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High Frequencies of Myeloid-Derived Suppressor Cells Seen in Patients With Myeloproliferative Neoplasms

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May 10, 2023

Vicki Morre, PhD

A study involving patients with myeloproliferative neoplasms (MPNs) revealed high frequencies of myeloid-derived suppressor cells (MDSCs) in bone marrow. The study findings were reported in the journal Advances in Molecular Pathology.

In their report, the study investigators explained that while MDSCs have been shown to be more frequent in the peripheral blood of patients with MPNs, the frequency of these in the bone marrow had not been well understood.

In this study, they evaluated the frequencies of MDSCs in the peripheral blood and bone marrow of patients with MPNs and correlated these levels with other clinical and laboratory parameters.

Overall, 64 patients with MPNs were included in the study. For bone marrow analyses, the study recruited 17 patients with essential thrombocythemia (ET), 29 patients with polycythemia vera (PV), and 18 patients with primary myelofibrosis (PMF), in addition to 5 healthy donors. Analyses of peripheral blood included 11 patients with ET, 11 patients with PV, 9 patients with PMF, and 11 donors without hematologic malignancies.

Included patients had been previously untreated, and multiple clinical and laboratory parameters, including JAK2 and CALR variant status, were obtained from them at the time of diagnosis. MDSCs were evaluated through flow cytometry, and other assays were also performed.

Median ages were 56 years for patients with ET, 60 years for patients with PV, and 62 years for patients with PMF. Assays showed that in the bone marrow percentages of total MDSCs (T-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) were significantly greater across patients with MPNs than in healthy donors.

These differences were greatest for patients with PMF, who had a mean T-MDSC level of 55.37%, compared with healthy donors, who had a mean T-MDSC level of 25.36% (P =.004). The mean PMN-MDSC level was 54.58% for patients with PMF, compared with 18.8% for healthy donors (P =.008), as well.

Peripheral blood analyses also showed significant elevations in T-MDSC and PMN-MDSC levels in patients with MPNs, compared with healthy donors, apart from a trend of moderately higher percentage of circulating T-MDSCs in patients with ET that did not reach significance.

There were, however, not correlations seen between elevated MDSCs in the bone marrow and parameters of age, hepatomegaly, leukocytes, hemoglobin, or platelet levels. JAK2 or CALR status also appeared uncorrelated with MDSC levels.

The study investigators reported an additional finding of an apparent immunosuppressive function of MDSCs from patients with MPNs. In patient samples that had undergone MDSC depletion, T-cell proliferation rates were significantly higher than they were without MDSC depletion, across MPN types.

“In summary, this study demonstrated increased frequency levels of MDSCs in the bone marrow of MPNs patients,” the investigators wrote in their report. Although MDSC levels did not show correlations with multiple clinical parameters or with mutations of JAK2 or CALR genes, the investigators pointed out myelofibrosis intensity appeared associated with MDSC frequency in bone marrow.

Reference

Kapor S, Momčilovič S, Kapor S, et al. Increase in frequency of myeloid-derived suppressor cells in the bone marrow of myeloproliferative neoplasm: potential implications in myelofibrosis. Adv Exp Med Biol. 2023;1408:273-290. doi:10.1007/978-3-031-26163-3_15

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Sobi to acquire CTI BioPharma Corp. enhancing Sobi’s position in rare haematology

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NOT FOR RELEASE, PUBLICATION OR DISTRIBUTION, IN WHOLE OR IN PART, IN, INTO OR FROM ANY JURISDICTION WHERE TO DO SO WOULD CONSTITUTE A VIOLATION OF THE RELEVANT LAWS OR REGULATIONS OF THAT JURISDICTION. THIS PRESS RELEASE DOES NOT CONSTITUTE AN OFFER OF OR THE SOLICITATION OF AN OFFER TO BUY SECURITIES IN ANY JURISDICTION.

Swedish Orphan Biovitrum AB (publ) (Sobi®) (STO:SOBI) today announced that it has entered into an agreement and plan of merger with CTI BioPharma Corp. (CTI) under which Sobi has agreed to acquire CTI, a biopharmaceutical company focused on blood related cancers and rare diseases, by means of a tender offer.

The acquisition complements and further strengthens Sobi’s leading haematology franchise by adding VONJO® (pacritinib), a novel oral kinase inhibitor that inhibits JAK2, IRAK1 and ACRV1, while sparing JAK1. VONJO obtained accelerated approval by the FDA in February 2022 for treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L.

Rationale of the acquisition and transaction in brief:

  • Adds VONJO, a differentiated product in the treatment of myelofibrosis, specifically addressing patients with severe thrombocytopenia, an unmet medical need.
  • Highly complementary to Sobi’s existing portfolio, specifically Doptelet®, expands Sobi’s leading position in rare haematology and accelerates access for patients to both therapies globally.
  • Both VONJO and Doptelet address rare haematological platelet disorders and are prescribed by haemato-oncologists and haematologists. The acquisition accelerates Sobi’s strategy to build a leading franchise in rare haematology.
  • The addition of VONJO brings a uniquely differentiated therapy, serving an unmet medical need for patients suffering from myelofibrosis.
  • The acquisition is expected to accelerate Sobi’s revenue growth, and to improve margins, adding a commercial-stage asset in the U.S., with the potential for further expansion globally.
  • Sobi to commence a cash tender offer to acquire all issued and outstanding shares of CTI for USD 9.10 per share, corresponding to a total equity value of USD 1.7 billion (approximately SEK 17.1 billion).
  • Fully funded through committed debt financing, up to half of which is anticipated to be refinanced through a rights issue after the closing of the acquisition, with a commitment from Investor AB to subscribe for its pro rata share of the rights issue, corresponding to approximately 34.7% of the shares to be issued in the rights issue.

