Expanding Treatment Options Elevate Outcomes for Patients With Myelofibrosis

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Megan Hollasch

John Mascarenhas, MD, discusses the shifts from monotherapy to combination therapies in the evolving field of myelofibrosis care.

Therapies continue to expand for myelofibrosis as anticipated approvals, additional sequencing options, and JAK inhibitors continue to provide new avenues for the treatment of patients, according to John Mascarenhas, MD.

Mascarenhas presented “Updates in Myelofibrosis (MF) Management” at the 40th Annual CFS® detailing the dominant use of ruxolitinib (Jakafi), second-line options after ruxolitinib failure, and recently approved agents that can help fill unmet needs in the treatment paradigm.

“The highlight [of my presentation] was to be aware of the 3 approved JAK inhibitors, the niches that they could fill, and that there’s a fourth JAK inhibitor that will likely be approved,” Mascarenhas said. “Most importantly and most excitingly is the move to combination therapies upfront in the salvage setting and non-JAK inhibitor-based therapies with an overarching goal of improving responses, as well as progression-free survival and overall survival.”

In an interview with OncLive®, Mascarenhas, director of the Center of Excellence for Blood Cancers and Myeloid Disorders at the Icahn School of Medicine at Mount Sinai in New York, New York, discussed the shifts from monotherapy to combination therapies in the evolving field of myelofibrosis care.

Onclive®: What were the key takeaways from your presentation?

Mascarenhas: [As part of the presentation] I provided an update on the management of myelofibrosis geared towards the community provider. It covered that there are 3, soon to be 4, JAK2 inhibitors that will be approved for myelofibrosis. The only drug that was available for over a decade was ruxolitinib, now fedratinib [Inrebic] [has been approved] since 2019, pacritinib [Vonjo] since March of 2022, and [the approval of] momelotinib [is anticipated].

Practitioners must be aware of the different niches perhaps that one could use a JAK inhibitor [for]. There’s a lot of comfort and experience with [ruxolitinib, which] will [most likely] remain the mainstay of JAK inhibitor therapy for myelofibrosis, but there are other options now. Pacritinib fills an [unmet need] as an option for [patients with] low platelet [counts] as a second line JAK inhibitor and fedratinib, which has a broad label and can be used upfront or second line is another option. Fedratinib is a great second-line option in the community if patients have spleen progression or lack of spleen response with ruxolitinib.

Neither ruxolitinib nor fedratinib are great drugs for improving anemia and can be associated with myelosuppression. Drugs such as pacritinib [which has] a clinical improvement rate of approximately 25% in terms of hemoglobin response or momelotinib—MOMENTUM [NCT04173494] study results were presented at [2022 ASCO] and [EHA 2022]—are promising drugs for addressing spleen and other symptoms [and] improving anemia. Momelotinib beat out danazol in the randomized phase 3 study; a primary end point was symptom response, and a secondary end point was spleen response. Importantly, it was noninferior to danazol in terms of maintaining and/or attaining transfusion independence at week 24.

In 2023 [we may have] a level of complexity added to the management of myelofibrosis, as there will be multiple agents that one can use, but that’s not always a bad thing. What you have to plan out is your strategy of how you might sequence these drugs and the reality is that there are multiple options for any given patient and multiple second line options.

What are other factors that can affect choosing an agent during treatment?

The 3 approved drugs are agnostic to line of therapy. You could use pacritinib upfront, the label is but less than 50,000 [platelet count], but there are data from PERSIST-2 (PAC326; NCT02055781) for less than 100,000 [count]. Ruxolitinib and fedratinib can be used up front and any of the 3 drugs can be used as a second-line [option] after the failure of a first line JAK inhibitor.

It starts to become a little bit complicated beyond that to determine which is the optimal drug for any given patient because we don’t have clinical profiles or biomarkers that necessarily tell us which drug may be superior or optimal and which way to sequence them, [but] one can use toxicity profiles. For example, fedratinib and pacritinib are FLT3 inhibitors, they are associated with more [gastrointestinal] GI toxicity than ruxolitinib [and] if I had a patient who had underlying GI complaints—[such as] irritable bowel syndrome or even inflammatory bowel disorder or other comorbidities that might increase diarrhea and risk for complications—that may not be the ideal drug. Patients who [present] with anemia and or thrombocytopenia which would likely be exacerbated by ruxolitinib and fedratinib, would be patients for whom I might be more inclined to [give] pacritinib and momelotinib.

In the absence of mutational profiling that gives us a sense of which way to move or specific clinical features, we are not yet at the point where we can say from a workup of an individual patient this is the ideal JAK inhibitor and this is the next drug to use in sequence. The reality is we probably won’t develop that in the near future as the field is moving toward combination therapy.

The next exciting aspect or question is how do you choose which combination therapies make sense for a patient? I think we will move on from this sequencing monotherapy approach that we have become accustomed to [and] try to get deeper responses up front with combination therapies.

There’s a lot of different examples of trials that are trying to exploit the fact that there are multiple mechanisms that underlie the pathobiology of myelofibrosis and that there’s synergy behind inhibiting different pathways that can be active. A great example of that is ruxolitinib with the pan-BET inhibitor pelabresib (CPI-0610) in the MANIFEST study [NCT02158858] that has now inspired MANIFEST-2 [NCT04603495], which is randomized phase 3 study upfront [of] ruxolitinib and placebo vs ruxolitinib plus pelabresi.

This is a first attempt that I am aware of [to evaluate] efficacy in patients who are JAK inhibitor naïve. There are a lot of different salvage regimens that are under evaluation [such as] navitoclax, the BCL-2 inhibitor, parsaclisib, the PI3K inhibitor, and there are a number of drugs that are monotherapies that are not JAK inhibitor approaches that can be used second line after ruxolitinib failure, which is unfortunately a poor prognostic group of patients. This includes imetelstat, the MDM2 inhibitor, navtemadlin [KRT-232], bomedemstat[IMG-7289], and other drugs. There’s a lot going on in the field and I think we will see a move from a purely JAK inhibitor-based monotherapy approach to JAK inhibitor-based combination therapies early on or salvage and/or non-JAK inhibitor directed therapy as salvage.

