Vascular side effects prevent first-line ponatinib use in chronic phase CML

 

In continuation of my update on Ponatinib 

Ponatinib is highly active when given to patients within 6 months of developing chronic phase chronic myeloid leukaemia (CML), phase II results show, but its toxicity profile is unacceptable for first-line treatment.

The investigators, from the University of Texas MD Anderson Cancer Center in Houston, USA, report “deep and early responses” to the third-generation tyrosine kinase inhibitor (TKI) in The Lancet Haematology.

“However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting”, recommend Jorge Cortes and co-authors.

At 6 months, a complete cytogenetic response (CCyR) was achieved by 94% of 46 assessed patients and a major molecular response (MMR, BCR–ABL1 ≤0.1%) by 83%, with undetectable levels of BCR–ABL1 in 22% of assessed patients and a level of 1% or below in 96%.

The median times to a complete haematological response, CCyR and MMR were 0.6, 2.89 and 2.90 months, respectively, and there was 100% overall and transformation-free survival after 2 years.

But the initial starting dose of 45 mg/day in 43 patients was reduced to 30 mg/day or 15 mg/day for 18 patients after tolerability issues, while six of eight patients started on 30 mg/day had the dose reduced to 15 mg/day. At least one treatment interruption was required by 85% of patients, while 88% had their dose reduced due to adverse events (66%) or US Food and Drug Administration (FDA) advice (24%).

All of these patients finally discontinued ponatinib therapy and switched to an alternative TKI following adverse events or FDA concerns about an increased risk of thromboembolism.

In all, 49% of patients experienced cardiac or vascular events and 22% had more than one such episode. These included worsening or new-onset of hypertension, one case each of acute coronary syndrome and myocardial infarction, and three cases of vaso-occlusive disease. Two patients experienced cerebrovascular events, and one patient developed pulmonary hypertension within a month of discontinuing ponatinib.

Vascular side effects prevent first-line ponatinib use in chronic phase CML

MedDay announces additional positive results from MD1003 Phase III trial in patients with progressive MS

MedDay, a biotechnology company focused on the treatment of nervous system disorders, reports additional positive data from its pivotal Phase III clinical trial, MS-SPI, with MD1003, a highly-concentrated pharmaceutical grade biotin, in patients with Progressive Multiple Sclerosis. The data, to be announced on Saturday 20th June at The 1st Congress of the European Academy of Neurology (EAN), shows an improvement of the Clinical Global Impression of change observed after 12 months of treatment with MD1003 and confirms the positive results presented at the American Academy of Neurology in April 2015.

The Clinical Global Impression of change is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. During the MS-SPI trial, the Clinical Global Impression of change has been assessed by the clinician (clinician global impression, CGI) as well as by the patient (subject global impression, SGI) after 12 months of treatment. Mean CGI and SGI scores assessed at month 12 were statistically significantly better in the intervention group compared with the placebo group (p<0.0001 and p=0.0094, respectively).

These important results confirm the previously reported data of MS-SPI where the primary endpoint was defined as the proportion of patients who improved either on EDSS or on timed 25-foot walk (TW25) at M9, with a confirmation of the improvement at 12 months (M12) was met (p=0.0051). The mean change of EDSS between M0 and M12 decreased in the MD1003 group (-0.03) compared to progression in the placebo group (+0.13, p=0.014). In the MD1003 arm, only 4% of patients treated with MD1003 exhibited EDSS progression at M9 confirmed at M12 vs 13% in the placebo group (p=0.07), which equates to a 67% decreased risk of progression in the active arm within the studied period.

MedDay announces additional positive results from MD1003 Phase III trial in patients with progressive MS

Scientists identify new agent to combat tuberculosis

(Griselimycin)

Above pic: The protein forms a homodimeric ring (shown as blue cartoon & surface representation). Each polypetide chain binds one molecule of griselimycin (red). The optimized compound cyclohexylgriselimycin contains an additional cyclohexane moiety (yellow, shown only for the ligand in the foreground).

According to figures of the World Health Organization, some 8.7 million people contracted tuberculosis in 2012 and this disease is fatal for approximately 1.3 million people throughout the world each year. One of the main problems is that the tuberculosis pathogens have become resistant to the antibiotics used to fight them. Scientists from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) in Saarbrücken, the Helmholtz Centre for Infection Research (HZI) in Braunschweig and the German Center for Infection Research (DZIF) joined forces with scientists from Sanofi, a global health care company, and identified a new agent, which might potentially remedy these problems. The scientists just described this agent and its unique mechanism of action in the highly renowned scientific journal Science.

