FDA Approves RediTrex (methotrexate) for Rheumatoid Arthritis, Juvenile Idiopathic Arthritis, and Psoriasis

In continuation of my update on methotrexate

Cumberland Pharmaceuticals Inc. (NASDAQ: CPIX), a specialty pharmaceutical company, today announced that it has received approval from the U.S. Food and Drug Administration (FDA) for RediTrex, its new line of methotrexate products.

RediTrex (methotrexate) injection is designed for the treatment of adult and pediatric patients with rheumatoid arthritis, as well as adults with psoriasis. The approval of the product came after a number of communications with the FDA and several amendments to the New Drug Application we submitted to the FDA in late 2018.

Methotrexate is approved in the U.S. as both an oral and injectable treatment. While oral formulations are widely available, injectable methotrexate has been shown to result in increased efficacy, greater continuation rates and less discomfort for patients. Cumberland's methotrexate products will provide enhancements and patient benefits over conventional injectable methotrexate products currently available in the U.S.

Cumberland has acquired exclusive U.S. commercial rights to Nordic Group B.V.'s (Nordic) injectable methotrexate line of products. Nordic is a privately-owned European pharmaceutical company with a presence in 17 countries. The company focuses on the development and commercialization of niche hospital and orphan products, aiming to address unmet medical needs. Nordic's methotrexate products are established market leaders in multiple European countries.

"We are delighted by the FDA approval of RediTrex for the United States," said A.J. Kazimi, Chief Executive Officer of Cumberland Pharmaceuticals. "We are looking forward to bringing this important product to the patients seeking an easy-to-use methotrexate injectable."

Cumberland will launch two injectable methotrexate product lines within the U.S., with both product offerings intended for the treatment of active rheumatoid arthritis, juvenile idiopathic arthritis and severe psoriasis.

The injectable U.S. methotrexate market totaled over 670,000 prescriptions last year, with approximately $80 million in overall sales. This methotrexate market has grown at a rate of 72 percent over the previous three years. Cumberland's goal is to achieve a significant share of the injectable methotrexate market over time through the introduction of RediTrex.

https://en.wikipedia.org/wiki/Methotrexate

FDA Approves Rinvoq (upadacitinib), an Oral JAK Inhibitor for the Treatment of Moderate to Severe Rheumatoid Arthritis

In continuation of my update on Rinvoq (upadacitinib)

AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved Rinvoq (upadacitinib), a 15 mg, once-daily oral Janus kinase (JAK) inhibitor, for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX-IR).1 Rinvoq is expected to be available in the U.S. in late August 2019.

The FDA approval of Rinvoq is supported by data from the SELECT program, one of the largest registrational Phase 3 programs in RA with approximately 4,400 patients evaluated across all treatment arms in five studies.2-6 The studies include assessments of efficacy, safety and tolerability across a variety of RA patients, including those who failed or were intolerant to biologic disease-modifying anti-rheumatic drugs and who were naïve or inadequate responders to methotrexate. Rinvoq is not indicated for methotrexate-naïve patients.

"Despite the availability of multiple treatment options with varying mechanisms of action, many patients still do not achieve clinical remission or low disease activity—the primary treatment goals for rheumatoid arthritis," said Roy M. Fleischmann, M.D., primary investigator for SELECT-COMPARE and clinical professor at the University of Texas Southwestern Medical Center at Dallas. "With this FDA approval, Rinvoq has the potential to help additional people living with RA achieve remission who have not yet reached this goal."

Across the SELECT Phase 3 studies, Rinvoq met all primary and ranked secondary endpoints. The primary endpoints include:

• In SELECT-EARLY, 52 percent of MTX-naïve patients treated with Rinvoq 15 mg achieved ACR50 vs 28 percent treated with MTX at week 121
• In SELECT-MONOTHERAPY, 68 percent of MTX-IR patients treated with Rinvoq 15 mg achieved ACR20 vs 41 percent treated with continued MTX at week 141
• In SELECT-COMPARE, 71 percent of MTX-IR patients treated with Rinvoq 15 mg plus MTX achieved ACR20 vs 36 percent treated with placebo plus MTX at week 121
• In SELECT-NEXT, 64 percent of csDMARD-IR patients treated with Rinvoq 15 mg plus csDMARDs achieved ACR20 vs 36 percent treated with placebo plus csDMARDs at week 121
• In SELECT-BEYOND, 65 percent of biologic-IR patients treated with Rinvoq 15 mg plus csDMARDs achieved ACR20 vs 28 percent treated with placebo plus csDMARDs at week 121

"The discovery and development of Rinvoq is indicative of AbbVie's long-standing commitment to advancing the science for people living with immune-mediated conditions," said Michael Severino, M.D., vice chairman and president, AbbVie. "Today's FDA approval marks an important milestone in our pursuit to deliver innovative medicines that advance care for people living with rheumatoid arthritis."

