Catalyzing Sarcopenia Drug Development: Identifying Outcomes, Defining Disease

FDA’s patient-focused drug development initiative and its Drug Development Tool for qualifying endpoints are galvanizing efforts to establish sarcopenia as an indication for clinical development in what could be a very significant market of elderly patients with weakness and functional disability.

Lack of an accepted disease definition and outcome measures have held back R&D efforts in frailty and sarcopenia, but collaborative public/private efforts have recently made strides that could catalyze drug development for the progressive loss of skeletal muscle associated with aging and its associated weakness and functional disability.

Sarcopenia collaborations under the auspices of the Foundation for NIH and Aging in Motion, a coalition established by the Alliance for Aging Research, are part of a groundswell of sophisticated, multi-stakeholder disease advocacy activity that has accompanied FDA’s patient-focused drug development initiative (Also see "FDA’s Patient-Focused Drug Development Meetings Inspire Imitators" - Pink Sheet, 19 May, 2014.). FNIH has focused on diagnostic criteria, while Aging in Motion is supporting an effort to get a publicly available clinical outcome assessment qualified under FDA’s new Drug Development Tool qualification process.

Evolution Of A Disease Concept

Identification of physical frailty and sarcopenia in the elderly as a disease concept – and a target for medical intervention – has been driven by collaborations involving academia, industry and government. Momentum is increasing.

1988: Term “sarcopenia” coined by Dr. Irwin Rosenberg

1991: “Frail elderly” established as a Medline Medical Subject Heading (MeSH)

2003: First International Working Meeting on Frailty and Aging

2004: American Geriatrics Society/National Institute on Aging Conference on a Research Agenda on Frailty in Older Adults

2007: Foundation for the National Institutes of Health Biomarkers Consortium launches Sarcopenia Project

2012: Sarcopenia Consensus Summit co-organized by the Foundation of the National Institutes of Health, National Institute of Aging, and FDA and co-sponsored by Abbott, Amgen, Lilly, Merck and Novartis

2013: European Federation of Pharmaceutical Industries/European Commission’s Innovative Medicines Initiative issues project call on physical frailty and sarcopenia (PF&S) as a prototype geriatric indication

2014: Foundation for NIH publishes sarcopenia diagnostic criteria

“At present, there are no FDA-approved measures to guide the development of potential drug therapies and other treatments for sarcopenia, and no pathways for approval nor for Medicare reimbursement,” Dan Perry, president of the Alliance for Aging Research, emphasized at the recent first meeting of the AIM coalition.

But the sarcopenia field is at a “turning point” following the publication of diagnostic criteria proposed by the Foundation for the National Institutes of Health Biomarkers Consortium’s Sarcopenia Project on April 15, Alliance for Aging Research VP for Public Policy Cynthia Bens said in an interview (see box for criteria).

“There are multiple potential interventions being developed by drug companies that aim to treat or prevent muscle loss, but there are not necessarily any regulatory guidelines about which measures can be looked at when you evaluate the effectiveness of those interventions,” Foundation for NIH Biomarkers Consortium Senior Scientific Program Manager-Metabolic Diseases Maria Vassileva told AIM’s March 28 conference on sarcopenia PRO development. “The field is really in need of a clinical definition in order to proceed.”

Sarcopenia Project Diagnostic Criteria

The Foundation for NIH Biomarkers Consortium’s Sarcopenia Project published diagnostic criteria in Journals of Gerontology: Medical Sciences on April 15, 2014, providing specific characterizations of how low lean mass and low strength relate to mobility disability. Key elements are:

• Walking speed of less than 0.8 meters (2 feet, 7.5 inches) per second, chosen as the primary outcome because of its strong association with disability and death in observational studies and clinical trials.
• Weak grip strength, defined as less than 26 kg (about 57 pounds) for men and less than 16 kg (about 35 pounds) for women.
• Appendicular lean mass (the sum of lean mass in the arms and legs) of less than 19.75 kg (about 43 pounds) in men and less than 15.02 kg (about 33 pounds) in women. Body mass index is factored in to account for effects of obesity.