Mycobacterium tuberculosis is the main cause of tuberculosis. The treatment for drug-susceptible tuberculosis consists of the daily administration of multiple drugs for a minimum of six months. Lack of adherence to this regimen can result in treatment failure and the emergence of drug resistance. "Complexity and duration of the treatment are true issues and the main reasons for the development of resistant pathogens," says Prof Rolf Müller, who is the Executive Director and head of the Microbial Natural Substances department of the HIPS, an institution jointly sponsored by the HZI and Saarland University.

Consequently, there is an urgent need for new medications and therapeutic approaches to both fight the resistant pathogens, as well as to shorten the duration for the treatment of drug-susceptible organisms. Based on earlier reports, Müller, in collaboration with Prof Jacques Grosset from the Johns Hopkins University School of Medicine in Baltimore, and his colleagues from the HZI and Sanofi scientists, initially focused on the natural substance called griselimycin. The potential of this natural substance, was discovered in the 1960s. However, due to the success of other tuberculosis medications and its low efficacy in an infection model, the substance was not developed any further at the time.

"We resumed the work on this agent and optimised it such that it shows excellent activity in the infection model - even against multi-resistant tuberculosis pathogens," says Müller. In the course of their work, the scientists discovered that cyclohexylgriselimycin, a variant of griselimycin, is particularly effective against Mycobacterium tuberculosis, both in cells and in the animal model. Importantly, cyclohexylgriselimycin was effective when administered orally, which is key in tuberculosis treatment, non-orally available drugs are extremely burdensome to administer daily during the many months of treatment. Moreover, combining this substance with current TB antibiotics increases the efficacy compared to the antibiotic cocktail that is usually administered.

Scientists identify new agent to combat tuberculosis

Once-weekly Trulicity 0.75 mg shows promising results in Japanese patients with type 2 diabetes

In continuation of my update on dapagliflozin

Results from a new study of Japanese patients with type 2 diabetes showed once-weekly Trulicity™ 0.75 mg provided greater hemoglobin A1c (A1C) reduction compared to once-daily Victoza® 0.9 mg after 52 weeks of treatment. Eli Lilly and Company (NYSE: LLY) will present these data at the 75th American Diabetes Association (ADA) Scientific Sessions in Boston.

"These data not only reinforce once-weekly Trulicity as a safe and efficacious GLP-1 receptor agonist, but further support the value for Japanese patients, with greater A1C reductions compared to once-daily Victoza," said Jessie Fahrbach, M.D., medical director, Lilly Diabetes. "We are pleased to present these study findings, which capture important information about a key region where type 2 diabetes is on the rise."

The study's primary objective was met, with Trulicity 0.75 mg demonstrating a greater A1C reduction from baseline compared to placebo at 26 weeks. At the final endpoint of 52 weeks, which is the focus of the data presentation at the meeting, Trulicity 0.75 mg demonstrated statistically greater A1C reductions compared to Victoza 0.9 mg, the highest approved dose in Japan (-1.39 percent vs. -1.19 percent). Additional results showed:

Trulicity 0.75 mg provided statistically greater reductions in the average self-monitored blood glucose levels compared to Victoza 0.9 mg (-53.1 mg/dL vs. -46.8 mg/dL); and

Trulicity 0.75 mg significantly lowered average post-meal blood glucose levels from baseline compared to Victoza 0.9 mg (-63.7 mg/dL vs. -55.4 mg/dL).

Results from a new study of Japanese patients with type 2 diabetes showed once-weekly Trulicity™ 0.75 mg provided greater hemoglobin A1c (A1C) reduction compared to once-daily Victoza® 0.9 mg after 52 weeks of treatment. Eli Lilly and Company (NYSE: LLY) will present these data at the 75th American Diabetes Association (ADA) Scientific Sessions in Boston.

"These data not only reinforce once-weekly Trulicity as a safe and efficacious GLP-1 receptor agonist, but further support the value for Japanese patients, with greater A1C reductions compared to once-daily Victoza," said Jessie Fahrbach, M.D., medical director, Lilly Diabetes. "We are pleased to present these study findings, which capture important information about a key region where type 2 diabetes is on the rise."