What should patients know about the latest updates in myelofibrosis?

It’s important for patients to realize myelofibrosis is a relatively rare disease. It is critical to have a second opinion at a center where there’s a lot of familiarity and experience with myelofibrosis and myeloproliferative neoplasms. For most patients, clinical trials should always be considered if possible whether it’s upfront therapy or salvage therapy; it’s important for patients to realize that the only curative option that exists in 2022 leading into 2023 is still hematopoietic stem cell transplantation. That’s an important consideration early on in the disease course and a consultation when warranted with a transplanter is a good way of understanding whether that makes sense for a given patient and what’s involved because although it offers the potential for cure there are a lot of considerations, and it is an approach that has intrinsic toxicity and risk involved.

You must balance the potential benefits and risks and make sure that’s aligned with the patient’s expectations. Encouraging patients to be very vocal with their hematologists about what they’re looking to accomplish and make sure it’s aligned with what the hematologist is looking to provide is crucial.

What is a take-home message for colleagues regarding the evolving treatments for myelofibrosis?

One of the best examples that is paradigm shifting in many ways is the IMpactMF study [NCT04576156], which is a randomized phase 3 study in patients who have refractory myelofibrosis to ruxolitinib. Patients are randomly assigned to imetelstat, the telomerase inhibitor, or best available therapy and the primary end point is OS. It is an important study because it moves from spleen and symptom, which are not unimportant, but takes an end point that is the underlying reason why we try to intervene, [which is] to improve spleens and symptoms. Ultimately, we want [and] to extend life with a good quality of life.

It’s incumbent upon us as clinical researchers and as people that are passionate about what we do in this field, that we look at those kinds of end points and incorporate them in trials and elevate the goals of what we’re trying to accomplish with our patients.

It’s an exciting time to be involved in this field and it’s a great time to seek a second opinion if that’s a possibility

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A Patient Story: Message from a Vietnam Veteran

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I’ve had ET for 32+ years and probably longer just undetected. I am a Vietnam Veteran who was exposed to Agent Orange from 1968 until my tour of duty ended. After my ET was diagnosed I filed a claim in 1990, and the VA handled it very poorly, especially back in the early 90s. After many years, the claim was officially denied, but I tolerated Hydroxyurea and got on with my life.

Fast forward to just 4 years ago and a phone conversation with a woman named Ann from an MPN advocacy group. What an education I received that day. I was enlightened and realized I was being fed bogus information regarding MPNs and veterans for too many years. In 3 short weeks, I was attending a conference at the Marriott in St. Petersburg, Florida, and discussing MPNs and my ET with a specialist from the Moffitt Cancer Center. I now see Dr. Kuykendall annually at Moffitt in Tampa supplementing my VA appointments.

Sincere heartfelt thanks to you MPN Advocacy and Education International for the warp-speed education and reigniting my motivation to reengage with the VA. I did a bunch of research, obtained new Nexus statements from the Oncologists linking Agent Orange (AO) exposure to my MPN, and found numerous medical journal articles regarding MPNs and toxins. I submitted a new claim in 2019 and provided a detailed 3+ decade medical summary with new supporting resource documentation. As expected, my new claim was summarily rejected and kicked to the curb. The VA indicated the reason for denial was that nothing new had been submitted with the claim, go figure!

I naturally appealed the case and finally had a hearing with an appeals board judge in July of this year, 3 years after my initial claim. The judge seemed irritated and appalled the VA claim’s reviewer totally dismissed and ignored all of my supporting documentation, including nexus statements from 2 oncologists supporting the link between AO exposure and my ET.

I just received this past weekend the official VA letter indicating my claim and appeal has been granted. Again, many thanks to MPN Advocacy and Education International for emboldening me to reengage the VA.

It is unfortunate the VA has all the leverage in the MPN cases. As I discovered, even though there are probably hundreds of successful claims for MPNs, every case is handled individually and goes back to square one. So, unlike a conventional court of law, precedent is not taken into account and the entire burden of proof is on the veteran. The level of a veteran’s persistence and determination, individual skills for record keeping, and obtaining all the appropriate documentation over many years, govern the outcome when battling the VA bureaucracy. Thank you for being a large part of helping me navigate the maze.

Sincerely,

Lawrence M.

Protection Against Breakthrough Delta/Omicron Variants in Vaccinated Patients with Myeloproliferative Neoplasms (MPN)

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2022 Nov 15; 140: 6815–6818.
Published online 2022 Nov 15. doi: 10.1182/blood-2022-158902

Abstract

Background Information on breakthrough SARS-CoV-2 infections in MPN vaccinated patients (pts) is very limited. In these diseases, effectiveness of coronavirus disease 2019 (Covid-19) vaccines may be influenced not only by the MPN phenotype and the intrinsic reduced immunological competence, but also by the prior Covid-19 infection that can elicit a natural immunity against reinfections.

Patients In the European LeukemiaNet (ELN) observational registry, 863 MPN pts with Covid-19 have been enrolled since February 2020 and in 649 of them, information on the vaccination status is now available. To ensure that well characterized reinfections were considered, diagnosis of breakthrough Covid-19 included a positive naso-pharyngeal swab and symptoms highly suggestive for SARS CoV-2 infection.

Results

  • Breakthrough infections in vaccinated patients with previous Covid-19 infection

The effectiveness of previous Covid-19 infection in preventing reinfections was tested in a group of 131 and 287 unvaccinated and vaccinated MPN pts, respectively. Prior Covid-19 occurred during the first and second wave in 74% and 98% pts, respectively and the interval between Covid-19 and the breakthrough infection in unvaccinated and in vaccinated was similar (8.5 months). Administered vaccine doses (Pfizer in 71%) were 1-2 and 3-4 in 77% and 23% of vaccinated cases, respectively. The proportion of PV, ET, pre-PMF was similar in the two groups while the number of MF pts was lower (19%) than in the unvaccinated group (28%) (p=0.024). Reinfections occurred during delta (n=4) or omicron variants period (n=14) in 8 (6.1%) and 10 (3.5%) unvaccinated and vaccinated pts (p=ns) and hospitalization was required in 0 and 2 pts, respectively. Severity of the acute infection was variable and 1 death was registered.

