Lessons Learned from Failed Clinical Trials

Victoria Werth, MD, and Radhika Gupta

Clinical trials and patients with pemphigus or pemphigoid

Pemphigus and pemphigoid (P/P) comprise a group of rare, potentially life-threatening blistering autoimmune diseases which have significant physical and psychological impacts on patients and their families. The treatment options currently available for patients are limited to systemic corticosteroids, immunosuppressants, and immunomodulants, all of which have dramatically improved patient outcomes but are associated with significant adverse effects, such as metabolic complications and increased risk of infections, in part due to the high doses required for efficacy. In the past few decades, rituximab has been the only therapy approved for moderate to severe pemphigus vulgaris (PV), but it still requires the concomitant use of corticosteroids and is associated with disease relapses. Thus, there remains a high unmet need for therapies that provide both a sustained clinical response and have a favorable safety profile.

For the US Food and Drug Administration (FDA) to approve new therapies, they must be tested in rigorous clinical trials that assess the therapy’s efficacy and safety. In these trials, the therapies are often compared to a placebo or standard of care regimen to assess whether there is a meaningful benefit provided over and above existing treatment options. Every trial pre-specifies certain “endpoints” that must be met to indicate successful achievement of the desired benefit. Some of the factors to consider when evaluating these clinical trials include:

1. Study Design (How was the clinical trial designed?): Are patients randomized to the study groups? Is there a control or placebo group? How many patients were studied? What criteria were used to include or exclude patients during recruitment? How long was the therapy given? How was the therapy administered? What dose was given?

2. Endpoint Selection (What metrics were used to determine the efficacy or safety of the therapy in the trial?): Do the outcomes that are used to assess the efficacy of the treatment matter to patients? Are they too stringent to allow adequate measurement of therapeutics? Do they reflect disease activity? Do they capture relapses? Do they capture quality of life measures?

3. Data Reporting (What patient data was reported from the clinical trial?): How long was the follow-up period after treatment? Do they report the adverse effects experienced by patients? Are the adverse effects reported considered mild, moderate, or severe?

4. Mechanism of Action (How does the therapy work to help patients with pemphigus or pemphigoid?): Is there a reason to believe that the mechanism of this therapy even works? Is it suspected to provide symptomatic relief or sustained efficacy? Will it require the use of concomitant medications such as corticosteroids?

What have we learned from trials for patients with P/P that have failed?

Over the past few decades, autoimmunity has become an area of significant research efforts. While no new therapies besides rituximab have been approved by the FDA for pemphigus, trials have been ongoing; some of which are showing promising initial data readouts. Equally as important though is understanding why many prior clinical trials have “failed.” Here, we explain some of the salient reasons why some trials have been discontinued.

Development of several therapies have been discontinued due to lack of performance in clinical trials. Dompé Farmaceutici S.p.A was evaluating an oral small molecule targeting IL-8 receptors CXCR1 and CXCR2 called DF2156A for patients with active bullous pemphigoid (BP), and then later terminated their Phase 2 (NCT01571895) due to lack of efficacy after only onethird of patients had been enrolled at the target dosage. Similarly, Novartis’s Phase 2 study (NCT01688882) evaluating QGE031/ ligelizumab (humanized IgG1 anti-IgE mAb) for patients with PV and the National Institute of Allergy and Infectious Diseases’ (NIAID) Phase 2 study (NCT00283712) evaluating infliximab for patients with PV were both terminated due to lack of efficacy. Sanofi’s Phase 3 study (NCT03762265) for rilzabrutinib/PRN1008 (BTK inhibitor) for patients with moderate to severe PV or pemphigus foliaceous (PF) was stopped because the primary endpoint, which was complete remission, was not significantly different between rilzabrutinib and the placebo. In this case, the poor performance may have been due to the design of the study in which patients in the placebo arm received corticosteroids (CS), making it harder for the intervention arm to show a meaningful benefit. However, results from a prespecified sensitivity analysis using CS dose ≤5 mg/d did show a significant difference between the treatment and the control groups. AstraZeneca’s Phase 3 study (NCT04612790) of benralizumab (anti-IL5 mAb) for patients with BP was also terminated because the primary endpoint was not met, a similar outcome to the Phase 2 trial assessing mepolizumab (anti-IL5) for patients with BP. In the latter trial, the proportion of patients free of relapse did not differ between the intervention and placebo arms. There is reason to believe that the mechanism of these two therapies is not well suited for BP.

