PROTECTIVE-2 Phase 3 Trial [2022] Update

Ramon Mohanlal, MD Speaks about the PROTECTIVE-2 Phase 3 Trial [2022] Update


PROTECTIVE-2 Phase 3 Trial [2022] Update


Is Plinabulin a new compound? Has it been used in other disease states?

Plinabulin is a small molecule. It's a new compound. It is not yet approved. The program started as an anti-cancer program because Plinabulin has anti-cancer activity. In our phase 2 study with non-small cell lung cancer patients, we unexpectedly observed a benefit with chemo-induced (severe) neutropenia (chemotherapy induced neutropenia CIN, an adverse event). The chemo used for that was Docetaxel. Plinabulin is an anticancer agent that also has a benefit of preventing neutropenia.


And that then became a separate indication for the US. So, therefore, currently, we are developing Plinabulin separately for anti-cancer applications but also for the prevention of chemo-induced (severe) neutropenia (chemotherapy induced neutropenia CIN).


So we have studied Plinabulin within 2 different studies with 2 different chemotherapy regimens. One is with Docetaxel alone. In study 105 Protective-1, but also we studied Plinabulin with the TAC chemotherapy combination Taxotere, Doxorubicin, and Cyclophosphamide. The TAC regimen is a very aggressive chemo regimen that is highly suitable for evaluating your drug for CIN.


And that's why we selected TAC. Although currently, TAC is not that widely used in the US. It still has the 3 components, of which at least 2 are widely used. So instead of TAC, currently, what is widely used is either TA or AC. But, if we show a benefit with Plinabulin in TAC chemo, then we would, therefore, also benefit if you just take 2 of the 3 chemo components of TAC.


So Plinabulin is effective for TAC. Therefore, it will also be effective for AC and TC. I mentioned in Study 105. We used Docetaxel alone, which is still used in the US. So collectively, we gathered the data set based on Study 105 and 106.


It's still highly applicable for the US because that data (analysis) can be translated into different chemo settings currently being used.


So these 2 clinical trials is a clinical trial with Plinabulin in the TAC chemo combination. We designed Protective-2 in this way because we made an important observation with Plinabulin in that Plinabulin is fast acting. It is active against neutropenia within 24 hours of chemo administration.

Why Plinabulin has been chosen in the PROTECTIVE-2 trial to help these patients who develop chemotherapy-induced neutropenia (CIN), and why it is statistically significant?

In contrast, Plinabulin (PROTECTIVE-2 clinical trial) has a fast-acting mechanism of action, which is highly effective. G-CSF  is a standard of care with a slow action mechanism. It is very effective, but it takes at least a week for that effect to kick in and, therefore, protect patients against neutropenia late in the cycle.


Because, on the one hand, Plinabulin is fast acting, G-CSFs are slow acting. Therefore, we thought it would make sense to put the 2 agents together, and therefore, we would protect the patients (treated) throughout the entire (treatment) cycle early on and later. That was why we designed Protective-2 by combining the 2 agents and comparing that with (vs PEG alone) Pegfilgrastim alone. 


What we expected is that the combination is more effective than (vs PEG alone) Pegfilgrastim alone. And that data has now also been submitted to health authorities in different parts of the world and is being reviewed for approval.

What are the different arms of the trial and why the PROTECTIVE-2 trial was set up in this way?

So in PROTECTIVE-2, we treated patients with early-stage breast cancer in the adjuvant and neoadjuvant settings. We did that important because early-stage breast cancer patients (treated) don't have bone metastasis. That was important for the design of this trial because we aimed to demonstrate that Plinabulin also had a benefit in terms of bone pain (score). Patients (treated) who have concomitant bone metastasis may have bone pain because of the metastasis.