  • Breakthrough infections in vaccinated patients without previous Covid-19 infection

Breakthrough infections were reported in 231 vaccinated cases (ET=89, PV=75, MF=54 and pre-PMF=13) without prior Covid-19. In 51% of pts the administered vaccine doses were 1-2 and 3-4 in 49%. No relevant vaccine related side effects were registered. Time interval from vaccination to Covid-19 was 8.1 months. Twenty-six pts (11%) required hospitalization and 205 (89%) were managed at home. Hospitalized pts were older (median age 76), males (69%) with MF (39%), and prior exposure to ruxolitinib (42%, 7 MF and 4 PV). Of note, values of C-reactive protein (CRP) and neutrophil/lymphocyte ratio (NLR) were significantly more elevated in hospitalized cases (CRP=33.1 vs. 2.0 and NLR=5.9 vs. 3.3, p<0.001). Although some infections occurred in the second wave, corresponding to alpha/beta/gamma coronavirus infection (6%), the majority of breakthrough episodes occurred in delta and omicron variant periods (41% and 53%). Three deaths were registered in hospitalized pts. We explored the risk of hospitalization and evaluated the marginal effect of gender, age and ruxolitinib exposure in a logistic model fitted to predict this event. We found that the risk of hospitalization was substantially higher only in males on ruxolitinib and increased with age (Figure). We also found that the inflammatory status measured with NLR could explain these results (data not shown).

Conclusion The effectiveness of previous Covid-19 in preventing reinfection occurring during the delta and omicron variants of SARS-CoV-2 was robust (94% and 97% in unvaccinated and vaccinated pts, respectively). This is good news for MPN patients who recovered from Covid-19 and the hope is that this effectiveness can work against any future SARS-CoV-2 variant. In the cohort of vaccinated pts without prior Covid-19, we identified a subgroup of patients with more severe delta and omicron disease, at high risk of hospitalization, consisting of males who were on ruxolitinib and had elevated inflammatory biomarkers. Subsequent studies are needed to interpret these latest results.

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Merck to Acquire Imago BioSciences, Inc.

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November 21, 2022

Acquisition expands Merck’s growing hematology portfolio

RAHWAY, N.J. & SOUTH SAN FRANCISCO, Calif.–(BUSINESS WIRE)–Nov. 21, 2022– Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Imago BioSciences, Inc. (“Imago”) (Nasdaq: IMGO) today announced that the companies have entered into a definitive agreement under which Merck, through a subsidiary, will acquire Imago for $36.00 per share in cash for an approximate total equity value of $1.35 billion.

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20221121005295/en/

“We continue to invest in our pipeline with a focus on applying our unique capabilities to unlock the value of breakthrough science for the patients we serve,” said Robert M. Davis, president and chief executive officer, Merck. “This acquisition of Imago augments our pipeline and strengthens our presence in the growing field of hematology.”

Imago is a clinical stage biopharmaceutical company developing new medicines for the treatment of myeloproliferative neoplasms (MPNs) and other bone marrow diseases. Imago’s lead candidate bomedemstat (IMG-7289), an investigational orally available lysine-specific demethylase 1 (LSD1) inhibitor, is currently being evaluated in multiple Phase 2 clinical trials for the treatment of essential thrombocythemia (ET), myelofibrosis (MF), and polycythemia vera (PV), in addition to other indications.

“This milestone is a testament to more than a decade of pioneering research by Imago scientists and the entire Imago team’s unwavering dedication to improving the lives of patients,” said Dr. Hugh Y. Rienhoff, Jr., Founder and Chief Executive Officer, Imago BioSciences. “This agreement leverages Merck’s industry-leading clinical development expertise to maximize the therapeutic potential of bomedemstat while providing important value for shareholders. I would also like to acknowledge with gratitude the early investors – Blackstone Life Sciences, Frazier Healthcare, Omega Funds, Amgen Ventures, and MRL Ventures Fund who placed their faith in Imago beginning in 2014, as well as the outstanding study investigators and their patients who have made the clinical development of bomedemstat possible.”

“Evidence indicates that LSD1 plays an important role in the maturation of blood cells in the bone marrow,” said Dr. Dean Y. Li, president, Merck Research Laboratories. “We look forward to working with the Imago team to further investigate the potential of bomedemstat for patients with myeloproliferative neoplasms.”

Under the terms of the acquisition agreement, Merck, through a subsidiary, will initiate a tender offer to acquire all outstanding shares of Imago. The closing of the tender offer will be subject to certain conditions, including the tender of shares representing at least a majority of the total number of Imago’s outstanding shares, the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act and other customary conditions. Upon the successful completion of the tender offer, Merck’s acquisition subsidiary will be merged into Imago, and any remaining shares of common stock of Imago will be canceled and converted into the right to receive the same $36 per share price payable in the tender offer. The transaction is expected to close in the first quarter of 2023.

Myeloproliferative neoplasms
Myeloproliferative neoplasms are a group of diseases of the bone marrow characterized by excessive production of red blood cells, platelets, or certain white blood cells. Myeloproliferative neoplasms progress over time as the number of extra cells build up in the blood and/or bone marrow. This may lead to bleeding problems, anemia, infection, fatigue, thrombosis or other signs and symptoms. Certain myeloproliferative neoplasms may become acute myeloid leukemia (AML). Myeloproliferative neoplasms include chronic myelogenous leukemia (CML), polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, and chronic eosinophilic leukemia.

About lysine-specific demethylase 1 (LSD1)
LSD1, also called KDM1A, discovered in 2004, is a member of a group of epigenetic proteins that regulate gene expression through chemical modifications of proteins, RNA and DNA. LSD1 regulates the maturation of bone marrow stem cells and is essential for the differentiation of progenitor cells into mature megakaryocytes and granulocytes and production of blood cells. Given the role that LSD1 plays in the function of malignant blood cells, targeting LSD1 for the treatment of blood cancers offers a new mechanism for the treatment of diseases associated with high morbidity and mortality.

