Mathew Shanley

This morning, Pfizer announced that its investigational therapy for the treatment of patients with transthyretin (TTR) cardiomyopathy, tafamidis, received Breakthrough Therapy designation from the US Food and Drug Administration (FDA).

The FDA’s decision is supported by topline results from the phase 3 Transthyretin Cardiomyopathy (ATTR-ACT) study in which tafamidis exhibited a statistically significant reduction in the combination of all-cause mortality and frequency of cardiovascular-related hospitalizations. The 

TTR is a tetramer that is responsible in transporting the retinol-binding protein-vitamin A complex and minimally transporting thyroxine in the blood. Tafamidis is also being developed as a novel specific TTR stabilizer or dissociation inhibitor.

In the study, 441 participants were randomized into 3 arms that investigated the efficacy, safety, and tolerability of an oral dose of either 20 mg or 80 mg of tafamidis meglumine capsules or placebo. The preliminary safety data showed that, at 30 months, tafamidis was generally well tolerated in the patient population, and no new safety signals were identified.

“This designation is an important step forward in the path to bringing a potential new treatment option to those with transthyretin cardiomyopathy, a rare, fatal disease,” said Brenda Cooperstone MD, Senior Vice President and Chief Development Officer, Rare Disease, Pfizer Global Product Development in a 

. “We look forward to working with the FDA through this expedited process to fulfill an unmet patient need.”

In 2011, tafamidis was granted orphan drug designation for transthyretin cardiomyopathy in both the European Union (EU) and the US. Six years later in 2017, the FDA also granted the drug Fast Track designation for the indication.

Transthyretin cardiomyopathy is a rare, fatal, and underdiagnosed condition associated with progressive heart failure. The prevalence of transthyretin cardiomyopathy is presently unknown; however, approximately less than 1% of people with the disease receive a diagnosis.

Currently, there are no approved pharmacological medications specifically indicated for treatment of the progressive heart condition, and the average life expectancy of patients is 3 to 5 years after diagnosis.

“As health care professionals, all we can do right now is manage symptoms of the disease, as there are no approved pharmacological treatment options at this time. The need for medicines that treat transthyretin cardiomyopathy is critical,” said Mat Maurer MD, Arnold and Arlene Goldstein professor of Cardiology, Columbia University Vagelos College of Physicians and Surgeons.

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Articles

This morning, Pfizer announced that its investigational therapy for the treatment of patients with transthyretin (TTR) cardiomyopathy, tafamidis, received Breakthrough Therapy designation from the US FDA.

Tafamidis Gets Breakthrough Therapy Designation

For somebody in need of a diagnosis, the internet can be a dangerous tool.

However, for Darcy Tannehill, who had already dedicated most of her life to research and education, no potential search result was scary enough to deter her from trying to understand the health issues she was experiencing.

Until her death in April, Tannehill served as the Associate Professor of Education at Robert Morris University in Pittsburgh, PA. Previously, she worked as a manuscript editor and a research journal reviewer. Her undergraduate degree in psychology and sociology and her master’s degree in education are from Duquesne University. Her doctorate in administrative and policy studies - higher education management is from the University of Pittsburgh.

In 2012, the incredibly accomplished Tannehill was diagnosed with light chain—or AL&mdash;amyloidosis, but for the six years prior, she had been experiencing an array of symptoms characteristic of the disease’s typical early presentation. It started with gastrointestinal issues that she attributed to food allergies, and continued with differences noticed in her hair and fingernails, and eventually led to her having carpal tunnel syndrome. Her primary care physician (PCP) suggested that she might be vitamin deficient, but no vitamins ever made a difference.

“That’s just the background that I have,” she said to 

 in an interview before her passing. “I do research with my job, and I search for facts. I want to approach [whatever I have] from a factual way.”

At one point, she explained, each of the signs she had found pointed her in the direction of amyloidosis. She remembered, though, that Richard S. Caliguiri, the former mayor of Pittsburgh (her home city) had died from the same disease in 1988 after only 7 months of fighting it. “I can’t have [amyloidosis] because I’m not that sick,” she said. “I don’t feel well, but I am 

Tannehill’s PCP advised her to see an endocrinologist. Her endocrinologist suggested she see a rheumatologist. After tests run by her rheumatologist showed monoclonal gammopathy of undetermined significance (MGUS) in her blood, she was instructed to see an oncologist, due to the likelihood that the presence of MGUS could mean that she was living with multiple myeloma. After a bone marrow biopsy and more blood tests, it was nearly decided that Tannehill was in the early stages of the deadly cancer.

