On December 12, 2021 Protagonist Therapeutics (Nasdaq: PTGX) ("Protagonist" or "the Company") reported that updated data from two ongoing Phase 2 studies evaluating rusfertide in patients with polycythemia vera (PV), demonstrating its ability to essentially eliminate the need for phlebotomies in patients (Press release, Protagonist, DEC 12, 2021, View Source [SID1234596881]). Rusfertide also showed rapid and sustained hematocrit control in patients requiring frequent phlebotomies or those having high baseline hematocrit levels (>48%). The data were presented in two oral presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting, in addition to the Company’s three poster presentations: one describing the Phase 3 study design for rusfertide in PV; one presenting pre-clinical findings with a hepcidin analog in a mouse model of PV; and another poster on the Phase 2 clinical proof-of-concept data for rusfertide in hereditary hemochromatosis (HH).

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"The latest data continues to demonstrate rusfertide’s potential to maintain rapid and durable control of hematocrit and essentially eliminate the need for phlebotomies in phlebotomy-dependent PV patients, while offering meaningful improvements across various quality of life measures," said Ronald Hoffman, MD, Director of the Myeloproliferative Disorders Research Program at the Icahn School of Medicine at Mount Sinai, and principal investigator for the study. "Early findings for rusfertide induction therapy also demonstrate its ability to rapidly control hematocrit in patients with elevated hematocrit levels above 48 percent, and to sustain those effects in maintenance, highlighting rusfertide’s potential efficacy in a wider spectrum of PV patients."

"We are extremely encouraged by the totality and consistency of the positive results presented today at ASH (Free ASH Whitepaper) for rusfertide in polycythemia vera, and by the support we are garnering from the physician community as we continue to execute against our goal of addressing unmet medical needs through this natural hormone mimetic therapy," said Dinesh V. Patel, PhD, President and Chief Executive Officer of Protagonist. "The upcoming double-blinded, placebo-controlled Phase 3 PV study is a transformative step in the progressive journey of rusfertide, from de novo discovery to a registrational study. In addition, we look forward to providing clarity on our next steps in HH and other iron-overload related diseases in 2022, thereby expanding the potential utility of rusfertide into multiple indications."

Summary of Key Results

Updated Results from Phase 2 Study Evaluating Rusfertide in Patients with PV

In this Phase 2 study, 63 phlebotomy-dependent PV patients were treated with rusfertide for up to 18 months. The results of the study demonstrated the essential elimination of the need for therapeutic phlebotomy (TP). Rapid, sustained, and durable control of hematocrit levels below 45% was observed without a significant increase in white blood cell numbers or PV-related thromboses. During the first 28 weeks on treatment, 84% of patients required no phlebotomies, 14% required one, and 2% required two phlebotomies. The most frequent adverse events were injection site reactions which were transient in nature. Importantly, none of the treated PV patients suffered from thrombotic events. Serious and Grade 3-4 events were limited in number, less than 10 at the time of data cut-off. Two SAEs were previously reported as possible related to study drug.

Among patient reported outcomes, a third of the patients in the study also saw at least a 40% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Scores (MPN-SAF-TSS) from baseline at week 28. Sixty-nine percent of patients reported improvement in Patient Global Impression of Change from baseline at week 8.

New Results from Phase 2 Study Evaluating Rusfertide as an Induction Therapy in Patients with PV

In this Phase 2 study, induction therapy with twice weekly rusfertide was administered alone to patients with confirmed high hematocrit levels above 48%. In all 16 erythrocytotic PV patients, rusfertide demonstrated rapid reduction of hematocrit below 45% within weeks, without the need for TP. The drug was well tolerated. Post-induction, weekly rusfertide treatment maintained hematocrit levels without the need for TP. While this study remains ongoing, most reported drug related adverse events to date were grade 1-2, with injection site reactions being the most common adverse event.