The Osteoporosis Example

The “oldest old” population – people aged 85 and older – is projected to more than triple between 2010 and 2050, according to the National Institute on Aging. As a result, “functional decline associated with aging is going to be a great challenge and threat to our entire economy,” Perry declared. Medical interventions that can arrest functional decline, potentially delaying or preventing serious (and costly) events like falls that lead to intensive institutional care, represent a potentially massive market.

The enormity of the potential market also makes a clear definition vital to gaining acceptance by regulators and payers. “There is real concern about sarcopenia,” AIM Scientific Advisory Board member Bill Evans said. “If we have a medicine that treats a specific patient population and the outcomes are good, there’s real concern that now everybody that’s over 70 is going to want to use it.”

A definition focused on identifying older people at risk for mobility disability or at risk of falling over the next year could assuage some of those concerns, Evans suggested. A clear definition with hard endpoints is one that “we can actually make into an indication and at the same time we don’t have to have all the payers faint because now we have 80 million people we want to treat.”

Osteoporosis offers a model for sarcopenia. “Osteoporosis didn’t really have much in the way of a good definition until somebody had this indication of fracture prevention,” Eli Lilly & Co. Medical Fellow Charles Benson observed, referring to the 1992 definition of osteoporosis as a bone mineral density T-score of -2.5, a level associated with increased fracture risk. The definition made the market: osteoporosis drug development skyrocketed and bone mineral density osteoporosis became a recognized ICD category, a critical status for reimbursement. (Aging in Motion is working with CDC to establish an ICD-10 category for sarcopenia, Perry noted.)

Unleashing Pharma R&D

Benson confirmed the dampening effect the lack of defined diagnostic criteria and outcomes has on R&D.

“At Lilly, we actually have a number of drugs which we think will work for sarcopenia, but we are extremely challenged in finding an indication,” he said. “Just in the last few weeks, we went through this exercise again for the third time in the last 10 years of [identifying] all the diseases which are associated with sarcopenia, and there’s at least 136,” he reported. “We’ve now narrowed it down to the top 30 again,” where “we might be able to intervene with a drug which improves muscle.”

Identifying “the outcome is difficult and the regulatory path is very difficult as well,” Benson said. Lilly recently completed Phase II studies of a myostatin-inhibiting monoclonal antibody in sarcopenia-related populations of older patients undergoing hip arthroplasty and older patients who had fallen recently and had muscle weakness (see related story, (Also see "Nascent Sarcopenia Pipeline’s First Target Is Myostatin" - Pink Sheet, 22 May, 2014.)).

Evans, previously the head of GlaxoSmithKline PLC’s Muscle Metabolism Discovery Performance Unit, expressed similar frustration: “We’re all thinking about, what’s the initial indication for a muscle-acting drug?” Evans is now exec VP of KineMed Inc.’s Muscle and Health Division, the biomarker development company announced May 13.

With consensus criteria including grip strength and appendicular lean mass adjusted for body mass established, “we believe that now further biomarker analysis will become possible and they should be enabling for future clinical trials,” FNIH’s Vassileva said.

The Sarcopenia Project’s next step is to validate the clinical criteria in patients with substantial levels of physical impairment. Phase I of the project, which culminated in the April 15 publications, looked at pooled data from over 25,000 community-dwelling older adults. Phase II of the project, launched in January, will evaluate pre-existing data from 2,504 older adults, HHS Office on Disability Deputy Director Rosaly Correa-de-Araujo reported at the International Conference on Frailty and Sarcopenia Research, held in Barcelona March 12-14. “Analyses of populations more severely compromised by physical limitations are likely to demonstrate stronger associations of Phase I criteria with outcomes,” her abstract states.

While U.S. efforts focus specifically on defining and measuring sarcopenia – that is, age-related muscle wasting and its associated functional decline – European stakeholders are looking at sarcopenia as a component of a larger condition, frailty. Differing definitions could complicate drug development efforts (see sidebar).

Outcome Measure Advances Through FDA’s DDT

“Something that’s of interest to everyone who develops interventions in this field is, of course, demonstrating how changes in muscle mass really affect function,” Vassileva commented. “That’s the key question that still has to be addressed.”