Clinical Remission

Patients taking Rinvoq achieved clinical remission, a state characterized by almost no disease activity and symptoms, even without methotrexate.2-3,6 Approximately 30 percent of patients treated with Rinvoq achieved clinical remission (as assessed by DAS28-CRP<2.6) at week 12 in SELECT-COMPARE and week 14 in SELECT-MONOTHERAPY compared to six percent with placebo plus methotrexate and eight percent with methotrexate, respectively.1 In SELECT-EARLY, 36 percent of patients treated with Rinvoq achieved clinical remission (as assessed by DAS28-CRP<2.6) at week 12 compared to 14 percent with methotrexate.1 

Durable remission rates were observed up to week 26. Forty-eight percent of patients treated with Rinvoq alone in SELECT-EARLY and 41 percent of patients treated with Rinvoq plus methotrexate in SELECT-COMPARE achieved clinical remission at weeks 24 and 26, compared to nine percent with placebo plus methotrexate and 18 percent with methotrexate, respectively.1 Analysis at weeks 24 and 26 were not controlled for multiple comparisons.3,10

Radiographic Inhibition

Rinvoq significantly inhibited radiographic progression as measured by the change in modified total Sharp score (mTSS) from baseline compared to methotrexate in SELECT-EARLY (0.14 vs 0.67) and Rinvoq plus methotrexate compared to placebo plus methotrexate in SELECT-COMPARE (0.15 vs 0.78) through weeks 24 and 26, respectively.1 

Safety

The most common side effects associated with Rinvoq include upper respiratory tract infections (common cold, sinus infections), nausea, cough and pyrexia.1 Patients treated with Rinvoq are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include tuberculosis (TB), invasive fungal, bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.1 Lymphoma and other malignancies have been observed in Rinvoq-treated patients.1 Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with JAK inhibitors used to treat inflammatory conditions.1 Patients treated with RINVOQ also may be at risk for other serious adverse reactions, including gastrointestinal perforations, neutropenia, lymphopenia, anemia, lipid elevations, liver enzyme elevations, and embryo-fetal toxicity.1 

Ease of Use and Access

Designed to help accommodate the physical limitations of people living with RA, the packaging for Rinvoq includes a bottle cap with a wide, easy-to-grip texture and an embedded tool that punctures the foil liner to simplify medication access. This packaging design was awarded the Arthritis Foundation Ease of Use Commendation.

"Rheumatoid arthritis can have a debilitating impact on the lives of those with the chronic disease, including making it difficult to perform everyday tasks," said Cindy McDaniel, senior vice president, consumer health, Arthritis Foundation. "The Arthritis Foundation is committed to recognizing innovation that can help patients living with rheumatoid arthritis and we are proud to recognize AbbVie with our Ease of Use Commendation for the packaging design of Rinvoq."

AbbVie continues to work closely with key stakeholders to support patient access to Rinvoq, including offering a patient support program and a co-pay card that may reduce out-of-pocket costs to $5 per month for eligible, commercially-insured patients. For those with limited or no health insurance, AbbVie offers myAbbVie Assist, a patient assistance program that provides Rinvoq to qualifying patients.

https://en.wikipedia.org/wiki/Upadacitinib

https://www.drugbank.ca/drugs/DB15091

FDA Approves Boxed Warning About Increased Risk of Blood Clots and Death with Higher Dose of Tofacitinib (Xeljanz, Xeljanz XR)

In continuation of my update on tofacitinib 

The U.S. Food and Drug Administration has approved new warnings about an increased risk of blood clots and of death with the 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR), which is used in patients with ulcerative colitis. In addition, the approved use of tofacitinib for ulcerative colitis will be limited to certain patients who are not treated effectively or who experience severe side effects with certain other medicines. We approved these changes, including adding our most prominent Boxed Warning, after reviewing interim data from an ongoing safety clinical trial of tofacitinib in patients with rheumatoid arthritis (RA) that examined a lower and this higher dose of the medicine.

The 10 mg twice daily dose of tofacitinib is not approved for RA or psoriatic arthritis (PsA). This dose is only approved for ulcerative colitis for initial treatment and for long-term use in limited situations. While the increased risks of blood clots and of death were seen in patients taking this dose for RA, these risks may also apply to those taking tofacitinib for ulcerative colitis.

Tofacitinib works by decreasing the activity of the immune system; an overactive immune system contributes to RA, PsA, and ulcerative colitis. Tofacitinib was first approved in 2012 to treat adult patients with RA who did not respond well to the medicine methotrexate. In RA, the body attacks its own joints, causing pain, swelling, and loss of function. In 2017, we approved the medicine to treat patients with a second condition that causes joint pain and swelling, PsA, who did not respond well to methotrexate or other similar medicines. In 2018, we approved tofacitinib to treat ulcerative colitis, which is a chronic, inflammatory disease affecting the colon.

Patients should tell your health care professionals if you have a history of blood clots or heart problems, and talk to them about any questions or concerns. Stop taking tofacitinib and seek emergency medical attention right away if you experience any unusual symptoms, including those that may signal a blood clot such as:

• Sudden shortness of breath
• Chest pain that worsens with breathing
• Swelling of a leg or arm
• Leg pain or tenderness, or red or discolored skin in the painful or swollen leg or arm

Do not stop taking tofacitinib without first talking to your health care professional, as doing so can worsen your condition.

Health care professionals should discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis. Counsel patients about the risks and advise them to seek medical attention immediately if they experience any unusual symptoms, including those of thrombosis listed above. Reserve tofacitinib to treat ulcerative colitis for patients who have failed or do not tolerate tumor necrosis factor (TNF) blockers. Avoid tofacitinib in patients who may have a higher risk of thrombosis. When treating ulcerative colitis, use tofacitinib at the lowest effective dose and limit the use of the 10 mg twice daily dosage to the shortest duration needed (See Additional Information for Health Care Professionals for more recommendations).

