Novelty, Purity, And Potency: Three Pillars Of Biotherapeutics

By Wayne Koberstein, Executive Editor, Life Science Leader
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By Wayne Koberstein, contributing editor

Formulation Drives Innovation At The AAPS National Biotechnology Conference

Tiny pieces of gunk — formally known as particles or “aggregates” — almost completely dominated the discussion among some 7,000 participants at the 2012 AAPS (American Association of Pharmaceutical Scientists) National Biotechnology Conference (NBC) May 21 to 23 in San Diego. Aggregates in therapeutic proteins ultimately constrain their concentration, thus their potency and potential dosing in patients. But the work to produce the purest possible forms of new biotherapeutics begins long before they reach the first human beings. From the bench to clinical trials, and continuing even into commercial production, biotherapeutics stand or fall on their level of purity and potency.

WHAT’S IT ALL ABOUT, AGGREGATE?
Reducing an entire conference to a simple phrase — e.g. tiny pieces of gunk — is oddly appropriate. For the aim of this meeting could well be seen as an exercise in resolving extremely complex issues in living chemistry into comprehensible terms that scientists and nonscientists together can discuss.

Such issues critically inform and determine a host of decisions by companies, business executives, and investors, as well as regulators and policymakers, and of course, all the researchers, engineers, and industrial managers plodding along the path of product development. Characterization, another blanket term for the process of evaluating molecules for purity and potency, came up as a key element in virtually every session of this exhaustive and highly technical program. But a few common goals emerged from the depth of expert-level details:

• accelerating biotherapeutic development by improving the quality, e.g. pharmacokinetics/pharmacodynamics (PK/PD), of new molecules
• smoothing the regulatory path for new molecules and biosimilars
• expediting the translation of new discoveries into compounds testable in humans
• accommodating personalized medicine and novel drug delivery in the development of new drug-diagnostic or drug-device combinations.

Case in point: a roundtable with the intriguing if somewhat overpromising title, “Ask the Regulator: What Biopharma Scientists Always Wanted to Discuss with FDA and EMA Representatives.” Rather than a spontaneous panel-audience exchange, the session was highly structured as a veritable work session presenting and gathering feedback on regulators’ current plans for evaluating the biological effects of aggregation in biotherapeutics.

The FDA’s Susan Kirshner, associate chief of the laboratory of immunology, and Laura Salazar-Fontana, staff fellow, spotlighted some of the agency’s responses to the AAPS focus group on “Particle Aggregation and Biological Consequences” (PABC). They presented a set of questions and answers related to regulatory oversight and prioritization of process and product changes, comparability studies and protocols, surfactant specifications, and other aspects of product composition, from bench samples to bulk supply. Their answers gave some guidance on when and how producers must report process and composition changes with important side effects or risks.

One of the most far-reaching questions in the FDA’s presentation was, “How does the FDA decide when to ask for data from new technologies in the production of biotherapeutics in development?” New technologies may arise at any step in the process, but may include single-use components, aseptic blow-fill-seal, or novel purification tools. The FDA’s answer stressed the top priority of safety and the need for producers to look at the PK/PD implications of every change: “Applicants are required to demonstrate … the lack of adverse effect of the change on the identity, strength, quality, purity, or potency as they may relate to the safety or effectiveness of the product.”

An “industry view” presentation by Vicki Frydenlund, CMP compliance manager at Genentech, focused on how to structure company production operations to ensure purity, potency, and good PK/PD. She emphasized some basics, such as the need for sufficient “temporal segregation,” adequate analytical methods, and careful flow design to avoid cross contamination in multiproduct facilities. Genentech is conducting a QbD (quality by design) pilot program built on the principle of extensive quality and risk management. Key elements of its approach are sterility testing, comparability, and measurement of subvisible particles.

The ask-your-regulator session ended in a brief and mainly inaudible Q&A exchange with the audience. One person asked how his company could work with FDA to decide which of several possible new production methods to adopt. The FDA reps recommended that the company first evaluate the alternatives before making a proposal to the agency, comparing each method with clear aggregation data, some measure of potential immunogenicity, and an analysis of the method’s likely impact on the related “community” of producer, regulator, investigators, and patients.

ENDURING EDUCATION
Most of the sessions in this conference were more than 2 hours long and ran in several parallel tracks from early morning to evening, with some even carrying on through the lunch break. A typical afternoon saw concurrent sessions on plant-derived vaccines, preclinical immunogenicity assays, developability assessment, and biosimilars. Generally, except for FDA, no presenters shared their slides, and — because many of the speakers were from proprietary companies — recording by attendees was forbidden. So the audience became a sea of furious note-takers mottled with yellow tablets, laptops, and iPads. That setting alone characterizes the event as a whole: There was no substitute for being there.

The conference deserves high marks for sticking to the essentials of a physical meeting of people in a well-defined community. Not a second was wasted on “virtual” elements that could as well have been communicated online. Still, the event arguably suffered from a lack of networking among participants; there simply was no time left between the exhaustive sessions, other than two 1-hour receptions in the exhibition and a lunch area outside. Another drawback was poor acoustics and microphone management, which often made Q&A exchanges frustrating to follow, especially considering the admirable international mix of English speakers with sometimes challenging accents.

The opening plenary session on day one supported the conference’s overarching theme: “Advancing Health Through Innovations in Biotherapeutics.” Tony Coyle, head of the Pfizer-academia initiative, Centers for Therapeutic Innovation (CTI), pointed to the “perfect storm” of Big Pharma R&D shortfalls, collapse of VC funding for biotech, and growing participation of academic science in new discoveries, which he said creates a need for new ways and new partnerships for translating science into therapeutic breakthroughs. He laid out a clear rationale for the CTI model as a solution for funding and facilitating translational science for academic researchers, who now account for more than 50% of new therapeutic entities. (Note: An upcoming report on Pfizer R&D in Life Science Leader will share a closer look at the CTI model.)