Important Information About the Tender Offer
The tender offer described in this press release has not yet commenced. This press release is for informational purposes only and is neither an offer to purchase nor a solicitation of an offer to sell any shares of the common stock of Imago or any other securities, nor is it a substitute for the tender offer materials described herein. At the time the planned tender offer is commenced, a tender offer statement on Schedule (TO), including an offer to purchase, a letter of transmittal and related documents, will be filed by Merck Sharp & Dohme LLC (“Merck”) and M-Inspire Merger Sub, Inc., a wholly-owned subsidiary of Merck, with the Securities and Exchange Commission (the “SEC”), and a solicitation/recommendation statement on Schedule 14D-9 will be filed by Imago with the SEC. The offer to purchase shares of common stock of Imago will only be made pursuant to the offer to purchase, the letter of transmittal and related documents filed as a part of the Schedule TO.

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Rampal Reviews Data for First-line Therapy in Myelofibrosis With High Platelet Count

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Case-Based Roundtable Meetings Spotlight, Case-Based Roundtable Meetings Spotlight: November 1, 2022,
Pages: 54

During a Targeted Oncology case-based roundtable event, Raajit K. Rampal, MD, PhD, discussed recommendations and data on the use of JAK inhibitors to treat patients with myelofibrosis.

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figure image

Raajit K. Rampal, MD, PhD
Hematologic Oncologist
Associate Attending Physician
Memorial Sloan Kettering Cancer Center
New York, NY

Targeted OncologyTM: What nontransplant therapies do the National Comprehensive Care Network (NCCN) guidelines recommend for the management of higher-risk myelofibrosis (MF)?

RAMPAL: In the current NCCN guidelines, for patients with a platelet count of at least 50,000/μL, fedratinib [Inrebic], ruxolitinib [Jakafi], and [clinical trial are options].1 Ruxolitinib and fedratinib are supported by category 1 data, and I think a clinical trial is always a reasonable option. We’re fortunate these days because there are 3 phase 3 registration trials going on, where patients are randomly assigned to either ruxolitinib or ruxolitinib plus an investigational agent. The investigational agents are a BET inhibitor, a BCLX/BCL2 inhibitor, or a PI3K inhibitor. In this day and age, a clinical trial is absolutely a reasonable first-line consideration.

For patients with a platelet count of less than 50,000/μL, [the NCCN guidelines recommend a clinical trial or pacritinib [Vonjo] if the patient is not transplant eligible].1 The landscape changed with the approval of pacritinib,2 which has been studied as first-line and second-line [therapy] in MF, but has also been studied selectively in a patient population very different from those in the COMFORT-I [NCT00952289], COMFORT-II [NCT00934544], and JAKARTA [NCT01437787] studies, [whose data supported] the approvals of ruxolitinib and fedratinib, respectively.3,4

For patients [with a platelet count of 50,000/μL or greater] who get ruxolitinib or fedratinib as a first-line therapy [and then] lose response or have some degree of progression, you can switch to an alternative JAK inhibitor.1

What data support the management of MF with ruxolitinib?

Ruxolitinib was approved based on the COMFORT-I and COMFORT-II trials.3 These were randomized trials of ruxolitinib vs either placebo or best available therapy. Included in these trials were symptomatic patients with intermediate- or higher-risk disease and platelet counts of 100,000/μL or greater.

It’s important to remember the platelet count of these patients when [you consider the] data from these trials.5,6 The top-line data from the COMFORT-I and COMFORT-II studies were essentially similar, showing that [the rate of] spleen volume reduction by at least 35% was superior with ruxolitinib vs the comparator arm in each study with COMFORT-I: 41.9% vs 0.7%, respectively [odds ratio, 134.4; 95% CI, 18.0-1004.9; P < .001] and COMFORT-II: 28% vs 0%, respectively.

In both studies, almost all of the patients in the ruxolitinib arms experienced spleen volume reduction [COMFORT-II: 97% vs 56% in the experimental and control arms, respectively]. In the comparator arms, there was [more] spleen volume increase, although some patients in the COMFORT-I placebo arm, strangely enough, had a spleen volume reduction, which I still don’t understand.5,6 The [parameter of] spleen volume reduction by 35% is an FDA-mandated end point; there’s nothing particularly magical about 35%. But the degree of spleen size reduction does matter, and there are data that demonstrate that the amount of spleen volume [reduction] does influence a patient’s overall survival [OS].7

Is that because we are saving lives by shrinking spleens? I don’t think so. I think spleen volume reduction is a marker of disease responsiveness to the JAK inhibitor, but it is important to remember that the amount of spleen reduction does correlate with patient survival. These patients can be terribly symptomatic, as [we] know. In the COMFORT-I study, the symptom burden reduction [was measured by] the Total Symptom Score, a validated tool, and the majority of patients treated with ruxolitinib showed symptom improvement.

Night sweats, early satiety, itching, bone pain, inactivity, and abdominal discomfort all [improved] in the patients who received ruxolitinib and worsened in patients who received the placebo.5 The same pattern was observed in the COMFORT-II study, wherein symptom response was measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire.6

Survival was not an end point of the COMFORT studies. In the ad hoc analysis, there appeared to be a survival benefit in the COMFORT-I but not in the COMFORT-II study. This prompted a pooled analysis of the COMFORT-I and COMFORT-II data [that reflected] the patients in the intention-to-treat arm.

The data showed that there did seem to be a survival benefit. The median OS was 5.3 years vs 3.8 years in the ruxolitinib and control arms, respectively [HR, 0.70; 95% CI, 0.54-0.91; P < .0065].8,9 We have to take into account that this was a pooled analysis and this was not a primary end point of the studies. But these data suggest that there is improved survival [in treated patients].

The question is why: [Did the treatment] change the natural history of the disease or [did it] just change patients’ overall performance status? If a patient is terribly symptomatic and cachectic from their disease, are they living longer because they’re responding to treatment? I think there are 2 answers. There’s the real-world answer, which is that it [doesn’t] matter. If patients are living longer, they’re living longer. And then there’s the academic question as to why [we are seeing this survival benefit]. I don’t think we know the answer to that.

Of the patients who did die, death was most often caused by progression to acute myeloid leukemia [86 of 1054 patients]. [Other causes of death included] thrombosis, bleeding, infection, and portal hypertension, which can be a byproduct of the disease process itself.8,9 Infection is an important adverse event to remember. There are signals from other studies that ruxolitinib treatment may increase the risk of Herpes zoster infection or [tuberculosis] reactivation.