When FDA first approved tofacitinib in 2012, we required a postmarketing clinical trial in patients with RA on background methotrexate, to evaluate the risk of heart-related events, cancer, and infections. The trial is studying two different doses of tofacitinib (5 mg twice daily, which is the currently approved dose for RA, and a higher, 10 mg twice daily dosage) in comparison to a TNF blocker. An interim analysis of the trial’s results found an increased occurrence of blood clots and of death in patients treated with tofacitinib 10 mg twice daily compared to patients treated with tofacitinib 5 mg twice daily or a TNF blocker. Based on these results, the 10 mg twice daily treatment was stopped and patients were allowed to continue treatment on 5 mg twice daily.

This safety trial is ongoing. Patients in the 5 mg twice daily group and the TNF blocker group continue to be followed. FDA will reassess these safety issues when the trial has completed and final, verified data are available. We will update the public when additional information is available.

The interim results of the trial, as of January 2019, have identified the following:

• 19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 3 cases out of 3,982 patient-years in patients who received TNF blockers
• 45 cases of death from all causes out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 25 cases out of 3,982 patient-years in patients who received TNF blockers

https://en.wikipedia.org/wiki/Tofacitinib

FDA Approves Olumiant (baricitinib) 2 mg Tablets for the Treatment of Adults with Moderately-to-Severely Active Rheumatoid Arthritis

Eli Lilly and Company (NYSE: LLY) and Incyte Corporation (NASDAQ: INCY) announced today that the U.S. Food and Drug Administration (FDA) has approved the 2-mg dose of Olumiant (baricitinib), a once-daily oral medication for the treatment of adults with moderately-to-severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) inhibitor therapies.  Use of Olumiant in combination with other Janus kinase (JAK) inhibitors or biologic disease-modifying antirheumatic drugs (bDMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.  Olumiant may be used as monotherapy or in combination with methotrexate (MTX) or other non-biologic DMARDs.

"We are pleased to provide RA patients in the U.S. an effective treatment option with Olumiant, as people with RA who have had an inadequate response to TNF inhibitors are generally considered to be some of the most difficult to treat RA patients," said Christi Shaw, president, Lilly Bio-Medicines.

The Olumiant clinical trial program included the RA-BEACON study, a randomized, double-blind, placebo-controlled study in which patients were randomly assigned to receive Olumiant 2 mg, baricitinib 4 mg or placebo, in addition to conventional DMARDs that they were currently using.  This study included 527 patients who had an inadequate response or intolerance to one or more TNF inhibitor therapies.  Patients could have had prior therapy with other bDMARDs. 

The study results showed that significantly higher ACR20 response rates and improvement in all individual ACR20 component scores were observed at Week 12 with Olumiant.1 The study found that patients treated with Olumiant had significantly higher rates of ACR20 response versus placebo-treated patients at Week 12 (49% of Olumiant-treated patients versus 27% of placebo-treated patients).1Olumiant also demonstrated early symptom relief, with ACR20 responses seen as early as Week 1.1Patients treated with Olumiant reported significant improvements in physical function based on the Health Assessment Questionnaire Disability Index (HAQ-DI) (recording an average score of 1.71 before treatment and 1.31 at Week 12) compared to placebo-treated patients (who recorded an average score of 1.78 before treatment and 1.59 at Week 12). 

Olumiant is approved with a Boxed Warning for the risk of serious infections, malignancies and thrombosis. Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving Olumiant. Lymphoma and other malignancies have been observed in patients treated with Olumiant as well. Additionally, thrombosis, including deep venous thrombosis, pulmonary embolism and arterial thrombosis, some fatal, have occurred in patients treated with Olumiant.  Other warnings and precautions include gastrointestinal perforations, laboratory abnormalities (including neutropenia, lymphopenia, anemia, liver enzyme elevations, and lipid elevations) and a warning against the use of live vaccines with Olumiant.  The most common adverse events (occurring in greater than or equal to 1% of Olumiant 2 mg- and baricitinib 4 mg-treated patients in placebo-controlled trials) included upper respiratory tract infections, nausea, herpes simplex and herpes zoster. 

As part of the approval, the companies have agreed to conduct a randomized controlled clinical trial to evaluate the long-term safety of baricitinib in patients with rheumatoid arthritis.

"Despite the advancements we've seen in the RA treatment landscape over the past several decades, many patients are still failing to achieve their disease management goals," said Seth Ginsberg, co-founder and president of CreakyJoints and the Global Healthy Living Foundation. "As it's important for RA patients to have multiple treatment options available to best suit their disease characteristics and experiences, the approval of Olumiant is very encouraging for our community."

RA is a chronic, painful and progressive form of arthritis  It is estimated that about two-thirds of established RA patients will not reach clinical remission with their first TNF inhibitor therapy, and a significant percentage will not maintain efficacy as time goes on. 

"In my clinical practice, I continue to see patients who experience debilitating symptoms and who are waiting for a medicine that may be right for them," said Elizabeth L. Perkins, M.D., Rheumatology Care Center, Birmingham, Alabama. "Olumiant is an important option for rheumatologists to help address these patients' unmet needs."