Additional Poster Presentations

The design of Protagonist’s planned three-part, multicenter, global, double-blinded, placebo-controlled Phase 3 clinical trial was presented in a poster. This Phase 3 study is expected to commence in Q1 2022 and will evaluate rusfertide in patients with PV compared to placebo when added onto current therapy. The primary endpoint of the study will be the absence of phlebotomy during weeks 20-32 for patients on rusfertide.

Also presented in a poster were results from a pre-clinical study demonstrating that a rusfertide peptide analog reduced erythrocytosis by restricting iron needed for red blood cell production while normalizing body iron distribution in a murine model with JAK2-V617F mutations. These effects support the use of a hepcidin mimetic, such as rusfertide, for potential utility in PV through dose titration treatment to maintain hematocrit below 45%.

Results from a Phase 2a proof-of-concept study evaluating rusfertide in patients with HH were also presented in a poster, demonstrating that rusfertide reduced serum iron and maintained transferrin saturation below 45% with corresponding significant reductions in phlebotomies. Liver iron concentration measured by MRI were also maintained at pre-study levels in patients at the end of the six-month study. Rusfertide was generally well tolerated in patients with HH, with the most common adverse events being injection site reactions that were mild or moderate.

Details for ASH (Free ASH Whitepaper) 2021 presentations are as follows:

Oral Presentations

Title: "Rusfertide (PTG-300) Controls Hematocrit Levels and Essentially Eliminates Phlebotomy Requirement in Polycythemia Vera Patients"
Session Title: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Novel Therapies for MPNs and JAK inhibitors for Myelofibrosis
Authors: Ronald Hoffman, MD, et al.

Title: "Rusfertide (PTG-300) Induction Therapy Rapidly Achieves Hematocrit Control in Polycythemia Vera Patients without the Need for Therapeutic Phlebotomy"
Session Title: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Novel Therapies for MPNs and JAK inhibitors for Myelofibrosis
Authors: Yelena Ginzburg, MD, et al.

Posters

Title: "A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera"
Session Title: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster I
Authors: Srdan Verstovsek, MD, PhD, et al.

Title: "Regulation of Iron Homeostasis and Efficacy of Rusfertide Analog Peptide in a Mouse Model for Polycythemia Vera"
Session Title: 102. Iron Homeostasis and Biology: Poster II
Authors: Roopa Taranath, PhD, et al.

Title: "Rusfertide (PTG-300), a Hepcidin Mimetic, Maintains Liver Iron Concentration in the Absence of Phlebotomies in Patients with Hereditary Hemochromatosis"
Session Title: 102. Iron Homeostasis and Biology: Poster I
Authors: Kris V. Kowdley, MD, et al.

On December 12, 2021 MorphoSys AG (FSE: MOR; NASDAQ: MOR) reported that the latest data from the ongoing MANIFEST study, an open-label, Phase 2 clinical trial of pelabresib, an investigational BET inhibitor, in patients with myelofibrosis, a rare bone marrow cancer for which only limited treatment options are available (Press release, MorphoSys, DEC 12, 2021, View Source [SID1234596932]). These latest results, which included more patients and longer-term follow-up than previously reported data, suggest the potential of pelabresib in the treatment of myelofibrosis. These findings were presented during poster and oral sessions at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH 2021), held December 11 – 14, 2021 in Atlanta, Georgia and virtually.

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"These data reconfirm previously published results and reinforce the role pelabresib may play, if approved, in overcoming some of the challenges we face in treating myelofibrosis," said Malte Peters, M.D., MorphoSys Chief Research and Development Officer. "We are further exploring the effectiveness and safety of pelabresib as a first-line treatment for myelofibrosis in MANIFEST-2, an ongoing Phase 3 study. The latest results reaffirm our confidence in the MANIFEST-2 study, and we look forward to sharing findings from this trial once they become available."