What data support the idea that spleen response correlates with OS among ruxolitinib-treated patients?

An important [analysis addressed this relationship,] treating spleen response as a binary variable of response vs no response at 6 months, with response defined as a 35% spleen volume reduction. Patients who had a spleen response also had a better OS outcome [P = .04].

The OS [also correlated with] the durability of the spleen response. In that analysis, the nonresponders had the worst OS. [Separate analyses were performed for] patients who had a stable response and for patients who had an unstable response, [and these groups] had overlapping OS curves [P = .04].10 Those data might suggest that patients’ quality of life is being improved and that’s why they’re living longer.

What factors are associated with a lower spleen response?

The factors associated with a lower spleen response include high-risk disease, spleen size of at least 20 cm, high white blood cell count, delay in starting ruxolitinib after diagnosis, and using a dosage of less than 10 mg twice daily.11,12 I think that [the influence of dosage and of spleen size are both] important concepts. Both the patient and the physician are often reluctant to start therapy if the patient is not symptomatic, but [I think] you have to keep this warning in mind.

If [the spleen] is getting progressively larger, you’re going to reach a point where even a high dose of ruxolitinib may not achieve the optimal response. That could affect the patient’s OS. [Another way to look at this is that] if the maximal effect of the drug is going to be to reduce the spleen by a certain percentage volume, the bigger the spleen gets [before you start treatment], the larger the residual spleen will be even if you get a maximal percentage reduction.

How does ruxolitinib efficacy correlate with dosage?

[Analysis revealed that] spleen volume reduction correlated with ruxolitinib dosing. Maximal efficacy was achieved at a dose of at least 10 mg twice daily. There was some [efficacy] difference between the 10- and 15-mg doses, but not much of a difference between the 20- and 25-mg doses. There was a clear efficacy difference between a dose of less than 10 mg and the higher doses.13 One needs to try to optimize the dosing of ruxolitinib to achieve the best spleen response. The symptom response [showed a similar trend].

[Patients achieved] some degree of response at a dose of less than 10 mg twice daily, but doses of 10 mg twice daily and higher [conferred maximal] symptom response. We always worry about the hematologic parameters. When we start a patient on therapy, their blood counts start to decrease and we have to begin transfusing them, [we have to decide whether to dose reduce].

Do we reduce to 5 mg twice daily because the blood counts are more stable [at that dosage]? Sometimes when you reduce to that dose, the patient instantly feels better. They’re not completely better, but they are relatively better. That can give us a false sense of security, and [we] have to be careful of that. I think it is useful to start at a low [dose] and titrate up. I always start at 5 mg twice daily and titrate the dose up to [the target dose], which is usually approximately 10 mg twice daily. If you start at 20 mg twice daily, often that patient’s hemoglobin level or platelet count crashes, and then you have to back off and you don’t end up with the optimal dose.

What data can guide the use of ruxolitinib, with respect to patients’ platelet counts?

The dose of ruxolitinib is based on the patient’s platelet count. Per the package insert, the starting dose for patients with platelet counts of 50,000/μL to 100,000/μL is 5 mg twice daily. For patients with higher platelet counts, you can [start with] 10 mg twice daily.14 The problem is that if you leave patients with low platelet counts at 5 mg twice daily, they’re going to have an inferior outcome. [Keep in mind that, according to the] Dynamic International Prognostic Scoring System [DIPSS] and the DIPSS-Plus, patients with platelet counts under 100,000/μL are already prone to inferior outcomes, [which can be exacerbated by suboptimal dosing]. There are data to support the idea that you can safely increase the dose of ruxolitinib if the platelet count is between 50,000/μL and 100,000/μL. In the EXPAND study [NCT01317875], patients were divided into 2 strata, defined by a platelet count of either 50,000/μL to 74,000/μL or 75,000/μL to 99,000/μL.

All patients were started at a dose of 5 mg twice daily, and the dose was [gradually increased to] 15 mg twice daily. The safe dose was determined to be 10 mg twice daily in both strata.15,16 That’s an important thing to remember, because leaving patients at 5 mg twice daily can lead to suboptimal outcomes. In the EXPAND study, grade 3 and 4 thrombocytopenia was observed in 40% of patients with a higher platelet count and in 78% of patients with a lower platelet count. Platelet count decrease occurred in 25% vs 6% of the patients in those respective groups, and anemia occurred in 25% vs 17%, respectively.16 Most of the patients [in both strata] had some degree of spleen volume decrease, and some achieved 35% spleen volume reduction. That is an important end point that correlates with survival, so pushing the dose can be beneficial. The symptom score [data exhibited a similar trend] in both strata.15

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VIDEO: New treatments in myeloproliferative neoplasms signal ‘exciting’ time for field

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November 11, 2022

In this video, John O. Mascarenhas, MD, provided an overview of his presentation at 14th International Congress on Myeloproliferative Neoplasms that delved into new treatments, specifically focused on myelofibrosis.

“One theme in myelofibrosis, at least in clinical investigation, is the use of combination therapies, usually with a JAK-2 inhibitor-based backbone — usually ruxolitinib (Jakafi, Incyte) — with agents that have both preclinical rationale and already have emerging phase 2 data,” Mascarenhas, professor of medicine at Icahn School of Medicine at Mount Sinai, director of Center of Excellence for Blood Cancer and Myeloid Disorders, and member of Tisch Cancer Institute, said.

He said ongoing phase 3 trials are investigating the combination of ruxolitinib, parsaclisib (Incyte), pelabresib (Morphosys) and navitoclax (AbbVie). These agents have been used both as salvage therapy and upfront therapy.

“What we’ve seen from the phase 2 [trial] data that inspired these phase 3 studies is activity that does seem to be above and beyond singular agent ruxolitinib in treatment-naive patients and at least a third of patients in the salvage setting having spleen and symptom responses and even bone marrow fibrosis reduction,” Mascarenhas said.