"RA patients continue to experience unique challenges accessing the treatments prescribed by their healthcare providers. Therefore, we are determined to continue our work with stakeholders to demonstrate value across the healthcare system so providers have greater choice in prescribing treatments to fit individual patient needs," said Shaw.

Lilly will launch Olumiant in the U.S. by the end of the second quarter of 2018. The price of Olumiant will be 60% less than the leading TNF inhibitor.5 Lilly will be offering a patient support program, Olumiant Together™. For more information about this program, please call 1-844-Olumiant.

Incyte is now eligible to receive a $100 million milestone payment from Lilly as a result of the Olumiant approval, which Incyte expects to recognize in the second quarter of 2018. 

FDA Advisory Committee Recommends the Approval of Baricitinib 2mg, but not 4mg, for the Treatment of Moderately-to-Severely Active Rheumatoid Arthritis

Eli Lilly and Company (NYSE: LLY) and Incyte Corporation (NASDAQ: INCY) announced  that the U.S. Food and Drug Administration's (FDA) Arthritis Advisory Committee recommended approval of the 2-mg dose of baricitinib, a once-daily oral medication for the treatment of moderately-to-severely active rheumatoid arthritis (RA) for adult patients who have had an inadequate response or intolerance to methotrexate. While the Advisory Committee unanimously supported the efficacy of the 4-mg dose of baricitinib, it did not recommend approval of the 4-mg dose of baricitinib for the proposed indication based on the adequacy of the safety and benefit-risk profiles.

"We are confident that baricitinib, if approved, can help people in the U.S. manage the challenges of living with RA," said Christi Shaw, president of Lilly Bio-Medicines. "While we are disappointed with the Advisory Committee's assessment of the data for the 4-mg dose, we are confident in the positive benefit-risk profile of both the 2-mg and the 4-mg doses. We look forward to continuing our work with the FDA on our New Drug Application (NDA) and are hopeful that baricitinib will receive approval in the coming months."

Baricitinib 2-mg and 4-mg doses are approved in more than 40 countries, including the member states of the European Union and Japan.

For both doses, the Advisory Committee voted to support the assessment that baricitinib's data provide substantial evidence of efficacy. For the 2-mg dose, the Advisory Committee voted in favor of the assessment that baricitinib's safety data adequately support its approval. For the 4-mg dose, the Advisory Committee voted against the assessment that baricitinib's safety data was adequate to support its approval based on the proposed indication.

The Advisory Committee's recommendation was based on baricitinib's global development program, which included four completed Phase 3 studies. In total, 3,492 patients, who represented a range of treatment experiences, received baricitinib in the global RA development program. The Phase 3 studies evaluated baricitinib's treatment impact related to RA signs and symptoms, physical function, joint damage progression and other patient-reported outcomes. The Phase 3 program also evaluated recognized risks for RA patients, including serious infection, malignancy, major adverse cardiovascular events (MACE), venous thromboembolism (VTE), and gastrointestinal perforations, along with key laboratory changes. The safety profile of baricitinib is based on 7,860 patient-years of exposure.

"Despite advances in the management of RA over the last 20 years, which include early treatment, optimized use of traditional therapies for rheumatic disease and the advent of newer medications such as biologics, many patients are still struggling to meet treatment targets, and live with debilitating pain, fatigue and other symptoms of RA," said Peter Taylor, MA, PhD, professor, University of Oxford, an expert who attended the Advisory Committee Meeting. "Baricitinib could be a promising option for RA patients in the U.S. who are not achieving adequate disease control with currently available treatments."

The FDA is not required to follow the Advisory Committee's recommendation, but will consider it during its review of the NDA for baricitinib.

FDA Advisory Committee Recommends the Approval of Baricitinib 2mg, but not 4mg, for the Treatment of Moderately-to-Severely Active Rheumatoid Arthritis

Pfizer Announces FDA Approval of Xeljanz (tofacitinib) and Xeljanz XR for the Treatment of Active Psoriatic Arthritis

In continuation of my update on tofacitinib 

Pfizer Inc.  announced that the United States Food and Drug Administration (FDA) has approved Xeljanz 5 mg twice daily (BID) and Xeljanz XR (tofacitinib) extended release 11 mg once daily (QD) for the treatment of adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs). Xeljanz/Xeljanz XR is the first and only Janus kinase (JAK) inhibitor approved by the FDA for both moderate to severe rheumatoid arthritis (RA) and active PsA.

“Psoriatic arthritis is a complex and progressive disease with an unpredictable course,” said Angela Hwang, Global President, Inflammation and Immunology, Pfizer. “The approval of Xeljanz is an important step forward for patients seeking new treatments and is a testament to Pfizer’s unwavering commitment to advancing patient care.”

The recommended dose of Xeljanz/Xeljanz XR is in combination with nonbiologic DMARDs, and use in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

The FDA approval of Xeljanz for the treatment of adult patients with active PsA was based on data from the Phase 3 Oral Psoriatic Arthritis Trial (OPAL) clinical development program, which consisted of two pivotal studies, OPAL Broaden and OPAL Beyond, as well as available data from an ongoing long-term extension trial, OPAL Balance. The findings from OPAL Broaden and OPAL Beyond were published in October 2017 in the New England Journal of Medicine.