At ASH (Free ASH Whitepaper) 2021, the latest data evaluating pelabresib as a first-line combination with ruxolitinib – the current standard of care – for patients with myelofibrosis who had not previously been treated with a JAK inhibitor (JAK inhibitor-naïve) were presented. As of September 10, 2021, the data cut-off, a total of 84 JAK inhibitor-naïve patients have been enrolled and received the combination. The data showed 68 percent (n=57) of patients treated with the combination achieved a ≥35 percent reduction in spleen volume (SVR35) from baseline at week 24 and 60 percent (n=47) maintained SVR35 at week 48. Most patients also saw their symptoms reduced, with 56 percent (n=46) achieving ≥50 percent reduction in total symptom score (TSS50) from baseline at week 24. At the time of the data cut-off, 53 patients (63 percent of the 84 patients) were still on treatment. No new safety signals were identified in the study. The most common hematologic adverse events were thrombocytopenia (12 percent, grade 3/4) and anemia (34 percent, grade 3/4). Non-hematological events included dyspnea (5 percent, grade 3) and respiratory tract infections (8 percent, grade 3/4).

Additionally, analyses from an exploratory endpoint presented at ASH (Free ASH Whitepaper) 2021 showed a reduction of megakaryocyte clustering in bone marrow and correlation with spleen volume reduction. Megakaryocytes are the cells in the bone marrow responsible for making platelets, and the clustering of these cells are one of the signs of myelofibrosis. The exploratory data, which require further evaluation, suggest the potential pelabresib may have in changing the course of myelofibrosis treatment, if approved.

"In my opinion, a challenge in treating myelofibrosis is knowing that despite available treatment options the disease will ultimately progress in the majority of patients diagnosed," said Srdan Verstovsek, M.D., Ph.D., professor of medicine and hematologist-oncologist at the MD Anderson Cancer Center and a MANIFEST investigator. "Identifying new, first-line treatment options will improve physicians’ ability to better manage the disease from the time of diagnosis. These latest data, although early in the investigational process, suggest that by

combining pelabresib and ruxolitinib, we may have the potential to enhance the current standard of care in the first-line treatment of myelofibrosis."

Additional data from Arm 1 of the MANIFEST study were also presented in an oral presentation at ASH (Free ASH Whitepaper) 2021. In Arm 1, pelabresib is being evaluated as a monotherapy in patients with advanced myelofibrosis who are ineligible to receive, intolerant of, or refractory to JAK inhibitors, a population with very limited therapeutic options. Patients were divided into two cohorts, transfusion-dependent (TD) and non-transfusion-dependent (non-TD). For the TD cohort, the primary endpoint was conversion to transfusion independence (TI) for 12 consecutive weeks. In the non-TD cohort, the primary endpoint was SVR35 at week 24. At week 24, 11 percent (n=7) of patients reached SVR35. In addition, we observed 31 percent of patients had a spleen volume reduction of 25 percent or more (n=20) at week 24. Across all cohorts, 28 percent (n=18) of patients achieved TSS50. No new safety signals were identified in the study. The most common hematologic adverse events were thrombocytopenia (23 percent, grade 3/4) and anemia (15 percent, grade 3). Non-hematological events included diarrhea (6 percent, grade 3) and respiratory tract infections (5 percent, grade 3).

About Pelabresib
Pelabresib (CPI-0610) is an investigational selective small-molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. Pelabresib is currently being investigated as a treatment for myelofibrosis and has not yet been evaluated or approved by any regulatory authorities.

About MANIFEST
MANIFEST is an open-label, Phase 2 clinical trial of pelabresib (CPI-0610) in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells.

Constellation Pharmaceuticals, an affiliate of MorphoSys, is evaluating pelabresib in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. Constellation Pharmaceuticals is also evaluating pelabresib either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1) or as add-on therapy in combination with ruxolitinib in patients with a suboptimal response to ruxolitinib or MF progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on transfusion-dependent (TD) status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.