“CTI represents a perfect fit for Sobi’s haematology franchise today, adding a powerful and highly differentiated new product that will make a significant difference for patients”, said Guido Oelkers President and CEO of Sobi. “There is a large unmet medical need within myelofibrosis, in particular for patients suffering from thrombocytopenia who are inadequately treated by existing medicines. The combination of the talented team at CTI, together with Sobi’s broad US and global haematology capabilities, will help get this much needed new therapy to patients faster and more effectively. The acquisition of CTI is the latest in a series of transformative transactions Sobi has conducted to build its leading rare haematology franchise.”

Financial highlights

The acquisition is expected to be highly accretive to Sobi’s revenue and margins, starting in the near-term.  Revenue and cost synergies are expected from leveraging the highly complementary nature of Sobi’s existing U.S. commercial operations and global sales infrastructure in haematology and rare diseases.

Sobi has obtained committed debt financing from Bank of America and Danske Bank. Sobi anticipates that up to half of the merger consideration will be refinanced through an issuance of new ordinary shares of Sobi with preferential rights for existing shareholders of Sobi, after the closing of the acquisition.

Sobi’s main shareholder, Investor AB, has undertaken to vote in favor of the implementation of the rights issue at an extraordinary general meeting. Investor AB has also undertaken to subscribe for its pro rata share of the rights issue, corresponding to approximately 34.7% of the shares to be issued in the rights issue. A detailed time plan and the forms for the implementation of the rights issue will be announced at a later stage.

Transaction details

Under the terms of the merger agreement, Sobi, through a wholly owned, indirect subsidiary, will initiate a tender offer to acquire all the outstanding shares of CTI for a cash purchase price of USD 9.10 per share, representing a premium of 95% based on CTI’s 30-day volume-weighted average price of USD 4.67 preceding announcement of the transaction price of USD 9.10. The Board of Directors of CTI has unanimously approved the transaction and recommended that the shareholders of CTI tender their shares in the tender offer. Sobi has received an irrevocable undertaking from certain entities affiliated with BVF Partners L.P. (BVF) to tender all of their common shares, representing 6.7% of all outstanding common shares.

The closing of the tender offer will be subject to customary conditions, including the tender of shares which represent at least a majority of the total number of CTI’s outstanding common shares and the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act. Upon the successful completion of the tender offer, Sobi would acquire any shares of CTI’s common stock not tendered through a second-step merger effected for the same per common share consideration. The transaction is expected to close in Q3 2023.

 Advisors

Bank of America Europe DAC, Stockholm branch (“BofA Securities”) is acting as Sobi’s exclusive financial advisor in connection with the transaction and Latham & Watkins LLP is acting as legal advisor to Sobi on this transaction. Mannheimer Swartling is acting as legal advisor to Sobi in relation to the debt financing and rights issue.

About VONJO

VONJO is approved for the treatment of adults with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. This indication is approved under FDA accelerated approval based on spleen volume reduction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). CTI is conducting the Phase 3 PACIFICA study of VONJO in patients with myelofibrosis and severe thrombocytopenia as a post-marketing requirement. For more information, please visit https://www.ctibiopharma.com.

 About CTI

CTI is a commercial biopharmaceutical company focused on the development and commercialization of novel targeted therapies for blood-related cancers that offer a unique benefit to patients and their healthcare providers. CTI has one FDA-approved product, VONJO® (pacritinib), a JAK2, ACVR1, and IRAK1 inhibitor, that spares JAK1. CTI is based in Seattle, USA, and has approximately 144 employees. In 2022, CTIs revenue amounted to USD 53.9 million.  For more information, please visit www.ctibiopharma.com.

Important information

The tender offer for the outstanding shares of CTI common stock referenced in this press release has not yet commenced. This document is for informational purposes only and it is neither an offer to purchase nor a solicitation of an offer to sell shares of CTI’s common stock, nor is it a substitute for the tender offer materials that Sobi and Cleopatra Acquisition Corp., a Delaware corporation and indirect, wholly owned subsidiary of Sobi (“Purchaser”) will file with the United States Securities and Exchange Commission (the “SEC”), upon commencement of the tender offer. At the time any such tender offer is commenced, Sobi and Purchaser will file a tender offer statement on Schedule TO, containing an offer to purchase, a form of letter of transmittal and other related tender offer documents with the SEC, and CTI will file a Solicitation/Recommendation Statement on Schedule 14D-9 relating to such tender offer with the SEC. CTI’s stockholders are strongly advised to read these tender offer materials carefully and in their entirety when they become available, as they may be amended from time to time, because they will contain important information about such tender offer that CTI’s stockholders should consider prior to making any decisions with respect to such tender offer. Once filed, stockholders of CTI will be able to obtain a free copy of these documents at the website maintained by the SEC at www.sec.gov. or on CTI’s website at https://www.ctibiopharma.com.

The press release is for informational purposes only and does not constitute an offer to sell or issue, or the solicitation of an offer to buy or acquire, or subscribe for, any securities in Sobi mentioned herein (collectively, the “Securities”) or any other financial instruments in Sobi. Any offer in respect of any Securities will only be made through the prospectus that Sobi expects to publish in due course. Offers will not be made to, and application forms will not be approved from, subscribers (including shareholders), or persons acting on behalf of subscribers, in any jurisdiction where applications for such subscription would contravene applicable laws or regulations, or would require additional prospectuses, filings, or other measures in addition to those required under Swedish law. Measures in violation of the restrictions may constitute a breach of relevant securities laws.

No Securities have been or will be registered under the United States Securities Act of 1933, as amended (the “Securities Act”), or the securities laws of any state or other jurisdiction in the United States, and may not be offered, pledged, sold, delivered or otherwise transferred, directly or indirectly, except pursuant to an exemption from, or in a transaction not subject to, the registration requirements of the Securities Act and in compliance with applicable other securities laws. There will not be any public offering of any Securities in the United States.

This announcement does not constitute an investment recommendation. The price and value of securities and any income from them can go down as well as up and investors could lose their entire investment. Past performance is not a guide to future performance. Information in this announcement cannot be relied upon as a guide to future performance.

