follow-up can be provided in different ways. In one model, oncologists provide follow-up care related to cancer and general practitioners provide other health care at the same time. In another model, survivors of cancer are transferred to PCPs for continued care. In a more complex model, oncologists and general practitioners have complementary roles.

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New study paves the way for precision drugs to treat blood cancers

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by Tampere University

April 4, 2024

The Janus kinase 2 (JAK2) protein mediates signaling from several cytokine receptors in the regulation of hematopoiesis and immune responses. Somatic mutations in human JAK2 lead to constitutive activation and cytokine-independent signaling and underlie several hematological malignancies from myeloproliferative neoplasms (MPN) to acute leukemia and lymphomas. JAK2 contains an active kinase domain and an inactive pseudokinase domain. Interestingly, pathogenic mutations mainly occur in the regulatory pseudokinase domain.

Due to its critical pathogenic role, JAK2 has become an important therapeutic target. The four currently approved JAK2 inhibitors relieve symptoms but do not heal the patient or affect survival. These drugs target the highly conserved kinase domain and affect both normal and mutated JAK2 and, due to side effects, carry a black box warning that limits their use in elderly, cardiac and cancer patients. The selective inhibition of pathogenic JAK2 is a key pending goal in drug discovery that requires a precise mechanistic understanding of the regulation of JAK2 activation.

“To understand the molecular and structural basis of the physiological and pathogenic activation of JAK2, we used single-molecule microscopy and erythropoietin receptor (EpoR) as a model system.

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A new mouse model highlights the need for better JAK inhibitors in myeloproliferative neoplasms

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Charles E. de Bock

The discovery that the gain of function JAK2 V617F mutation is present in myeloproliferative neoplasms (MPNs) has led to numerous clinical trials assessing the efficacy of JAK inhibitors. Most notably, ruxolitinib, a combined JAK1/2 selective inhibitor, has gained approval in patients with myeolofibrosis (MF), and additional JAK2 inhibitors including fedratinib, pacritinib, and momelotinib also under evaluation for patients with MF. However, while these inhibitors demonstrate some clinical benefit, they do not adequately reduce the mutant clone fraction. 1 , 2 Consequently, a critical question for the field has been whether the lack of a durable response is attributed to either (i) the inability of current JAK inhibitors to completely block the pathway or (ii) the possibility that mutant clones are not entirely dependent on this activated pathway.

To address these two possibilities, a new study from the laboratory of Ross Levine, published in Cancer Discovery,developed an innovative mouse model of Jak2 V617F alone or in combination with Tet2 loss. The novel aspect of this mouse model lies in the ability to control the expression and genetic deletion of Jak2 V617F allele from mutant clones upon development of MPN. To do so, it utilizes two orthogonal site‐specific recombinases which exert precise control over the temporal expression and deletion of the Jak2 V617F allele.

The mouse model uses the well‐established Cre recombinase that recognises short nucleotide target sequences called Lox sites, in conjunction with the relatively new Dre recombinase which recognizes short nucleotide sequences called Rox sites. Importantly, the strategic arrangement and orientation of these sequences can lead to either flipping or deletion of the intervening DNA sequence. In this context, Dre recombinase is employed to initiate the expression of the Jak2 V617F allele. Subsequently, a modified CreER recombinase, translocated to the nucleus upon tamoxifen treatment, can delete the Jak2 V617F allele (Figure 1A). This intricate mouse model provided a powerful tool for comparing the durability of response between JAK inhibitors and the genetic loss of Jak2 V617F in the context of MPNs.

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Childbirth rates in women with myeloproliferative neoplasms

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Anna Ravn Landtblom, Therese M-L Andersson, Anna L. V. Johansson, Frida E. Lundberg, Jan Samuelsson, Magnus Björkholm & Malin Hultcrantz

Abstract

Myeloproliferative neoplasms (MPN) are associated with inferior pregnancy outcome, however, little is known about fertility and childbearing potential in women with MPN. In this study we aimed to describe reproductive patterns, as well as to quantify risk of miscarriage and stillbirth. Women aged 15–44 years with an MPN diagnosis 1973–2018, were identified in Swedish health care registers, and age-matched 1:4 to population controls. We identified 1141 women with MPN and 4564 controls. Women with MPN had a lower rate of childbirth (hazard ratio [HR] with 95% confidence interval was 0.78 (0.68–0.90)). Subgroup analysis showed that the rate was not significantly reduced in essential thrombocythemia, HR 1.02 (0.86–1.22) while the HR was 0.50 (0.33–0.76) in PV and 0.45 (0.28–0.74) in PMF. The risk of miscarriage was not significantly increased before MPN diagnosis, the HR during follow-up after diagnosis was 1.25 (0.89-1.76). Women with MPN were more likely to have had a previous stillbirth. Women with MPN had fewer children at diagnosis, and fewer children in total. In conclusion, the childbirth rate was lower among women with MPN than controls, but not among women with essential thrombocythemia.