The study's primary objective was met, with Trulicity 0.75 mg demonstrating a greater A1C reduction from baseline compared to placebo at 26 weeks. At the final endpoint of 52 weeks, which is the focus of the data presentation at the meeting, Trulicity 0.75 mg demonstrated statistically greater A1C reductions compared to Victoza 0.9 mg, the highest approved dose in Japan (-1.39 percent vs. -1.19 percent). Additional results showed:

Trulicity 0.75 mg provided statistically greater reductions in the average self-monitored blood glucose levels compared to Victoza 0.9 mg (-53.1 mg/dL vs. -46.8 mg/dL); and Trulicity 0.75 mg significantly lowered average post-meal blood glucose levels from baseline compared to Victoza 0.9 mg (-63.7 mg/dL vs. -55.4 mg/dL).

Once-weekly Trulicity 0.75 mg shows promising results in Japanese patients with type 2 diabetes

Ibrutinib (IMBRUVICA) improves survival in treatment-naïve patients with chronic lymphocytic leukemia

In continuation of my update on Ibrutinib

Pharmacyclics LLC, an AbbVie company, announced that ibrutinib (IMBRUVICA®) improved progression-free survival (PFS; primary endpoint) and multiple secondary endpoints including overall survival (OS) and overall response rate (ORR) in treatment-naïve patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL, respectively) in the final analysis of the Phase III RESONATE™-2 (PCYC-1115) trial. RESONATE-2 is a randomized, multi-center, open-label study assessing the use of ibrutinib versus chlorambucil in treatment-naïve CLL/SLL patients aged 65 years or older. This is the first head-to-head trial in the clinical program that evaluates the safety and efficacy of ibrutinib versus traditional chemotherapy. IMBRUVICA is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

"In collaboration with our partner Janssen, we are very excited by the findings from RESONATE-2 and look forward to sharing the results from what we see as a potentially transformative study for CLL patients," said Danelle James, M.D., M.S., Head of Oncology at Pharmacyclics. "These results from the first IMBRUVICA study for front-line CLL patients may support future treatment paradigms where some CLL patients requiring therapy may not need to be exposed to traditional cytotoxic chemotherapy."

"Over the past several years we've made tremendous progress in treating CLL, thanks in part to therapies such as IMBRUVICA," said Richard A. Gonzalez, Chairman of the Board and Chief Executive Officer at AbbVie. "Based on the results from RESONATE-2, IMBRUVICA continues to demonstrate its strong value and we are very optimistic that it will eventually move into the front-line treatment setting, becoming an alternative option to chemotherapy for previously untreated CLL patients."

Ibrutinib (IMBRUVICA) improves survival in treatment-naïve patients with chronic lymphocytic leukemia

Tentative FDA approval of lopinavir/ritonavir oral pellet formulation closes treatment gap for children with HIV

The Paediatric HIV Treatment Initiative welcomes this important step towards closing the treatment gap for children with HIV

Infants and young children living with HIV will finally have access to an improved formulation of an antiretroviral (ARV) treatment, following the U.S. Food and Drug Administration's (FDA) tentative approval last week of lopinavir/ritonavir (LPV/r) oral pellets developed by the Indian generic company Cipla.

(lopinavir)  (ritonavir)

"The announcement of tentative FDA approval of the lopinavir/ritonavir oral pellet formulation is an important step forward in increasing access to World Health Organization-recommended antiretroviral treatment for children under three years of age," said Ambassador Deborah L. Birx, M.D., U.S. Global AIDS Coordinator and U.S. Special Representative for Global Health Diplomacy. "This supports the goals of key PEPFAR initiatives to improve paediatric HIV/AIDS services, including the Accelerating Children's HIV/AIDS Treatment Initiative and the Global Pediatric ARV Commitment to Action".

Until now, the only available version of this combination treatment was a harsh-tasting syrup that required refrigeration and contained 40% alcohol. Only a quarter of children with HIV are currently on treatment and the lack of child-adapted formulations contributes to this unacceptable situation.

"UNITAID and its partners in the Paediatric HIV Treatment Initiative (PHTI)* also welcome the approval of these oral pellets, which brings us a step nearer to closing the shameful treatment gap for the 3.2 million children living with HIV around the world," said Lelio Marmora, Executive Director of UNITAID which is funding the development of paediatric formulations for HIV.

Importantly, intellectual property issues around access to future LPV/r combinations will be reduced, thanks to a licensing agreement the Medicine Patent Pool (MPP) signed in in December 2014 with AbbVie, the patent holder for LPV/r. "This is a crucial licence for paediatric programmes as it benefits low- and middle-income countries where 99% of children with HIV in the developing world live," said Greg Perry, Executive Director of the MPP.

