On December 11, 2017 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported findings from the phase 2 KEYNOTE-170 trial investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in the cohort of patients with relapsed or refractory primary mediastinal large B-cell lymphoma (PMBCL), a type of non-Hodgkin lymphoma (Press release, Merck & Co, DEC 11, 2017, View Source [SID1234522530]). In the PMBCL cohort of KEYNOTE-170, KEYTRUDA demonstrated an overall response rate (ORR) of 41 percent (n=12/29), including a 24 percent (n=7/29) complete response rate and a 17 percent (n=5/29) partial response rate, in patients who relapsed after or were refractory to autologous stem cell transplant (ASCT), or were ineligible for ASCT and failed two or more prior lines of therapy. These data were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta on Sunday, Dec. 10 (Abstract #2833).

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"There is a significant unmet need for patients with relapsed or refractory primary mediastinal large B-cell lymphoma," said Pier Luigi Zinzani, M.D., Ph.D., associate professor of hematology, Institute of Hematology "L. e A. Seràgnoli," University of Bologna. "These encouraging results represent another step in understanding the potential of KEYTRUDA to help these patients who have already tried and progressed on prior therapies."

Based on data from KEYNOTE-170 and the phase 1b KEYNOTE-013 trial, which is evaluating the safety, tolerability and efficacy of KEYTRUDA monotherapy in patients with various blood cancers, the U.S. Food and Drug Administration (FDA) has accepted for review a supplemental Biologics License Application (sBLA) for KEYTRUDA (pembrolizumab) for the treatment of adult and pediatric patients with refractory primary mediastinal B-cell lymphoma, or who have relapsed after two or more prior lines of therapy. The FDA granted Priority Review status with a PDUFA, or target action, date of April 3, 2018. In January 2017, KEYTRUDA was granted Breakthrough Therapy Designation by the FDA for this indication.

"These findings in patients with PMBCL are promising for a rare lymphoma that affects mainly young adults and has few effective treatment options in the relapsed or refractory treatment setting," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "If approved by the FDA, this would be our second blood cancer indication for KEYTRUDA, following FDA approval for certain patients with classical Hodgkin Lymphoma earlier this year. The acceptance of our sBLA reinforces our ongoing commitment to finding new treatment advances in hematology."

The KEYTRUDA hematology program includes more than 50 ongoing studies – including company sponsored, investigator sponsored and collaborative studies; several of these are registration-enabling trials.

Data from KEYNOTE-170 at ASH (Free ASH Whitepaper) (Abstract #2833)

KEYNOTE-170 is an ongoing, non-randomized, two-cohort, multicenter, phase 2 study evaluating the efficacy and safety of KEYTRUDA (200 mg fixed dose every three weeks) in patients with relapsed or refractory PMBCL and in patients with relapsed or refractory Richter syndrome. The PMBCL cohort enrolled patients who relapsed after or were refractory to ASCT, or were ineligible for ASCT; patients ineligible for ASCT had to have relapsed or refractory disease after two or more lines of prior therapy. The primary endpoint was ORR by blinded independent central review; key secondary endpoints included duration of response and safety and tolerability.

In the efficacy population (n=29), ORR was 41 percent (n=12) (95% CI, 24-61), with a complete response rate of 24 percent (n=7) (95% CI,10-44) and a partial response rate of 17 percent (n=5) (95% CI, 6-36). Median duration of follow-up was 10.5 months (range: 0.1-17.7). Median time to response was 2.8 months (range: 2.4-5.5). Median duration of response was not reached (range: 1.1+ to 13.6+ months).

Treatment-related adverse events (TRAEs) were consistent with previously reported safety data for KEYTRUDA. Of the 53 patients evaluated for safety, 57 percent (n=30) experienced TRAEs, including 21 percent (n=11) who experienced Grade 3-4 TRAEs. The most common TRAEs (greater than or equal to 5%) were neutropenia (n=11), hypothyroidism (n=4), asthenia (n=3) and pyrexia (n=3). Immune-mediated adverse events of all grades occurred in 11 percent (n=6) of patients; these include hypothyroidism (n=4), hyperthyroidism (n=2), pneumonitis (n=1) and thyroiditis (n=1). There were no treatment-related deaths.

