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What Is an Investigator-Initiated Trial?

When most people think of a clinical trial, they picture a pharmaceutical company designing, funding and running the study. That is how many trials work, and company-sponsored trials remain the core of developing any medicine. But there is another important model in clinical development: the investigator-initiated trial, or IIT.

IN SHORT

An IIT is a clinical trial that begins with doctors rather than a company.

What is an IIT?

An IIT is a clinical trial that begins with doctors rather than a company. A physician or research team at a hospital, university or academic research organization spots an important scientific or clinical question that no existing trial is addressing, and decides to answer it.

The investigators write the trial plan, obtain the regulatory and ethics approvals, recruit patients and run the trial. Their institution is the sponsor, which means it carries the legal responsibility for the trial and oversees how it is run.

The company that manufactures or develops the medicine is not the sponsor and does not control the trial or its results. Depending on the agreement, it may provide the medicine and other support, but the question, the design, the conduct and the reporting remain with the investigators. Results from academic trials have also contributed to the approval of medicines, although that always depends on the data and on regulatory review.

Why do investigators start IITs?

Doctors and researchers see unmet medical needs every day. Drawing on their clinical experience and scientific work, they may spot a new interesting combination, a different stage of disease or a biological question that deserves testing. An IIT lets them explore that idea in a properly designed prospective clinical trial, following the principles of evidence-based medicine.

It also takes real commitment. Designing and running a trial demands years of work, expertise and institutional resources, and investigators do not spend them on ideas they do not believe in. Their choice to test a medicine reflects their own scientific conviction that the approach is worth examining. That is not evidence that the medicine works, and it says nothing about how any trial will turn out. Only the data can answer that.

IITs and bexmarilimab

Faron sponsors its own trials, such as BEXMAB and BEXERA. Alongside them, independent investigators are studying, or preparing to study, bexmarilimab in several settings:

Investigator-initiated trials of bexmarilimab

TRIALWHAT IT STUDIESLED BY
BEXARBexmarilimab together with the chemotherapy doxorubicin in metastatic soft-tissue sarcomaDr César Serrano, Vall d’Hebron, Barcelona. Sponsored by MEDSIR
BLAZEBexmarilimab together with the immunotherapy nivolumab in metastatic lung cancer or melanoma that has stopped responding to earlier anti-PD-1 treatmentInstitute of Cancer Research with the Royal Marsden, United Kingdom
City of Hope trial
In planning		Bexmarilimab together with decitabine-cedazuridine, an oral medicine already used in myelodysplastic syndromes (MDS), in MDS that has returned or stopped responding to treatmentDr Brian Ball, City of Hope, United States
BEAM-X
Being prepared		Bexmarilimab in acute myeloid leukemia (AML) after a stem-cell transplant, when traces of leukemia remain in blood tests but the disease has not yet relapsedNordic AML Group


Each trial asks a different question, and each began with investigators who saw a scientific and clinical rationale for studying bexmarilimab. That breadth is worth noting: experienced researchers in different institutions, countries and diseases have each decided, independently, that this is a question they want to answer.

In every case, the investigators and their institutions are responsible for the trial. Faron collaborates with them, and may supply bexmarilimab, but does not sponsor, lead or direct their work.

Why IITs matter for Faron

Company-sponsored and investigator-initiated trials play different roles. Faron’s own trials are the core of its development program, designed to answer the questions that matter most for the medicine’s development. IITs complement them by letting independent and experienced investigators examine further questions across new diseases, treatment combinations and stages of illness.