Forward-looking statements

This press release contains forward-looking statements by Sobi that involve risks and uncertainties and reflect Sobi’s judgment as of the date of this press release. These forward-looking statements generally are identified by words such as “believe,” “project,” “expect,” “anticipate,” “estimate,” “intend,” “strategy,” “future,” “opportunity,” “plan,” “may,” “should,” “will,” “would,” and similar expressions. Forward-looking statements are predictions, projections and other statements about future events that are based on current expectations and assumptions and, as a result, are subject to risks and uncertainties. These forward-looking statements include, without limitation, statements regarding: the timing of the anticipated acquisition and when and whether the anticipated acquisition ultimately will close; the potential contributions the acquisition is expected to bring to Sobi; and the expected impact on Sobi’s future financial and operating results. Actual events or results may differ from Sobi’s expectations due to risks and uncertainties inherent in Sobi’s business, including, without limitation: the risk that the conditions to the closing of the transaction are not satisfied, including the risk that Sobi may not receive sufficient number of shares tendered from CTI’s stockholders to complete the tender offer; litigation relating to the transaction; uncertainties as to the timing of the consummation of the transaction and the ability of each of Sobi, Purchaser or CTI to consummate the transaction; risks that the proposed transaction disrupts the current plans and operations of Sobi or CTI; the ability of CTI to retain key personnel; competitive responses to the proposed transaction; unexpected costs, charges or expenses resulting from the transaction; potential adverse reactions or changes to business relationships resulting from the announcement or completion of the transaction; Sobi’s ability to achieve the growth prospects and synergies expected from the transaction, as well as delays, challenges and expenses associated with integrating CTI with its existing businesses; legislative, regulatory and economic developments; and other risks described in Sobi’s prior press releases. These forward-looking statements are made only as of the date hereof and Sobi disclaims any intent or obligation to update these forward-looking statements after the date hereof, except as required by law.

Invitation to conference call

Following the announcement of the acquisition, investors, analysts and media are invited to participate in a conference call which will include a presentation and a Q&A session today, 10 May at 15:00 CEST. The event will be hosted by Sobi’s President and CEO, Guido Oelkers, and the presentation will be held in English. The presentation can be followed live or afterwards on sobi.com. The slides will be made available on sobi.com.

To participate in the conference call, please use the following dial-in details:

Sweden: +46 (0)8 5051 0031

United Kingdom: +44 (0) 207 107 06 13

United States: +1 (1) 631 570 56 13

Other international numbers available HERE

Webcast

Participants’ Link: https://media.choruscall.eu/mediaframe/webcast.html?webcastid=9tQW6rrU

 Sobi
Sobi is a specialised international biopharmaceutical company transforming the lives of people with rare and debilitating diseases. Providing reliable access to innovative medicines in the areas of haematology, immunology and specialty care, Sobi has approximately 1,600 employees across Europe, North America, the Middle East, Asia and Australia. In 2022, revenue amounted to SEK 18.8 billion. Sobi’s share (STO:SOBI) is listed on Nasdaq Stockholm. More about Sobi at sobi.com, LinkedIn and YouTube.

Important notice

BofA Securities, a subsidiary of Bank of America Corporation, is acting exclusively for Sobi in connection with the transaction and for no one else and will not be responsible to anyone other than Sobi for providing the protections afforded to its clients or for providing advice in relation to the transaction.

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MANIFEST-2 Study of Pelabresib Plus Ruxolitinib Completes Enrollment in Myelofibrosis

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Kristi Rosa

Enrollment to the phase 3 MANIFEST-2 trial, which is examining the safety and efficacy of pelabresib plus ruxolitinib vs ruxolitinib alone in patients with JAK inhibitor–naïve myelofibrosis, has completed and topline findings are anticipated by the end of 2023.

Enrollment to the phase 3 MANIFEST-2 trial (NCT04603495), which is examining the safety and efficacy of pelabresib plus ruxolitinib (Jakafi) vs ruxolitinib alone in patients with JAK inhibitor–naïve myelofibrosis, has completed and topline findings are anticipated by the end of 2023.1

The multicenter, double-blind, placebo-controlled, trial enrolled patients with primary, post–polycythemia vera, or post–essential thrombocytopenia myelofibrosis who were at least 18 years of age, had advanced disease requiring therapy, splenomegaly by computed tomography or magnetic resonance imaging, were symptomatic, and had a prognostic risk-factor score of intermediate-1 or higher per the Dynamic International Prognostic Scoring System (DIPSS).2,3

After a screening period that lasted for up to 28 days, participants were randomly assigned 1:1 to receive ruxolitinib plus oral pelabresib or matched placebo daily for 14 consecutive days, followed by 7 days off treatment.1 Pelabresib had a starting dose of 125 mg daily, with additional dose increases allowed in accordance with trial protocol. Ruxolitinib was given in twice-daily doses of 10 mg or 15 mg based on baseline platelet counts for all 21 days of each cycle; again, dose increases were allowed per protocol criteria.

Treatment was continued until progressive disease and withdrawal of treatment. Notably, those in the control arm who experience disease progression following 24 weeks of treatment are allowed to crossover to receive the pelabresib doublet.

Patients were stratified based on DIPSS risk category (intermediate-1 vs intermediate-2 vs high), platelet count (>200 x 109/L vs 100 to 200 x 109/L), and spleen volume (≥1800 cm3 vs <1800 cm3).3

The primary end point of the trial is the proportion of patients who achieve a reduction in spleen volume of at least 35% (SVR35) at week 24 vs baseline, and a key secondary end point is the proportion of patients achieving a total symptom score improvement of at least 50% (TSS50) at week 24 vs baseline.

Other secondary end points include percentage change in TSS at week 24 vs baseline, improvement in bone marrow fibrosis by at least 1 grade at week 24 compared with baseline, SVR35 and TSS50 response at week 48 vs baseline, red blood cell (RBC) transfusion rate over the first 24 weeks of treatment, and conversion from RBC transfusion dependence to independence. Other end points include category change of Patient Global Impression of Change at week 24 vs baseline, progression-free survival, overall survival, percentage of patients with transformation to acute myeloid leukemia, toxicities, and pharmacokinetics.

