By Patrick Daly – Last Updated: January 17, 2024

Treatment with fedratinib, a Janus kinase inhibitor (JAKi), induced superior spleen volume reduction (SVR) and symptom response rates compared with best available therapy in patients with myelofibrosis (MF) who previously received ruxolitinib, according to data from the open-label phase III FREEDOM2 study, presented at the 65th American Society of Hematology Annual Meeting & Exposition.

“Most patients on best available therapy received ruxolitinib, highlighting a need for an alternative JAKi,” stated lead author of the study, Claire Harrison, MD, FRCP, from Guy’s and St. Thomas’ NHS Foundation Trust in London, England.

The FREEDOM2 trial enrolled patients aged 18 years or older with primary, post-polycythemia vera, or post-essential thrombocythemia MF with splenomegaly who were intolerant or refractory to, or relapsed after ruxolitinib. The primary endpoint was SVR ≥35% (SVR35) at the end of the sixth 28-day cycle.

Fedratinib for Myelofibrosis Treatment Superior to Ruxolitinib

In total, 201 patients were randomized to fedratinib (n=134) or best available therapy (n=67). The cohort had a median age of 70 (interquartile range, 64-74), 52.2% were male, 54.7% had primary MF, and 76.1% had a Dynamic International Prognostic Scoring System risk score of intermediate-2.

Overall, 70.1% of patients in the best available therapy arm received ruxolitinib, 10.4% received hydroxyurea, and 7.5% received ruxolitinib plus hydroxyurea. Additionally, 46 (68.7%) patients in the best available therapy arm crossed over to fedratinib after either disease progression or the sixth cycle response assessment.

With a median follow-up of 15 months at the data cutoff, researchers reported the fedratinib group had a significantly higher SVR35 rate of 35.8% at the end of cycle six compared with best available therapy at 6.0% (P<.0001). Fedratinib also yielded superior SVR ≥25% at the cycle six assessment and superior SVR35 at any point during treatment. The rate of symptom response at the end of cycle six was 34.1% with fedratinib versus 16.9% with best available therapy (P=.0033).

In short, “fedratinib demonstrated superior SVR and symptom response rates compared with [best available therapy]” in patients with MF and prior ruxolitinib treatment, concluded Dr. Harrison and colleagues.

Reference

Harrison CN, Mesa RA, Talpaz M, et al. Efficacy and safety of fedratinib in patients with myelofibrosis previously treated with ruxolitinib: results from the phase 3 randomized FREEDOM2 study. Abstract #3204. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

Read more

January 16, 2024

Kyle Doherty

The potential first-in-class, oral, lysyl oxidase-like 2 (LOXL2) inhibitor GB2064 displayed efficacy with a generally acceptable tolerability profile in the treatment of patients with myelofibrosis, according to topline findings from the phase 2a MYLOX-1 trial (NCT04679870).¹

Among evaluable patients with myelofibrosis who were treated with GB2064 monotherapy for a minimum of 6 months (n = 10), 6 experienced a reduction in collagen fibrosis of the bone marrow of at least 1 grade. All patients who achieved this reduction in bone marrow fibrosis displayed stable hematological parameters, including hemoglobin, white blood cell count, and platelet count. This indicates the agent’s potential impact on disease progression and disease-modifying capabilities. At 6 months of treatment, 1 patient experienced a reduction in spleen volume of at least 35%, 2 reduced their Total Symptom Score (TSS) by over 50%, and another patient experienced an anemia response.

“It is exciting and encouraging to see that the data from the MYLOX-1 trial affirms the safety and effectiveness of LOXL-2 inhibition in the challenging landscape of myelofibrosis,” Claire Harrison, MD, FRCP, FRCPath, chair of the Safety Review Committee for the MYLOX-1 trial, a professor of myeloproliferative neoplasms, and the clinical director of Guy’s and St Thomas’ NHS Foundation Trust in London, England, said in a press release. “I am especially intrigued by the unique observed improvements in bone marrow collagen fibrosis, showcasing the targeted impact on a crucial aspect of this relentless disease.”