On December 12, 2021 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that updated initial safety and efficacy findings from the Phase 1b/2 study of IMGN632 in combination with Vidaza (azacitidine) and Venclexta (venetoclax) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were presented in an oral session at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, ImmunoGen, DEC 12, 2021, View Source [SID1234596824]). Data for IMGN632 in frontline patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) were also presented in a poster session at the conference.

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"The unmet need in AML remains large, as patients typically have low survival rates despite initial response," said Naval Daver, MD, Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. "Together, the observed anti-leukemia activity and tolerability of IMGN632 in the relapsed/refractory setting are compelling and support the continued evaluation of this triplet in AML patients. I look forward to the next steps for IMGN632 in combination with azacitidine and venetoclax, with preparations for Phase 2 expansion cohorts already underway in both the relapsed and frontline AML settings."

IMGN632 TRIPLET DATA IN AML

Title (Abstract #372): "Safety and Efficacy from a Phase 1b/2 Study of IMGN632 in Combination with Azacitidine and Venetoclax for Patients with CD123-Positive Acute Myeloid Leukemia"
Oral Session: 616
Session Date: Sunday, December 12, 2021
Session Time: 9:30 am – 11:00 am

Updated key findings from the Phase 1b/2 study of IMGN632 in combination with azacitidine and venetoclax include:

Safety

IMGN632 was administered to 51 patients at 15 mcg/kg or 45 mcg/kg, azacitidine at 50-75 mg/m2 for 7 days, and venetoclax at 400 mg daily for 8-21 days per 28-day cycle.
IMGN632 continued to display a manageable safety profile in R/R AML patients.
The most common treatment emergent adverse events all grades [grade 3+ events] seen in >20% of patients were infusion-related reactions (33% [2%]), febrile neutropenia (31% [26%]), dyspnea (28% [8%]), fatigue (28% [0%]), hypophosphatemia (26% [2%]), diarrhea (22% [0%]), hypokalemia (22% [2%]), nausea (22% [0%]), vomiting (22% [0%]), and pneumonia (20% [16%]).
No tumor lysis syndrome, veno-occlusive disease, capillary leak, or cytokine release were reported.
Efficacy

Responses were seen across all cohorts/doses and schedules (efficacy evaluable population, n=46). The objective response rate (ORR) was 48%, with a composite complete remission (CCR) rate of 30% (4 CR, 8 CRh, 1 CRp, 1 CRi).
Higher intensity cohorts (n=29) were associated with higher response rates including an ORR of 59% and a CCR rate of 38% (4 CR, 6 CRh, 1 CRp).
Significant activity was also observed in the FLT3 mutant subset (n=9), with ORR and CCR rates of 89% and 78%, respectively.
Enrollment continues at the putative recommended Phase 2 dose (IMGN632 45 mcg/kg IV on day 7, azacitidine 50 or 75 mg/m2 on days 1-7, and venetoclax 400 mg on days 1-14).
"These data reinforce the potential of IMGN632 as a new therapy for patients with relapsed/refractory AML. We are very encouraged by the manageable safety profile and 38% composite complete remission rate seen in the higher intensity cohorts," said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen. "We look forward to further exploring the safety and efficacy of this triplet in Phase 2 expansion cohorts planned for next year. We believe IMGN632 also has the potential to become a best-in-class monotherapy treatment option for patients with BPDCN. Based on the results seen in three frontline patients, we continue to enroll patients in our pivotal study, CADENZA, and look forward to sharing top-line data in the second half of 2022."

IMGN632 MONOTHERAPY IN FRONTLINE BPDCN

Poster Presentation, Abstract #1284

IMGN632, administered as a brief outpatient infusion, was evaluated as monotherapy in frontline BPDCN patients. Three patients received IMGN632 prior to commencement of the enrolling pivotal cohort and achieved a clinical complete remission (CRc). IMGN632 in these three frontline BPDCN patients was associated with a favorable safety profile and limited grade 3+ TEAEs. Enrollment continues in the pivotal frontline and R/R cohorts.