Another randomized phase 3 study he highlighted explored a primary endpoint of overall survival with the use of a single agent, imetelstat (Geron), in patients with relapsed/refractory myelofibrosis following JAK-inhibitor therapy.

“There is a lot going on in the field,” Mascarenhas said. “It’s pretty exciting to be in it as a clinical investigator.”

References:

  • Mascarenhas J. Promising new MPN treatments. Presented at: 14th International Congress on Myeloproliferative Neoplasms; Oct. 27-28, 2022; Brooklyn, New York.
  • Pemmaraju N. Combining novel agents for treating myelofibrosis. Presented at: 14th International Congress on Myeloproliferative Neoplasms; Oct. 27-28, 2022; Brooklyn, New York.

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Imago BioSciences Reports Third Quarter 2022 Financial Results and Provides Recent Business Updates

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 | Source: Imago Biosciences, Inc.

– Data updates for Bomedemstat Phase 2 trials in Essential Thrombocythemia (ET) and Myelofibrosis (MF) to be presented at the American Society of Hematology (ASH) Annual Meeting in December 2022 –

– Start-up activities for Bomedemstat pivotal Phase 3 ET and Phase 2 PV trials continuing to advance –

REDWOOD CITY, Calif., Nov. 09, 2022 (GLOBE NEWSWIRE) — Imago BioSciences, Inc. (“Imago”) (Nasdaq: IMGO), a clinical stage biopharmaceutical company discovering and developing new medicines for the treatment of myeloproliferative neoplasms (MPNs) and other bone marrow diseases, today reported financial results for the third quarter ended September 30, 2022 and provided a corporate update.

“Imago continues to make progress in the clinical development of Bomedemstat for the treatment of MPNs including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF). Enrollment in the ongoing Phase 2 ET study is complete and all patients remaining on study will have been treated for 24 weeks by year end. Imago has announced positive data for Bomedemstat in the treatment of ET and MF and will present additional data in an oral presentation for ET and a poster for MF at the ASH Annual Meeting on December 12, 2022,” said Hugh Young Rienhoff, Jr., M.D., Chief Executive Officer of Imago. “In addition, start-up activities continue to progress nicely for our planned Bomedemstat pivotal Phase 3 ET and Phase 2 PV trials, and we expect the investigator-sponsored study of Bomedemstat in combination with ruxolitinib for the treatment of MF to begin enrolling patients in the coming weeks.”

Third Quarter 2022 and Subsequent Highlights

  • Announced Oral and Poster Presentations at the Upcoming 64th American Society of Hematology Annual Meeting. On November 3, Imago announced that an abstract entitled “A Phase 2 Study of the LSD1 Inhibitor Bomedemstat (IMG-7289) for the Treatment of Essential Thrombocythemia (ET)” had been accepted for an oral presentation on December 12, 2022 at the ASH Annual Meeting. A second abstract entitled “A Phase 2 Study of the LSD1 Inhibitor Bomedemstat (IMG-7289) for the Treatment of Advanced Myelofibrosis (MF): Updated Results and Genomic Analyses” will be presented as a poster.
  • Study Start-up Activities. During the quarter, Imago advanced important study start-up activities for both the Bomedemstat pivotal Phase 3 ET and Phase 2 PV trials, including submission of both protocols to the U.S. Food and Drug Administration (FDA) for review. The Company anticipates initiation of both studies in early 2023.

Third Quarter 2022 Financial Results

  • Cash, Cash Equivalents, and Short-Term Investments: As of September 30, 2022, Imago had cash, cash equivalents, and short-term investments of $178.4 million compared to $217.4 million as of December 31, 2021. Based on current operating plans and financing arrangements, management believes its cash runway extends into 2025.
  • Research & Development (R&D) Expenses: R&D expenses for the quarter ended September 30, 2022 were $13.5 million (including stock-based compensation expense of $0.5 million), compared to $8.7 million for the same period in 2021. The overall increase in R&D expenses was primarily related to the start-up activities related to preparations for the planned Phase 3 clinical trial for ET and Phase 2 clinical trial for PV, continued development of commercial material and material to support the ongoing and new clinical trials, and salaries and non-cash stock-based compensation expense related to R&D employees, as we ramped up our operations.
  • General and Administrative (G&A) Expenses: G&A expenses for the quarter ended September 30, 2022 were $4.1 million (including stock-based compensation expense of $1.2 million), compared to $3.0 million for the same period in 2021. The increase of $1.1 million was primarily due to an increase of $0.7 million in stock-based compensation expense, as a result of increased headcount, and $0.3 million in professional fees attributable to accounting, legal, audit costs, and other public company expenses.
  • Net Loss: Net loss for the quarter ended September 30, 2022 was $16.8 million, compared to $11.7 million for the same period in 2021.

About Imago BioSciences

Imago BioSciences is a clinical-stage biopharmaceutical company discovering and developing novel small molecule product candidates that target lysine-specific demethylase 1 (LSD1), an enzyme that plays a central role in the production of blood cells in the bone marrow. Imago is focused on improving the quality and length of life for patients with cancer and bone marrow diseases. Bomedemstat, an orally available, small molecule inhibitor of LSD1, is the lead product candidate discovered by Imago for the treatment of certain myeloproliferative neoplasms (MPNs), a family of related, chronic cancers of the bone marrow. Imago is evaluating Bomedemstat as a potentially disease-modifying therapy in two Phase 2 clinical trials for the treatment of essential thrombocythemia (NCT04254978) and myelofibrosis (NCT03136185). Bomedemstat has U.S. FDA Orphan Drug and Fast Track Designation for the treatment of ET and MF, European Medicines Agency (EMA) Orphan Designation for the treatment of ET and MF, and PRIority MEdicines (PRIME) Designation by the EMA for the treatment of MF. The company is based in Redwood City, California. To learn more, visit www.imagobio.com, www.myelofibrosisclinicalstudy.com, www.etclinicalstudy.com and follow us on Twitter @ImagoBioRx, Facebook and LinkedIn.

Forward Looking Statements

This press release contains forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “anticipate,” “may,” “will,” “should,” “expect,” “believe” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements.