MYLOX-1 was an open-label, single-arm study that enrolled adult patients with primary or secondary myelofibrosis who were ineligible, refractory, or intolerant to treatment with a JAK inhibitor. Patients had intermediate-2 or high-risk disease by the Dynamic International Prognostic Scoring System-plus, or low-risk disease with symptomatic splenomegaly. Eligible patients were also required to have an ECOG performance status of 2 or less, not be receiving JAK inhibitor therapy, display required baseline laboratory counts, and have a documented history of transfusion records in the preceding 12 weeks to day 1 of study treatment.²

All patients on the study treatment received 1000 mg of oral GB2064 twice daily for 9 months. Patients underwent bone marrow biopsies at the beginning of the trial and again at 3, 6 and 9 months. The primary end point was the safety and tolerability of GB2064; key secondary end points included evaluating hematological parameters and the direct anti-fibrotic activity of GB2064 by blocking LOXL2 in an indication that allows for repeated tissue biopsies.^1,2

The study dosed a total of 18 patients with myelofibrosis. Most patients (61%) had previously received the JAK inhibitor ruxolitinib (Jakafi); 8 of these patients were refractory to JAK inhibitor therapy and 3 were intolerant.¹

Additional assessment of bone marrow biopsies in MYLOX-1 revealed that GB2064 penetrated the bone marrow and could exert its anti-fibrotic effect directly in the disease compartment. Additionally, the agent displayed systemic target engagement by binding to LOXL2 in plasma. Four patients who experienced clinical benefit with GB2046, as determined by the treating physician, have entered the extension phase of MYLOX-1. Notably, 1 of these patients has received treatment for over 30 months.

GB2064 displayed a tolerable safety profile, with 8 of the 18 dosed patients completing treatment in the core phase of MYLOX-1. The remaining 10 patients discontinued treatment due to adverse effects or progressive disease. The most common any-grade treatment-related adverse effects were manageable with standard therapy and gastrointestinal in nature. The lone treatment-related serious adverse effect was a case of fall, which was determined to be possibly related to GB2064 treatment.

“We believe that the topline results from the MYLOX-1 trial reaffirm the anti-fibrotic activity observed in the intermediate assessment of the trial announced in September 2022,” Hans T. Schambye, MD, PhD, the president and chief executive officer of Galecto, said in the press release. “We are very excited with the proof of principle achieved with GB2064, showcasing its strong anti-fibrotic impact in a very challenging patient population. The encouraging topline results from the MYLOX-1 trial reinforce our confidence in GB2064’s potential as a transformative therapy for various cancers and a range of fibrotic diseases, but we will not make any decisions relating to funding additional trials with GB2064 until we complete our previously announced strategic alternative process.”

In September 2023, Galecto announced that it completed a review of its business and would conduct a comprehensive exploration of strategic alternatives focused on maximizing shareholder value. Galecto did not set a timetable for completion of the evaluation and said it did not intend to disclose further developments or guidance on the status of its programs unless it determined that further disclosure is appropriate or necessary.³

References

1. Topline results from MYLOX-1 trial demonstrate reduction in fibrosis of the bone marrow in patients with myelofibrosis. News release. Galecto, Inc. December 21, 2023. Accessed January 16, 2024. https://www.biospace.com/article/releases/topline-results-from-mylox-1-trial-demonstrate-reduction-in-fibrosis-of-the-bone-marrow-in-patients-with-myelofibrosis/
2. A study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of oral GB2064 in participants with myelofibrosis. ClinicalTrials.gov. Updated May 6, 2023. Accessed January 16, 2024. https://clinicaltrials.gov/study/NCT04679870
3. Galecto announces plans to explore strategic alternatives. News release. Galecto, Inc. September 26, 2023. Accessed January 16, 2024. https://ir.galecto.com/news-releases/news-release-details/galecto-announces-plans-explore-strategic-alternatives

Read more

January 12, 2024

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

INCA-033989 overview

INCA-033989 is under development for the treatment of myelofibrosis (MF), essential thrombocythemia (ET). The drug candidate is a monoclonal antibody which acts by targeting calreticulin (CALR).

It was also under development for post-essential thrombocythemia myelofibrosis (Post-ET MF) and primary myelofibrosis (PMF).

Incyte overview

Incyte is a biopharmaceutical company, which discovers, develops and commercializes proprietary cancer therapeutics. The company’s lead product, Jakafi (ruxolitinib) is marketed in the US for the treatment of patients with high-risk myelofibrosis; and polycythemia vera who are intolerant to hydroxyurea. The company distributes Jakafi through a network of specialty pharmacy providers and wholesalers. In collaboration with Incyte, Novartis International Pharmaceutical Ltd (Novartis) develops and commercializes ruxolitinib outside the US for hematologic and cancer indications under the name Jakavi. The company’s pipeline portfolio encompasses drugs for the treatment of lung cancer, graft versus host disease, b-cell malignancies, solid tumors, non-small cell lung cancer, glioblastoma, liver cancer, and advanced malignancies. Incyte is headquartered in Wilmington, Delaware, the US.

