Jenna Payesko

The US Food and Drug Administration (FDA) has accepted the new drug application (NDA) of the investigational drug ulipristal acetate (UA) for the treatment of abnormal bleeding in women with uterine fibroids.

While UA has been available in Europe and Canada for several years, the FDA recently notified Allergan extending the review with an expected target Prescription Drug User Fee Act (PDUFA) date of August 2018.

“Currently approved treatment options for uterine fibroids are mostly surgical, and these surgeries can take weeks to recover from,” said Ayman Al-Hendy, MD, director of interdisciplinary translational research, Augusta University in Georgia, and member of Allergan’s advisory board, in an interview with 

 “That is why ulipristal acetate is a valuable option for treating uterine fibroids. For the first time, doctors and patients will have access to an oral treatment option to manage symptoms. I am optimistic that with a new oral treatment option, fewer women will suffer in silence and leave their uterine fibroids untreated.”

UA belongs to a group of drugs classified as selective progesterone receptor modulators (SPRM), which block progesterone from feeding the fibroids, causing them to shrink. The SPRM acts directly on the progesterone receptors in 3 target tissues - the endometrium, uterine fibroids, and the pituitary gland - to quickly and dramatically decrease and stop vaginal bleeding, which is then typically reduced within 5—6 days.

The once-a-day pill is be consumed for 3 months, then stopped for 1 menstrual cycle to allow the endometrium to shed.

The safety and efficacy of UA has been evaluated in VENUS I and VENUS II, 2 phase 3 studies of more than 500 adult women. Additionally, the efficacy of UA has been demonstrated in a series of 4 phase 3 European trials involving more than 1,000 women with uterine fibroids.

UA appears to have fewer side effects than the injectable Lupron, the only medication available in the US to shrink fibroids. Side effects such as headaches and hot flashes affected less 10% of women in UA trials.

Lupron effectively sends women into early menopause, which can result in bone loss and hot flashes, as women must often take it with hormone replacement therapy.

UA, along with 2 other medications in the pipeline, would provide a new treatment option for a condition often treated with a hysterectomy. 

Bayer launched a phase 3 clinical trial for vilaprisan, a similar drug, this summer, while AbbVie is currently underway in 2 phase 3 trials for 

 to treat uterine fibroids and endometriosis.

Similar to Lupron, elagolix decreases sex hormones that causes fibroids to grow, however it is fast acting and easier to reverse the effects if stopped. Studies show it significantly reduces heavy menstrual bleeding and decreases the thickness of the endometrium by 6 months.

While the most common treatment option for uterine fibroids is a hysterectomy, women who wish to still undergo childbirth can have a myomectomy, a surgery that removes fibroids and keeps the uterus intact.

The FDA has issued a complete response letter (CRL) to Allergan for its marketing application for UA as a treatment of abnormal uterine bleeding in women with uterine fibroids.

Allergan's FDA filing for EA was supported by phase 3 data from the VENUS I and VENUS II trials.

Allergan reported that the FDA requested additional information in its CRL, and also cited safety concerns regarding the investigative therapy's post-marketing reports outside the US. The therapy is already approved in Europe, marketed by partner Gedeon Richter and indicated for pre-operative and intermittent treatment of moderate-to-severe symptoms of uterine fibroids in adult women at an age of reproduction. In Canada, UA is marketed by Allergan under the name Fibristal and is indicated for the intermittent treatment of moderate-to-severe signs and symptoms of uterine fibroids.

A European Medicines Agency committee concluded in May this year that EA may have contributed to the development of serious liver injuries in some patients. The committee recommented measures be implemented to minimize the risk of further injuries, leading to the imposition of several temporary restrictions on the therapy in Europe.

In a statement regarding the CRL, Allergan R&D chief David Nicholson reiterated the company's advocacy for novel, non-surgical treatment options for uterine fibroids.

"We intend to meet with the FDA to discuss the Complete Response Letter and determine the potential next steps for our ulipristal acetate NDA," Nicholson said.

