||effectively compete with other products should any be successfully developed and approved; and|
||maintain a continued acceptable safety profile of vonapanitase following launch.|
If we develop vonapanitase for other indications,
including arteriovenous grafts, brachiocephalic fistula and symptomatic PAD, or develop additional product candidates, we will
face similar risks and challenges.
Clinical development is a lengthy and expensive process with
an uncertain outcome due to many factors. Because the results of early clinical trials are not necessarily predictive of future
results, vonapanitase may not have favorable results in current or future clinical trials or receive regulatory approval.
Clinical development is expensive, difficult
to design and implement, takes many years to complete and its outcome is inherently uncertain. Failure can occur at any time during
the clinical trial process and vonapanitase is subject to the risks of failure inherent in drug and biological development, including
failure to demonstrate efficacy in a pivotal clinical trial or in the patient population we intend to enroll, the occurrence of
severe or medically or commercially unacceptable adverse events, failure to comply with protocols or applicable regulatory requirements
and determination by the FDA or any comparable foreign regulatory authority that a drug and biological product is not approvable.
Results observed in earlier clinical trials may not be replicated in current or future clinical trials. For example, our first
Phase 3 clinical trial of vonapanitase failed to meet its primary endpoint of primary unassisted patency, despite encouraging results
from our Phase 2 trial. In addition, as is common with clinical trials, we explored a number of endpoints in our Phase 2 clinical
trial of vonapanitase. We also analyzed the data from our Phase 2 and Phase 3 clinical trials of vonapanitase in a number of ways.
Product candidates such as vonapanitase in Phase 3 clinical trials may fail to demonstrate sufficient efficacy despite having progressed
through earlier clinical trials, even if certain analyses of primary, secondary or tertiary endpoints in those early trials showed
statistical significance. Companies may suffer significant setbacks in late-stage clinical trials due to lack of efficacy, site
or investigator issues, manufacturing or formulation changes or adverse safety profiles, even after earlier clinical trials have
shown promising results. During the course of our clinical development, we modified our vonapanitase drug product formulation for
our Phase 3 trials and commercial launch in order to facilitate ease of administration and fill and finish of vials at our 30 microgram
dose. Our formulation changes could adversely affect results in our clinical trials, requiring us to make further formulation changes.
In addition, following our review of the data from our first Phase 3 clinical trial of vonapanitase and discussions with the FDA,
we amended the protocol for our second Phase 3 trial to include co-primary endpoints of secondary patency and fistula use for hemodialysis,
each of which was studied in earlier clinical trials. Our reordering of the endpoints could adversely affect the success of the
second Phase 3 trial. Additional changes or interactions with the FDA could also cause us to delay or repeat clinical trials, or
could cause FDA to request additional studies or data, and we could incur unexpected costs that would have an adverse effect on
our business, operating results, financial condition and prospects.
The design of a clinical trial can determine
whether its results will support approval of a product, and flaws in the design of a clinical trial may not become apparent until
the clinical trial is well advanced or completed. We have limited experience in designing clinical trials and we may be unable
to design and execute a clinical trial to support marketing approval. In addition, preclinical and clinical data are often susceptible
to varying interpretations and analyses. Many companies that believed their product candidates performed satisfactorily in preclinical
studies and clinical trials have nonetheless failed to obtain marketing approval for the product candidates. Even if we believe
that the results of clinical trials for our product candidates warrant marketing approval, the FDA or comparable foreign regulatory
authorities may disagree and may not grant marketing approval of vonapanitase or any additional product candidates.
In some instances, there can be significant
variability in safety or efficacy results between different clinical trials of the same product candidate due to numerous factors,
including changes in trial procedures set forth in protocols, differences in the size and type of the patient populations, changes
in and adherence to the clinical trial visit schedule or protocols, changes in practice patterns outside of the protocols and the
rate of dropout among clinical trial participants. Any Phase 3 or other clinical trial that we may conduct may not demonstrate
the efficacy and safety necessary to obtain regulatory approval to market vonapanitase or any additional product candidate.
Any delay or failure in our clinical trials
would delay our obtaining, or make us unable to obtain, applicable regulatory approvals, which would prevent us from commercializing
vonapanitase or any additional product candidates, generating revenues and achieving and sustaining profitability.