Both pivotal studies met their two primary efficacy endpoints, demonstrating statistically significant improvements in American College of Rheumatology 20 (ACR20) response and change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI) score at three months in patients receiving Xeljanz 5 mg BID treatment in combination with a nonbiologic DMARD, compared to those treated with placebo. In OPAL Broaden, 50% of patients taking Xeljanz 5 mg BID achieved an ACR20 response, compared to 33% of patients taking placebo (p≤0.05), at three months. In OPAL Beyond, 50% of patients achieved an ACR20 response with Xeljanz 5 mg BID, compared to 24% of patients taking placebo (p≤0.05), at three months. In both studies, statistically significant improvements in ACR20 response was also seen with Xeljanz 5 mg BID compared to placebo at week 2, a secondary endpoint and the first post-baseline assessment (OPAL Broaden: 22% and 6% [p=0.0003], respectively; OPAL Beyond: 27% and 13% [p=0.0046], respectively).

“As a practicing rheumatologist, I’ve seen the significant physical impact psoriatic arthritis has on people living with the disease, and many patients are looking for additional therapeutic options,” said Philip Mease, M.D., Swedish Medical Center, University of Washington and study investigator. “I’m pleased that Xeljanz is now available for use in the treatment of this chronic condition.”

The safety profile observed in patients with active psoriatic arthritis treated with Xeljanz was consistent with the safety profile observed in rheumatoid arthritis patients. The most common adverse events observed occurring in greater than 3% of patients on Xeljanz 5 mg BID were nasopharyngitis, upper respiratory tract infection, headache and diarrhea.

“Psoriatic arthritis is a serious and debilitating chronic illness that should be diagnosed and treated early,” said Randy Beranek, president and CEO, National Psoriasis Foundation. “As an organization that advocates for people living with psoriatic arthritis, we welcome the availability of new therapies for treating this disease.”

Pfizer Announces FDA Approval of Xeljanz (tofacitinib) and Xeljanz XR for the Treatment of Active Psoriatic Arthritis

Drug improves disease-free, overall survival after hematopoietic stem cell transplants

In continuation of my update on Abatacept (Orencia)

Results from a phase 2 clinical trial, presented by Seattle Children's Research Institute at the 59th American Society of Hematology (ASH) Annual Meeting, show that the drug Abatacept (Orencia) nearly eliminated life-threatening severe acute graft-versus-host disease (GvHD) in patients receiving hematopoietic stem cell transplants.

Abatacept, when added to the standard drug regimen used to prevent GvHD, reduced the occurrence of acute, grade III-IV GvHD from 32 to 3 percent in pediatric and adult patients who underwent mismatched unrelated donor stem cell transplants to treat advanced cancer and other blood disorders. As a result, patients receiving the post-transplant regimen with abatacept experienced improved disease-free and overall survival compared to those who did not.

Acute GvHD is the most deadly complication that can arise after stem cell transplantation. Graft-versus-host disease occurs when the donated T cells, white blood cells in the immune system that fight infection, launch a vigorous attack on a patient's organs, including the skin, liver, kidneys, lung, and the gastrointestinal tract. For patients receiving cells from an unrelated donor, the rate of mild-to-severe forms of acute GvHD can reach as high as 80 percent, with up to half of patients dying from the most severe forms.

"Given the serious threat of graft-versus-host disease, new approaches to make stem cell transplants safer for patients remain a critical unmet need," said Dr. Leslie Kean, the trial's principal investigator and associate director of the Ben Towne Center for Childhood Cancer Research at Seattle Children's. "To see such striking results in patients at extremely high risk for graft-versus-disease is incredibly encouraging."

Kean first became interested in using abatacept to prevent GvHD based on the immunotherapy drug's success in treating patients with rheumatoid arthritis. In rheumatoid arthritis, abatacept inhibits T-cell activation and prevents the chain of events that lead to debilitating joint inflammation.

Similarly, feasibility studies conducted by Kean found that abatacept blocks the activation of certain T cells after transplant. In their models, abatacept reduced the proliferation and activation of effector T cells. Effector T cells incite GvHD when they become overactive as the patient's immune system starts to rebuild itself from the donor stem cells.

"Preventing graft-versus-host disease and relapse after transplant requires a difficult balance of eliminating the bad, overactive effector T cells, without suppressing the good, regulatory T cells," said Kean, who is also an associate professor of pediatrics at the University of Washington School of Medicine and a member of the Fred Hutchinson Cancer Research Center. "As we make improvements to our toolbox of agents capable of achieving this Holy Grail of stem cell transplant, it's essential to include targeted approaches like abatacept."

The multicenter data presented included two patients cohorts who were enrolled across 18 sites. In the cohort of patients who received transplants from mismatched unrelated donors, all 43 patients received four doses of abatacept with a calcineurin inhibitor and methotrexate. To serve as the control, researchers looked at data from a national database of matched patients receiving two commonly used regimens to prevent GvHD - a calcineurin inhibitor and methotrexate (CNI/MTX) or a calcineurin inhibitor and methotrexate plus anti-thymocyte globulin (+ATG).