About Primary Mediastinal Large B-Cell Lymphoma

PMBCL is a sub-type of diffuse large B-cell lymphoma (a type of non-Hodgkin lymphoma) that starts in the space between the lungs, called the mediastinum. PMBCL mainly affects young adults (with a median age of 35), and occurs slightly more often in women. PMBCL accounts for two to four percent of all non-Hodgkin lymphomas in the U.S.

About KEYTRUDA (pembrolizumab) Injection 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program, which currently involves more than 650 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA (pembrolizumab).

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA (pembrolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA (pembrolizumab) is 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC, occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA (pembrolizumab), including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may occur in any organ system. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA (pembrolizumab). Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA (pembrolizumab) occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

In KEYNOTE-021(G1), when KEYTRUDA was administered in combination with carboplatin and pemetrexed (carbo/pem) in advanced nonsquamous NSCLC, KEYTRUDA was discontinued in 10% of 59 patients. The most common adverse reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 39% of patients; the most common (≥2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%).The most common adverse reactions (≥20%) with KEYTRUDA compared to carbo/pem alone were fatigue (71% vs 50%), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), decreased appetite (31% vs 23%), headache (31% vs 16%), cough (24% vs 18%), dizziness (24% vs 16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%), peripheral edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs 3.2%), upper respiratory tract infection (20% vs 3.2%), and arthralgia (15% vs 24%). This study was not designed to demonstrate a statistically significant difference in adverse reaction rates for KEYTRUDA as compared to carbo/pem alone for any specified adverse reaction.

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA (pembrolizumab) was discontinued due to adverse reactions in 5% of 210 patients with cHL, and treatment was interrupted due to adverse reactions in 26% of patients. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. The most common adverse reactions (occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reactions (in ≥20% of patients) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and 3 patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients, the most frequent (≥2%) of which were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). The most common adverse reactions (≥20%) in patients who received KEYTRUDA vs those who received chemotherapy were fatigue (38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs 13%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients, the most frequent (≥2%) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

There is limited experience in pediatric patients. In a study, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors were administered KEYTRUDA (pembrolizumab) 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving KEYTRUDA for 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On December 11, 2017 Bellicum Pharmaceuticals, Inc. (NASDAQ:BLCM), a leader in developing novel, controllable cellular immunotherapies for cancers and orphan inherited blood disorders, reported data highlighting results from three preclinical studies of its controllable switch technology for T cell immunotherapies at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (ASH) (Free ASH Whitepaper) in Atlanta, Georgia (Press release, Bellicum Pharmaceuticals, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322102 [SID1234522549]).

"These data continue to support our excitement over the technology’s potential to make cell therapies safer and more effective in more tumor types," said Rick Fair, Bellicum’s President & Chief Executive Officer. "We are currently validating our platform in the clinic in three different product candidates, and look forward to reporting results on these programs in 2018. With the most advanced controllable cell technologies in our industry, we believe we are well positioned to move additional preclinical CAR-T projects into clinical trials that have the potential to be best-in-class."

The Company’s novel technology platform is designed to enable full control over the activation, persistence, and elimination of cell therapies to safely elicit the full effect of CAR-T and TCR activity in the body. Unlike traditional approaches, Bellicum’s controllable CAR-T and TCR constructs are designed to provide anti-tumor surveillance, even in the absence of cancer antigen. The switch technologies covered in the posters include:

Technology Description
GoCAR-T CAR-T cells incorporated with the inducible MyD88/CD40 (iMC) costimulatory switch to provide ligand-regulated control over the activation and persistence of cells
CIDeCAR CAR-T construct that includes the MC costimulatory domain with the CaspaCIDe safety switch
Dual-Switch CAR-T CAR-T cells with both the iMC costimulatory switch and CaspaCIDe safety switch to provide greater control over the activation and persistence of therapeutic cells, as well as the ability to rapidly eliminate them by activating the safety switch
8Summary of Study Results