Tentative FDA approval of lopinavir/ritonavir oral pellet formulation closes treatment gap for children with HIV

AWMSG recommends Daklinza (daclatasvir) for treatment of adult patients with chronic HCV infection

In continuation of my update on daclatasvir 

The All Wales Medicines Strategy Group (AWMSG) has recommended Daklinza®(daclatasvir) for the treatment of adult patients with chronic hepatitis C virus (HCV) infection. The recommendation is specifically for patients with advanced liver disease, for whom treatment options can be limited. Daclatasvir is used in combination with other agents to treat adult patients with chronic HCV genotypes 1, 3 and 4 (which include most of the cases seen in Wales). This decision could enable some of the most ‘at-risk’ patients in Wales with chronic HCV to access a new, first-in-class treatment which has been shown, when used with other agents, to clear the viral infection in most of these patients after 12 or 24 weeks of therapy.

AWMSG recommends Daklinza (daclatasvir) for treatment of adult patients with chronic HCV infection

PALOMA3 supports palbociclib use in advanced breast cancer

In continuation of my update on palbociclib... 

Advanced breast cancer patients who have failed prior endocrine treatment may receive a progression-free survival (PFS) benefit if palbociclib is added to fulvestrant, a phase III trial indicates.

The advantage accorded by the small-molecule inhibitor of CDK4 and CDK6 was irrespective of the menopausal status of the women, the team reports in The New England Journal of Medicine.

The research was concurrently presented at the annual meeting of the American Society of Clinical Oncology, held in Chicago, Illinois, USA.

The double-blind PALOMA3 trial comprised women with advanced breast cancer positive for oestrogen and/or progesterone hormone receptors but negative for epidermal growth factor receptor 2 who had progressed or relapsed during endocrine therapy.

PALOMA3 supports palbociclib use in advanced breast cancer

ASCO 2015: AMGEN presents new data evaluating less-frequent dosing of kyprolis for multiple myeloma patients

Amgen announced the initiation of the ARROW trial, a global Phase 3 study evaluating the benefit of Kyprolis®(carfilzomib) for Injection administered once-weekly with dexamethasone versus the current U.S. Food and Drug Administration (FDA) approved twice-weekly administration schedule in patients with relapsed and refractory multiple myeloma who have received prior treatment with bortezomib and an immunomodulatory agent (IMiD). The trial was initiated based on results from the Phase 1/2 CHAMPION study, which were presented (abstract no. 8527) at the 51stAnnual Meeting of the American Society of Clinical Oncology (ASCO) on Sunday, May 31 at 8:00 a.m. CT.

Results from the Phase 1 and 2 portions of CHAMPION were presented for 104 patients (Phase 1, n=15; Phase 2, n=89) with relapsed or refractory multiple myeloma who had received one to three prior treatment regimens at the determined maximum tolerated dose (MTD) of 20/70 mg/m2. In the Phase 2 portion of the study, the overall response rate (ORR; defined as the percentage of patients achieving a partial response or better) was 77 percent. The clinical benefit rate (CBR; defined as the percentage of patients with minimal response or better) was 84 percent; the median time to response for patients who achieved a partial response or better was 1.6 months (range, 0.7-7.2); Kaplan-Meier median duration of response (DOR) was 15 months (95 percent CI 9-not estimable); and the Kaplan-Meier median progression-free survival (PFS) was 10.6 months (95 percent CI 9.0-16.1).

ASCO 2015: AMGEN presents new data evaluating less-frequent dosing of kyprolis for multiple myeloma patients

Combining targeted drug with chemotherapy offers longer life to b-cell cancer patients

Because of the significant benefit found in combining the targeted drug ibrutinib with standard chemotherapy for relapsed chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), an interim analysis has closed the international HELIOS phase III clinical trial.

Ibrutinib

Led by Mayo Clinic, researchers found that ibrutinib and chemotherapy (bendamustine and rituximab, known as BR) reduced the risk of death or cancer progression by almost 80 percent in patients with previously treated CLL or SLL, compared to use of BR alone.

The announcement was made at a press briefing at the 2015 meeting of the American Society of Clinical Oncology by HELIOS' senior investigator Asher Chanan-Khan, M.D., professor of medicine and chair of Hematology & Oncology, Mayo Clinic Cancer Center in Jacksonville, Florida.

"This finding represents a significant advancement in the management and treatment of this leukemia," says Dr. Chanan-Khan. "Although CLL remains incurable, this new regimen offers longer disease control and a decreased risk of relapse for our patients."