At 100 days post-transplant, the cumulative incidence of grade III-IV acute GvHD occurred in 3 percent of patients receiving abatacept compared to 32 percent receiving CNI/MTX and 22 percent receiving +ATG. Patients receiving abatacept had intact immune reconstitution, significant improvement in transplantation-related mortality, no major uncontrolled infection and no increase in disease relapse. Significant survival advantages for the abatacept group were demonstrated at one year post-transplant. Overall survival improved to 85 percent (vs. 57 percent in CNI/MTX and 68 percent in +ATG controls); 79 percent of patients experienced disease-free survival (vs. 50 percent in CNI/MTX and 63 percent in +ATG controls).

The second cohort of 140 patients with human leukocyte antigen-matched unrelated donor transplants completed enrollment in November 2017, with data expected from this randomized double-blind arm of the study in the next six months.

"As a transplant physician, it's beyond heartbreaking to witness a patient develop severe acute graft-versus-host disease after having their leukemia cured through bone marrow transplant," said Kean. "To have a therapy at our disposal that safely targets just the T cells causing graft-versus-host disease would represent a major step forward in stem cell transplantation. It not only offers new hope that we can prevent graft-versus-host disease upfront, but that we can also significantly improve outcomes for patients requiring high-risk transplants."

Drug improves disease-free, overall survival after hematopoietic stem cell transplants

Methotrexate drug holiday improves flu vaccine efficacy in rheumatoid arthritis patients

In continuation of my update on methotrexate

People with RA who stop taking methotrexate treatment for just two weeks after they have a seasonal flu shot can improve the vaccine's efficacy without increasing RA disease activity, according to new research findings presented this week at the 2017 ACR/ARHP Annual Meeting in San Diego.

Rheumatoid arthritis (RA) is a chronic disease that causes   pain,  stiffness,  welling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3million Americans have RA, and the disease typically affects women twice as often as men.

Methotrexate, a widely used immunosuppressant, can lower vaccine efficacy in people with RA. So researchers in Seoul, Republic of Korea, set out to investigate whether patients with RA could improve their response to influenza vaccinations by temporarily pausing methotrexate use for two weeks after their flu shot.

"RA patients are more susceptible to infections, including seasonal flu, due to their underlying abnormal immune function and the treatment-associated immune suppression," said Jin Kyun Park, MD, Assistant Professor of Medicine at Seoul National University Hospital, and a lead author of the study. "RA patients taking methotrexate are at even higher risk of infection and infection-related complications, so it's important that they be vaccinated against preventable infectious diseases. However, the immune suppression decreases vaccine response.

To overcome this shortcoming, our group has been working on a novel immunization protocol for RA patients to optimize vaccine response,  including increasing immunogenicity of flu vaccines."

In this prospective, multicenter, randomized, parallel-group trial conducted from October 2016 to January 2017, 316 RA patients who were taking a stable methotrexate dose were randomly assigned to two groups: 156 continued their regular methotrexate and 160 discontinued their dose for two weeks after receiving their flu shot. All participants were vaccinated with a seasonal, quadrivalent influenza vaccine containing H1N1, H3N2, B-Yamagata and B-Victoria.

Methotrexate drug holiday improves flu vaccine efficacy in rheumatoid arthritis patients

Mylan announces U.S. launch of generic Fusilev for Injection

Mylan N.V. (Nasdaq: MYL) today announced the U.S. launch of Levoleucovorin Calcium Injection 10 mg (base)/mL; 175 mg (base)/17.5 mL and 250 mg (base)/25 mL Single-use Vials, which is the generic version of Spectrum Pharmaceuticals' Fusilev® for Injection. Mylan received final approval from the U.S. Food and Drug Administration (FDA) for its Abbreviated New Drug Application (ANDA) for this product, which is indicated for rescue use after high-dose methotrexate therapy in osteosarcoma. Levoleucovorin is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.

Levoleucovorin Calcium Injection 10 mg (base)/mL; 175 mg (base)/17.5 mL and 250 mg (base)/25 mL Single-use Vials had U.S. sales of approximately $200 million for the 12 months ending June 30, 2015, according to IMS Health.

Currently, Mylan has 259 ANDAs pending FDA approval representing $98.5 billion in annual brand sales, according to IMS Health. Fifty of these pending ANDAs are potential first-to-file opportunities, representing $33.4 billion in annual brand sales, for the 12 months ending December 31, 2014, according to IMS Health.

Mylan announces U.S. launch of generic Fusilev for Injection

AbbVie reports positive results from ABT-494 Phase 2 clinical trials in patients with rheumatoid arthritis

AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced results from two Phase 2 clinical trials evaluating its investigational selective JAK1 inhibitor, ABT-494, in patients with inadequate response to either methotrexate or TNF inhibitors. The clinical trials, BALANCE-I and BALANCE-II, achieved ACR20 at week 12 across all dose levels, except the lowest dose in BALANCE-II. BALANCE-I and BALANCE-II evaluated patients with moderate to severe rheumatoid arthritis with inadequate responses to prior anti-TNF (TNF-IR) or methotrexate (MTX-IR) treatment, respectively.

"We believe ABT-494 has the potential to become a best-in-class therapy, particularly in the most challenging patient population of TNF-inadequate responders," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "We are encouraged by the results of our Phase 2 studies and we will advance ABT-494 to Phase 3 studies with a once-daily formulation."