"Dual-Switch CAR-T cells: Orthogonal Molecular Switches to Control Activation and Elimination of CAR-T Cells to Target CD123+ Cancer" (Abstract 3184)

Researchers targeted CD123—which is highly expressed in acute myeloid leukemia (AML) and leukemic stem cells—with a novel construct consisting of a first-generation CAR combined with regulated activation and apoptotic signaling elements. T cell costimulation was controlled by rimiducid, and a rapamycin-controlled pro-apoptotic safety switch was designed to induce rapid dimerization of caspase-9 to mitigate possible CAR-T cell toxicity. Results demonstrate that when combined with a first-generation CD123-specific CAR, these molecular switches enable controlled, robust expansion of engineered T cells to control tumor growth in vitro and in vivo, and provide a rapid and efficient safety mechanism to block excessive cytokine release.

"Inducible MyD88/CD40 (iMC) Costimulation Enhances Polyclonal Epstein-Barr Virus-Specific Cytotoxic T Lymphocyte (EBV-CTL) Proliferation and Anti-Tumor Activity" (Abstract 3337)

Using peripheral blood mononuclear cells from healthy donors, researchers generated EBV-specific T cells, which were genetically modified with iMC. They concluded that modifying EBV-CTL with iMC resulted in increased T cell proliferation and persistence and improved anti-tumor efficacy, suggesting that iMC may have broad applications, such as modifying tumor-infiltrating lymphocytes, virus-specific T cells and other polyclonal T cell products to increase their potency.

"MyD88/CD40 enhanced CD19-specific CAR-T cells maintain therapeutic efficacy following resolution of cytokine-related toxicity using inducible caspase-9" (Abstract 4615)

Scientists demonstrated that CD19-specific CAR-T cells modified with a constitutively active form of the potent fusion protein MC were effective at eliminating aggressive tumors, with efficacy associated with cytotoxic cytokine release. However, this toxicity was effectively resolved with rimiducid-mediated activation of co-expressed iC9 or by selecting distinct T cell populations without affecting long-term efficacy of the CAR-T treatment.

The presentations can be found in the Investors & Media section of the Company’s website.

On December 11, 2017 Fate Therapeutics, Inc. (NASDAQ:FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported Day 100 clinical data from the Phase 1 stage of its PROTECT clinical trial of ProTmune, the Company’s next-generation hematopoietic cell graft for patients with hematologic malignancies (Press release, Fate Therapeutics, DEC 11, 2017, View Source [SID1234522554]). All seven subjects receiving ProTmune remained alive and relapse-free during the first 100 days following hematopoietic cell transplantation (HCT). Three of the seven subjects experienced acute graft-versus-host disease (GvHD) during the first 100 days following HCT. Each of these three subjects responded to standard-of-care steroid treatment with a median time to resolution of the maximum GvHD grade of 7 days [range: 5-8 days].

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"The significant risk of GvHD limits broad application of allogeneic transplant due to uncertainty of its short- and long-term impact on the recipient. It occurs frequently with variable intensity and can be a devastating disease when unresponsive to treatment. The requisite extended use of immunosuppressive agents to treat GvHD compromises the anti-leukemia activity of the transplant procedure and can significantly increase the risk of cancer relapse and mortality while also placing patients at risk for opportunistic infection," said Richard Maziarz, M.D., Principal Investigator, Oregon Health Sciences University. "The administration of a hematopoietic cell graft that is optimized to attenuate T-cell alloreactivity and maintain the graft’s anti-leukemia activity is a novel and highly-attractive therapeutic approach to decrease the risk and enhance the curative potential of allogeneic transplantation."