The AIM coalition is trying to address the functional disability aspect of sarcopenia by supporting the efforts of its scientific advisory board, chaired by Jack Guralnick of the University of Maryland School of Medicine, to get a clinical outcome assessment formally qualified by FDA under the agency’s new Drug Development Tool process (see box).

FDA published its final guidance on the Drug Development Tool qualification process on Jan. 6, 2014.

The agency’s Study Endpoints and Label Development (SEALD) team has so far qualified only one measure under the new tool, the EXACT patient-reported outcome instrument for chronic obstructive pulmonary disease (Also see "COPD Patient-Reported Outcome Questionnaire Is Early Example of FDA Drug Development Tool “Approval” Process" - Pink Sheet, 21 Jan, 2014.).

Proposed Clinical Outcome Assessment For Sarcopenia

The performance measure submitted to FDA under the agency’s Drug Development Tool qualification process centers on two elements:

• Short Physical Performance Battery, an instrument developed by the National Institute on Aging which includes timed standing balance measures, a timed four-meter walk, and timed multiple chair rises
• Usual gait speed

The sarcopenia clinical outcome assessment (COA) is “in the second phase of the DDT process,” Bens said in an interview. FDA accepted the coalition’s second letter of intent, and the collaborators are “in the process of finalizing our briefing package,” which will be submitted “probably in the next two months.”

FDA prefers outcome measures that are narrowly defined by the disease context, as opposed to using broader measures that are more widely available like the SF-36 short form health survey (see related story, (Also see "Using FDA’s New Drug Development Tool: Start With Narrow Context Of Use" - Pink Sheet, 22 May, 2014.)). In sarcopenia, SEALD Clinical Outcome Assessment Qualification Scientific Coordinator Ashley Slagle commented, “the real challenge” is that “we don’t quite yet understand what domains we should be measuring fully in this very broad patient population or narrow patient population, however we define it.”

Sarcopenia’s Chicken-And-Egg Problem

Sarcopenia presents a conundrum: which comes first, the indication or the outcomes measures? “It’s easier to come up with the outcome than to figure out what the indication is” for a sarcopenia drug, Guralnick commented. “And it’s a little bit funny. It’s traditionally gone in the other direction.”

“You try and have a definition but, yet, we don’t have an indication,” Lilly’s Benson said. “And without an indication and an outcome, it’s really hard to decide what the definition is.”

AIMS’ Bens acknowledged the expense and challenge entailed in developing a definition of sarcopenia while also validating instruments to measure the condition in clinical trials, and she pointed to Alzheimer’s disease as a cautionary case study. “There’s been a lot of money thrown into Alzheimer’s drug development based on what we all believed we knew about the disease,” but now “everyone wants to intervene earlier,” she noted. “We’re faced with a disease definition problem … and also an instrumentation problem,” because measures to assess the efficacy of interventions are based on “a much later population.”

The AIM coalition is trying to “work through some of these issues now rather than companies going and spending a lot of money on these trials and then ultimately having a definition and an instrumentation problem,” Bens said. The Alliance for Aging Research, which established AIM, is drawing on lessons learned from its ongoing collaborative initiative in Alzheimer’s disease.

FDA’s efforts to qualify publicly available clinical endpoints, embodied in the DDT process, can provide necessary structure and a stable platform for drug development in conditions like sarcopenia that are just emerging as potential indications. But interwoven questions of disease definition, clinical outcomes and indication may need to be sorted out before that platform can really be built.

“What’s concerning to me is that I hear there are compounds out there that you think might have some utility. And because there’s no disease definition and there’s no outcome assessment settled on yet, they’re not moving forward,” FDA study endpoints reviewer Slagle said. But “until you have an IND opened or in the pre-IND stage, it’s difficult to talk to us.”

“We need to figure out how we can work with individual sponsors even earlier in the process to talk about some of these things. And unfortunately, we don’t have a mechanism for that yet,” she said. “But I’ve been to several of these meetings” of collaborative groups working to establish the ground rules for drug development in complicated indications, “and that’s something that I’m hearing a lot.”

“We’re moving a big ship sometimes at the agency, but we’ll see what we can figure out,” Slagle promised.