Because she had done hours and hours of research, though, and been unbelievably detailed when describing her medical history, her oncologist suggested one final test: a biopsy of the fat pad of her abdomen. This was intended to “rule out” an alternate diagnosis.

It was intended to rule out AL amyloidosis.

“Truthfully, she wanted to get the diagnosis,” Tannehill told 

. “She said she wanted to rule it out, but she wasn’t trying to rule it out. I think she was convinced that she had caught it. She just needed this one determining test to figure it out.”

Tannehill was scheduled to see a surgeon in less than 48 hours, and it took less than four days before she got the call she expected, but had been dreading.

The biopsy came back positive. Her amyloidosis diagnosis was confirmed.

As she recalled, the only thought in her head was “I’m going to be dead within the next few months,” she said, because that’s was what had happened to everyone else that she had ever heard of who previously received the same diagnosis.

Despite her circumstances, Tannehill thrived. She underwent multiple rounds of chemotherapy, was the recipient of successful bone marrow and stem cell transplants, and never experienced any significant organ damage. She continued working, playing the piano, rescuing Shetland sheepdogs, and watching as her only grandchild, Alaina, grew every day, right before her eyes.

Still, regardless of what was her seemingly positive quality of life, she noted the existence of significant treatment gaps for this rare disease. Too many cases of amyloidosis are borrowing therapy methods from the multiple myeloma space.

Living with an uncommon condition like AL amyloidosis isn’t as easy as Tannehill made it seem. In the weeks before her death, she gave a talk at the University of Pittsburgh about what the lifestyle entails. Historical data don’t give patients much of a chance, and looking for hope in previous studies can leave patients expecting the worst. A trio of tips from Tannehill’s presentation should serve as commandments for patients in the rare disease community:

“You can’t take to your bed and say, ‘I’m too sick to do this.’ You need to be able to fight with everything that you have, and find whatever it is [that makes you want to keep fighting],” Tannehill said about resilience. “For me, it’s my determination to make a difference, and it’s my family. I’m fighting to stay here for them.”

Tannehill believed that, in the life of a rare disease patient, feeling apathetic doesn’t get anybody anywhere. To play the victim is be a disservice to oneself and the potential for recovery. A patient’s willingness to be an active participant in the treatment process is necessary; to know light chain counts and how to read the results of blood tests are not optional. It is simply not enough to be told what to do by doctors and caregivers while sitting idly on the sidelines.

Until her death, Tannehill worked tirelessly to raise awareness and funds for research for the amyloidosis community as an active member of the Board of Directors for the national Amyloidosis Foundation. In 2016, she served as the chair of the first Pittsburgh Amyloidosis Research Benefit — an event so successful, it has become an annual occurrence. The most recent took place in October 2017, and awarded over $1.4 million to young researchers pursuing a cure for amyloidosis. The next is scheduled for October 26, 2018.

“Other people have the same problems [that I have],” Tannehill said. “I see people, every week, dying from this, and I can’t just sit back and watch that happen. I figure that while I’m trying to save my own life, there are a lot of other people who need to be saved, too. If I can have any kind of an impact on that then — to me – something good has come from this disease. Maybe that’s why I have it.”

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Until her death in April, Tannehill served as the Associate Professor of Education at Robert Morris University in Pittsburgh, PA. This story is about her journey to her AL Amyloidosis diagnosis.

Researching Rare: Darcy Tannehill's AL Amyloidosis Journey

Can enzyme replacement therapies (ERTs) reduce the risk for wheelchair dependency in the adult Pompe disease patient population? According to recent results from an ongoing survey, the answer is “yes.”

Findings from the survey were published by the 

Enzyme replacement therapy reduces the risk for wheelchair dependency in adult Pompe patients

.” In it, study authors Jan C. van der Meijden and colleagues from the Erasmus MC University Medical Center in the Netherlands investigate results from the IPA/Erasmus MC Pompe survey. The prospective international examination was designed with the intention to investigate whether ERT can reduce patients’ risk of needing either a wheelchair, respirator, or both.

While the findings could not demonstrate the effect of ERT on respiratory support, they were consistent with historical data that has shown the positive clinical benefits of the therapeutic option on motor outcomes.

Data were collected annually between 2002 and 2016, and patients who were already using a wheelchair or respirator were excluded in addition to patients who had incomplete information on the events or disease duration.

Overall, 458 patients participated in the survey, and inclusion criteria for evaluating the risk of wheelchair use was met by 189 patients between the ages of 18 years and 75 years with a median age of 47 years. Time-dependent Cox proportional hazard models were utilized to calculate the effect of ERT on the risk of using a wheelchair or respiratory support, and models were developed separately for both outcomes.