The HELIOS study -- which enrolled 578 patients from centers around the world -- was the first to compare, head-to-head, chemo immunotherapy alone to chemo immunotherapy plus a targeted drug in patients with CLL.

Combining targeted drug with chemotherapy offers longer life to b-cell cancer patients 

Possible New Combination Chemotherapy for Patients with Advanced Prostate Cancer

For more than a decade, oncologists using cytotoxic chemotherapy to treat patients with advanced metastatic castration-resistant prostate cancer (mCRPC) have relied on the sequential use of single agent taxanes such as docetaxel and cabazitaxel. For example, docetaxel is commonly used as the "first-line" therapy, while cabazitaxel is used as the "second-line" therapy. A role for combination therapy using two or more chemotherapy agents at the same time has not been well studied. This week, however, results of a clinical trial presented at the American Society of Clinical Oncology meeting by researchers at The University of Texas MD Anderson Cancer Center may change the perspective on a role for combination chemotherapy in advanced disease.

 Carboplatin  Cabazitaxel   Docetaxel

The study compared the effectiveness of cabazitaxel alone versus cabazitaxel combined with carboplatin -- a type of platinum chemotherapy -- in patients with metastatic castrate-resistant prostate cancer (mCRPC). To date, 160 men have been randomized to treatment with either the single or dual chemotherapy drug regimen. Each patient received up to 10 cycles of chemotherapy.

To monitor the effects of treatment, MD Anderson researchers tracked several variables including Progression Free Survival, as well as changes in blood levels of prostate-specific antigen (PSA) and bone-specific alkaline phosphatase (BAP, a marker of prostate cancer in bone cells). In addition, safety and toxicity were monitored for both patient groups.

Analysis and comparison of the data demonstrated that median PFS was significantly longer for patients receiving combination versus single agent chemotherapy (6.7 months vs 4.4 months, respectively, p = 0.01). Furthermore, reductions in both PSA and BAP were greater for the combination therapy group. PSA reductions greater than 50 percent occurred 60 percent of the time with combined chemotherapy vs. 44 percent with the single drug. PSA reductions greater than 90 percent occurred 28 percent of the time with two chemotherapy drugs vs. 20 percent with one. In addition, BAP reductions greater than 50 percent for combination vs. single drug were 63 percent and 25 percent respectively.

Side effects, such as fatigue, anemia and neutropenia were comparable for both the single-drug regimen and two-drug regimen. In addition, there were no significant toxicity events.

"We believe cabazitaxel-carboplatin combination chemotherapy may become the clinical standard for advanced prostate cancer once additional safety, efficacy and overall survival data is generated," explained Paul Corn, M.D., Ph.D., an associate professor of genitourinary medical oncology at MD Anderson. "Dr. Ana Aparicio's lab is currently developing tumor-specific biomarkers to identity patients with an aggressive variant of prostate cancer most likely to benefit from this approach."

Possible New Combination Chemotherapy for Patients with Advanced Prostate Cancer 

Targeted drug can ‘diminish the suffering’ of myelofibrosis

Investigators further found that pacritinib could be used safely in patients with myelofibrosis who have thrombocytopenia, a life-threating loss of blood platelets that can lead to deadly bleeding. The only currently approved therapy for myelofibrosis   ruxolitinib   is not recommended in patients who have severe thrombocytopenia.

 Pacritinib  Ruxolitinib

Ruben A. Mesa, M.D., chair of Hematology and Medical Oncology at Mayo Clinic in Arizona, will present these results at a press conference held during the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

"Use of pacritinib can alleviate the burden and diminish the suffering that this cancer causes," says Dr. Mesa. "For many of the patients who used it, pacritinib is a very good drug. The agent was significantly superior to other medical treatments.

"It is too early to know if pacritinib has an impact on survival, but that is clearly our expectation," he adds.

Mayo researchers led by Dr. Mesa were also part of a phase 2 trial that found pacritinib offered significant benefit in treating the disorder.

Myelofibrosis is a chronic bone-marrow disorder that can lead to lowering of blood counts, scarring in the bone marrow, severe symptoms and enlargement of the spleen. Myelofibrosis can be life threatening for afflicted patients because of the debilitation the disease causes and/or progression to acute leukemia, Dr. Mesa says.

Myelofibrosis is one of three blood cancers classified as myeloproliferative neoplasms (MPNs), and MPN affects about 350,000 people in the U.S., he says.