Read more

Pelabresib and ruxolitinib combination significantly reduced spleen size, with an SVR35 response rate nearly double that of placebo plus ruxolitinib

Showed a strong positive trend in reducing symptom burden and a twofold increase in patients achieving both SVR35 and TSS50 versus placebo plus ruxolitinib

Improved measures of anemia, including higher hemoglobin response rates, fewer patients requiring transfusions and fewer anemia adverse events versus placebo plus ruxolitinib

Improved bone marrow fibrosis by at least one grade in more patients versus placebo plus ruxolitinib

Demonstrated safety results consistent with prior clinical trials, with fewer grade ≥3 adverse events compared with placebo plus ruxolitinib

MorphoSys will host an investor event to review findings on Monday, December 11

MorphoSys AG (FSE: MOR; NASDAQ: MOR) today announced comprehensive results from the Phase 3 MANIFEST-2 study investigating pelabresib, an investigational BET inhibitor, in combination with the JAK inhibitor ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis. These findings were presented in an oral presentation at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.

Myelofibrosis is characterized by four hallmarks: an enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms. In MANIFEST-2, all hallmarks were improved with the pelabresib and ruxolitinib combination versus placebo plus ruxolitinib, which is the standard of care in myelofibrosis. Ruxolitinib dosing was similar in both arms of the study and was determined based on its approved myelofibrosis indication.

“The MANIFEST-2 results demonstrated clear benefits across the four hallmarks of myelofibrosis, including a significant reduction in spleen size – a key finding given the known association between spleen volume reduction and patient survival,” said Raajit K. Rampal, M.D., Ph.D., Director, Center for Hematologic Malignancies, and Director, Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center. “The comprehensive results presented at ASH also show that the pelabresib combination improves anemia, disease-associated symptoms and bone marrow fibrosis, and that it is well-tolerated. These findings point to pelabresib and ruxolitinib as a potential paradigm-shifting first-line treatment of this debilitating disease.”

MANIFEST-2 Comprehensive Findings

MANIFEST-2 is a global, multicenter, double-blind, Phase 3 study of 430 JAK inhibitor-naïve adults with myelofibrosis, randomized 1:1 to receive the pelabresib and ruxolitinib combination or placebo plus ruxolitinib. MANIFEST-2 is one of the largest studies in this disease to date.

Strong Reductions in Spleen Size and Symptoms

In the MANIFEST-2 study, pelabresib and ruxolitinib demonstrated a near doubling in the proportion of patients achieving a ≥35% reduction in spleen volume (SVR35) at 24 weeks, the primary endpoint, versus placebo plus ruxolitinib (p<0.001).

For the first key secondary endpoint assessing symptom reduction, absolute change in total symptom score (TSS) at 24 weeks, there was a strong numerical improvement for patients receiving pelabresib and ruxolitinib versus placebo plus ruxolitinib. The response rate for the second key secondary endpoint, proportion of patients achieving ≥50% reduction in symptom score (TSS50) at 24 weeks, was also numerically greater for patients receiving pelabresib and ruxolitinib. Significant improvements in both key secondary endpoints were observed with the pelabresib combination for patients classified as intermediate-risk (Dynamic International Prognostic Scoring System [DIPSS] Int-1 and Int-2), who account for over 90% of the MANIFEST-2 population.

The proportion of patients achieving both SVR35 and TSS50 at 24 weeks was doubled with pelabresib and ruxolitinib versus placebo plus ruxolitinib (40.2% vs. 18.5%, respectively).

Details are included in the table below.

*Difference calculated using Cochran–Mantel–Haenszel (CMH) common risk difference

**Least square mean estimate

Improvement in Anemia

Patients receiving pelabresib in combination with ruxolitinib reported fewer anemia adverse events (43.9%, grade ≥3: 23.1%) compared with placebo plus ruxolitinib (55.6%, grade ≥3: 36.4%). Additionally, by week 24, fewer patients in the pelabresib and ruxolitinib arm required red blood cell transfusions compared with the placebo arm (30.8% vs. 41.2%, respectively).

A greater proportion of patients achieved a hemoglobin response — defined as a ≥1.5 g/dL mean increase in hemoglobin levels over baseline in the absence of transfusions during the previous 12 weeks — with pelabresib and ruxolitinib versus placebo plus ruxolitinib (9.3% vs. 5.6%, respectively). Average hemoglobin levels were greater in patients receiving pelabresib and ruxolitinib than in those receiving placebo plus ruxolitinib, starting at week 9 and continuing to week 24. Anemia benefits were observed across all studied patient risk groups.