“Now that MANIFEST-2 has completed enrollment earlier than anticipated, we look forward to the coming insights into the therapeutic potential of pelabresib in combination with ruxolitinib for JAK inhibitor–naïve patients with myelofibrosis,” Tim Demuth, MD, PhD, chief research and development officer at MorphoSys AG, stated in a press release. “MANIFEST-2 is the latest milestone in our efforts to improve outcomes for [patients with] blood cancer and is a testament to our continued commitment to the myelofibrosis community.”

The launch of the trial was supposed by findings from the phase 2 MANIFEST trial (NCT02158858).4 Data from the latest analysis of the trial, which had a data cutoff date of July 29, 2022, showed that 68% of JAK inhibitor–naïve patients with myelofibrosis who received pelabresib plus ruxolitinib (n = 84) achieved SVR35 at 24 weeks; at week 48, this rate was 61%, and at week 60, this rate was 54%.

Moreover, of 82 evaluable patients, 56% achieved TSS50 at week 24, indicative of a reduction in symptom burden with the combination. At week 48, 44% achieved TSS50; this rate was 43% at week 60.

Findings from an exploratory analysis of the trial showed that 27% of 63 evaluable patients experienced an improvement of at least 1 grade by week 24. This improvement was maintained at week 48 for 59% of these patients.

In terms of safety, 55% of patients experienced thrombocytopenia and 43% had anemia; these effects were grade 3 or higher in 18% and 34% of patients, respectively. Other common any-grade treatment-emergent toxicities included diarrhea (43%), respiratory tract infection (41%), asthenic conditions (38%), musculoskeletal pain (32%), constipation (30%), nausea (29%), dizziness (27%), and abdominal pain (26%).

“I think the data are exciting because they continue to demonstrate over a number of patients, over a number of centers, the benefit of combining these 2 therapies,” John Mascarenhas, MD, director of the Center of Excellence for Blood Cancers and Myeloid Disorders at Mount Sinai in New York, New York, said in a past interview with OncLive®. “We’ve done analysis that showed whether you separate patients by their prognostic score, by their molecular profile, etc, the benefit seems to be across these patients’ subgroups. It really provides additional confidence in moving this therapy into the phase 3 setting.”

References

  1. MorphoSys completes enrollment of phase 3 MANIFEST-2 study of pelabresib in myelofibrosis with topline results expected by end of 2023. News release. MorphoSys AG. April 4, 2023. Accessed May 8, 2023. https://www.morphosys.com/en/news/morphosys-completes-enrollment-phase-3-manifest-2-study-pelabresib-myelofibrosis-topline
  2. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2). ClinicalTrials.gov. Updated April 6, 2023. Accessed May 8, 2023. https://clinicaltrials.gov/ct2/show/NCT04603495
  3. Harrison CN, Gupta VK, Gerds AT, et al. Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naïve myelofibrosis. Future Oncol. 2022;18(27):2987-2997. doi:10.2217/fon-2022-0484
  4. MorphoSys presents new longer-term phase 2 results on pelabresib in myelofibrosis, including potential disease-modifying activity, at ASH 2022. News release. MorphoSys AG. November 12, 2022. Accessed May 8, 2023. https://www.morphosys.com/en/news/morphosys-presents-new-longer-term-phase-2-results-pelabresib-myelofibrosis-including

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‘Knowledge Is Exponential’ in the Rare Blood Cancer Space

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Brielle Benyon

The treatment landscape for myeloproliferative neoplasms (MPNs) is ever-changing. “It’s hard to keep up, but it’s exciting,” said Dr. Steven Applebaum, a hematologist oncologist at UCLA Health in Pasadena, California.

In an interview with CURE®, Applebaum, who was recognized at 10th Annual MPN Heroes® event in December, explained that discoveries in other diseases could pave the way for a better understanding of MPNs, a rare group of blood cancers including polycythemia vera, essential thrombocythemia and myelofibrosis.

“Knowledge is somewhat exponential,” he said. “You make one discovery, which seems big, and then that kind of leads to not one more, but five more.”

Of note, Applebaum said that researchers and clinicians continue to learn more about genetic mutations and targeted therapies that will help personalize MPN therapies and make them more effective — helping patients with the disease to live longer and with a better quality of life.

Transcription

Looking at a lot of other diseases, I mean, knowledge is somewhat exponential. You make one discovery, which seems big, and then that kind of leads to not one more, but five more. The guys doing research in the lab, I expect us to learn a lot more different mutations, you know, targeted therapy. So I think we’re all really excited just looking at a lot of other diseases as a model, that there’s going to be increasing numbers of treatments that again, are going to help people live longer, but also improve their quality of life.

So the thing about being an oncologist is that (when) you’ve finished your training, you realize you don’t know anything; everything’s in evolution. So, the things I knew back then are really so cursory relative what we know now, so it’s part of what motivates us to keep going as you know that the changes in the discoveries and new treatments are going to be coming almost daily. I mean, it’s hard to keep up but it’s exciting.

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Blood cancer trial finds ruxolitinib better than current treatments

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Results from a new trial sponsored by the Cancer Research UK Clinical Trials Unit at University of Birmingham have found that ruxolitinib is better for treating patients with polycythaemia vera (PV) than the existing treatments.

PV is an incurable blood cancer and part of some conditions that affect the blood called myeloproliferative neoplasms (MPNs).

During the Phase II MAJIC-PV randomised trial, researchers studied ruxolitinib in patients who do not respond well to first line treatment.

Altogether, 180 PV patients were included in the trial, which saw the participation of various hospitals under the co-ordination of the Cancer Research UK Clinical Trials Unit.

The researchers compared the ruxolitinib drug and existing therapies.

Ruxolitinib has been designed to target JAK2 and already approved for use in PV. However, the drug is not available in the UK.

Data from the trial showed that ruxolitinib led to better disease control with normal blood counts and a minimised spleen size.

It was also found that both controlling the blood count and minimising mutated JAK2 by 50% led to fewer disease related events.