Additional information can be found at www.hematology.org, including abstracts.

ABOUT IMGN632

IMGN632 is a CD123-targeting ADC in clinical development for hematological malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), and other CD123+ hematologic malignancies. IMGN632 is currently being evaluated in multiple cohorts, including monotherapy for patients with BPDCN and minimal residual disease positive (MRD+) AML and in combinations with Vidaza (azacitidine) and Venclexta (venetoclax) for patients with relapsed/refractory AML. IMGN632 uses one of ImmunoGen’s novel indolinobenzodiazepine (IGN) payloads, which alkylate DNA and cause single strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. The FDA granted IMGN632 Breakthrough Therapy Designation in relapsed/refractory BPDCN.

ABOUT ACUTE MYELOID LEUKEMIA (AML)

AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems, and anemia. It is estimated that, in the U.S. alone, more than 20,000 people will be diagnosed with AML this year and more than 11,000 will die from the disease.

ABOUT BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM (BPDCN)

BPDCN is a rare form of blood cancer that has features of both leukemia and lymphoma, with characteristic skin lesions, lymph node involvement, and frequent spread to the bone marrow. This aggressive cancer requires intense treatment often followed by stem cell transplant. Despite the approval of a CD123-targeting therapy, the unmet need remains high for patients, both in the frontline and in the relapsed/refractory setting.

ABOUT CD123

CD123, the interleukin-3 alpha chain, is expressed on multiple myeloid and lymphoid cancers including AML, BPDCN, ALL, chronic myeloid leukemia, and myeloproliferative neoplasms. With limited expression on normal hematopoietic cells, rapid internalization, and expression on AML leukemia stem cells, CD123 is a validated therapeutic target, with the approval of a CD123-targeting therapy for BPDCN.

On December 12, 2021 Loxo Oncology at Lilly, a research and development group of Eli Lilly and Company (NYSE: LLY), reported updated clinical data from the pirtobrutinib global Phase 1/2 BRUIN clinical trial in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL) (Press release, Eli Lilly, DEC 12, 2021, View Source [SID1234596826]). Pirtobrutinib is an investigational, highly selective, non-covalent (reversible) Bruton’s tyrosine kinase (BTK) inhibitor. These data are being presented in oral presentations at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (abstracts 391 and 381).

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"BRUIN is now the largest clinical trial conducted to date that has enrolled CLL/SLL patients previously treated with modern standards of care including BTK and BCL2 inhibitors. In this real-world population of relapsed/refractory patients, pirtobrutinib continues to demonstrate robust activity with a safety profile amenable to chronic administration. Now with the longer follow-up that this analysis affords, we are encouraged by evidence of durable disease control in this very heavily pretreated CLL/SLL population," said Anthony Mato, M.D., MSCE, director of the CLL Program at Memorial Sloan Kettering Cancer Center and a presenting author. "As recently detailed by a global panel of experts in Clinical Cancer Research, there are currently no evidence-based treatment options for patients following covalent BTK and BCL2 inhibitor therapy. Pirtobrutinib has the potential to offer a meaningful new approach for these CLL/SLL patients, as well as those patients who are less heavily pretreated."

"I’m pleased to share the pirtobrutinib data in MCL patients with the hematology community at ASH (Free ASH Whitepaper)", said Michael Wang, M.D., Puddin Clarke Endowed Professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center and a presenting author. "Since our last analysis of these data, we have doubled the number of evaluable BTK pretreated patients and observed a nearly-identical response rate. New treatment options following covalent BTK therapy represent an area of urgent unmet need and the durable response rate observed with pirtobrutinib demonstrates its potential to provide a significant clinical advancement for patients with MCL following covalent BTK therapy."