These statements may relate to, but are not limited to, the results, conduct, progress and timing of Imago clinical trials, timing of data presentations, the regulatory approval path for Bomedemstat, plans for future operations, and expected cash runway, as well as assumptions relating to the foregoing. Forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified. Important factors that could affect future results and cause those results to differ materially from those expressed in the forward-looking statements include: our limited operating history and lack of products for commercial sale; our significant losses since inception and for the foreseeable future; our need for substantial additional financing; our unpredictable operating results, due to, for example, general economic conditions in the United States and abroad; our business’s dependence on development, regulatory approval and commercialization of our product candidates; difficulties in enrolling patients and risks of substantial delays in our clinical trials; our minimal control over product candidates in investigator-initiated clinical trials; uncertainties in the cost and outcomes of our clinical studies and the acceptance for presentation at medical meetings of data from our clinical studies; uncertainties in the regulatory review and approval of our product candidates if our pivotal studies are positive; potentially material changes to the interim, top-line and preliminary data from our clinical trials; potential undesirable effects of our product candidates and safety or supply issues, in each case with respect to our product candidates alone or in combination with other compounds or products; our potential inability to obtain and maintain orphan drug designation and delays in approvals despite Fast Track designation; risks related to clinical trials outside of the United States; our need to manufacture multiple batches of Bomedemstat using a commercial current Good Manufacturing Practice; risks related to COVID-19 or other pandemics, natural disasters and wars; risks related to competition; difficulties in expanding our organization and managing growth, attracting and retaining senior management and key scientific personnel and establishing sales and other commercialization functions; risks related to information technology system and cybersecurity; risks related to misconduct of our employees and independent contractors; risks related to hazardous materials and our compliance with environmental laws and regulations; risks related to litigation and other claims; risks related to reliance on third parties to conduct and support preclinical studies and clinical trials, and to manufacture our product candidates; risks related to third-party intellectual property infringement claims and our ability to protect our own intellectual property; risks related to governmental policies and regulations including with respect to drug prices and reimbursement, and changes thereof; risks related to our common stock; risks related to our public company, “emerging growth company” and “smaller reporting company” status; risks related to material weaknesses and failure to maintain effective internal control over financial reporting; and other risks and uncertainties, including those listed in the section titled “Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2021 and our subsequent quarterly reports. You should not put undue reliance on any forward-looking statements. Forward-looking statements should not be read as a guarantee of future performance or results and will not necessarily be accurate indications of the times at, or by, which such performance or results will be achieved, if at all.

Except as required by law, Imago does not undertake any obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future developments, or otherwise.

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Imago BioSciences to Participate in Upcoming Investor Conferences

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Imago Biosciences, Inc.
·2 min read.

SOUTH SAN FRANCISCO, Calif., Nov. 07, 2022 (GLOBE NEWSWIRE) — Imago BioSciences, Inc. (“Imago”) (Nasdaq: IMGO), a clinical stage biopharmaceutical company discovering and developing new medicines for the treatment of myeloproliferative neoplasms (MPNs) and other bone marrow diseases, today announced that Hugh Young Rienhoff, Jr., M.D., Imago’s Chief Executive Officer, will participate in two upcoming investor conferences.

Details of the events are as follows:

H.C. Wainwright 3rd Annual Precision Oncology Conference. Dr. Rienhoff will present on Monday, November 14 at 12:30 pm ET.

Stifel Healthcare Conference. Dr. Rienhoff will present on Wednesday, November 16th at 8:00 am ET.

Interested parties can access the live webcasts for these conferences from the Investor Relations section of the company’s website at www.imagobio.com. The webcast replays will be available after the conclusion of each conference for approximately 90 days.

About Imago BioSciences
Imago BioSciences is a clinical-stage biopharmaceutical company discovering and developing novel small molecule product candidates that target lysine-specific demethylase 1 (LSD1), an enzyme that plays a central role in the production of blood cells in the bone marrow. Imago is focused on improving the quality and length of life for patients with cancer and bone marrow diseases. Bomedemstat, an orally available, small molecule inhibitor of LSD1, is the lead product candidate discovered by Imago for the treatment of certain myeloproliferative neoplasms (MPNs), a family of related, chronic cancers of the bone marrow. Imago is evaluating Bomedemstat as a potentially disease-modifying therapy in two Phase 2 clinical trials for the treatment of essential thrombocythemia (NCT04254978) and myelofibrosis (NCT03136185). Bomedemstat has U.S. FDA Orphan Drug and Fast Track Designation for the treatment of ET and MF, European Medicines Agency (EMA) Orphan Designation for the treatment of ET and MF, and PRIority MEdicines (PRIME) Designation by the EMA for the treatment of MF. The company is based in Redwood City, California. To learn more, visit www.imagobio.com, www.myelofibrosisclinicalstudy.com, www.etclinicalstudy.com and follow us on Twitter @ImagoBioRx, Facebook and LinkedIn.

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Risk Assessment and Treatment Approaches for Myelofibrosis

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November 7, 2022
Targeted Oncology Staff

During a Targeted Oncology case-based roundtable event, Pankit Vachhani, MD, discussed with participants how to assess risk and begin treatment for myelofibrosis. This is the second of 2 articles based on this event.

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of fatigue and abdominal pain lasting 4 months. She also reported increased bruising and unexplained weight loss. Her spleen was palpable 8 cm below the left costal margin. Genetic testing showed a JAK2 V617F mutation. A bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis. Blood smear revealed leukoerythroblastosis.

Laboratory results

Values

Red blood cells

3.40×106/µL

Hematocrit

9.1 g/dL

Mean corpuscular volume

94 μm3

White blood cells

32,000/µL

Platelets

98×103/µL

Peripheral blood blasts

2%

 

DISCUSSION QUESTIONS

  • Given the multiple risk-assessment tools for myelofibrosis (MF), how do you choose between them?
  • Based on your experience, what are the survival outcomes for patients with low-, intermediate-, and high-risk disease?
    • What percentage of your patients are high risk?

PANKIT VACHHANI, MD: [Would you] pick the Dynamic International Prognostic Scoring System [DIPSS] for one patient but some other tool for another patient?

KHALEEL K. ASHRAF, MD, MBBS, DMRD: I’ve been using the DIPSS Plus. It helps us decide when to [send] patients to referral centers for transplant and so on and also when to start treatment.