Other trials have been terminated due to companyspecific reasons. Clinical trials are expensive endeavors to undertake, and substantial funding is required throughout the development process. The University of California Irvine terminated their Phase 1 study (NCT01313923) of sirolimus (mTOR inhibitor) in patients with PV due to lack of funding. Similarly, Immune Pharmaceutical was evaluating bertilimumab (anti-eotaxin-1 mAb) for patients with BV in a Phase 2 trial (NCT02226146) that was terminated due to company bankruptcy. Companies like Alkahest had to discontinue their Phase 2 trial (NCT04499235) evaluating AKST4290 (CCR3 inhibitor) for patients with mild to moderate PV due to operational challenges. On the other hand, large corporations often shift their development strategy. GlaxoSmithKline’s ofatumumab (anti-CD20 mAb) was acquired by Novartis. Novartis then terminated the asset while in Phase 3 trials (NCT02613910, NCT01920477) for patients with PV. To prioritize other assets in their portfolio, Novartis also terminated their Phase 2 study (NCT01930175) of ianalumab/ VAY736 (anti-BAFF-R mAb) in patients with PV.

Some clinical trials have also been stopped due to lack of patient recruitment. This includes the NIAID’s Phase 1 trial (NCT03239470) investigating PolyTregs in patients with PV, Northwestern University’s Phase 1 trial (NCT00278642) investigating hematopoietic stem cells in patients with PV and PF, and Incyte Incorporation’s Phase 2 trial (NCT03780166) investigating parsaclisib (a PI3Kδ inhibitor) in patients with mild to moderate PV.

In summary, when reflecting on the outcomes of prior P/P clinical trials, we have identified a few reasons why several therapies seemed to have “failed” to make it to the finish line.

• Systemic corticosteroids have been shown time and time again to provide relief from disease burden. Trials for therapies such as [FcRn) and Sanofi’s rilzabrutinib (NCT03762265) have given patients in the placebo arm corticosteroids as well, making it harder for the intervention arm to meet primary endpoints and show clinically meaningful benefits. To differentiate treatment from placebo arms in a trial it is important to have a low enough dose of corticosteroid at the end of the trial for a treatment to be called a success.

• Large-scale clinical trials that are required to adequately assess the safety and efficacy of new therapies are often conducted by biotech and pharmaceutical companies who have ever evolving financial positions and corporate goals. Assets such as Novartis’s ianalumab (NCT01930175), GlaxoSmithKline’s (later Novartis’s) ofatumumab (NCT02613910, NCT01920477), and Immune Pharmaceutical’s bertilimumab (NCT02226146) are examples of potential therapies that were discontinued due to either a shift in corporate strategy and or inadequate funding.

• While preclinical studies may support the potential role of a certain biological pathway leading to P/P, the drug may not perform as expected due to a flaw in the mechanism of action. This was seen in the case of mepolizumab and AstraZeneca’s benralizumab (NCT04612790).

• Achievement of primary and secondary endpoints is an essential part of clinical trial success. Selecting appropriate endpoints and their corresponding threshold values is challenging. This process is in part dictated by the FDA.

• Pemphigus and pemphigoid are rare diseases and only a handful of institutions across the world have experts in the field caring for these patients. This, along with prespecified inclusion/exclusion criteria and provider and patient preferences and restrictions, can make patient recruitment into trials difficult. For example, most patients with BP are elderly and it can be challenging for them to get to study sites.

LEGEND

BAFF = B cell activating factor

BTK = Bruton’s tyrosine kinase inhibitor

mAb = monoclonal antibody

PolyTregs = polyclonal regulatory T cells

IL = interleukin

Victoria Werth, MD, is a Professor of Dermatology and Medicine at the Hospital of the University of Pennsylvania and the Veteran’s Administration Medical Center. She is the Chief of Dermatology at the Philadelphia VA Hospital. Her clinical and research interests lie in autoimmune skin diseases, including autoimmune blistering diseases.

Radhika Gupta is a rising fourth-year medical student at the Perelman School of Medicine at the University of Pennsylvania. Radhika has a particular interest in autoimmune diseases and hopes to pursue the cutaneous manifestations of these diseases during residency.