Investigator sponsored trials begin making waves in R&D

Increasing numbers of pharma companies are forgoing CROs to partner with academic centres on investigator sponsored trials (ISTs).

Context Therapeutics is one such company, choosing this route for the development of their investigational drug onapristone ER for progesterone receptor positive (PR+) breast, ovarian, and endometrial cancers.

We spoke with Context’s CEO Martin Lehr to find out why the company chose this route and what advantages it can have over more common trial formats.

What made you decide to use investigator sponsored trials?

Most emerging biopharmaceutical companies partner with clinical research organisations (CROs) to execute clinical trials. CROs provide robust trial management services that are particularly well-suited for large, randomised Phase 3 trials. Given the infrastructure that CROs provide, there is a significant cost associated with them. For emerging companies in Phase 2, a CRO may not be the optimal clinical trial partner.

We used a CRO to conduct our Phase 1 and we have since chosen to partner with leading academic centres on ISTs to support our Phase 2 trials.

In an IST, the academic institution is the sponsor, not the company. The academic institution files their own IND, which can be a new, comprehensive IND or a mini-IND that cross-references the company’s existing IND.

While ISTs are devised and led by academic Investigators, that does not mean the trials are not as creative, large, or complex as CRO-led trials.

Context’s first IST is a partnership with Memorial Sloan Kettering Cancer Center on an adaptive Phase 2 trial to evaluate onapristone ER across a basket of 84 ovarian and endometrial cancer patients who have progressed on prior chemotherapy and anti-estrogen therapy.

This is a large trial that will deliver key proof of concept data to support advancement into a future registrational trial.

What factors made you want to take this approach to your clinical trials?

Each year in the lead up to the major cancer congresses like ASCO and ESMO, sell-side analysts send out their top presentations to attend. I started noticing that depending on the year, 25-50% of those “can’t miss” presentations were ISTs.

That was a startling observation since ISTs have such a negative perception in the investment community in which I worked before coming to Context.

Investors typically associate ISTs with poor data quality and investigator bias. Yet, the sell-siders were effectively saying the data was fantastic and should be paid attention to.

The other odd thing I noticed is that ISTs are often an afterthought for emerging companies, but they are a core focus of large pharmaceutical companies.

Too often emerging companies avoid ISTs because they believe investors look down upon them as mentioned.

Yet, large pharmaceutical companies readily pursue ISTs because ISTs create more shots on goal and amplify clinical budget dollars, which in turn enables them to pursue riskier clinical trials than they would otherwise pursue with internal funding.

That’s why ISTs have produced remarkable academic-driven discoveries that led to the approval of Herceptin and Ibrance in breast cancer and Gleevec in chronic myelogenous leukemia, to name a few.

Was there anything about onapristone ER that made ISTs more suitable for this specific drug?

There is no one size fits all approach to clinical trials. In our case, there exists the right mix of preliminary efficacy and safety data on our lead drug, clear unmet need in target indications, and strong inbound desire from investigators to lead ISTs.

Onapristone ER has been evaluated in over 100 cancer patients who are positive for our biomarker, progesterone receptor. In these early studies, onapristone ER exhibited clinical activity and good tolerability. Onapristone ER is also an oral drug in tablet form that is administered twice per day in a small dose.

In turn, investigators felt that the drug was active, there was a low risk of serious adverse events, and the administration format was patient-friendly.

Therefore, working with onapristone ER is relatively straightforward compared to more complicated cell therapy and immunotherapy approaches.

Hormone driven cancers have been treated in largely the same manner since the 1980s. First line metastatic treatment is typically cytoreductive surgery, if possible, followed by chemotherapy if there is a high burden of disease and then long-term antiestrogen therapy. Upon relapse, patients are typically cycled through antiestrogen and chemotherapy.

Given the significant side effects associated with chemotherapy, investigators and patients are more inclined to trial novel combinations that seek to improve antiestrogen activity, which generally are well tolerated.

Taken together, you have motivated investigators and patients who are willing to trial new drugs that have antiestrogen-like tolerability and administration convenience compared to chemotherapy or cell therapies.

What specific advantages and disadvantages do ISTs and CROs have in comparison to one another?

CROs and ISTs both have advantages and disadvantages. The key considerations for choosing and IST or CRO-led trial is time, cost, and control.

In general, CRO trials are faster than ISTs because a sponsor can always add more trial sites in a CRO trial to offset slow enrollment. Interestingly, ISTs can also have multiple sites, just a like a CRO; however, the process of adding sites to an IST once up and running is more complicated and time consuming.

From a cost perspective, CRO trials are typically 5-20 times more expensive for small molecule oncology programs than ISTs.

The added cost is due to redundancies the CRO provides to ensure quality, which is essential for large, complex trials but may be overkill for a small company that is looking for preliminary efficacy signals in their trial as opposed to product registration.

Lastly, a CRO provides full control for the sponsor over the trial whereas an IST is the Investigator’s trial and, by definition, an academic endeavor. Companies can mitigate the control risk by identifying Investigators who are seasoned trialists.

What benefits have you personally seen from taking this approach?

External validation is essential for emerging companies. In the case of ISTs, it is the investigator’s trial – the investigator generated the idea for the trial and is dedicating 2-3 years of their academic life to the trial. Therefore, the investigator takes on considerable reputational risk when conducting an IST.

For the Investigator, a successful trial could be career defining, so they have significant skin in the game – maybe even more than the company providing the drug.

Therefore, partnering with a top Investigator on an IST is a strong signal to other investigators, investors, and business development partners that the drug has potential.

About the interviewee

Martin Lehr is the co-founder and CEO of Context Therapeutics, a member of the Scientific Advisory Board of Integral Molecular, and Board member of CureDuchenne