In community practice, this is not a very common disease. You stick with one [risk-assessment tool]. I don’t use all of them. I have not used the Mutation-Enhanced [International Prognostic Scoring System in Adults 70 and Younger (MIPSS70)], even though I’m sure it must have its place. I have been using DIPSS Plus for a good while.

KEVIN M. GALLAGHER, MD: I use the DIPSS Plus [because] this is what I have used historically, so I’m comfortable with it. I stick with the same method for each patient. [As to] the question of how [often the patients are] high risk, the numbers are very small, maybe 1 per year.

VACHHANI: The IPSS risk-stratification schema was the first schema that came out in modern times. The IPSS incorporates 5 different points: age, hemoglobin level, white blood cell count, peripheral blood blast count, and constitutional symptoms.1

I don’t use IPSS anymore. That system was only supposed to be used at the time of diagnosis. I don’t think it’s wrong to use it, but I think that there are better risk-stratification schemas that you could use. This brings us to the DIPSS.2

The difference [between DIPSS and IPSS] is that with DIPSS, more weight is given to anemia.1,2 For example, a hemoglobin level of less than 10 g/dL gets 2 points with the DIPSS and only 1 with the IPSS. [Additionally,] the D in DIPSS, which stands for “dynamic,” means that you can use this risk-stratification schema at any time [during] a patient’s journey.2

The DIPSS Plus includes 3 additional things. [This schema] incorporates karyotype information. It also gives additional weight to anemia; [not only does] anemia feature in the risk calculation, but also, if the patient is transfusion dependent, they get an extra point. [Finally,] with the DIPSS Plus, a platelet count of less than 100 × 109/L is recognized as a prognostic factor.3

[There are some circumstances in which] you would not use the DIPSS Plus. If you don’t have the karyotype information for some reason—if a prior physician saw the patient and bone marrow [biopsy] was never done, or [if the biopsy] was done, but you couldn’t get the karyotype information—DIPSS Plus won’t be [very] helpful. In those scenarios, DIPSS would be the better thing to use.

[For patients stratified according to the DIPSS, an analysis showed] the median survival of low-risk patients [was not reached]. The median survival of intermediate-1–risk patients was approximately 14 years, and the median survival of intermediate-2–risk patients was approximately 4 years. The high-risk patients’ median survival, which was the worst, was 1.5 years.2

All these schemas were made for patients who had primary MF. If your patient has secondary MF, you could use one of these schemas. We did it for a long time, and we still do it [occasionally]. But there is another risk-stratification schema: the MF Secondary to PV and Essential Thrombocythemia [ET]–Prognostic Model [MYSEC-PM], which was made specifically for those patients.4

According to the latest version of the National Comprehensive Cancer Network guidelines, if you have a patient with primary MF, [the preferred options are] the MIPSS70 or MIPSS70 Plus [version 2.0] schemas, which incorporate some additional molecular results like U2AF1 and ASXL1.5-7

In routine practice, if you were not seeing many different patients with MF and you had to pick just one [schema] that could be applied to almost every patient without knowing the patient’s karyotype or genetic mutation profile beyond JAK2, MPL, and CALR, maybe the single schema to remember would be DIPSS. The key here is that we should risk stratify every patient if possible.

DISCUSSION QUESTIONS

  • What is the trigger to initiate therapy for a patient with MF?
    • What is the timing to start Janus kinase (JAK) inhibitor therapy, and how do you choose?
    • How does the nature and burden of symptoms influence your decision to initiate JAK inhibitor therapy?
  • How important is it to initiate therapy early?
  • When do you consider clinical trial enrollment?

JOSÉ L. MENDOZA, MD: Typically, these patients with MF are symptomatic, and they need a diagnosis in order to be able to treat the symptoms. I would say that as soon as you have a diagnosis, if the patient is symptomatic [with] splenomegaly, cytopenias, or both, that is an indication to initiate therapy in most cases.

ASHRAF: I agree. Most patients, by the time I see them, have symptoms, and JAK inhibition quickly improves their symptoms.

VACHHANI: Is there anyone who [uses a JAK inhibitor] for patients whose risk status is high or intermediate-2 but not intermediate-1? Does that [factor into your decision], or is [your decision based] purely on symptoms and spleen?

DAVID YOUNG KAHN, MD: Often if the patient has splenomegaly, I like to start JAK inhibitor therapy. In terms of what to choose, [although] I hate to say it, it often depends on cost, insurance, and what’s on the patient’s formulary.

MENDOZA: My response was a general [one] but was applicable to higher-risk patients. But in the lower-risk situation, it’s more likely that you [will find yourself diagnosing] an asymptomatic patient, [so] you will have more time to plan your strategy. I would probably wait [to treat] unless there were issues like cytopenias or organomegaly. If a low-risk patient does develop high-bulk disease, I still treat, but the treatment [might] be a little different. [In this situation,] I think you might have a chance to try treatments that you wouldn’t use in a higher-risk population.

VACHHANI: The pivotal studies that led to the approval [of JAK inhibitor therapy] were done with intermediate-2 and high-risk patients, although there are data for intermediate-1–risk patients as well.8 In fact, recent data have shown that starting patients [on treatment] earlier led to better outcomes.9

DISCUSSION QUESTIONS

  • Have you used fedratinib (Inrebic)? If so, what line have you used it in?
  • How does it compare with your use of ruxolitinib (Jakafi)?

CANDICE BALDEO, MD: I haven’t had the chance [to use] fedratinib yet. My patients have been doing well on ruxolitinib.

VACHHANI: Is there a reason that you would not use fedratinib? Does anything concern you?

BALDEO: I think the risk of encephalopathy scares my patients.

QUILLAN HUANG, MD: I haven’t [used fedratinib]. I’ve seen my colleagues use it in the second-line setting after ruxolitinib failure.

VACHHANI: Is that because you just haven’t [found yourself in] that scenario, or is there any other reason?

HUANG: I think fedratinib is a very reasonable choice in the second line. I just haven’t had that situation yet.

VACHHANI: Personally, I restrict fedratinib use to the second-line setting or beyond if I cannot get someone on a clinical trial.

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