Guest Column | May 12, 2023

Phase 1 Strategies To Optimize Orphan Drug Development

By Dirk Huebner, MD, CMO, Aptevo Therapeutics, and Miriam Weber Miller, head of investor relations and corporate communications, Aptevo Therapeutics


The cost of drug development continues to increase as does the competition for a place in the market, making it increasingly important to design Phase 1 trials that can strategically inform next steps in the development pathway. While all sponsors face these challenges, those seeking orphan drug indications, with small patient pools and high unmet medical needs, face even more pressure to establish (or not) potential viability as early in the development process as possible.

It remains that the primary purpose of a Phase 1 trial is to establish safety, tolerability, and dose level in a monotherapy setting. This makes sense because these variables must be solved for at a base level to justify further development. While evidence of clinical activity is often sought and collected, it is not typically the primary trial endpoint. But in later-stage trials such as a Phase 1b dose expansion study, there are opportunities to collect additional critical data that will help to guide further development. This includes clinical activity, biomarker and genetic mutation assessments, and preliminary impact in combination therapy.

Considering Strategic Collection Of Additional Data

From a strategic perspective, incorporating collection of additional data beyond those traditionally collected in a Phase 1 trial can support decisions for next-stage development, but it also comes at a cost of both time and money. Sponsors must choose whether to make these investments while in early-stage development or wait until the candidate progresses. On one hand, more information sooner can help sponsors structure advanced trials that have a greater chance for success. On the other hand, gathering and analyzing these data requires resources that not all companies want to invest at the earliest development stages.

Included in the basket of possible additional data is evaluation of two dose levels for clinical exploration related to all established endpoints. The FDA’s Project Optimus has been launched to encourage sponsors to ensure “dose optimization and dose selection paradigm in oncology drug development.”1  This is “[i]n response to (sponsor) mischaracterizations associated with optimal dose level and duration of dosing, especially in oncology where added toxicity must be finely balanced with efficacy to determine clinical benefit to the patient.”1 

Biomarker analysis supports dose optimization and duration and has the potential to clarify the signals required and inform the next steps by providing prognostic and predictive values for future trials. Cost is a factor here, and some sponsors may choose to postpone this work until safety and tolerability have been demonstrated or where the information is not immediately needed to inform the decision processes.

If biomarker analysis is employed, sponsors must also consider if a test assay is needed to select patients who are most likely to benefit from the treatment. If an assay is required for optimal patient selection, sponsors will benefit from incorporating the development of a companion diagnostic into their approval plan.

Determining Clinical Activity And Efficacy Early On

Efficacy data collected in Phase 1 is considered preliminary as results from the usually small sample size may not be reflected in a larger pool. Still, assessing clinical activity can help sponsors determine if the drug is active against the disease target and affirm the dosing level(s) identified in the dose escalation phase of the trial.

In this context, biomarkers and pharmacodynamic assessments can be helpful to identify the right dose, particularly in circumstances where no dose-limiting toxicities are observed. This is particularly applicable for sponsors evaluating immune-oncology candidates. Pharmacokinetic (PK) data are also of interest because they can provide additional strategic direction, especially if preclinical models suggest a particular exposure level should be achieved for maximum benefit.

The presence or absence of genetic mutations taken from the larger pool of patients can characterize a risk profile of subgroups in an early clinical study. Early-stage detection of clinical activity in potentially poor characteristic patients can lead to the identification of an early regulatory path for approval.

Overall, while efficacy is not established in the Phase 1 setting, the collection and analysis of biomarkers and pharmacokinetic data, as well as the presence in the treated population of genetic mutations, can be used as the foundation for advanced trials. While time-consuming and costly, this data reduces some risk associated with the cost of later-stage development and can drive advanced program strategy.

Exploring The Pros And Cons Of Phase 1 Combination Therapy

Some sponsors, especially those with therapies intended for indications with an established standard of care, may include combination therapy in Phase 1. This requires a trial with multiple cohorts, however, and is usually more expensive and more time consuming than a monotherapy study. Still, there is the potential for significant benefit, and combination Phase 1 trials are becoming more prevalent, especially in oncology where immunotherapy has demonstrated potential to improve outcomes when administered in concert with established chemotherapy regimens or other treatment modalities.

Benefits may include enhanced understanding of how a drug candidate interacts with standard of care regimens, which will be of interest to guide future study designs for further development. An early understanding of combinability also can lead to a defined regulatory path if the addition of the experimental therapy shows superiority to an otherwise standard of care regimen. While it is true that integration of combination therapy cohorts makes a Phase 1 study more complex and more time consuming, in the long term it could save time and costs if combinations are needed or desired for the regulatory approval path.

The Phase 1 trial, while an early stage, is increasingly becoming a strategic inflection point beyond the safety and tolerability parameters traditionally associated with this development stage. To ensure the most robust outcomes possible sponsors should at least consider all available parameters to drive the go-forward decision process, including clinical safety, clinical activity, biomarker analysis, and PK data. The goal is to set expectations appropriately and design a rational trial that contemplates all parameters. Set trial halt rules for safety and size the population sufficiently to assess pharmacodynamic and clinical activity with the idea of generating a clinical signal, although this does not need to be statistically significant.

Leveraging the Phase 1 platform to secure data beyond the trial’s traditional purpose can help sponsors to make a go/no go decision to further develop a drug candidate and inform a strategic Phase 2 trial and help maximize the potential for success.



About The Authors:

Dirk Huebner, MD, chief medical officer of Aptevo Therapeutics, is a medical advisor consultant with approximately 29 years of academic and industry-based clinical drug development experience in the biotech and pharmaceutical industries. In the course of his career, he has led multiple clinical programs spanning all stages of development from Phase 1 through Phase 3 registration trials. Before becoming a consultant, Dr. Huebner served as chief medical officer and senior medical advisor for Mersana from November 2018 to January 2021, where he built their clinical development department and oversaw the development of their antibody-drug conjugate (ADC) pipeline. Dr. Huebner has previously served in clinical leadership and R&D roles at Boston Biomedical, Millennium, Takeda, Genzyme, Roche, and Bristol-Myers Squibb. 

Dr. Huebner received his medical doctor degree from Freie Universitaet Berlin, Germany, and pursued a medical residency in the Department of Urology, University Hospital Eppendorf, Hamburg.

Miriam Weber Miller, head of investor relations and corporate communications at Aptevo, is responsible for corporate brand, reputation, and investor communications. She provides expertise in content creation, events, marketing, investor relations, issues management, social engagement, and strategic planning. Miriam has helped to build healthcare brands for three leading public relations consultancies, in the process working with more than 100 public, private, and not-for-profit organizations spanning the healthcare and innovation technology sectors. Miriam has launched more than two dozen pharmaceutical products and is an expert in navigating FDA processes. A published author and invited speaker, Miriam holds an undergraduate degree in journalism from Rowan University and an MBA in finance from Fordham University. She sits on the Advisory board of Tangerine Energy Partnerships and Pay it Forward, People.