Key Data Presented at ASH (Free ASH Whitepaper)
As of July 16, 2021, 618 patients were enrolled in the study, including 296 with CLL/SLL, 134 with MCL, and 188 with other B-cell malignancies. The efficacy data presented at ASH (Free ASH Whitepaper) are based on investigator response assessments. Patients were considered efficacy-evaluable if they had at least one post-baseline response assessment or if they discontinued treatment prior to their first post-baseline response assessment.

Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
Among the 296 CLL/SLL patients enrolled, 261 were previously treated with a BTK inhibitor and are the subject of this analysis. The median number of prior lines of therapy was three with 100% receiving a prior BTK inhibitor, 88% an anti-CD20 antibody, 79% chemotherapy, 41% venetoclax, 20% a PI3K inhibitor, 6% CAR-T therapy and 2% stem cell transplant.

In 252 efficacy-evaluable patients (an additional nine patients ongoing prior to first restaging), 171 responded including two complete responses (CR), 137 partial responses (PR), 32 partial responses with ongoing lymphocytosis (PR-L), and 62 stable disease (SD), resulting in an overall response rate (ORR) of 68% (95% CI: 62-74). Responses continue to deepen over time, with the ORR rising to 73% (88/119) for those followed 12 months or more, and ORR remains consistent regardless of reason for prior BTK discontinuation, type or number of prior therapies or BTK C481 or PCLG2 mutational status.

Pirtobrutinib demonstrated evidence of durable activity with a median progression-free survival (PFS) not reached in patients who had received at least a prior BTK inhibitor (lower limit of 95% confidence interval of 17.0 months, median of three prior lines of therapy). In patients who had received at least a BTK inhibitor and BCL2 inhibitor (median of five lines of prior therapy), the estimated median PFS was 18 months, although these data remain immature and unstable due to the small percentage of patients with progression. As of the data cut-off, 74% (194/261) of BTK pre-treated patients remained on pirtobrutinib. Median follow-up for all BTK pre-treated patients was 9.4 months (range 0.3-27.4 months).

In an exploratory analysis in patients with prior progression on a BTK inhibitor, the PFS with pirtobrutinib was similar in patients with BTK C481-mutated and BTK C481-wildtype CLL and SLL.

Mantle cell lymphoma (MCL)
The 134 patients with MCL received a median of three prior lines of therapy, with 90% receiving a prior BTK inhibitor, 97% an anti-CD20 antibody, 91% chemotherapy, 22% stem cell transplant, 17% immunomodulatory (IMiD) drugs, 15% venetoclax, 13% proteasome inhibitor, 5% CAR-T cell therapy, and 4% PI3K inhibitor.

Of the 100 efficacy-evaluable patients with BTK pre-treated MCL (an additional 23 patients ongoing prior to first restaging, 11 patients had not received a prior BTK inhibitor), 51 responded including 25 CRs and 26 PRs resulting in an ORR of 51% (95% CI: 41-61). Among 11 BTK naïve MCL patients, nine responded including two CRs and seven PRs resulting in an ORR of 82% (95% CI: 48-98). Responses in MCL were observed in patients who received prior stem cell transplant and prior CAR-T therapy.

Median duration of response was 18 months (lower limit of 95% confidence interval of 4.6 months). Median follow-up for all responding MCL patients was 8.2 months (range of 1.0-27.9 months) with 60% (36/60) of responses ongoing as of the data cut-off.

Safety data were presented for the entire enrolled BRUIN population. Across all 618 patients enrolled in the study, the most commonly reported adverse events, regardless of attribution, were fatigue (23%), diarrhea (19%), neutropenia (18%) and contusion (17%). In addition, adverse events commonly associated with covalent BTK inhibitors occurred at a low rate, with the majority being Grade 1 or 2. During the Phase 1 dose escalation, no dose limiting toxicities were reported and a maximum tolerated dose (MTD) was not reached. Permanent discontinuations for drug-related adverse events were observed in 1% (n=6) of patients.