PROTECT Phase 1 Day 100 Clinical Results

Clinical data from the Phase 1 stage of PROTECT were presented today by Dr. Maziarz during a poster session at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition. The Phase 1 stage included seven adult subjects with hematologic malignancies undergoing matched unrelated donor HCT following myeloablative conditioning. During the first 100 days following HCT, all seven subjects receiving ProTmune remained alive and relapse-free. Three of the seven subjects experienced acute GvHD during the first 100 days following HCT, all of whom responded to standard-of-care steroid treatment. The median time to resolution of the maximum GvHD grade was 7 days [range: 5-8 days]. There were no events of graft failure, and there were no ProTmune-related serious adverse events reported by investigators.

PROTECT Day 100 Clinical Data
Subject 1 2 3 4 5 6 7
Hematologic Malignancy MDS AML AML ALL ALL ALL AML
CD34+ cell dose (x106/kg) 10.3 4.6 10.9 4.8 3.2 3.0 9.4
CD3+ cell dose (x108/kg) 3.1 1.8 2.6 2.8 2.0 1.2 2.8
ProTmune-related SAEs None None None None None None None
Day of Neutrophil Engraftment 1 Day 14 Day 18 Day 22 Day 15 Day 16 Day 18 Day 19
Acute GvHD / Grade (CIBMTR) None None Grade 2 None Grade 2 Grade 3 None
Treatment Responsive — — Yes — Yes Yes —
Time to Resolution of Maximum Grade — — 7 days — 8 days 5 days —
Cancer Relapse-free Yes Yes Yes Yes Yes Yes Yes
Survival Yes Yes Yes Yes Yes Yes Yes
1 As measured from the day following HCT

"The Day 100 clinical results from our Phase 1 stage of PROTECT support the unique therapeutic potential of ProTmune to reduce graft-versus-host disease and promote relapse-free survival. We are very encouraged by these initial clinical findings and the potential of ProTmune to deliver transformative benefits to cancer patients," said Chris Storgard, M.D., Chief Medical Officer of Fate Therapeutics. "The randomized, controlled and double-blinded Phase 2 stage of PROTECT is enrolling subjects at 14 U.S. centers of excellence. Given the high rates of morbidity and mortality underlying hematopoietic cell transplantation, we have also engaged the FDA, under our Fast Track designation for ProTmune, to discuss the necessary activities for product registration."

All subjects receiving ProTmune in the PROTECT Phase 1 stage are being followed for a period of two years following HCT. As of a November 29, 2017 data cut-off, all subjects remained relapse-free, and there were no events of graft failure and no serious adverse events related to ProTmune reported by investigators. Non-relapse mortality was reported in two subjects (Subject 1 on Day 228; Subject 3 on Day 151). Five of seven subjects remained on study with median time on study of 154 days [Day 106 — 254].

PROTECT Phase 2 Design
The Phase 2 stage of PROTECT is a randomized, controlled and double-blinded clinical trial assessing the safety and efficacy of ProTmune in up to 60 adult subjects with hematologic malignancies undergoing matched unrelated donor HCT following myeloablative conditioning. Subjects are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional matched unrelated donor mobilized peripheral blood cell graft. The primary efficacy endpoint of PROTECT is cumulative incidence of Grades 2-4 acute GvHD by Day 100 following HCT, where prospective clinical studies have shown that 40% to 80% of patients undergoing matched unrelated donor transplant experience Grades 2-4 acute GvHD. Immunosuppressant treatments are effective in only about half of affected HCT patients and are associated with a marked increase in severe infections and cancer relapse. Additional endpoints, such as rates of cancer relapse, chronic GvHD, non-relapse mortality and overall survival, are also being assessed. Fourteen U.S. centers are currently open for enrollment in the Phase 2 stage of PROTECT.

About Acute GvHD
Acute graft-versus-host disease (GvHD) is a severe immunological disease that commonly arises in patients during the first weeks following allogeneic HCT when newly-transplanted donor immune cells attack the patient’s tissues and organs, resulting in a potentially fatal immune system reaction. Prospective clinical studies have shown that 40% to 80% of patients undergoing matched unrelated donor transplant experience Grades 2-4 acute GvHD, with most incidents occurring by Day 60 following HCT despite the use of standard prophylaxis regimens. The disease is the leading cause of early morbidity and mortality in matched unrelated donor transplant, where death directly attributable to acute GvHD or its treatment occurs in 10% to 20% of patients. There are currently no FDA-approved preventive therapies and very few treatment options for acute GvHD.