In this study, two-thirds of the 327 patients with primary and secondary myelofibrosis were treated with pacritinib. The other one-third were treated with best available therapy (BAT), but were able to cross over to use of pacritinib if their cancer was largely nonresponsive. BAT was chosen by the patient's physician, but did not include ruxolitinib because many patients were not eligible for it due to existing thrombocytopenia.

Pacritinib, an oral drug, is known as a JAK2/FLT3 inhibitor. JAK2 is a protein that acts like an on-off growth switch in blood cells.

"The JAK2 pathway is abnormally turned on in patients, which leads to this chronic leukemia. This drug turns off that switch," Dr. Mesa says.

PERSIST-1 investigators found that medium duration of treatment on the study was 16-plus months, and that by six months, spleen size was reduced in 25 percent of evaluable patients treated with pacritinib compared to 6 percent in the BAT group. Almost 80 percent of BAT patients crossed over to use of pacritinib, and 21 percent of all pacritinib patients had achieved a reduction in spleen volume of 35 percent or more. Symptoms of the cancer were reduced in more than 46 percent of pacritinib-treated patients compared to 9 percent in patients given BAT.

Targeted drug can ‘diminish the suffering’ of myelofibrosis 

Promising preliminary results for AKB-9778 in diabetic macular oedema

AKB-9778, a small molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase (VE-PTP), has a good safety and efficacy profile in patients with diabetic macular oedema, suggests a preliminary dose-escalation study. 

By blocking VE-PTP, AKB-9778 promotes the activation of Tie2, a protein involved in the regulation of vascular permeability, explain the researchers. In preclinical studies, AKB-9778 has been shown to suppress vascular leakage as well as neovascularisation of the retina and choroid, they add.

In this phase Ib trial, four groups of six patients were treated with open-label AKB-9778 self-administered twice daily via subcutaneous injections at doses of 5.0 mg, 15.0 mg, 22.5 mg or 30.0 mg for 4 weeks.

Participants treated with the higher 22.5 mg and 30.0 mg doses, but not those given the 5.0 mg and 15.0 mg doses, experienced headache, dizziness and vasovagal events such as presyncope or syncope – adverse events that are consistent with the anticipated vasodilatory activity of AKB-9778, say the researchers.

“Modest decreases” in resting systolic blood pressure were also observed in the 22.5 mg and 30.0 mg groups, they report, adding that these effects and the adverse events were “transient” and “generally resolved” shortly after dosing.

At 4 weeks, best-corrected visual acuity (BCVA) improved from intake in the 15.0 mg, 22.5 mg and 30.0 mg groups; of 18 participants, 10 achieved an improvement of five to 10 letters, one improved by 11 letters and two by over 15 letters.

Moreover, seven patients who received AKB-9778 at doses of 15.0 mg or more showed decreases in study eye central subfield thickness (CST) from baseline, with reductions of over 100 μm in five patients and of 50 to 100 μm in two patients.

Promising preliminary results for AKB-9778 in diabetic macular oedema

JAK2 inhibitor ruxolitinib shows promise in treating CMML patients

In continuation of my update on Ruxolitinib

Chronic myelomonocytic leukemia (CMML) is a rare type of myelodysplastic, myeloproliferative neoplasm characterized by increased numbers of peripheral monocytes and less than 20 percent blasts. CMML has few treatment options and patients only survive on average for 12 to 24 months. Preclinical studies suggest that JAK2 inhibitors may be an effective treatment option for CMML. Eric Padron, M.D., assistant member of the Malignant Hematology Program at Moffitt Cancer Center will report on the first phase 1 study of the JAK2 inhibitor ruxolitinib in CMML patients at the 2015 American Society of Clinical Oncology Annual Meeting in Chicago.

The Moffitt team and their collaborators performed a dose-escalation study of ruxolitinib in 19 CMLL patients. Ruxolitinib displayed minimal toxicity, with no dose-limiting toxicities observed and only one grade 3 or higher adverse event.

Efficacy data suggest that ruxolitinib is a promising treatment option for CMML patients. Out of fifteen patients who were evaluable for response, 3 displayed hematologic improvement and 1 patient had a partial response. Nine of the patients entered the trial with an enlarged spleen, and 5 of these patients had a greater than 50 percent reduction in their spleen size.

Ruxolitinib may be particularly beneficial for patients who have B symptoms, as 10 out of 11 patients with disease related symptoms had a clinically meaningful or complete resolution of their symptoms.

The researchers determined a phase 2 recommended dose of 20 mg twice a day, and a phase 2 study of ruxolitinib in CMML patients is planned.