AbbVie reports positive results from ABT-494 Phase 2 clinical trials in patients with rheumatoid arthritis

EMA extends approval of Vectibix plus FOLFIRI as first-line treatment for wild-type RAS mCRC

Amgen (NASDAQ: AMGN) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion to extend the marketing authorization for Vectibix® (panitumumab) to include combination with FOLFIRI- FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer. It is made up of the following drugs:

• FOL – folinic acid (leucovorin), a vitamin B derivative used as a "rescue" drug for high doses of the drug methotrexate, but increases the cytotoxicity of 5-fluorouracil;
• F – fluorouracil (5-FU), a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis; and
• IRI – irinotecan (Camptosar), a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating.

 (an irinotecan-based chemotherapy) as first-line treatment in adult patients with wild-type RAS metastatic colorectal cancer (mCRC). About half of the patients with mCRC have wild-type RAS tumors.

"Adding Vectibix to chemotherapy as first-line treatment in patients with wild-type RASmetastatic colorectal cancer has been shown to result in better responses than chemotherapy alone," said Elliott M. Levy, M.D., senior vice president of Global Development at Amgen. "The CHMP recommendation is an important step toward increasing the treatment options for patients with this aggressive disease and helping improve outcomes in the European Union."

EMA extends approval of Vectibix plus FOLFIRI as first-line treatment for wild-type RAS mCRC

New drug combination shows promise as effective, safe treatment for rheumatoid arthritis

A new drug combination for rheumatoid arthritis treats the disease just as well as other intensive treatment strategies but with less medication and fewer side effects at a significantly lower cost. Doctoral researcher Diederik De Cock (KU Leuven) describes the strategy in a new study published in Annals of Rheumatic Diseases.

Rheumatoid arthritis (RA) is a chronic auto-immune disease that causes pain and stiffness in the joints, fatigue, bone damage and, eventually, loss of mobility. RA afflicts around 1% of people in the western world; in Belgium, 80,000 to 100,000 people currently live with the disease.

Because there is no known cure for RA, physicians focus treatment on suppressing disease activity. Therapies have improved in recent years, and clinical studies show that intensive treatment of early RA can prevent joint damage and improve patients' quality of life.

In the two-year study, called 'CareRA' (Care in early RA), researchers and clinicians in the rheumatology unit at University Hospitals Leuven examined various therapies for early RA. Their goal: to find the optimal combination and dosage of three commonly prescribed antirheumatic drugs (methotrexate, sulfasalazine and leflunomide) in combination with glucocorticoids (a class of steroid hormones).

The researchers divided 290 early RA patients into three treatment groups. Each group received a different combination therapy: 'COBRA Classic' (methotrexate, sulfasalazine and a high first dose of glucocorticoids), 'COBRA Slim' (methotrexate and a moderate dose of glucocorticoids) or 'COBRA Avant-Garde' (methotrexate, leflunomide and a moderate dose of glucocorticoids).

New drug combination shows promise as effective, safe treatment for rheumatoid arthritis

Oral afatinib significantly improves progression-free survival in patients with head and neck cancer

The tyrosine kinase inhibitor afatinib significantly improved progression-free survival compared to methotrexate in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after failure of platinum-based chemotherapy, the results of a phase III trial show.

Presented at the ESMO 2014 Congress in Madrid, the Lux-Head & Neck 1 trial showed that patients who received treatment with 40 mg/day oral afatinib had a 20% reduction in risk of progression or death compared to patients who received methotrexate, with a median progression-free survival of 2.6 months.

"The improvement in progression-free survival was associated with a significant delayed worsening of symptoms (such as pain, swallowing and global health status) versus chemotherapy. Patients treated with afatinib had less pain over time than patients treated with methotrexate. "These are important outcomes for patients with these conditions," notes study author Dr Jean-Pascal Machiels, a medical oncologist at Institut Roi Albert II, Cliniques Universitaires St. Luc, in Brussels, Belgium.

Recurrent or metastatic squamous cell carcinoma of the head and neck often has a poor outcome, Machiels explains. "This is a poor prognosis population and a disease that does not get enough attention from the scientific community, because this group of patients often has severe co-morbidities and social problems such as alcoholism and tobacco use."

"Frequently these patients have a relapse in the head and neck area. This location is responsible of many symptoms that are difficult to palliate: pain, breath disorder and swallowing difficulties."

Afatinib is a compound that irreversibly blocks the ErbB family of cell surface receptors, which includes epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), HER3 and HER4. Around 90% of squamous cell carcinomas of the head and neck overexpress EGFR.

Oral afatinib significantly improves progression-free survival in patients with head and neck cancer

RA Study Misses Primary Endpoint (CH-4051)...

In continuation of my update on CH-4051

Chelsea Therapeutics International, Ltd. (Nasdaq:CHTP) announced that a preliminary analysis of its dose-ranging exploratory Phase II trial of CH-4051, a non-metabolized antifolate, in patients with rheumatoid arthritis (RA) who experience an inadequate response to methotrexate (MTX) treatment indicates that CH-4051 did not demonstrate superior efficacy to methotrexate in the dose range evaluated.