Dr. C. Anthony Blau of the University of Washington gave a much smaller scale but no less significant view of his own initiative stemming from academic research. Called “Partners in Personal Oncology” (personaloncology.org), his open, Web-based “institute” aims to be a “network of networks” dedicated to integrating all the best possible resources and bringing them to bear as an optimally tailored treatment for every cancer patient. Blau is a hematologist, but after a trip to a large cancer meeting with his oncologist wife, saw the need for oncology to restructure itself in the way his own field refined its approaches from the early, stem-cell-transplantation-for-all philosophy to the quite different, patient-specific treatment programs of today. He issued a challenge to the cancer-research community.

“We still treat cancer as a black box,” he said. “We need to deal with the heterogeneity of cancer among patients and see who responds best to which treatment. Current clinical trial design does not allow for such variability. All we can do is compare an experimental therapy against standard therapy and pick the winner.”

Orphan drugs were the focus of another plenary presentation by Tim Cote, longtime rare disease advocate and chief medical officer of NORD (National Organization for Rare Disorders). Cote was an early associate of Abbey Myers, who decades ago founded NORD, which became the principal force behind the revolutionary U.S. Orphan Drug Act (ODA). ODA gave companies big incentives to develop drugs for orphan conditions and inspired similar approaches internationally.

Cote traced the amazing growth of orphan drugs since then, from zero to more than 200 now on the market, with orphans gaining 38% of all FDA drug approvals last year. He gave credit to the drugs for contributing greatly to the expansion of biotech. But he noted problems such as companies’ tendency to herd together around similar orphan areas and modalities. “People want to do the same thing others have done — to achieve the same success,” he said. “But the government has a right to push companies toward diseases with no existing treatments.”

He implied that big companies may distort the intent of ODA by using orphan status as only a starting point for a drug’s development into wider indications and larger markets over time — as well as high profits from day one, considering the record-setting price tags on the more recent “orphan blockbusters.” Indeed, Myers warned years ago that high prices could severely limit rare-disease patients’ accessibility to the very drugs designed to treat them.

SAMPLE ANALYSIS
For any nonexpert in the given topic, attending any session was like jumping into a swift and tumbling stream. Every session was but a brief excursion down a single tributary in the grand flow of biotherapeutic discovery, characterization, and production. A good example was the session on early assessment of biological development candidates. Two large companies, one small one, and an academic researcher shared details of their short- and long-term efforts to identify optimum development candidates in the formative stages of preclinical research. (See the sidebar, “Session Sampler.”)

As with most sessions, this one closed with a speaker roundtable, further exploring lessons from early candidate selection of small molecules, unique CMC (chemistry, manufacturing, and control) challenges with biomolecules, ways to build in stability, the feasibility of platform approaches, and the question of how early is early enough. Experts in the audience peppered the panel with questions about conjugated antibodies, immune response, PEG (polyethylene glycol) interference, the effects of high concentration on charge interaction, relationship of viscosity to aggregation, and other queries ranging from mystified to skeptical to prescient.

And so went this extraordinary assemblage of sessions packed into the three days of the NBC. (Additional work sessions sandwiched the main conference on the preceding weekend and following day.) There may be many other even more scientifically intensive meetings in this field, but in this one AAPS seems to have hit on a unique formula that puts the expert science in a strategic context, making it accessible to the full range of players in biotherapeutic R&D, manufacturing, and business. Thus, the conference offered both immersion in the stream of technological progress and inspiration at the headwaters of discovery.

SESSION SAMPLER: EVALUATING CANDIDATES EARLY

A seminar and roundtable on early biotherapeutic development selection at the AAPS National Biotechnology Conference yielded details of large- and small-company as well as academic initiatives to adopt new technologies, and methods to characterize new molecules and predict their effects in humans, as well as manufacturing and delivery.

Bristol-Myers Squibb (BMS) is building molecular “scaffolds” to generate “millimolecules” — essentially smaller antibodies with multiple targets, according to Sharon Cload, VP at Adnexus, a BMS R&D company. The goals are superior potency and specificity, aggregation propensity, and immunogenicity potential, all leading to in vitro selection of candidate molecules with “high affinity, selectivity, and binding.” Presumably, over time, as tools improve, in vitro selection will occur earlier and earlier, and it should also yield better results as the “biophysical triage” of scaffolds and molecules more accurately reflects PK/PD (pharmacokinetics/pharmacodynamics) in patients.

Novartis has teamed with MIT in a computer-based approach to early developability assessment, reported Bernard Helk, global executive director of technology development at Novartis Biologics/Process Sciences. The aim is “biophysical profiling” of molecules based on such factors as charge distribution, self-interaction, surface hydrophilicity, and conformational stability.

George Makhatadze, professor of biology at Rensselaer Polytechnic Institute, expanded on the charge factor, specifically charge-charge interactions over the surface of a molecule, as a function or predictor of purity and potency. Molecules designed to have an “optimum” charge distribution have shown greater thermostability, protolytic degradation, and protein aggregation versus their “wild-type” precursers, he said.

Naturally, in addition to the academic and large-company efforts to improve early candidate selection, there will be plenty of small companies vying to help out. Tudor Arvinte of Therapeomic described how his company specializes in “enabling formulations” with superior stability, using a variety of technologies and assays individually “tailored” to the evaluation of specific proteins, not only for chemical and physical stability, but also easy application procedures, optimal release and delivery, optimal presentation of the molecule at the target site, minimum side effects, and manufacturability. “Companies trying proof-of-concept with poor formulations raise the risk of a failure,” he maintained.