Who does what

COMPANY-SPONSORED TRIALINVESTIGATOR-INITIATED TRIAL
Who has the ideaThe companyDoctors and researchers
Sponsor, with the legal responsibilityThe companyA hospital, university or academic research organization
Who runs the trialThe company and its partnersThe investigators and their institution
Who pays for running itThe companyMostly the academic sponsor
Faron’s roleLeads the trial and carries the responsibilityCollaborates and supports, with scientific input, potential financial support and supply of bexmarilimab. No operational lead
Rules that applyRegulatory and ethics approvals, informed consent and Good Clinical PracticeRegulatory and ethics approvals, informed consent and Good Clinical Practice


They also make careful use of resources. Running a company-sponsored trial means paying for hospital sites, monitoring, safety reporting, regulatory work and data management. In an IIT, those responsibilities and most of that cost sit with the academic sponsor. Faron’s support is agreed separately for each trial. It can include scientific input, financial support and supplying bexmarilimab, but Faron takes no operational lead and carries no responsibility for how the trial is run.

In return, and subject to the collaboration terms, Faron may gain access to clinical data and to the results of laboratory analyses of patient samples. For a fraction of the cost of sponsoring such trials ourselves, these exploratory studies of novel combinations and tumor types have the potential to generate valuable new findings and add to the evidence around bexmarilimab.

What an IIT is not

Not a guarantee of results. Every clinical trial carries uncertainty. Bexmarilimab is an investigational medicine, and its safety and efficacy have not been established.

Not controlled by Faron. The investigators and their institutions decide how an IIT is conducted, analyzed and reported.

Not a shortcut. Like company-sponsored trials, IITs require regulatory and ethics approvals, informed consent and compliance with Good Clinical Practice. The standard is the same. What differs is who sponsors and runs the trial.


Looking beyond a single trial

No single trial can tell the whole story of a new medicine. Evidence builds up from different researchers, patients, hospitals and clinical settings. IITs add independent research expertise to that picture, alongside Faron’s own trials. We find the continued interest of investigators encouraging, while recognizing that every trial will ultimately be judged on the data it produces. Importantly, IITs complement Faron sponsored drug development by exploring important clinical questions and generating new evidence in areas of unmet need.

As our clinical program progresses, we will continue to share more about the science, the development process and the work needed to turn an idea into evidence that can matter for patients with high unmet need.

— Petri Bono, Chief Medical Officer

Forward-looking statements: This blog post contains forward-looking statements, including statements about the planning, design, timing and potential results of clinical trials, among them trials sponsored and run by independent investigators, and about the development of bexmarilimab. Forward-looking statements are based on Faron’s current expectations and are subject to risks and uncertainties that could cause actual results to differ materially. These include the uncertain outcome of clinical trials; the fact that investigator-initiated trials are sponsored and conducted by third parties, so that their planning, start, timing, conduct, results and reporting are outside Faron’s control; the need for regulatory and ethics approvals; and the availability of funding. Faron undertakes no obligation to update these statements, except as required by applicable law and regulation.

Bexmarilimab is an investigational medicine and has not been approved by any regulatory authority for any use.

What the EHA data showed, and how it may shape the future of HR-MDS

In June, we presented updated data from the BEXMAB Phase 1/2 trial at the European Haematology Association Congress in Stockholm. Our Chief Medical Officer, Petri Bono, set out last week why higher-risk MDS (HR-MDS) has proved so resistant to treatment, and why we believe we have been asking a different and more useful question than what the field has asked before. This post focuses on evidence — what the data showed at EHA, and why the translational findings within the bone marrow are, in my opinion, a crucial part of the story.


Of course, we should appreciate from the outset that BEXMAB is a Phase 1/2 study. The efficacy data are from an uncontrolled, single-arm trial, and therefore need to be interpreted accordingly. What it gives us is signal, mechanism and direction. Together with what the field has learned before, it is what allows us to design a trial that can provide proof, which is why the randomised, placebo-controlled BEXERA trial is now in preparation.


With that context in place, the signal is worth examining carefully.