“Anemia can reduce patients’ quality of life by causing severe fatigue and necessitating blood transfusions,” said Professor Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom. “In MANIFEST-2, patients receiving the combination therapy showed clear benefits on anemia, including greater hemoglobin levels, fewer red blood cell transfusions and fewer anemia and fatigue adverse events. Given its strong efficacy, safety profile and signs of disease modification, the pelabresib and ruxolitinib combination has the potential to become the new standard of care in the first-line treatment of myelofibrosis.”

Improvement in Bone Marrow Fibrosis

Bone marrow fibrosis, or the replacement of bone marrow with fibrous scar tissue, is a central pathological feature of myelofibrosis. In MANIFEST-2, fibrosis was improved by at least one grade in a greater proportion of patients receiving pelabresib and ruxolitinib (38.5% vs. 24.2% with placebo plus ruxolitinib) and worsened by at least one grade in a smaller proportion of patients receiving pelabresib and ruxolitinib (16.3% vs. 28.3% with placebo plus ruxolitinib) at 24 weeks. Bone marrow fibrosis is graded on a scale from 0 (normal) to 3 (most severe) based on fiber density; studies suggest a correlation between the grade of bone marrow fibrosis and patient prognosis.

Biomarker Analysis Suggests Disease Modification

In a biomarker analysis, average plasma levels of inflammatory cytokines (IL-8, IL-6, TNF-α and NF-κB-regulated cytokines) were reduced in patients receiving pelabresib and ruxolitinib compared with placebo plus ruxolitinib at 24 weeks. Increased cytokine levels are associated with all four disease hallmarks; increased IL-8 levels are also associated with worse survival outcomes. These biomolecular improvements suggest early evidence of a disease-modifying effect.

Well-Tolerated Safety Profile

Overall, grade ≥3 treatment-emergent adverse events (TEAEs) were reported less frequently with pelabresib and ruxolitinib than with placebo plus ruxolitinib (49.1% vs. 57.5%, respectively).

In the pelabresib and ruxolitinib arm, the most common (≥10%) hematologic TEAEs were anemia (43.9%; grade ≥3: 23.1%), thrombocytopenia (32.1%; grade ≥3: 9.0%) and platelet count decrease (20.8%; grade ≥3: 4.2%). In the placebo plus ruxolitinib arm, the most common hematologic TEAEs were anemia (55.6%; grade ≥3: 36.4%), thrombocytopenia (23.4%; grade ≥3: 5.6%) and platelet count decrease (15.9%; grade ≥3: 0.9%).

The most common (≥10%) nonhematologic TEAEs in the pelabresib and ruxolitinib arm were diarrhea (23.1%; grade ≥3: 0.5%), dysgeusia (18.4%; grade ≥3: 0.5%), constipation (18.4%; grade ≥3: 0%), nausea (14.2%; grade ≥3: 0.5%), cough (12.7% grade ≥3: 0), asthenia (11.8% grade ≥3: 0.5%), fatigue (11.8%; grade ≥3: 0.5%), dizziness (11.3%; grade ≥3: 0%), headache (11.3% grade ≥3: 0.5%) and COVID-19 (11.3%; grade ≥3: 0%). The most common nonhematologic TEAEs in the placebo plus ruxolitinib arm were constipation (24.3%; grade ≥3: 0%), diarrhea (18.7%; grade ≥3: 1.4%), fatigue (16.8%; grade ≥3: 0.9%), COVID-19 (15.9%; grade ≥3: 1.9%), nausea (15.0%; grade ≥3: 0%), asthenia (13.6%; grade ≥3: 0%), dyspnea (13.1%; grade ≥3: 0.9%), cough (11.2%; grade ≥3: 0%) and headache (10.7%; grade ≥3: 0%). Discontinuation rates due to adverse events were 10.7% with pelabresib and ruxolitinib and 6.5% with placebo plus ruxolitinib.

The safety profile of the pelabresib and ruxolitinib combination therapy was consistent with previous clinical studies. No new safety signals were observed.

“The four hallmarks of myelofibrosis – enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms – have a strong impact on a patient’s life. In MANIFEST-2, the combination of JAK and BET inhibition addressed all four of these hallmarks with the potential to modify the course of the disease,” said Tim Demuth, M.D., Ph.D., MorphoSys Chief Research and Development Officer. “We are confident that the comprehensive data package will provide impactful insights into the promising and well-tolerated combination of pelabresib and ruxolitinib. Our goal now is to bring this first-line therapy to patients with intermediate- and high-risk myelofibrosis as quickly as possible. We look forward to meeting with regulatory agencies regarding these data and are diligently preparing regulatory filings with the intention of submitting applications to the U.S. Food and Drug Administration and the European Medicines Agency in the middle of 2024.”