JAK2 inhibitor ruxolitinib shows promise in treating CMML patients

Metformin can reduce risk of open-angle glaucoma in people with diabetes

In continuation of my update on metformin

Taking the medication metformin hydrochloride was associated with reduced risk of developing the sight-threatening disease open-angle glaucoma in people with diabetes, according to a study published online by JAMA Ophthalmology.

Medications that mimic caloric restriction such as metformin can reduce the risk of some late age-onset disease. It is unknown whether these caloric mimetic drugs affect the risk of age-associated eye diseases such as macular degeneration, diabetic retinopathy, cataract or glaucoma.

Researcher Julia E. Richards, Ph.D., of the University of Michigan, Ann Arbor, and co-authors examined metformin use and the risk of open-angle glaucoma (OAG) using data from a large U.S. managed care network from 2001 through 2010.

Of 150,016 patients with diabetes, 5,893 (3.9 percent) developed OAG. Throughout the study period, 60,214 patients (40.1 percent) filled at least one metformin prescription; 46,505 (31 percent) filled at least one sulfonylurea prescription; 35,707 (23.8 percent) filled at least one thiazolidinedione prescription; 3,663 (2.4 percent) filled at least one meglitinide prescription; and 33,948 (22.6 percent) filled at least one insulin prescription. Some patients filled prescriptions for multiple medications.

Metformin can reduce risk of open-angle glaucoma in people with diabetes

Amgen announces AMG 416 Phase 3 results for treatment of secondary hyperparathyroidism in CKD patients

Amgen announced THE pooled data from two pivotal Phase 3, global, randomized, placebo-controlled trials evaluating AMG 416, a novel calcimimetic, for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) receiving hemodialysis. Both studies met the primary endpoint, demonstrating that a greater proportion of patients in the AMG 416 groups achieved a greater than 30 percent reduction in parathyroid hormone (PTH) during the Efficacy Assessment Phase compared with placebo. The data were presented today at the 52nd ERA-EDTA Congress in London.

"Secondary hyperparathyroidism is a complex and challenging condition that can be difficult to manage, as it may require patients to take demanding drug regimens multiple times a day," said John Cunningham, lead author of the studies, professor of Nephrology at the University College London Medical School and consultant physician at The Royal Free Hospital, London. "Providing patients with chronic kidney disease on hemodialysis with a calcimimetic that can be administered intravenously on the same schedule as dialysis has the potential to fulfill an unmet need in this patient population."

AMG 416 is a novel calcimimetic agent in clinical development for the treatment of SHPT in patients with CKD who are receiving hemodialysis. In the registrational programs, AMG 416 is administered intravenously at the end of dialysis. AMG 416 acts by binding to and activating the calcium-sensing receptor on the parathyroid gland, thereby causing decreases in PTH. Sustained elevations in PTH are known to lead to significant clinical consequences for patients with CKD.

In the two Phase 3 placebo-controlled studies, an aggregate of 1,023 patients with moderate-to-severe SHPT (PTH greater than 400 pg/mL) on hemodialysis were randomized to receive intravenous AMG 416 or placebo three times a week. The primary endpoint of both studies was the proportion of patients achieving greater than 30 percent reduction in PTH during the Efficacy Assessment Phase, defined as weeks 20 through 27. Secondary endpoints included the proportion of patients with PTH less than or equal to 300 pg/mL, and percent reductions in PTH, albumin adjusted calcium (cCa), phosphate (P) and cCa x P. In the AMG 416 group, 74.7 percent of patients achieved a greater than 30 percent reduction from baseline in PTH compared with 8.9 percent in the placebo arm.

Amgen announces AMG 416 Phase 3 results for treatment of secondary hyperparathyroidism in CKD patients

Study expands understanding of the production of ET-743 compound

In continuation of my update on Trabectedin

For decades, scientists have known that ET-743, a compound extracted from a marine invertebrate called a mangrove tunicate, can kill cancer cells. The drug has been approved for use in patients in Europe and is in clinical trials in the U.S.

Scientists suspected the mangrove tunicate, which is a type of a sea squirt, doesn't actually make ET-743. But the precise origins of the drug, which is also known as trabectedin, were a mystery.

By analyzing the genome of the tunicate along with the microbes that live inside it using advanced sequencing techniques, researchers at the University of Michigan were able to isolate the genetic blueprint of the ET-743's producer--which turns out to be a type of bacteria called Candidatus Endoecteinascidia frumentensis.