"As the pirtobrutinib data continue to mature we remain extremely excited by its potential to meaningfully improve the treatment landscape for patients with CLL, SLL and MCL", said David Hyman, M.D., chief medical officer, oncology at Lilly. "We have initiated a robust Phase 3 program for pirtobrutinib and look forward to further exploring its potential as monotherapy, in combination, and in earlier lines of therapy."

Real-world evidence studies
A real-world evidence database study on outcomes for patients with CLL previously treated with a covalent BTK inhibitor and a BCL2 inhibitor will be presented in a poster presentation on Monday, December 13 from 6-8 p.m. ET (abstract 3743). Additionally, a study on outcomes for patients with MCL following covalent BTK inhibitor therapy was published as an online-only abstract (abstract 4523).

Loxo Oncology at Lilly is studying pirtobrutinib in multiple Phase 3 studies. Details on the trials can be found in Trials in Progress posters (abstracts 2422, 3732, 3736 and 3742) and on lillyloxooncologypipeline.com.

About Pirtobrutinib (LOXO-305)
Pirtobrutinib is an investigational, highly selective, non-covalent (reversible) Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia, and marginal zone lymphoma. Currently available covalent BTK inhibitors irreversibly inhibit BTK and the long-term efficacy of these therapies can be limited by acquired resistance, most commonly through BTK C481 mutations. In rapidly growing tumors with inherently high rates of BTK turnover, resistance to covalent BTK therapies may be the result of incomplete target inhibition. Pirtobrutinib was designed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, preserve activity in the presence of the C481 acquired resistance mutations, and avoid off-target kinases that have complicated the development of both covalent and investigational non-covalent BTK inhibitors. Interested patients and physicians can contact the Loxo Oncology at Lilly Physician and Patient BTK Clinical Trial Hotline at 1-855-LOXO-305 or email [email protected].

About the BRUIN Phase 1/2 Trial
This first-in-human, global, multi-center Phase 1/2 trial evaluates pirtobrutinib as a single agent in patients with previously treated chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or non-Hodgkin’s lymphomas (NHL). The trial includes a Phase 1 dose escalation phase and a Phase 2 dose expansion phase. The Phase 1 dose escalation enrolls patients with CLL/SLL or NHL who have received at least two prior lines of therapy and have progressed or are intolerant to standard of care. The dose escalation phase followed a "3+3" design with pirtobrutinib dosed orally in 28-day cycles. As dose cohorts were cleared, additional patients could enroll in cleared cohorts and intra-patient dose escalation was permitted. The primary objective of the Phase 1 portion of the trial is to determine the maximum tolerated dose and recommended Phase 2 dose. Key secondary objectives include measures of safety, pharmacokinetics, and anti-tumor activity (i.e. Overall Response Rate (ORR) and Duration of Response, as determined by appropriate histology-specific response criteria). In the Phase 2 dose expansion, patients are enrolled across various cohorts, depending on disease type and prior therapy. The primary endpoint for Phase 2 is ORR. Secondary endpoints include duration of response (DOR), overall survival (OS), safety, and pharmacokinetics (PK).

About Loxo Oncology at Lilly
Loxo Oncology at Lilly was created in December 2019, combining the Lilly Research Laboratories oncology organization and Loxo Oncology, which was acquired by Lilly in early 2019. Loxo Oncology at Lilly brings together the focus and spirit of a biotech with the scale and resources of large pharma, with the goal of rapidly delivering impactful new medicines for people with cancer. Our approach centers on creating new oncology medicines that unequivocally work early in clinical development and will matter to patients.

On December 12, 2021 Imago BioSciences, Inc. ("Imago") (Nasdaq: IMGO), a clinical stage biopharmaceutical company discovering new medicines for the treatment of myeloproliferative neoplasms (MPNs), reported that positive data from its ongoing global Phase 2 clinical study evaluating bomedemstat in patients with essential thrombocythemia (ET) (Press release, Imago BioSciences, DEC 12, 2021, View Source [SID1234596827]). The data were presented in an oral session during the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place December 11-14, 2021. Previously, a Phase 2 data set with a cut-off date of May 18, 2021 was presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Congress.