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Mindfulness Minute: Sitting With Uncomfortable Feelings

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By Natalie Giocondo

One of the benefits of regular yoga and meditation practice is the cultivation of tolerance. We become more tolerant of ourselves, more tolerant of others, and more tolerant of the way things are.

A dear friend and mentor, Ken Rosen, once told me that suffering is the place that exists between what is and what we want it to be. Ken was an MPN patient, a Zen Buddhist teacher, and a therapist who passed away not long after he presented on Mindfulness at an MPNA&EI conference in 2018. His yoga and meditation practice helped him to manage his yearslong experience with essential thrombocythemia, gave him peace during a major thrombotic episode that resulted in a month-long hospital stay, and I believe it gave him peace during the last months of his life.

Sitting with uncomfortable feelings is not just a useful skill when we are faced with illness or mortality, it also comes in handy when we are in a hurry and stuck behind a chatty Cathy in the supermarket checkout, or when someone cuts us off in traffic, or when we are waiting for important news. In many of these scenarios, our sympathetic nervous system is triggered and the body tells the mind to respond. This process, while useful in survival situations, is not so good for us when it happens multiple times a day or week and can produce.

In a recent Conversation with an MPN Specialist, Dr. Ellen Richie touched on some things we can do to reduce the body’s inflammatory response in addition to a low-inflammation diet, such as reducing stress by disconnecting from technology for periods of the day, finding quiet time, or listening to good music.

Another way to lower stress is to learn how to better tolerate it by practicing yoga and meditation. Now, this is not a no pain, no gain philosophy so when we talk about tolerating stress here, we do not mean how to grin and bear it. Instead, we learn to better observe the way our mind behaves when stress arises and then we train it to behave in a way that better supports us. The result? Stress reduction.

Join us online Thursday, April 18th from 12:00-12:40 pm EST for a Yin-Yoga practice. Yin-Yoga requires longer holds in each pose to encourage the fascia (webbing around the muscles) to release. Longer holds also allow us to sit and observe our body and mind. This is a great practice to create flexibility in the body and mind.

Emerging Data Continue to Evolve Treatment Utilization in MPNs

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Laura Joszt, MA

Emerging data are continually changing the knowledge base around how interferons should be used, despite being around for decades, in patients with myeloproliferative neoplasms (MPNs), says Raajit Rampal, MD, PhD, hematologic oncologist, associate attending physician, Memorial Sloan Kettering Cancer Center.

Transcript

How has the landscape for MPN treatment evolved since the introduction of interferons? How does it look different today?

I guess it’s more a question of utilization than the landscape, in the sense that both things like hydroxyurea and interferons and drugs, like an anagrelide for ET [essential thrombocythemia], have been around for quite some time. And I think that it hasn’t been clear for the majority of that time which drugs should be used when and by whom.

There is now randomized clinical trial data for pegylated interferon vs hydroxyurea, but more recently, particularly with regards to polycythemia vera, there’s randomized data with ropeginterferon and hydroxyurea. And at least in that data set, the [blood] count control was superior with ropeginterferon vs hydroxyurea over the course of a number of years. Initially, at 1 year, there wasn’t so much of a difference, but as time went on, there was clearly a difference that favored the use of ropeginterferon in terms of controlling the blood counts. Similarly, over time, there does seem to be a decrease in the JAK [Janus kinase] 2 mutation burden in the patients who got the ropeginterferon.

I think that there is an emerging data set that is arguing that there are benefits to interferon. Going back to the initial point here, the landscape has changed to some degree—with the introduction of something like ropeginterferon—but I think it’s more that the data is evolving, which is beginning to tell us maybe which drugs might be best for which patients. We’re not completely there by any stretch of the imagination, but the data is beginning to coalesce around the message.

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Disease Progression for Patients With Low-Risk Myelofibrosis Participating in the MOST Study

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Grace Taylor

03/26/2024

A group of researchers presented data on disease progression for patients with low-risk myelofibrosis (MF) participating in the prospective observational Myelofibrosis and Essential Thrombocythemia Observational Study (MOST) at the 2023 ASH Annual Meeting & Exposition.

In order to qualify for the MOST study, participants were required to have a physician-reported diagnosis of MF (primary myelofibrosis [PMF], post progression of polycythemia vera [post-PV], or post essential thrombocythemia [post-ET). They also could not have any risk factors per the Dynamic International Prognostic Scoring System (DIPSS) criteria. However, participants could be aged 65 years or older. The number of patients with MF enrolled in the study was 232. Of this population, 205 met the study criteria and were included in cohort A. Although the remaining 27 patients had  ≥1 DIPSS risk factor, they were included in the study in a separate cohort B.

For the study, disease progression was defined by the worsening of clinical or laboratory parameters, which included one or more of the following criteria: hemoglobin (Hb) <10 g/dL, platelets <100×109/L, presence of constitutional symptoms (weight loss, fever, or sweats), new or worsening splenomegaly, blasts >1%, white blood cell count >25×109/L, death due to disease progression, leukemic transformation (LT), or >1 red blood cell transfusion. The median follow-up was 52.9 months (42-68).

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