About ProTmune
ProTmune is an investigational next-generation hematopoietic cell graft for the prevention of acute graft-versus-host disease (GvHD) in patients undergoing allogeneic hematopoietic cell transplantation. ProTmune is manufactured by pharmacologically modulating a donor-sourced, mobilized peripheral blood graft ex vivo with two small molecules (FT1050 and FT4145) to decrease the morbidity and mortality of acute GvHD while maintaining the anti-leukemia activity of the graft. ProTmune has been granted Orphan Drug and Fast Track Designations by the U.S. Food and Drug Administration, and Orphan Medicinal Product Designation by the European Commission.

On December 11, 2017 Actinium Pharmaceuticals, Inc. (NYSE American:ATNM) ("Actinium" or "the Company") reported positive preliminary data from its ongoing Phase 2 trial of Actimab-A in patients newly diagnosed with Acute Myeloid Leukemia (AML) who are over the age of 60 and not able to tolerate induction chemotherapy (Press release, Actinium Pharmaceuticals, DEC 11, 2017, View Source [SID1234522522]). Actinium Pharmaceuticals is a clinical-stage biopharmaceutical company focused on developing and commercializing targeted therapies for safer myeloablation and conditioning of the bone marrow prior to a bone marrow transplant, and for the targeting and killing of cancer cells. Actimab-A is an ARC or Antibody Radio-Conjugate comprised of the anti-CD33 antibody lintuzumab labeled with the alpha-emitting isotope Actinium-225. Actimab-A is the lead candidate from Actinium’s CD33 Program, which now includes two additional indications; Actimab-M in Multiple Myeloma and Actimab-MDS as a bridge to transplant in TP53 positive patients with Myelodysplastic Syndrome.

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Patients in the Phase 2 trial had an Overall Response Rate (ORR) of 69% when treated with 2.0 µCi/kg/fraction of Actimab-A administered as a single agent via two infusions administered on day 1 and day 8. In addition, patients that were evaluable had a median reduction in bone marrow blasts of 98%. Actinium had previously reported a 56% response rate in patients that were evaluable at time of the abstract submission when data were available on 9 patients compared to the 13 patients reported in the poster. The Phase 2 trial of Actimab-A is designed to enroll 53 patients, with a formal interim analysis scheduled when 31 patients have been enrolled with the target ORR for the study being thirty-five percent. This hurdle rate has been exceeded with the first thirteen patients treated at 2.0 µCi/kg/fraction and the number of responses needed at the interim analysis of 31 patients to progress the trial to the full 53 patients was also cleared in these initial 13 patients. Consequently, the Company has elected to continue the trial at a lower dose in order to develop the best therapeutic profile based on balancing the myelosupressive effect seen at 2.0 µCi/kg/fraction versus the efficacy seen at both the 2.0 µCi/kg/fraction (50% ORR in Phase 1 and 69% ORR in Phase 2) and the 1.5 µCi/kg/fraction (67% ORR in Phase 1). After making suitable protocol modifications the trial is again robustly enrolling patients who will now receive Actimab-A at 1.5 µCi/kg/fraction. This dose had the highest response rate of any dose cohort in the most recent Phase 1 trial of Actimab-A with patients receiving this dose having a 67% ORR.

Dr. Mark Berger, Actinium’s Chief Medical Officer, said, "It is incredibly exciting to see these high response rates and the huge reduction in bone marrow blasts from Actimab-A as a single agent, which I attribute to the targeting ability and potency of our ARC based approach. Having led the development and initial approval of Mylotarg, the only CD33 targeting agent approved in AML, I have since had tremendous interest in this field and today’s results confirm my initial inclination that Actimab-A has the potential to be highly differentiated and potentially best-in-class. In addition to these highly encouraging results, we have gained invaluable insights into the profile of Actimab-A that we will leverage to drive value going forward. Given that Actimab-A had a higher response rate of 67% at the 1.5 µCi/kg/fraction compared to a 50% response rate at 2.0 µCi/kg/fraction in our most recent Phase 1 trial, I am excited to be moving ahead with our new dose level, which I believe will be associated with strong efficacy, acceptable myelosuppression and meet the goals for the remainder of the study. Given Actimab-A’s highly differentiated mechanism of action, we believe it can be used synergistically with other treatments to increase efficacy but with minimal increase in toxicities."