Furthermore, patients with reduced JAK2 mutation survived longer and had lower disease progression risk.

University of Birmingham Cancer Research UK Clinical Trials Unit director Pamela Kearns said: “Working on new treatments for incurable cancers is just the kind of thing that the Birmingham Cancer Research UK Clinical Trials Unit is about.

“I am really pleased that this important clinical trial has found that ruxolitinib has long-term clinical benefit for the ongoing treatment of patients with PV, and that further trials will be able to identify whether the drug can be used as an effective first line treatment.”

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Learn About Rare Cancer Because ‘Uncertainty Creates Anxiety,’ Expert Says

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Brielle Benyon

After a patient is diagnosed with a rare disease such as a myeloproliferative neoplasm, learning about their condition and seeking expert clinicians can help put their mind at ease.

When it comes to rare diseases such as myeloproliferative neoplasms (MPNs), gaining an understanding of the disease and seeking a specialist for treatment can help patients feel more at ease with their diagnosis, explained Dr. Raajit Rampal, an associate attending physician at Memorial Sloan Kettering Cancer Center in New York City.

MPNs are a group of rare blood cancers that many people have not heard of at the time of their diagnosis, according to Rampal, who was recognized at CURE®’s 10th Annual MPN Heroes® program in December. However, learning more about the disease and its treatment can help ease patients’ minds, as “uncertainty creates anxiety,” according to Rampal.

When it comes to developing new treatments and sparking new scientific discoveries in the MPN space, specialized doctors and researchers are essential, Rampal said.

“Sometimes (a patient will say), ‘You know, this disease is a one-in-a-million diagnosis.’ And I’ll say, ‘Yes, but you are the 10th or 11th person who I’m going to see today with it.’ That helps to further this type of research,” Rampal said in an interview with CURE.

Transcription

Well, (there are) a couple of things, a couple of challenges.

No. 1 is education. You know, when patients get diagnosed … this is a rare disease, as I often say to the patients, “This is not something your neighbor has, you’re not going to have a chat with them about that in all likelihood.” And oftentimes, what is lacking when we meet somebody who’s newly diagnosed is them having an education about this disease, they, in most cases, have never heard of this. And the doctors who see them or their primary care doctors, they’ve read about it, they don’t have seen many of these cases.

So part of our job is to educate them thoroughly. This is what you have, this is what it’s about, these are the things we can do about it. That’s partly just for the sake of education of patients, but partly because, to some extent, it relieves anxiety, right? Uncertainty creates anxiety. I’m a firm believer in that. And so, giving any type of education that will alleviate that or give somebody a better understanding will help with anxiety.

Now, on the other side of things, it’s a rare disease, and how do you bring ideas forward? You’re dealing with small numbers of patients, right? I think if you have good ideas, they are translatable. But it doesn’t stop there. Because you’re right, you can have a fantastic scientific idea. How are you going to get patients on to the study? Part of it is building a cohort and having a specialization. Doctors and researchers who are specialized in these diseases, this is most of what they see. Sometimes … (a patient will) say, “Well, you know, this disease is a one in a million diagnosis.” And I’ll say “Yes, but you are the 10th or 11th person who I’m going to see today with it.”

That helps to further this type of research. It’s not everyone (who is) going to qualify for every trial. But if you don’t have the numbers, you can’t do the research. And so making sure that, you know, us, we, as specialists, have a focus in these diseases makes a difference and that allows us to bring concepts forward for clinical trials because then we have the patients who are going to be eligible.

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PharmaEssentia Initiates Phase 3b Trial of Ropeginterferon alfa-2b-njft Investigatng New Dosing Regimen for Patients With Polycythemia Vera (PV)

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Published: May 03, 2023

Single-arm trial will evaluate an accelerated dosing schedule

BURLINGTON, Mass.–(BUSINESS WIRE)– PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, today announced that the first patients are now being dosed in ECLIPSE PV, a Phase 3b clinical study evaluating an accelerated dosing schedule for ropeginterferon alfa-2b-njft using a prefilled syringe for the treatment of adults with polycythemia vera (PV).

Ropeginterferon alfa-2b-njft (marketed as BESREMi®) was approved by the U.S. Food and Drug Administration in November 2021 as a treatment for adults with PV.1 PV is a rare, chronic and life-threatening blood cancer caused by a mutation in hematopoietic stem cells in the bone marrow, resulting in the overproduction of red blood cells, white blood cells and platelets. Individuals with PV are at risk for serious health problems, including blood clots, stroke and heart attack.2,3 Without proper management, this debilitating cancer can progress into myelofibrosis and other malignancies, including acute myeloid leukemia.4

“This therapy represents an important addition to the treatment arsenal for PV in the U.S., and clinical data supports its use across a broad range of patients regardless of their treatment history,” said John Mascarenhas, M.D., professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai in New York. “This new study is addressing an important therapeutic and clinical question regarding whether treatment utilizing accelerated dosing leads to a more rapid hematologic and molecular response, indicating potential disease modifying activity and long-term disease control.”

The study will evaluate an accelerated dosing schedule for ropeginterferon alfa-2b-njft compared to the current labeled dosing. The primary endpoint is the proportion of patients achieving a CHR, defined as hematocrit <45% for at least 3 months since last phlebotomy, platelets ≤ 400 x 109/L, leukocytes ≤10 x 109/L, at 24 weeks of treatment. Approximately 100 adults with PV in the U.S. and Canada will be randomized to receive either the accelerated dosing (i.e., starting dose of 250 mcg, then 350 mcg at week 2, with a target optimal dose of 500 mcg at week 4, and then dosing will remain fixed at the highest tolerated dose for the remainder of the treatment period) or patients will receive the current labeled dosing (50 or 100 mcg starting dose with 50 mcg titration every 2 weeks). There is a 48-week study period followed by a 28-day safety follow-up. Those who respond to treatment will be eligible to participate in a long-term extension phase of the study.

