we receive marketing approval for vonapanitase or any additional product candidates, we and our contract manufacturers will continue
to expend time, money and effort in all areas of regulatory compliance, including manufacturing, distribution, product surveillance,
post-marketing studies and quality control.
Vonapanitase may cause undesirable
side effects or have other properties that could delay or prevent their regulatory approval, limit the commercial profile of approved
labeling, or result in significant negative consequences following any potential marketing approval.
As with many pharmaceutical
and biological products, treatment with vonapanitase or any additional product candidates may produce undesirable side effects
or adverse reactions or events. These adverse events may occur despite our belief, based on our preclinical and clinical trials
to date, that vonapanitase has a favorable safety profile. For instance, vonapanitase shows a high degree of structural similarity
with other human serine proteases, which are proteins that cut other proteins to activate, inactivate or degrade these other proteins,
and it is theoretically possible that if anti-vonapanitase antibodies are developed that they could cross-react with one or more
of those other proteases because of the structural similarity, and prompt an adverse reaction. However, we have not seen any evidence
of such cross-reactivity in our preclinical or clinical trials to date.
Based on our Phase
2 and Phase 3 trials, adverse side effects that could occur with treatment with vonapanitase include fistula surgical incision
pain, venous stenosis, procedural pain, fistula thrombosis, steal syndrome and hypoesthesia. If any of these adverse events occur
in rates or severity exceeding placebo and unacceptable to regulatory authorities or IRBs, if anti-vonapanitase antibodies develop
and are associated with cross-reactivity to other proteases, or unknown serious events emerge, our clinical trials could be suspended
or terminated by us, IRBs, or the applicable regulatory authorities, and the FDA, the EMA or other foreign regulatory authorities
could order us to cease further development of, or deny approval of, vonapanitase or any additional product candidates for any
or all targeted indications. The product-related side effects could affect patient recruitment or the ability of enrolled patients
to complete the trial. If we elect or are required to delay, suspend or terminate any clinical trial of vonapanitase or any additional
product candidates, the commercial prospects of these product candidates will be harmed and our ability to generate product revenues
from any of these product candidates will be delayed or eliminated.
In addition, even if
we were to obtain approval, regulatory authorities may approve any of our product candidates for fewer or more limited indications
than we request, including more limited patient populations, may require that contraindications, warnings or precautions be included
in the product labeling, including a boxed warning, may grant approval contingent on the performance of costly post-marketing clinical
trials or other post-market requirements, or may approve a product candidate with labeling that does not include the labeling claims
necessary or desirable for the successful commercialization of that product candidate. Any of these occurrences may harm our business,
financial condition and prospects significantly.
We may not be able to maintain orphan
drug designation or obtain or maintain orphan drug exclusivity for vonapanitase.
We have obtained orphan
drug designation from the FDA for vonapanitase. In the United States, under the Orphan Drug Act, the FDA may designate a product
as an orphan drug if it is intended to treat a rare disease or condition, which is generally defined as a patient population of
fewer than 200,000 individuals annually in the United States for a preventive drug. The first NDA or BLA applicant to receive FDA
approval for a particular drug or biologic to treat a particular disease with FDA orphan drug designation is entitled to a seven-year
exclusive marketing period in the United States for that product, for that indication. During the seven-year exclusivity period,
the FDA may not approve any other applications to market the same drug or biologic for the same disease, except in limited circumstances.
Orphan drug exclusivity may be lost if the FDA determines, among other reasons, that the request for designation was materially
defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs of patients with the
rare disease or condition.
Even if we obtain
orphan drug exclusivity for vonapanitase, that exclusivity may not effectively protect the product from competition because different
products can be approved for the same condition. Even after an orphan product is approved, the FDA can subsequently approve a product
containing the same principal molecular structural features for the same condition if the FDA concludes that the later product
is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care.
In response to a recent
court decision regarding the plain meaning of the exclusivity provision of the Orphan Drug Act and increased scrutiny by legislators,
the FDA may undertake a reevaluation of aspects of its orphan drug regulations and policies. We do not know if, when, or how the
FDA may change the orphan drug regulations and policies, and it is uncertain how any changes might affect our business. Depending
on what changes the FDA may make to its orphan drug regulations and policies, our business could be harmed.