That's why we excluded those patients. With this patient population without bone metastasis, we, therefore, could demonstrate that the addition of Plinabulin was effective in reducing bone pain that is typically caused by Pegfilgrastim (versus PEG alone). So the combination not only has a benefit for chemo-induced neutropenia prevention (prevention of chemotherapy induced neutropenia), but also prevent bone pain. And importantly also has a safety benefit in terms of the overall AE profile. The combination has a better safety profile. That is somewhat remarkable because typically, when we put  2 agents together, we expect more toxicity. In this case, we also had less toxicity and, as I mentioned, less bone pain.

Please highlight the key data points from the PROTECTIVE-2 trial

So the key measure in PROTECTIVE-2 formals is neutropenia prevention (prevention of chemotherapy induced neutropenia). We had as the primary endpoint grade 4 neutropenia frequency because that is a more sensitive measure. To evaluate the effectiveness of the combination. In addition, we also had traditional neutropenia endpoints that included the duration of severe neutropenia, febrile neutropenia, hospitalization, and other consequences of neutropenia.


We see a benefit broadly looking at the different ways to look at neutropenia and neutropenia prevention with this combination. We also measure the quality of life in this trial. And there, we also could demonstrate benefit a statistically significant benefit in quality of life by adding Plinabulin to Pegfilgrastim (for the prevention of neutropenia). So the addition of Plinabulin to Pegfilgrastim (for the prevention of neutropenia) has both efficacy and safety benefits. And as I mentioned, also, quality of life benefits (and no life threatening effects).

What was the secondary clinical outcomes measures of the PROTECTIVE-2 Trial?

So in terms of the secondary endpoints (clinical outcomes) of those I mentioned partly in my previous response, we looked at the duration of severe neutropenia. We looked at febrile neutropenia. We looked at a number of what we call the clinical consequences of neutropenia. In the end, neutropenia relates to the counting of neutrophil numbers (absolute neutrophil count).


Neutrophils (absolute neutrophil count) are our first line of defense against infections. And therefore, it's also important to look at the consequences of neutropenia, and the clinical consequences, such as FN, hospitalization (FHN), antibiotic use, and others . So overall, the data is going in the right direction of the postsecondary endpoint, but we did not  power for that.


But you look at overall trends overall broadly. The data is going in the right direction. In terms of secondary endpoints. Importantly, we also looked at the quality of life, where we saw a statistically significant benefit is a company based in Manhattan. Headquarters in Manhattan, we are publicly traded and listed on NASDAQ. The company essentially has 1 lead asset, called Plinabulin, a drug that has anti-cancer effects but also prevents chemotherapy-induced neutropenia, which we are developing in anti-cancer indications and in neutropenia prevention indications the company.


It has a focus on Development, and where we are now with Plinabulin is in the late stage phase 3. We have broadly demonstrated effectiveness and activity in CIN (protection) intervention, and for cancer , we just completed last year a very large trial in non-small cell lung cancer (NSCLC), basically a global trial. And we reported that trial also met the primary endpoint of overall survival benefit. In addition, we also met the important secondary endpoint that relates to anti-cancer activity, such as OR PFS. Importantly, what we there also evaluated is the survival rate at 1 year, 2 years, 3 years, and 4 years.


And with Plinabulin, the Plinabulin was added to Docetaxel and compared with Docetaxel alone. We saw that at 4 years, we had approximately a 10% OS rate with the combination versus 0% with Docetaxel. So in that anti-cancer trial, we importantly demonstrated the anti-cancer effect of Plinabulin in terms of overall survival with also a long duration of survival for patients who respond to Plinabulin; the secondary endpoint also came out positive (in breast cancer). 

BeyondSpring Pharmaceuticals

BeyondSpring Pharmaceuticals currently is focusing on maximizing the value around Plinabulin in these 2 indications moving forward. We would like to develop Plinabulin further by combining Plinabulin with a number of immuno oncology agents, in particular checkpoint inhibitors, PD-1 inhibitors, and CTLA-4 inhibitors.