"Results of this study provide evidence of the clinical activity of CH-4051, in a dose dependent manner, across multiple RA assessment criteria," commented Dr. Simon Pedder, president and CEO of Chelsea Therapeutics. "However, the outcome of the trial was confounded by the unexpectedly robust response reported by patients treated with methotrexate. While we believe that higher doses of CH-4051 could provide enhanced therapeutic benefit in RA and that CH-4051 could be developed for other anti-inflammatory and autoimmune indications, we believe our current resources would be better allocated toward the planned completion of our Northera™ (droxidopa) development program in neurogenic orthostatic hypotension. Consequently, we have no immediate plans to continue development of CH-4051."

Voraxaze receives FDA approval for treatment of toxic methotrexate levels

Voraxaze receives FDA approval for treatment of toxic methotrexate levels: The U.S. Food and Drug Administration today approved Voraxaze (see structure, glucarpidase) to treat patients with toxic levels of methotrexate in their blood due to kidney failure.  

Pfizer RA Drug Meets Study Goals

We knew that,  Tofacitinib (see structure, formerly tasocitinib is a drug being investigated by Pfizer for the treatment of rheumatoid arthritis (RA), psoriasis,inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection. It is an inhibitor of the enzyme Janus kinase 3 (JAK3), which means that it interferes with the JAK-STAT signaling pathway that transmits information outside the cell into the cell nucleus, influencing DNA transcription.

Now Pfizer now claims that the drug has   met its key goals of reducing signs and symptoms of the condition in separate studies on patients over a 12-month and six-month period. Rheumatoid arthritis is a chronic inflammatory disease typically affecting joints.

The company's Oral Standard study involved 717 patients over a 12-month period with moderate-to-severe rheumatoid arthritis who had an inadequate response to the drug methotrexate. Meanwhile, the Oral Step study involved 399 patients over a six-month period with moderate-to-severe rheumatoid arthritis who did not have an adequate response to TNF inhibitor drugs.  Pfizer said no new safety signals emerged in the Oral Standard and Oral Step studies. A more detailed analysis off the data will be submitted to a future scientific meeting. 

The most common side effects of treatment with tofacitinib have included bronchitis, headache, infections, and gastrointestinal symptoms like nausea, vomiting, and diarrhea. More serious side effects in a mid-stage trial included lower levels of a type of white blood cell called neutrophils, higher cholesterol levels and increased creatinine levels.

Tofacitinib is a key developing drug for Pfizer and is also being studied as a potential treatment for psoriasis, inflammatory bowel disease, and renal transplant. A topical version of the drug is being studied as a psoriasis treatment and a dry eye disease treatment....

Press Release...

FDA approves Chelsea Therapeutics' Phase II protocol for CH-4051 antifolate in rheumatoid arthritis

Chelsea Therapeutics International, Ltd. announced the  confirmation by the U.S. FDA,  that its proposed Phase II protocol for CH-4051  in rheumatoid arthritis has been approved by the agency. Chelsea plans to initiate patient screening next month and initiating treatment in October.

This multi-national, double-blind, randomized Phase II trial of CH-4051, an orally available metabolically stable antifolate, is intended to evaluate the safety and efficacy of CH-4051 in a 250-patient head-to-head study against methotrexate (MTX). Patients with rheumatoid arthritis who are experiencing an inadequate response to MTX treatment will be randomized to receive daily oral doses of 0.3 mg, 1.0 mg, 3.0 mg or 3.0 mg plus folate of CH-4051 or 20 mg weekly dose of MTX plus folate supplement for 12 weeks following a two-week MTX-washout. The primary efficacy analysis will be conducted using the hybrid American College of Rheumatology, or ACR, score (hACR), which allows for a more comprehensive assessment of treatment benefit across all seven symptomatic and functional components of the standard ACR 20/50/70 evaluations historically used in RA trials.

"Although MTX is considered the standard of care in RA, both as a monotherapy and in combination with other RA treatments, the dosing and maximal therapeutic benefit of MTX is limited by well-documented tolerability issues, long-term safety concerns and variable bioavailability," commented Dr. Simon Pedder, president and CEO of Chelsea Therapeutics. "Given that CH-4051 is metabolically stable and that all of our preclinical and clinical work suggests enhanced absorption, dramatically increased potency and improved tolerability over MTX, we believe CH-4051 will be safe and highly efficacious in a historically treatment-resistant patient population."

Chelsea intends to conduct an un-blinded interim efficacy analysis after approximately 50% of patients in the two lower CH-4051 dose groups complete treatment and expect to report results from this analysis in the third quarter of 2011. Full study results, inclusive of all dose groups, are expected in mid-2012.

As previously reported, results from Chelsea's Phase I single and multiple ascending dose studies demonstrated that CH-4051 was well tolerated at doses up to and including 7.5mg, a dose range likely to be effective for multiple autoimmune disorders. The 5mg dose was as well tolerated as placebo. No serious adverse events occurred during the study and pharmacokinetic data indicated dose proportionate increases in plasma levels of CH-4051. Furthermore, it was revealed that plasma concentrations in the study were comparable to those seen in animal pharmacology studies in which CH-4051 demonstrated superior suppression of RA than both the maximally tolerated dose of methotrexate and equivalent doses of CH-1504 (see structure)....

Ref : http://www.irconnect.com/chtp/pages/news_releases.html?d=200159