During follow-up, 66.6% of participants (

Of those who were administered ERT, 12.7% (n=66) became wheelchair dependent over 1,120 person-years of follow-up (median 5 years). Comparatively, of the 63 participants who were not administered ERT, 47.6% (n=30) became wheelchair dependent in the same median follow-up period.

After adjustment for disease duration, sex, and country, it was proven that ERT reduced the risk for wheelchair use (HR 0.36; 95% CI 0.17—0.75).

For analyses of respirator use, 177 patients met the inclusion criteria (median age 46 years; range 18—73). Over 1,190 person-years of follow-up (median 6 years), 71% (n=125) of patients were treated, and 27.1% (n=48) started respiratory support, 15.8% (n=28) of whom received ERT. No association between ERT and the risk for respirator use was found.

Patients are continually included into the open cohort IPA survey.

Since its initiation, it has been shown to be an accurate reflection of the clinical spectrum of adult patients with Pompe disease. While some bias could potentially have occurred as patients become lost to follow-up due to the study duration, bias has been mostly minimized through the time dependent nature of the analysis as the same patient could contribute to both the treated and untreated period.

“The difference between being able to walk and needing a wheelchair is very tangible, and ERT’s reduction of the risk for becoming wheelchair dependent is an important improvement,” the study authors concluded. “Nevertheless, a proportion of treated patients still become wheelchair dependent at some point in their life. Hence, while ERT shows positive clinical effects in adult patients with Pompe disease, we also conclude that there is still room for improvement.”

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1. van der Meijden JC, et al. Enzyme replacement therapy reduces the risk for wheelchair dependency. Orphanet Journal of Rare Diseases. 2018;13:82. doi: 0.1186/s13023-018-0824-4.

Survey results from the IPA/Erasmus MC Pompe survey investigated whether ERT can reduce Pompe disease patients’ risk of needing either a wheelchair, respirator, or both.

ERTs Reduce Risk for Wheelchair Dependency in Adult Pompe Patients

Supported by positive data from an ongoing Phase 2/3 study, bluebird bio’s Lenti-D has been granted Breakthrough Therapy designation by the US Food and Drug Administration (FDA) for the treatment of patients with cerebral adrenoleukodystrophy (CALD), or Lorenzo’s Oil disease.

The gene therapy is comprised of a patient’s own immature bone marrow cells and modifies them to include a functional copy of the 

 gene. The alteration permits the expression of functional 

, the deficient protein in the patient population.

Preliminary findings from the ongoing Starbeam Study (ALD-102) evaluating the investigational gene therapy in boys with CALD aged 17 years or younger who do not have a matched sibling donor were published in the 

) in October 2017 and showed that the drug hit its primary efficacy endpoint. In the study, 88% (n=15) of patients infused with Lenti-D remained alive and free of major functional disabilities at 2 years post-treatment.

Additionally, the data showed that the safety profile of Lenti-D remains consistent with myeloablative chemotherapy. No instances of engraftment failure, graft versus host disease (GVHD) or treatment-related mortality were reported, nor was there any evidence of insertional oncogenesis.

 sat down with Mohammed Asmal, Vice President, Clinical Development at bluebird bio, to learn about the data published in 

the motivation behind the development of this potential therapeutic option.

“The impetus for the start of the study came from the patients who don’t have matching donors; they don’t have good outcomes,” he said. “We needed to find an alternative, and the theory that gene therapy can correct something like this was certainly out there.”

“The mechanism by which this would work is very much like how stem cell therapy transplantation is able to correct the disease. The theory was certainly there, it just relied on someone, essentially, being willing to develop the vector and then try it on patients who did not have any other feasible options for transplant, and who had poor predicted outcomes for transplant survival.”

At present, the only available therapeutic option for patients with CALD is allogeneic hematopoietic stem cell transplant (HSCT). While clinical benefit has been reported if performed early during CALD progression, potential complications of allogeneic HSCT can be fatal.

Previously, bluebird’s Lenti-D investigational gene therapy had been granted Orphan Drug designation by both the FDA and European Medicines Agency (EMA) in addition to Rare Pediatric Disease designation by the FDA for the treatment of adrenoleukodystrophy (ALD).

“The FDA’s Breakthrough Therapy designation for Lenti-D brings us one step closer to realizing this mission to bring new hope to the patients and families affected by this devastating disease,” said David Davidson, MD, chief medical officer, bluebird bio in a 

. “We look forward to continuing to work closely with the FDA and EMA to expedite development of Lenti-D as a treatment for CALD.”

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Supported by positive data from an ongoing Phase 2/3 study, bluebird bio’s Lenti-D has been granted Breakthrough Therapy designation by the US FDA for the treatment of patients with cerebral adrenoleukodystrophy.