We are, we already have made progress in, in that space. We have conducted and are still conducting a number of earlier stage studies, phase 1/2 studies with adding to Immuno-oncology combinations. We have a study ongoing in small cell lung cancer; that data was presented  at ASCO, we demonstrated more than doubling of overall objective response rate by adding Plinabulin compared to Nivolumab and Ipilimumab without Plinabulin. So doubling with overall response rate and objective response rate by adding Plinabulin to this IO combination. In addition to that study, we also have a broad program with MD Anderson, where we evaluate a combination of checkpoint inhibitors and radiotherapy in a number of solid cancer. That study is ongoing, and we are currently early to report on that study. But we expect to have presentations on that study some time next year. So a number of trials  are aiming to maximize value around Plinabulin, CIN (protection) prevention, and in a number of oncology indications. As I mentioned, with the future focus on combinations of immuno-oncology regimens.


In terms of Plinabulin, it is a very unique new agent. It is a small molecule for CIN. We give Plinabulin on the same day of chemo, whereas G-CSF and TAC same is given on the next day of chemo with Plinabulin. Also, we have minimal bone pain. And importantly, Plinabulin has anti-cancer activity throughout all our programs. We collect quality of life data, and we have demonstrated continuously that Plinabulin also has a benefit in terms of quality of life. Therefore, this CIN agent has very attractive characteristics in terms of anti-cancer application. Plinabulin is an immune-enhancing agent and has already demonstrated anti-cancer activity in the phase 3 study in non-small cell lung cancer.


That trial is called DUBLIN-3. The additional data we are gathering has preliminary evidence of anti-cancer activity. And we'll report more on that. We believe that Plinabulin as an anti-cancer agent is unique because it is an immune-enhancing agent activating Dendritic cells (DCs). Plinabulin is not only an immune-enhancing agent but also has a direct anti-cancer effect on a number of cancer types. The combination of being an immune-enhancing agent while also having anti-cancer effects, we believe, is very unique last but not least. We have safety data now collected from more than 700 patients that shows that Plinabulin has a very favorable safety profile. And at the very last point, as I mentioned, we collect quality of life data throughout all our files and consistently demonstrate the benefits of quality of life. Therefore, the combination of being an anti-cancer agent with an anti-cancer activity that also prevents neutropenia that has a favorable safety profile that also improves the quality of life. We believe life is a very important characteristic of Plinabulin, and we will continue to develop this asset in the future.

Ramon Mohanlal, MD, Ph.D., MBA - About The Author, Credentials, and Affiliations

He is currently the EVP, R&D, and CMO, at BeyondSpring Pharmaceuticals. Dr. Ramon Mohanlal has over 20 years of global expertise in strategic drug development at large pharmaceutical companies and biotech start-ups, such as GlaxoWellcome (GSK), Pharmacia (Pfizer), Vertex, Interleukin Genetics, Syntium, Novartis, and AstraZeneca. His areas of expertise include medication development in all phases (preclinical, 1, 2, 3, 4, and post-marketing), regulatory submissions, and market maintenance. Dr. Mohanlal played a pivotal role in bringing five medications to market and was intimately involved in the development of fifteen other marketed drugs, including Wellferon, Atovaquone, Lamivudine, Zomig, Advexin, Abilify IM Depot, Zometa, Femara, Aredia, Proleukin, Cardioxane, and Exjade. Dr. Mohanlal was most recently the Clinical Head of Established Oncology Products for Novartis. He oversaw the division's clinical and regulatory maintenance work, generating about $2 billion in annual revenue. At AstraZeneca, he also created immuno-oncology development projects based on checkpoint inhibitor combo therapy. Prior to this, Dr. Mohanlal was Chief Medical Officer at Interleukin Genetics and Medical Director at Vertex Pharmaceuticals. Dr. Mohanlal has considerable licensing and business development experience at Syntium Inc. Dr. Mohanlal received his MD and Ph.D. in Experimental CV Pharmacology from the University of Leiden, The Netherlands, as well as an MBA from the American Intercontinental University in Illinois and postgraduate management training from the MIT Sloan School of Management in Cambridge, Massachusetts.