Compared to other AML agents, very few possibly related extramedullary toxicities were observed with only two (pneumonia and septic shock) being observed in more than one patient, both of which were observed in two patients each. Importantly, no case of veno-occlusive disease, a potentially fatal complication of the liver that can preclude a patient from receiving a stem cell transplant, was observed in any of the patients. Grade 4 myelosuppression was observed in all evaluable patients.

Dr. Berger continued, "These additional data are consistent with previous data indicating that an anti-CD33 antibody labeled with Actinium-225 has minimal extramedullary toxicities and is highly potent. The combination of these factors has allowed us to pursue Actimab-MDS as a bridge to transplant for patients with myelodysplastic syndrome that have a genetic mutation of the TP53 gene. We are excited to leverage the strengths of the Actimab-A trial to expand the patient population that we can treat with this agent."

Sandesh Seth, Actinium’s Chairman and CEO, said, "In less than a year we have expanded our CD33 Program from a single asset, Actimab-A, to a full-fledged drug development program with the addition of Actimab-M and Actimab-MDS. This is early evidence of the potential of the newly infused talent and upgraded functionality that is being developed in the Company. We take comfort in the fact that now our team has enrolled more patients in our three trials in the second half of 2017 than the combined total enrollment in the four years prior. In 2018, we expect to have topline results with both Actimab-A and Actimab-M, in line with prior guidance, and also begin the newly announced Actimab-MDS trial. Our CD33 targeting ARC’s are showing promise to be utilized for both therapeutic and safer myeloablative purposes. Exemplifying the unique therapeutic promise of our CD33 targeting ARC’s compared to other modalities is the recent involvement of thought leader Dr. Gail Roboz and her consortium who will spearhead the new Actimab-MDS initiative. With these new data in hand, we look forward to continuing to develop our CD33 program as the leading one in the industry in 2018 and beyond."

About Actimab-A

Actimab-A, Actinium’s most advanced CD33 Program candidate, is currently in a multi-center, open-label Phase 2 trial for patients newly diagnosed with AML, age 60 and above, that are ineligible for standard induction chemotherapy. Actimab-A is being developed as a first-line therapy and is a monotherapy that is administered via two 30-minute infusions that are given 7 days apart. Actimab-A is an ARC or Antibody Radio-Conjugate that targets CD33, a protein that is expressed in virtually all patients with AML cells via the monoclonal antibody, lintuzumab, which carries the potent cytotoxic radioisotope Actinium-225 to the AML cancer cells. Actinium-225 gives off high-energy alpha particles as it decays, which kill cancer cells and as actinium-225 decays it produces a series of daughter atoms, each of which gives off its own alpha particle, increasing the chances that the cancer cell will be destroyed by crossfire. Actimab-A is a second-generation therapy from the Company’s CD33 Program, which was developed at Memorial Sloan Kettering Cancer Center and has now been studied in over 100 patients in four clinical trials. Actimab-A has been granted Orphan Drug Designation for newly diagnosed AML in patients 60 and above by the U.S. Food and Drug Administration and the European Medicines Agency.