In the treatment-naïve cohort, 85% of patients responded to bexmarilimab plus azacitidine, with a complete remission (CR) rate of 45%. Among those who achieved complete remission, the median duration of CR has now extended to 16.1 months with longer follow-up; up from 12.1 months at the previous data cut. That extension matters with the safety profile remaining tolerable in a vulnerable older population: no grade 5 bexmarilimab-related adverse events were reported in HR-MDS patients and bexmarilimab did not increase the rates of severe side effects commonly associated with azacitidine, such as neutropenia and anaemia.


Consequently, what I found most scientifically informative at EHA was the translational data from bone marrow samples collected before and after treatment.

“The translational data give us a biological account of mechanism that is independent of the efficacy readout.”

Using single-cell RNA sequencing and spectral flow cytometry on samples from BEXMAB patients, we were able to show consistent changes in the bone marrow microenvironment across treatment. In the treatment-naïve patients, we observed increases in erythroid progenitor and haematopoietic progenitor cells alongside activation of cytotoxic CD8 T cells. These are the precursors of healthy blood cells, and the immune cells whose function is to kill cancer respectively. Seeing both types of cells increase during bexmarilimab and azacitidine treatment provides a biologically coherent signal. The combination may help restore, at least in part, the conditions for normal haematopoiesis while simultaneously promoting immune activity consistent with an anti-tumour response, although the clinical significance of these findings remains to be confirmed in a prospective randomised setting.


In the relapsed/refractory cohort, patients who had already progressed on or become refractory to azacitidine, the translational picture is particularly coherent. Target engagement, measured as reduction of soluble Clever-1 in the bone marrow, correlated significantly with depth of clinical response. HLA-DR activation, a marker associated with a shift towards a more immunostimulatory macrophage phenotype, increased in 65% of evaluable patients. Cytotoxic T cell engagement occurred in 64%, and regulatory T cells decreased in 68%. In patients with HMA-refractory disease, at least two of these three immune changes were present in every patient with available data. In this same cohort, 64% of patients responded to treatment. We must remember that these are patients with very limited treatment options and a historically poor prognosis. This response data, supported by the mechanistic evidence above, provides a meaningful signal for this setting.


It is also worth noting that the BEXMAB population includes a significant proportion of patients with complex cytogenetics and high-risk mutations, including biallelic TP53 mutations; a subgroup with historically poor outcomes regardless of treatment. That context matters for interpreting the survival data as it matures.


Why does this matter? Because one of the central challenges in HR-MDS drug development has been the gap between single-arm signal and randomised outcome. Programs that looked encouraging in Phase 1/2 have repeatedly failed to demonstrate benefit when randomised against azacitidine. The translational data give us a biological account of mechanism that is independent of the efficacy readout. The response rates themselves do not prove the biology works; however, the biology observed directly in bone marrow tissue corroborates, and to a certain degree, explains the demonstrated response rates. The clinical and translational observations point in the same direction, supporting further evaluation of the hypothesis in a randomised trial.


I should also note what the data does not yet tell us. Importantly, the overall survival (OS) data in the treatment-naïve cohort are immature: at the current follow-up of 14.9 months, the median has not been reached in the full cohort, and the only subgroup to have hit a median OS is the biallelic TP53-mutated population at the June data cut. That subgroup has historically very poor outcomes, and a median OS of 8.8 months in that context is in line with historical data rather than a signal of concern. It is a reminder, however, that the full OS story in treatment-naïve patients will take more time and more data to tell.


The BEXERA trial is the next step. It is the trial that will tell us whether these signals hold in a randomised controlled setting against single agent azacitidine. Until then, what EHA gave us is a biologically coherent and clinically encouraging dataset, interpreted with appropriate caution. That is a sound foundation to build on.


In the coming weeks, we will look at how this work extends beyond HR-MDS, and at the investigator-initiated trials taking bexmarilimab into new indications.

— Aneel Nimba, Medical Director

Forward-looking statements: This post contains forward-looking statements regarding the development of bexmarilimab. Bexmarilimab is investigational and has not been approved by any regulatory authority.

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