Assess Safety and Efficacy of Vilaprisan in Subjects with Uterine Fibroids Compare to Ulipristal (ASTEROID 5)

VENUS II: The second US-based Phase 3 Study of Ulipristal Acetate for Treatment of Symptomatic Uterine Fibroids (UF)

” were published on ClinicalTrials.gov and 

Articles

A potential first-in-class, oral medication to treat uterine fibroids has been accepted by the FDA.

New Uterine Fibroids Oral Treatment Could Replace Surgery (UPDATE)

Amgen and UCB announced the resubmission of the biologics license application to the US Food and Drug Administration (FDA) for romosozumab (EVENITY) for the treatment of osteoporosis in postmenopausal women at high risk for fracture.

Resubmission now includes results from 2 additional recent pivotal phase 2 trials: the ARCH study and the BRIDGE study.

The FDA will evaluate the clinical benefit and risk profile of EVENITY, which includes the cardiovascular safety signal seen in the ARCH study for the potential to reduce the risk of fractures and increase bone mineral density in postmenopausal women with osteoporosis.

“A fracture due to osteoporosis can be a life-altering event, and EVENITY has the potential to reduce fracture risk in patients at high risk due to a prior fracture,” Sean Harper, MD, executive vice president of research and development, Amgen, said in a 

. “We look forwarding to continuing our work with the FDA to demonstrate the benefit risk profile for EVENITY. Our hope is to bring to patients an innovative treatment option that addresses a serious unmet medical need.”

The ARCH study, an alendronate-active comparator trial, includes 4093 postmenopausal women with osteoporosis at high risk for fracture based on previous fracture history. The study evaluated 12 months of 210 mg treatment of EVENITY followed by at least 12 months of 70 mg alendronate treatment, compared with alendronate treatment alone in order to determine effectiveness in reducing the incidence of clinical fracture and new vertebral fracture.

The randomized, double-blind, placebo-controlled BRIDGE study includes 245 men aged 55—90 years old with osteoporosis and a history of fragility fracture or vertebral fracture. The BRIDGE study evaluated the effectiveness of EVENITY treatment for 12 months, compared with placebo, in increasing bone mineral density at the lumbar spine and the effect on the bone mineral density at the femoral neck and total hip.

The investigational monoclonal antibody works to increase bone formation and reduce bone resorption simultaneously, increasing bone mineral density and reducing the risk of fracture.

The original biologics license application included data from a comprehensive phase 1 and phase 2 program and the phase 3 placebo-controlled FRAME study, which included 7180 postmenopausal women with osteoporosis.

The European Medicines Agency and the Pharmaceuticals and Medical Device Agency in Japan are currently reviewing marketing applications for EVENITY.

The resubmitted biologics license application includes data from pivotal phase 3 studies of more than 11,000 patients.

Romosozumab Biologics License Application Resubmitted to FDA for Osteoporosis

Acceleron Pharma announced that the US Food and Drug Administration (FDA) granted orphan drug designation for ACE-083 for treatment of patients with facioscapulohumeral muscular dystrophy (FSHD).

In May 2018 the FDA granted fast track designation to ACE-083 for FSHD, which could facilitate its development and potentially expedite its review.

“We are pleased to receive orphan drug designation for ACE-083, which has shown the potential to address an area of high unmet medical need,” Robert Zeldin, MD, chief medical officer, Acceleron, said in a

 “We believe that ACE-083 could become an important new treatment for patients with FSHD whose muscle weakness negatively affects their functional abilities. We presented positive preliminary data from part 1 of our phase 2 trial in patients with FSHD earlier this year and look forward to sharing part 2 results later next year.”

Study A083-02 is a multicenter phase 2 study designed to evaluate the safety, tolerability, pharmacodynamics, efficacy and pharmacokinetics of ACE 083 in those with FSHD.

Part 1, an open-label, dose-escalation study of ACE-083, consisted of up to 6 cohorts (A to F) of patients and evaluated multiple ascending dose levels in either the tibialis anterior (TA) or biceps branchii (BB) muscle. Preliminary results demonstrated positive safety and tolerability along with unprecedented mean increases in total muscle volume of more than 12% in the 2 distinct areas evaluated.