“Our goal with this study is to deliver evidence on the potentially enhanced benefits of treating patients with BESREMi through this accelerated dosing schedule and to bring additional confidence to clinicians and patients in the utility of the treatment to manage this chronic cancer,” said Raymond Urbanski, M.D., Ph.D., U.S. Head of Clinical Development and Medical Affairs. “We believe this study will deliver further insight into the potential of BESREMi to meet the needs of PV patients.”

More information on the study including eligibility criteria can be found by visiting www.eclipsepv.com or www.clinicaltrials.gov and searching for the trial identifier NCT05481151. Topline data from the trial are expected by 2024.

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Determinants of Covid19 disease and of survival after Covid19 in MPN patients treated with ruxolitinib

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Authors: Francesca Palandri, Elena M. Elli, Giuseppe Auteri, Massimiliano Bonifacio, Giulia Benevolo, et al.

Blood Cancer Journal  volume 13, Article number: 65 (2023) 

Introduction

The coronavirus disease 2019 (Covid19) pandemic caused by the spreading of the coronavirus SARS-CoV-2 has led to substantial mortality in patients with hematological diseases [1]. During the first wave of pandemic, patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) were reported at higher risk of acquiring SARS-CoV-2 and of having a poor outcome after infection, with a mortality rate of about 30%, increasing to 48% in MF patients [2].

Ruxolitinib is a JAK1/2 inhibitor that is widely used both in MF and PV [3]. It may affect immunological response by decreasing the production of pro-inflammatory cytokines and by altering the function of several immune cells, including macrophages and B/T-lymphocytes [4]. Its use and discontinuation have been identified as risk factors for SARS-CoV-2 infection and Covid19-related death [5] Additionally, ruxolitinib-treated patients show lower serological response to anti-SARS-CoV-2 vaccination [6, 7].

Previous studies on Covid19 in MPN patients have included patients regardless of treatment type, with few patients treated with ruxolitinib at the time of the pandemic. Here, we explored features associated with Covid19 disease and survival after Covid19 in a large cohort of ruxolitinib-treated PV and MF patients.

This analysis could provide useful information for identifying those ruxolitinib-treated patients that are at higher risk of SARS-CoV-2 infection and assessing prognostic factors for survival in a homogeneously treated cohort. The final objective is to provide decision-support tools for viral therapy and/or hospitalization.

Methods

Study setting

The observational retrospective cohort studies “RUX-MF and “PV-ARC” were promoted by the IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy. The PV-ARC study involves 934 PV patients, while the “RUX-MF” study collects 886 MF patients in chronic phase who received ruxolitinib outside clinical trials. Details of protocol design, list of participating Centres and operational procedures have already been reported [8, 9]. For the purposes of this analysis, data concerning MF/PV and characteristics related to first Covid19 infections during ruxolitinib therapy were recorded. The data cut-off date was January 2022.

Waves of the Covid19 pandemic were divided into three periods, according to the type of predominant circulating variants in Europe: first (wild-type variant, February–June 2020); second (alpha/beta/gamma variants, July 2020–June 2021) and third (delta variant, July 2021–January 2022).

Covid19 severity was categorized according to the NIH Guidelines [10].

Statistical analysis

Statistical analysis was carried out at the biostatistics laboratory of the MPN Unit at the Institute of Hematology “L. and A. Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria, Bologna.

Continuous variables have been summarized by their median and range, and categorical variables by count and relative frequency (%) of each category. Comparisons of quantitative variables between groups were carried out by Wilcoxon–Mann–Whitney rank-sum test; association between categorical variables was tested by the χ2 test. By Receiver Operating Characteristic (ROC) curve, the optimal cut-off for neutrophil to lymphocyte ratio (NLR) was found at 5.5 (AUC: 0.66) for hospitalization and at 6.8 (AUC: 0.71) for death.

Using Cox proportional hazard model, association with COVID-19 hospitalization and Covid19-related survival was evaluated for the following variables: age ≥ 70 years, sex, presence of at least one comorbidity, MPN type, NLR ≥ 5.5 (hospitalization), NLR ≥ 6.8, vaccination, wave, previous thrombosis, and platelet count/hemoglobin at infection. The same factors were evaluated using a logistic regression model for PV and MF patients (adding DIPSS and spleen response at Covid19 infection in the latter). The association between thromboses that occurred during the pandemic and Covid19 infection, MPN type and NLR was also investigated.

For all analyses, the starting time was February 2020, corresponding to the pandemic start.

Overall survival was calculated by Kaplan–Meier analysis, starting from the date of Covid19 infection and considering only Covid19-related deaths.

Pearson’s test was used to measure the collinearity of covariates.

Akaike’s Information Criterion (AIC) and Schwarz’s Bayesian Information Criterion (BIC) were used to choose the model that best fits the data.

For all tested hypotheses, two-tailed p-values < 0.05 were considered significant. Statistical analyses were performed using STATA Software, 15.1 (StataCorp LP, College Station TX, USA).

Results

Study cohort

Overall, 886 MF and 172 PV patients treated with ruxolitinib outside clinical trials have been registered in the RUX-MF and in the PV-ARC databases, respectively. At pandemic start, 560 patients (413 MF and 147 PV) were receiving ruxolitinib and were included in this analysis. Ruxolitinib dose was evaluable in 135 and 409 PV and MF patients, respectively. Median dose at pandemic start was 5–10 mg BID in all PV and 189 (46.2%) MF patients, 15 mg BID and 20 mg BID in 114 (27.9%) and 106 (25.9%) MF patients.

From February 2020 to January 2022, 83 (14.2%) patients acquired the Covid19 disease (PV n = 16, 10.8%; MF n = 67, 16.2%; p = 0.12), with an overall incidence rate of 10.5 per 100 patient-years. Overall, 15, 41, and 27 infections were observed during the first, second, and third pandemic wave, with incidence rates of 6.5, 7.8, and 7.3 per 100 patient-years in the three waves, respectively (p = 0.75).

Infection was asymptomatic/mild in 21 patients (25.3%), moderate in 17 (20.5%), severe in 18 (21.7%), critical in 6 (7.2%) and fatal in 21 (25.3%) patients (Supplementary Fig. 1).