On December 11, 2017 Italfarmaco Group, a specialty pharmaceutical company, reported the positive results from two clinical trials evaluating its proprietary histone deacetylase (HDAC) inhibitor givinostat in Polycythemia Vera patients -Italfarmaco Group, a specialty pharmaceutical company, reported the positive results from two clinical trials evaluating its proprietary histone deacetylase (HDAC) inhibitor givinostat in Polycythemia Vera patients. The data were presented in an oral and a poster presentation on Saturday December 9th, 2017 at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting & Exposition held in Atlanta, Georgia. In the oral presentation, the company discussed positive safety and efficacy data from a two-part study of givinostat in which over 80% of patients responded to the treatment. These results were further supported by a poster presentation of a long-term evaluation of givinostat’s effect in patients over four years. Combined, the data provide a basis for the company’s decision to proceed with a pivotal Phase III trial in this indication. Polycythemia Vera is a rare blood disease characterized by an increased number of red blood cells, white blood cells and platelets, which significantly raises the risk for thromboembolic and hemorrhagic complications.

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"Polycythemia Vera patients have limited treatment options that currently only ameliorate the symptoms of the disease. We look forward to initiating the planned pivotal study in this indication."
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In the oral presentation at ASH (Free ASH Whitepaper), the principal investigator described the multi-center, open label Phase Ib/II givinostat study, which included a dose-escalation and an evaluation of preliminary efficacy and tolerability. The data demonstrated that givinostat was well tolerated overall at the defined dose of 100 mg twice daily and the majority of adverse events were mild to moderate in severity. The overall response rate was more than 80% according to European Leukemia Net standard response criteria, which measure a range of parameters including reduction of the size of spleen and liver, peripheral blood count, absence of hemorrhagic and thrombotic events and bone marrow analysis.

In the larger study investigating long-term safety and efficacy, Italfarmaco researchers and collaborators presented data supporting the potential of givinostat as a durable treatment option that reduces the symptoms and underlying risks of the disease while remaining well-tolerated. Overall, 80% of patients maintained at least a partial response for more than four years. After four years of treatment no patient reported microvascular symptoms or headaches. Pruritus (itchiness), one of the typical symptoms of Polycythemia Vera, was absent in 67% of the patients. Furthermore, the overall incidence of thrombosis (1.13% patients per year) was reduced in comparison to the expected incidence rate in this patient population (3% patients/year). Givinostat treatment additionally reduced the levels of mutated Janus Kinase 2 (JAK2), a key underlying cause of the disease, by 25% in over 40% of the patients.

"The givinostat Phase II proof-of-concept and long-term data are very encouraging and demonstrate the potential of this compound to address the underlying mechanism of the disease while remaining well-tolerated," said Dr. Paolo Bettica, Vice President Research and Development. "Polycythemia Vera patients have limited treatment options that currently only ameliorate the symptoms of the disease. We look forward to initiating the planned pivotal study in this indication."

"Italfarmaco is particularly gratified that these results were selected for presentation at ASH (Free ASH Whitepaper) because they underscore the value of our internal research and development efforts," added Dr. Francesco De Santis, President of Italfarmaco.

About Polycythemia Vera

Polycythemia Vera is a rare blood disease characterized by an overproduction of red blood cells, white blood cells and platelets, which thickens the blood and increases the risk of blood clots, a major underlying cause of life-threatening conditions such as thrombosis, embolisms, heart attack or stroke. The disease is associated with mutations in the Janus Kinase 2 (JAK2) gene and disease-related symptoms include headaches, itching and microvascular symptoms. The current standard of care ranges from phlebotomy alone or in combination with low-dose aspirin, to drugs such as the cytoreductive hydroxycarbamide or the JAK inhibitor ruxolitinib. These reduce symptoms, but no treatments targeting the underlying disease mechanism are available.