The results include data from 23 patients evaluable for magnetic resonance imaging (MRI) among 2 different cohorts (11 patients with tibialis anterior weakness and 12 patients with biceps brachii weakness). Patients received either ACE-083 150 mg or 200 mg as a unilateral intramuscular injection once every 3 weeks for 12 weeks. Total muscle volume changes were measured by MRI relative to baseline at 3 weeks after last injection.

The TA cohorts generated a mean total muscle volume increase of 12.6% and produced a mean decrease or improvement in muscle fat fraction of 5.3%. The BB cohorts generated a mean total muscle volume increase of 13.2%, while producing a mean decrease or improvement in muscle fat fraction of 0.6%.

There were no reports of serious adverse effects. The most common adverse effects were injection site related and grades 1—2.

ACE-083 is a locally active agent that is designed to increase strength and function in specific target muscles for improved patient function and quality of life by binding to and inhibiting select proteins in the TGF-beta protein superfamily. According to Acceleron, the “Myostatin+” approach is expected to increase muscle mass and strength in the muscle where the drug is administered.

The Part 2 portion will be randomized, double-blind and placebo-controlled and will include an open-label extension. Prior to the initiation of part 2, researchers will review the safety and efficacy data from part 1 to determine whether cohorts for 1 or both muscles will be pursued in part 2, as well as the recommended dose level for each muscle. A total of up to 56 new patients (28 per muscle) may be enrolled and randomized to receive either ACE-083 (n=14/muscle) or placebo (n=14/muscle) bilaterally to either the TA or BB muscles, but not both.

Patients in part 2 will receive the blinded study drug once every 3 weeks for approximately 6 months—9 doses. The study duration for each patient is approximately 15 months, including a 1-month screening period, a 12-month treatment period, and a 2-month follow-up period after the last dose.

Those who complete the double-blind treatment period will immediately roll over to the open-label treatment with ACE-083 and receive the same dose of active drug, bilaterally in the TA or BB muscle, once every 3 weeks for approximately 6 months—8 doses.

Acceleron is expected to release preliminary results from part 2 of the trial in the second half of 2019.

ACE-083 is currently being evaluated in 2 phase 2 trials, 1 in FSHD and 1 in Charcot-Marie-Tooth disease.

Preliminary results from part 2 of the trial in patients with are expected in the second half of 2019.

Orphan Drug Designation Granted by FDA to ACE-083 for Facioscapulohumeral Muscular Dystrophy

Medtronic announced the approval by the US Food and Drug Administration (FDA) for a less-invasive implant approach of its HVAD System, a left ventricular assist device (LVAD), for patients with advanced heart failure.

The approval for HVAD implantation via thoracotomy is based on data from the LATERAL prospective clinical trial where 144 patients with end-stage heart failure eligible for heart transplant were enrolled at 26 centers in the US and Canada.

“We have demonstrated that a thoracotomy is a safe and effective implant technique for the HVAD System, which gives physicians added flexibility in treating a broad range of patients,” Edwin McGee, Jr., MD, principal investigator of the LATERAL trial, professor and director, Heart Transplant and Ventricular Assist Device Program, Loyola University Medical Center, said in a 

. “Implanting the HVAD via thoracotomy preserves the chest for a subsequent procedure that patients may need, such as a heart transplant. It also has been shown to result in shorter hospital stays.”

The trial met its primary endpoint of non-inferiority as data indicated an 88.1% rate of survival at 6 months free from disabling stroke or device explant or exchange due to malfunction. Being as the success outcome exceeded the pre-specific performance goal of 77.5%, the trial achieved its primary endpoint ( 

The key secondary endpoint revealed a reduction in hospital stay length, which decreased from an average of 26.1 days to 18 days ( 

Medtronic said that at 1-year, overall survival among those receiving HVAD via the thoracotomy procedure was 88.8%.

The HVAD system is the only LVAD approved in the US for implant via thoracotomy and median sternotomy, and is approved to treat those with advanced, refractory heart failure as a bridge to cardiac transplantation and as a destination therapy in patients where subsequent transplantation is not planned.

Along with the approval, Medtronic released new surgical implant tools, now available in the US and CE Marked countries, tailored to assist with the thoracotomy approach for the HVAD System.

The HVAD system is the only approved LVAD approved for implant via thoracotomy or median sternotomy.