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Updated Highlights (as of November 1, 2021 cutoff):

Of the 29 patients treated with bomedemstat for more than 6 weeks:
100% (29/29) of patients experienced platelet count reduction to within normal ranges (150 – 400 x 109/L).
90% (26/29) of patients achieved a platelet count of less than 400 x 109/L without thromboembolic events, the primary composite endpoint of this study.
Of the 17 evaluable patients at 24 weeks:
71% (12/17) showed a decrease in Total Symptom Score (TSS).
53% (9/17) showed a ≥50% decrease in TSS.
Patients with all genotypes identified in the study (CALR, JAK2V617F, Triple Negative) responded to bomedemstat.
"As of the most recent data cut-off in this Phase 2 trial, bomedemstat as a monotherapy in a 2nd line ET population demonstrated significant and durable hematologic control and symptom improvement while maintaining normal hemoglobin levels. I am delighted with the progress we are making with this study and would like to take this opportunity to thank all of the investigators and patients involved," said Hugh Young Rienhoff, Jr., M.D., CEO, Imago BioSciences. "Even with only 36 of the up-to 60 patients we plan to enroll, we have commenced planning for a registrational clinical trial for ET. We expect an End-of-Phase 2 meeting and discussion of the Phase 3 Protocol in the second half of 2022."

Safety & Tolerability

Bomedemstat was generally well-tolerated.
The most common AEs (>20%) were dysgeusia (altered taste), constipation, arthralgia, and fatigue.
4 patients have discontinued due to AEs.
"We are pleased with the safety and tolerability of Bomedemstat in this trial in a patient population, most of whom were intolerant or resistant to hydroxyurea," said Wan-Jen Hong, M.D., CMO, Imago BioSciences. "In addition, the data presented provide evidence of continued durability of the response."

Details on Imago’s ASH (Free ASH Whitepaper) Presentation

Oral Presentation Title: A Phase 2 Study of the LSD1 Inhibitor IMG-7289 (Bomedemstat) for the Treatment of Essential Thrombocythemia (ET)
Session: Myeloproliferative Syndromes: Clinical and Epidemiological: Non-JAK inhibitor Therapies for Myelofibrosis
Presenter: Francesca Palandri, M.D., Ph.D., Institute of Hematology "L. & A. Seràgnoli," Sant’Orsola-Malpighi University Hospital, Bologna, Italy
Date and Time: Sunday, December 12, 2021, at 9:45 AM ET

For further details, please see the ASH (Free ASH Whitepaper) 2021 abstract and presentation on the Imago website here.

About Imago’s Phase 2 Essential Thrombocythemia Program

Essential thrombocythemia (ET) is a rare blood cancer resulting from the overproduction of platelets, which increases the risk of blood clots and bleeding. It is one of the myeloproliferative neoplasms (MPN) family of rare bone marrow diseases, and affects approximately 80,000 – 100,000 patients in the U.S. Imago BioSciences is developing bomedemstat (IMG-7289), an orally administered LSD1 inhibitor, as a potential therapy for patients with ET.

This Phase 2b multi-center, open-label study is designed to assess the safety, efficacy, and pharmacodynamics of bomedemstat, an oral inhibitor of the epigenetic enzyme lysine-specific demethylase 1 (LSD1) (www.clinicaltrials.gov Identifier NCT04254978). Eligible patients aged 18 or older with ET who have failed at least one standard therapy and require treatment in order to lower their platelet count will be considered for participation in this study. Exploratory assessments include the serial measurement of mutant allele frequencies and changing plasma cytokine profiles. The trial is being conducted in the United States, the United Kingdom, Europe, New Zealand, and Australia. Imago BioSciences announced first patient dosed on October 1, 2020. As of November 1, 2021, the trial has enrolled 36 of up to 60 planned study participants.