About Givinostat

Givinostat is a potent, orally-available, class I and II histone deacetylase (HDAC) inhibitor and an investigational product discovered through Italfarmaco’s internal research and development efforts. Through the pharmacological modulation of cell growth, differentiation and apoptosis and the additional specific inhibition of the proliferation of cells bearing the JAK2V617F mutation, givinostat may represent a novel disease modifier in Polycythemia Vera. Besides these properties, givinostat has shown immuno-modulatory activity that may specifically target other diseases, making it a very promising candidate for Duchenne Muscular Dystrophy (Phase III) and Becker Muscular Dystrophy (Phase II). The data were presented in an oral and a poster presentation on Saturday December 9th, 2017 at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting & Exposition held in Atlanta, Georgia. In the oral presentation, the company discussed positive safety and efficacy data from a two-part study of givinostat in which over 80% of patients responded to the treatment. These results were further supported by a poster presentation of a long-term evaluation of givinostat’s effect in patients over four years. Combined, the data provide a basis for the company’s decision to proceed with a pivotal Phase III trial in this indication. Polycythemia Vera is a rare blood disease characterized by an increased number of red blood cells, white blood cells and platelets, which significantly raises the risk for thromboembolic and hemorrhagic complications.

"Polycythemia Vera patients have limited treatment options that currently only ameliorate the symptoms of the disease. We look forward to initiating the planned pivotal study in this indication."
Tweet this
In the oral presentation at ASH (Free ASH Whitepaper), the principal investigator described the multi-center, open label Phase Ib/II givinostat study, which included a dose-escalation and an evaluation of preliminary efficacy and tolerability. The data demonstrated that givinostat was well tolerated overall at the defined dose of 100 mg twice daily and the majority of adverse events were mild to moderate in severity. The overall response rate was more than 80% according to European Leukemia Net standard response criteria, which measure a range of parameters including reduction of the size of spleen and liver, peripheral blood count, absence of hemorrhagic and thrombotic events and bone marrow analysis.

In the larger study investigating long-term safety and efficacy, Italfarmaco researchers and collaborators presented data supporting the potential of givinostat as a durable treatment option that reduces the symptoms and underlying risks of the disease while remaining well-tolerated. Overall, 80% of patients maintained at least a partial response for more than four years. After four years of treatment no patient reported microvascular symptoms or headaches. Pruritus (itchiness), one of the typical symptoms of Polycythemia Vera, was absent in 67% of the patients. Furthermore, the overall incidence of thrombosis (1.13% patients per year) was reduced in comparison to the expected incidence rate in this patient population (3% patients/year). Givinostat treatment additionally reduced the levels of mutated Janus Kinase 2 (JAK2), a key underlying cause of the disease, by 25% in over 40% of the patients.

"The givinostat Phase II proof-of-concept and long-term data are very encouraging and demonstrate the potential of this compound to address the underlying mechanism of the disease while remaining well-tolerated," said Dr. Paolo Bettica, Vice President Research and Development. "Polycythemia Vera patients have limited treatment options that currently only ameliorate the symptoms of the disease. We look forward to initiating the planned pivotal study in this indication."

"Italfarmaco is particularly gratified that these results were selected for presentation at ASH (Free ASH Whitepaper) because they underscore the value of our internal research and development efforts," added Dr. Francesco De Santis, President of Italfarmaco.

About Polycythemia Vera

Polycythemia Vera is a rare blood disease characterized by an overproduction of red blood cells, white blood cells and platelets, which thickens the blood and increases the risk of blood clots, a major underlying cause of life-threatening conditions such as thrombosis, embolisms, heart attack or stroke. The disease is associated with mutations in the Janus Kinase 2 (JAK2) gene and disease-related symptoms include headaches, itching and microvascular symptoms. The current standard of care ranges from phlebotomy alone or in combination with low-dose aspirin, to drugs such as the cytoreductive hydroxycarbamide or the JAK inhibitor ruxolitinib. These reduce symptoms, but no treatments targeting the underlying disease mechanism are available.

About Givinostat

Givinostat is a potent, orally-available, class I and II histone deacetylase (HDAC) inhibitor and an investigational product discovered through Italfarmaco’s internal research and development efforts. Through the pharmacological modulation of cell growth, differentiation and apoptosis and the additional specific inhibition of the proliferation of cells bearing the JAK2V617F mutation, givinostat may represent a novel disease modifier in Polycythemia Vera. Besides these properties, givinostat has shown immuno-modulatory activity that may specifically target other diseases, making it a very promising candidate for Duchenne Muscular Dystrophy (Phase III) and Becker Muscular Dystrophy (Phase II).