The findings greatly expand understanding of the microbe and of how ET-743 is produced, the researchers reported online May 27 in the journal Environmental Microbiology. They're optimistic that the insights will help make it possible to culture the bacteria in the laboratory without its host.

"These symbiotic microbes have long been thought to be the true sources of many of the natural products that have been isolated from invertebrates in the ocean and on the land. But very little is known about them because we're not able to get most of them to grow in a laboratory setting," said study senior author David Sherman, the Hans W. Vahlteich Professor of Medicinal Chemistry in the College of Pharmacy and a faculty member of the U-M Life Sciences Institute, where his lab is located.

"Currently, many of these compounds can only be harvested in small amounts from host animals, which is unsustainable from an economic and environmental perspective," said Michael Schofield, one of two first authors on the study and a member of the Sherman lab before she graduated from U-M this spring. "Our hope is that understanding the genomes of these micro-organisms and the chemical reactions that occur inside of them will provide new avenues to economical and sustainable production of the medicinal molecules they make."

ET-743 is currently made using a complicated, partially synthetic process.

"A major challenge of sequencing genomes from samples containing a mixture of different organisms is figuring out which DNA sequences go with which organisms. We used bioinformatic approaches that allowed us to tease that apart," said Sunit Jain, a bioinformatics specialist in the U-M Department of Earth and Environmental Sciences, and the study's other first author.

Study expands understanding of the production of ET-743 compound

Omega-3 fatty acids improve cognitive flexibility in older adults at risk of late-onset Alzheimer's disease

A study of older adults at risk of late-onset Alzheimer's disease found that those who consumed more omega-3 fatty acids did better than their peers on tests of cognitive flexibility -- the ability to efficiently switch between tasks -- and had a bigger anterior cingulate cortex, a brain region known to contribute to cognitive flexibility.

 

[alpha-linolenic acid (ALA), an essential omega-3 fatty acid, (18:3Δ9c,12c,15c, which means a chain of 18 carbons with 3 double bonds on carbons numbered 9, 12, and 15)].

The analysis suggests, but does not prove, that consuming DHA and EPA, two omega-3 fatty acids found in fish, enhanced cognitive flexibility in these adults in part by beefing up the anterior cingulate cortex, the researchers report in the journal Frontiers in Aging Neuroscience.

"Recent research suggests that there is a critical link between nutritional deficiencies and the incidence of both cognitive impairment and degenerative neurological disorders, such as Alzheimer's disease," said University of Illinois neuroscience, psychology, and speech and hearing science professor Aron Barbey, who led the study with M.D./Ph.D. student Marta Zamroziewicz. "Our findings add to the evidence that optimal nutrition helps preserve cognitive function, slow the progression of aging and reduce the incidence of debilitating diseases in healthy aging populations."

The researchers focused on aspects of brain function that are sometimes overlooked in research on aging, Zamroziewicz said. "A lot of work in cognitive aging focuses on memory, but in fact cognitive flexibility and other executive functions have been shown to better predict daily functioning than memory does," she said.

"Executive function" describes processes like planning, reasoning, paying attention, problem solving, impulse control and task switching.

"These functions tend to decline earlier than other cognitive functions in aging," Zamroziewicz said.

The new research built on previous studies that found associations between omega-3 fatty acid consumption, cognitive flexibility and the size of the anterior cingulate cortex.

"There's been some work to show that omega-3 fatty acids benefit cognitive flexibility, and there's also been work showing that cognitive flexibility is linked to this specific brain region, the anterior cingulate. But there's been very little work actually connecting these pieces," Zamroziewicz said.

The new study focused on 40 cognitively healthy older adults between the ages of 65 and 75 who are carriers of a gene variant (APOE e4) that is known to contribute to the risk of developing late-onset Alzheimer's disease.

The researchers tested participants' cognitive flexibility, measured levels of the fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) in their blood, and imaged their brains using MRI. Statistical analyses teased out the relationships between these factors.

"We wanted to confirm that higher omega-3 fatty acids related to better cognitive flexibility, and we did in fact see that," Zamroziewicz said. "We also wanted to confirm that higher omega-3 fatty acids related to higher volume in the anterior cingulate cortex, and we saw that. Finally, we were able to show that higher volume in the anterior cingulate cortex was an intermediary in the relationship between omega-3 fatty acids and cognitive flexibility."

 Docosahexaenoic acid

  Eicosapentaenoic acid

Omega-3 fatty acids improve cognitive flexibility in older adults at risk of late-onset Alzheimer's disease