By Edward Maggio, Ph.D.
Peptide and protein drugs are among the most useful and effective drugs yet discovered, exhibiting potent biological activity, high binding specificity for specific biological targets, and essentially no chemical toxicity with few or no drug interactions. There are more than 140 peptide and protein drugs in current use today, and their number and importance is rapidly increasing. While these new drugs demonstrate high potency and high selectivity, their inherent susceptibility to denaturation, poor transmucosal absorption, and hydrolysis in the gastrointestinal tract make them generally unsuitable for oral administration. Most protein or peptide therapeutics are therefore administered by injection — an inconvenient and expensive delivery mode — and patient acceptance of injectable therapeutics in situations where the medical consequences may not be immediate or life-threatening, and especially in cases where administration must be frequent and chronic, is a serious issue. As a result, while the range of potential clinical indications for therapeutic proteins and peptides is quite broad, the actual number of such therapeutics in general use is small compared to the number of approved chemically synthesized and orally active drugs.
New Therapeutic and Commercialization Options
Advances in noninvasive transmucosal delivery of peptides and small proteins are creating new therapeutic options across the entire spectrum of human disease. Effective routes of noninvasive peptide administration include aqueous metered nasal sprays, pulmonary dry powder formulations, sublingual or oral cavity sprays or “flash-dissolve” wafers, and rectal or vaginal suppositories. A few peptides that are intrinsically stable to conditions in the GI tract have even proven amenable to oral administration, and newly developed chemical modification techniques promise to expand the range of such orally bioavailable peptides. Reformulation of injectable peptide or protein drugs into these more patient-friendly forms offers a particularly large, attractive, and as yet untapped opportunity for all stakeholders in the pharmaceutical field — patients, pharma companies, physicians, and third-party payers alike. To date, nasal delivery has proven to be the most effective route of noninvasive peptide administration. Where adequate bioavailability is attainable, the advantages of intranasal administration in terms of greater patient comfort, convenience, and the elimination of needlestick injuries and concerns surrounding syringe disposal associated with daily injections make this a particularly attractive mode of delivery and one that is well-accepted by patients. This is clearly evidenced by the fact that total annual sales for nasally delivered products exceed U.S. $6 billion. More to the point, sales of nasally delivered versions of previously injectable-only therapeutics have demonstrated up to a 33-fold increase in annual sales compared to the original injectable formulations.
For smaller biotech companies, reformulation of existing injectables into noninvasive formats is responsive to investors’ increasing disenchantment with the long development time frames and high risk of failure associated with the development of so-called NCEs (new chemical entities) — novel drugs that offer the potential for new therapeutic modalities. For larger public pharma companies, reformulation is responsive to equity market pressure to focus on drug development programs that promise shorter times to market. Reformulation is a proven life cycle management strategy as well. Thus reformulation of approved drugs has garnered the attention of both venture investors and pharmaceutical companies as a low-cost/low-risk route to increased product sales and perceived company value in the relatively near term. In any event, and for opposite reasons, both small and large companies should pay close attention to this trend, because when an innovator fails to exploit opportunities to replace suboptimal formulations using newly enabling technologies or fails to take advantage of well-established branding efforts through reformulation, prime opportunities arise for small pharma companies to enter into and exploit proven markets with dramatically reduced regulatory and business risks.
Dr. Maggio is CEO of Aegis Therapeutics, a company that out-licenses patented formulation technologies for peptide and nonpeptide macromolecular drugs. He has founded eight public and private life sciences companies in the United States and Denmark and serves on advisory boards for UCSD, Polytechnic Institute of NYU, and California State University and on the San Diego Consortium for Regenerative Medicine Industry Council.