Characteristics associated with Covid19 infection and hospitalization

Differences between non-Covid19 and Covid19 ruxolitinib-treated patients are summarized in Table 1. Overall, 371/467 evaluable patients (79.4%) received ≥ 1 dose of anti-SARS-CoV2 vaccine. All but one patient received an mRNA vaccine (BioNTech/Pfizer n = 327 [88.1%], Moderna n = 43 [11.6%]).

Compared to Covid19 patients, those who did not acquire the infection had more frequently received ≥ 1 dose of anti-SARS-Cov2 vaccine (p < 0.001). The protective effect of vaccination was confirmed also in the MF and in the PV population separately (39.5% and 56.3% of vaccinated patients vs. 82.5% and 86.8% of unvaccinated patients with Covid19 infection in MF and PV, p < 0.001 and p = 0.003, respectively).

All the 45 (54.2%) patients with severe, critical, fatal infections were hospitalized. The frequency of hospitalization in the first and second waves (66 and 68%) was higher compared to the third one (26%), (p = 0.002). Compared to outpatients, those admitted to hospital were more likely to be ≥ 70 years (p = 0.05), had a significantly lower median platelet counts (150 vs. 226 × 109/L, p = 0.02) and higher neutrophil counts (7.2 vs. 4.2 × 109/L, p = 0.04), with a significant increase of neutrophil to lymphocyte ratio (NLR) (5.6 vs. 3.5, p = 0.04). At Covid19 diagnosis, ruxolitinib was reduced in 11 (13.3%) patients. Ruxolitinib discontinuation occurred in 9 patients (10.8%) in the 1st, 2nd and 3 wave in 4, 4 and 1 patients, respectively, and comparably in MF and PV. The cause of discontinuation was severe Covid19 infection in all cases, together with severe thrombocytopenia (platelet < 50 × 109/l) in 2 cases.

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Incyte Reports 2023 First Quarter Financial Results and Provides Updates on Key Clinical Programs

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Published May 2, 2023

– Total net product revenues of $693 million in Q1’23 (+14% Y/Y)

– Jakafi® (ruxolitinib) net product revenues of $580 million (+7% Y/Y) in Q1’23; raising the bottom end of full year guidance to new range of $2.55 – $2.63 billion for FY 2023

– Opzelura® (ruxolitinib) cream approved as the first and only treatment for repigmentation of nonsegmental vitiligo in Europe; continued strong U.S. launch in atopic dermatitis and vitiligo

– Multiple positive data readouts from dermatology portfolio at AAD and EHSF 2023

WILMINGTON, Del.–(BUSINESS WIRE)– Incyte Corporation (Nasdaq:INCY) today reports 2023 first quarter financial results, and provides a status update on the Company’s clinical development portfolio.

“Our first quarter results demonstrate continued year-over-year double-digit revenue growth driven by Jakafi, which grew across all indications, and Opzelura, which is on track to become one of the most successful dermatology launches in recent years. In addition, we further expanded our commercial portfolio with several regulatory approvals including Opzelura for vitiligo in Europe.” said Hervé Hoppenot, Chief Executive Officer, Incyte. “Furthermore, in Q1 we made a decision to focus our development efforts on eight programs that have high potential value for us and discontinued six other programs. This allows us to optimize our allocation of resources on programs that can have a high impact for patients and for Incyte.”

Key Product Sales Performance

Jakafi:

Net product revenues of $580 million:

  • Net product revenues grew 7% compared with the first quarter of 2022, driven by strong underlying patient demand growth (+7% Y/Y) including an 8% growth in new patients. Total patients grew across myelofibrosis (MF), polycythemia vera (PV) and graft-versus-host disease (GVHD).
  • Net product revenues were unfavorably impacted by:
    • Higher gross-to-net deductions, compared to fourth quarter of 2022, as a result of the Medicare coverage gap and higher commercial patient deductibles at the beginning of the plan year, as well as an increase in 340B orders.
    • Lower than normal levels of channel inventory at the end of Q1, representing an $11 million impact.

Opzelura:

Net product revenues of $57 million:

  • Net product revenues grew 343% compared with the first quarter of 2022, driven by growth in patient demand and expansion in payer coverage as the launch in atopic dermatitis (AD) and vitiligo continues.
  • Compared to the fourth quarter of 2022, net product revenues were unfavorably impacted by:
    • Increase in co-pay assistance due to higher commercial patient deductibles at the beginning of the plan year, consistent with first quarter dynamics and higher Medicaid utilization volume.
    • Acceleration of refills in December 2022 driven by patient demand in advance of annual deductible reset or health plan changes that negatively impacted refills during the months of January and February this year.

Pipeline Updates

MPNs and GVHD – key highlights

LIMBER (Leadership In MPNs and GVHD BEyond Ruxolitinib): Our LIMBER development program encompasses multiple monotherapy and combination strategies, with the goal of improving upon the standard of care in MF, PV, GVHD and now, essential thrombocythemia (ET).

  • Combination trials of ruxolitinib BID with zilurgisertib (ALK2) and INCB57643 (BET) are ongoing and progressing well.
  • In early development, INCA33989 (mCALR) is on track for initiating first-in-human study in MF and ET in 2023. Additionally, a Phase 1 study evaluating ruxolitinib BID in combination with Cellenkos’ CK0804 in MF is continuing to recruit patients.
  • AGAVE-201, a global pivotal Phase 2 trial of axatilimab in patients with cGVHD is ongoing and results are on track for mid-2023. A Phase 1/2 combination trial of axatilimab in combination with ruxolitinib is being planned.
  • The Phase 3 LIMBER-304 trial, evaluating parsaclisib in combination with ruxolitinib BID in suboptimal responders in MF and the Phase 3 LIMBER-313 trial, evaluating parsaclisib in combination with ruxolitinib BID in first-line MF, were discontinued following results of interim analyses that indicated that the studies were unlikely to meet their primary endpoints in the intent-to-treat patient population. The studies were not stopped due to safety.
  • The U.S. Food and Drug Administration (FDA) issued a complete response letter for ruxolitinib extended-release (XR) tablets for once-daily (QD) use in the treatment of certain types of MF, PV and GVHD. Incyte will work with the FDA to determine appropriate next steps.