Read more

Biomarker Data from Phase 1 Study of Selinexor in Combination with Ruxolitinib in Treatment-Naïve Myelofibrosis (MF) Suggestive of Disease Modification

Data Reinforce the Potential for Selinexor in Combination with Ruxolitinib to Become a Novel, First-Line Treatment for JAKi-Naïve Patients with MF

NEWTON, Mass., Dec. 10, 2023 /PRNewswire/ — Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced long-term follow up of treatment-naïve patients with myelofibrosis (MF) who participated in the Phase 1 portion of its study evaluating once-weekly selinexor in combination with ruxolitinib (NCT04562389). The data, featured in an oral presentation at the 65th American Society of Hematology Annual Meeting and Exposition (ASH 2023), show patients treated with 60mg selinexor, and who achieved ≥35% reduction in spleen volume (SVR35) at week 24, continued to remain in radiographic response. In addition, all patients who achieved TSS50 at Week 24 remained in response as of the data cut-off.

The data included in the oral presentation for ASH 2023 were based on the Phase 1 portion of the Phase 1/3 study evaluating the safety and efficacy of once-weekly selinexor in combination with ruxolitinib in patients with treatment-naïve MF (NCT04562389). As of August 1, 2023, 24 patients had been assigned to either selinexor 40mg (N= 10) or 60mg (N=14), in combination with ruxolitinib. The maximum duration of follow-up was 78 weeks with a median duration of 32 weeks for SVR35 durability, and a maximum duration of follow-up was 64 weeks with a median duration of 51 weeks for TSS50 durability.

An exploratory biomarker analysis showed a reduction of variant allele frequency (VAF) at week 24 for all three MF driver genes (CALR, MPL, and JAK2) and rapid and sustained reduction of pro-inflammatory cytokine production. Early cytokine reduction at Week 4 was associated with spleen volume reduction (SVR) at Week 24 and was sustained until the end of treatment. The clinical efficacy associated with biomarkers impacting MF biological hallmarks may suggest disease modification.

“The growing body of data from this study suggests that selinexor in combination with ruxolitinib may provide spleen reduction, symptom improvement, long-term durability and disease modification, expanding the benefit this combination may provide to patients with treatment-naïve myelofibrosis, ” said Reshma Rangwala, MD, PhD, Chief Medical Officer of Karyopharm. “We’re excited about the potential to change treatment paradigms for these patients – and expand the number of patients who benefit from first-line therapy.”

The safety profile was consistent with previous data cuts with no new safety signals observed as of Aug 1^st.

“The current standard of care is not associated with consistent molecular or pathologic responses,” said Dr. Sri Tantravahi, University of Utah. “The long-term findings are very exciting as they underscore the potential for durable, clinically relevant responses and modification of disease course. The wait for new options has been long and difficult for the myelofibrosis community, and we welcome this important research to help advance the understanding of XPO1 and JAK inhibitor combinations as a meaningful treatment option for patients.”

“We are encouraged by the attention MPNs (Myeloproliferative Neoplasms) are getting in recent years from companies like Karyopharm,” said Kapila Viges, Chief Executive Officer of MPN Research Foundation. “With patients waiting for more answers to these chronic yet serious blood cancers, we look forward to the data readouts at ASH this year. Efforts to develop better therapies and now combinations of therapies bring hope to the myelofibrosis community and open the potential for more options in the treatment paradigm. For patients, options matter.”

About XPOVIO® (selinexor)

XPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor and the first of Karyopharm’s Selective Inhibitor of Nuclear Export (SINE) compounds to be approved for the treatment of cancer. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in multiple oncology indications, including: (i) in combination with Velcade® (bortezomib) and dexamethasone (XVd) in patients with multiple myeloma after at least one prior therapy; (ii) in combination with dexamethasone in patients with heavily pre-treated multiple myeloma; and (iii) in patients with diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. XPOVIO (also known as NEXPOVIO® in certain countries) has received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including but not limited to the European Union, the United Kingdom, China, South Korea, Canada, Israel and Taiwan. XPOVIO and NEXPOVIO is marketed by Karyopharm’s partners, Antengene, Menarini, Neopharm and FORUS in China, South Korea, Singapore, Australia, Hong Kong, Germany, Austria, Israel and Canada.

Please refer to the local Prescribing Information for full details.

Selinexor is also being investigated in several other mid- and late-stage clinical trials across multiple high unmet need cancer indications, including in endometrial cancer and myelofibrosis.

Read more