Indication and status

Ruxolitinib XR (QD)

(JAK1/JAK2)

Myelofibrosis, polycythemia vera and GVHD

Ruxolitinib + zilurgisertib

(JAK1/JAK2 + ALK2)

Myelofibrosis: Phase 2

Ruxolitinib + INCB57643

(JAK1/JAK2 + BET)

Myelofibrosis: Phase 2

Ruxolitinib + CK08041

(JAK1/JAK2 + CB-Tregs)

Myelofibrosis: Phase 1 (LIMBER-TREG108)

Axatilimab (anti-CSF-1R)2

Chronic GVHD: Pivotal Phase 2 (third-line plus therapy) (AGAVE-201)

Ruxolitinib + axatilimab2

(JAK1/JAK2 + anti-CSF-1R)

Chronic GVHD: Phase 1/2 in preparation

INCA33989

(mCALR)

Myelofibrosis, essential thrombocythemia: Entering clinic in 2023

1 Development collaboration with Cellenkos, Inc.

2 Clinical development of axatilimab in GVHD conducted in collaboration with Syndax Pharmaceuticals.

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FDA Grants Priority Review to Luspatercept for First-line Treatment of Anemia in Lower-risk MDS

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May 1, 2023

Chris Ryan

The FDA has granted a priority review to the supplemental biologics license application seeking to expand the current indication of luspatercep to include treatment of anemia in patients with very low- to intermediate-risk myelodysplastic syndrome who have not previously received erythropoiesis-stimulating agents and who may require red blood cell transfusions.

The FDA has granted a priority review to the supplemental biologics license application (sBLA) seeking to expand the current indication of luspatercept-aamt (Reblozyl) to include treatment of anemia in patients with very low- to intermediate-risk myelodysplastic syndrome (MDS) who have not previously received erythropoiesis-stimulating agents (ESAs) and who may require red blood cell (RBC) transfusions.1

Additionally, the European Medicines Agency (EMA) has validated the type II variation application for luspatercept in the same indication.

The applications were supported by data from the phase 3 COMMANDS trial (NCT03682536), which showed that luspatercept demonstrated a statistically significant and clinically meaningful improvement vs epoetin alfa in RBC transfusion independence of 12 weeks or more with a concurrent hemoglobin increase of at least 1.5 g/dL in patients with very low-, low- or intermediate-risk MDS requiring RBC transfusions.

Detailed findings from COMMANDS will be presented at an upcoming medical meeting.

The FDA has assigned a target action date of August 28, 2023, under the Prescription Drug User Fee Act. The EMA will also begin its centralized review process after validating the application.

“Initial treatment options for [patients with] very low- to intermediate-risk MDS, including ESAs, can alleviate anemia in some patients but others will either not respond or become resistant to therapy, and additional therapy options have remained urgently needed,” Noah Berkowitz, MD, PhD, senior vice president, Hematology Development, Bristol Myers Squibb, stated in a news release. “Results from the COMMANDS study showed [luspatercept] significantly improved transfusion independence and elevated hemoglobin compared [with the] ESA therapy, epoetin alfa. [Luspatercept] is an important option available for the treatment of anemia in patients with transfusion-dependent, lower-risk MDS who have experienced ESA failure, and we look forward to working with the FDA and EMA to expand its potential use as a first-line therapy in eligible patients.”

In November 2019, the FDA approved luspatercept for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions.2 Additionally, in April 2020, the FDA approved the agent for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.3

The open-label, randomized COMMANDS study enrolled patients with a documented diagnosis of MDS per World Health Organization 2016 classification meeting revised international prognostic scoring system (IPSS-R) classification of very-low, low-, or intermediate-risk disease.4 Other key inclusion criteria included bone marrow blasts of less than 5%, an endogenous serum erythropoietin level of less than 500 u/L, and an ECOG performance status of 0 to 2. Patients must have required RBC transfusions, which was defined by an average transfusion requirement of 2 to 6 units every 8 weeks of packed RBCs confirmed for a minimum of 8 weeks immediately preceding randomization.

Patients were excluded if they had clinically significant anemia due to iron, vitamin B12, or folate deficiencies; autoimmune or hereditary hemolytic anemia; hypothyroidism; or any type of known clinically significant bleeding or sequestration or drug-induced anemia. Other key exclusion criteria included a known history of acute myeloid leukemia or uncontrolled hypertension.

The study enrolled 363 patients who were randomly assigned to receive luspatercept or epoetin alfa.

RBC transfusion independence for 12 weeks with a mean hemoglobin increase at least 1.5 g/dL served as the trial’s primary end point. Key secondary end points included RBC transfusion independence for 24 weeks, and RBC transfusion independence for at least 12 weeks and erythroid response of at least 8 weeks during weeks 1 to 24.

Regarding safety, findings from COMMANDS were reported to be consistent with the toxicity profile of luspatercept observed in previous clinical trials and in the post-marketing setting.

References

  1. US FDA accepts for priority review supplemental biologics license application and EMA validates application for Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS). News release. Bristol Myers Squibb. May 1, 2023. Accessed May 1, 2023. https://news.bms.com/news/details/2023/
  2. FDA approves luspatercept-aamt for anemia in patients with beta thalassemia. FDA. November 8, 2019. Accessed May 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-patients-beta-thalassemia
  3. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. April 3, 2020. Accessed May 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds
  4. A study to compare the efficacy and safety of luspatercept (ACE-536) versus epoetin alfa for the treatment of anemia due to IPSS-R very low, low, or intermediate risk myelodysplastic syndromes (MDS) participants who require red blood cell transfusions and are ESA naïve (COMMANDS). ClinicalTrials.gov. Updated April 18, 2023. Accessed May 1, 2023. https://clinicaltrials.gov/ct2/show/NCT03682536

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