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Development and Regulatory Strategy for US and China

Worth Sharing?

20 May 2022


Dr Chen: Welcome to this third webinar of Pre-ASCO, China Summit 2022 series.  My name is Xiaoxiang Chen, the founder of Tenacia Therapeutics, and also executive member of USCACA, the Vice Chair of the CSCO New Drug Development Committee.  Let me introduce the distinguished Conference Chair, Dr Yi-Long Wu, of Guangdong General Hospital, to give a welcome remark. 

Dr Wu is my long-time friend.  If I may try to summarise his amazing work in clinical development, I want to say he’s the one of the most professional (03:27), so most aspiring investigators I ever collaborate.  Also, for the incredible creativity and global leadership, the true pioneer to drive the global development through China, and also lead the Chinese investigators to the global stage.  So today, we are thrilled to have him to chair our webinar today.  Dr Wu, please.  Thank you.

Dr Wu: Thank you, Dr Chen.  So we’re kind of (04:01) to join the hour, today, the webinar, Development and Regulatory Strategy for China and the USA.

I think that in the past 20 years we have three of most futures in the China or in the US.  The first lesson in the China, the regulatory environment (04:27) evolved in.  Since the 2017, the China, the CTA, is the open the eye, open the water to the [Grow Goal], and from that time, so the many, many (04:45) developed in the China.  And also, this also is dependent on the high (04:53) economic growth, and also the enormous investment into the farmer RND in the China.

Pharmaceutical industry has been undertaking a critical change of formation to (05:09) high the quality, enormous focus of development, and more and more the China pharmaceutical company, a shift in (05:18) strategies from the first of all, to nail the (05:22), including the different product with the same, the [MOA]. 

The second point is as the clinical oncologists started conducting the clinical trial around 20 years ago.  I think that the first so-called the (05:42) on global growth is the focus on the [EGAR].  Interesting that comparing the chemotherapy in the second line treatment for the (05:53) lung cancer.  So this is the base assess, and also the Chinese oncology experience on how to combat it, how to make the clinical trial.  I think they’re important.

After then the [EGAR TKI] and the (06:14) one, and even in the PD1 and the PD1, so many, many (06:20) the test (06:21), and the many (06:23) the product so quickly back in China, including the global product, and the China, the product. As part of this transformation, and more and more pharmaceutical company, Bio (06:39), Biotech, is (06:41) to go to global and (06:45) for the value of their innovation.  There could never be an easier task of the (06:50) global.  There are multiple (06:53) the challenge in every aspect, including the (06:58) of the high, the (06:58) for global clinical trial, different (07:04) regional (07:05) operational challenges on the ground, the reason stay back of the (07:10) global effort, like China best of pharmaceutical company.

The FDA decision to request the (07:19) to combat the new international trial of their PD1 antibody treatment, and remind us again, such a change of formation won’t be straightforward.  It is imperative for all of us from the different angle to walk together, continuing to improve in our sale, or our growth, development and (07:45) the strategies. 

Today we are very, very happy and very pleased to invite three global speaker; Dr Giovanni Selvaggi, Dr Michael Molyneaux, and Dr Patricia Keegan, to share with us their perspective, and then with the (08:03) and the (08:05) panel with the (8:07) doctors joined us.  Welcome and thank you.  Dr Chen.

Dr Chen: Thank you, Dr Wu for your very insightful work on [biomarkers].  I’d like again to express our appreciation to all our sponsors; Novotech Company, to support our webinar, to make this possible.  I also want to thank the other companies; Betta Pharmaceutical, Sirnaomics, and also TopAlliance to support this webinar. 

Please, during the webinar, feel free to ask a questions via the Q&A window.  The speakers or panellists can either reply to you by text message in the Q&A window or answer your question online.  We also have Chinese language and interpretation for this webinar.  Please choose the language icon and then choose Chinese, if you prefer to watch this webinar in Chinese language. 

So now, please let me introduce you the first speaker, Dr Giovanni Selvaggi.  He is the Chief Executive Officer and also Chief Medical Officer from Xcovery.  Dr Selvaggi, please.

Dr Selvaggi: Yes, thank you.  Let me share the screen and into the slides.  Okay, can you see the slides well?  Okay.  So thank you.  And also thank you for the nice introduction to Dr Wu.  And like you said, I will describe to you an example of global development that has international implications for Ensartinib.  Ensartinib is an ALK inhibitor.  So ALK is a driver mutation for a subgroup of non-small cell lung cancer.  It’s present in 5% of cases.  And the patients are slightly different than the average lung cancer patients.  They tend to be younger, in their 50s, sometimes in their 40s.  And also, most of them are never smokers, and their cancer is driven by the mutation, rather than the smoking.  And also they present with very symptomatic disease, they have pleural effusion, multiple lesions, so they’re very difficult to be a surgical candidate.  And also, during the course of the disease or a diagnosis, they have most often brain metastasis. 

There has been a lot of development in the ALK inhibitor space.  The first generation was a drug by Pfizer, Crizotinib.  And then there was a wave of second generation of drugs, like Ceritinib, Alectinib, and Ensartinib is part of this.  And recently Pfizer came up with a third generation agent.  These agents, across generations, they show an increased potency against the target, they increase the CNS penetration, that is a key to control the ALK disease, and also they are more potent against resistant mutations from the ALK cancers.  Ensartinib is a very potent ALK inhibitor, it is an oral once a daily drug, that showed very selective kinase profiling in inhibiting ALK, and less ROSS activity then Crizotinib, and some track fusion inhibition, when you look at the candidates profile.  That is important to look at to differentiate these drugs. 

In fact, when you compare Ensartinib kinase profile with Brigatinib or Alectinib, you see that besides the red dot, which is the most interesting and potent inhibition of the ALK kinase, these drugs, they do have different profile in terms of kinase inhibition, and so also some off-target effects.  Brigatinib is most of an EGFR inhibitor, and Alectinib can be a (12:59) inhibitor, and you see visually how different they are. 

For Ensartinib, what we did, we conducted a global, randomised open label Phase 3 study, to compare Ensartinib to Crizotinib in one to one randomisation in ALK positive non-small cell lung cancer in first line.  So ALK inhibitors, naive patients, and we were stratifying patients based on prior chemo, we allowed the patient to have received chemotherapy in our study.  And also importantly, we stratified patients based on region of the world, so the Asian region, and the rest of the world.  And, of course, the presence of brain metastasis.  And interestingly, in our study, 49% of patients, or almost half, were recruited in Asia, between China, Hong Kong and Korea.

The study was fully completed in 2018, and included 290 randomised patients.  Of these, 247 were able to be centrally confirmed for their mutation, so the ALK status, by fish.  So we are looking at the very selected, centrally confirmed ALK mutated population that we call the mITT, so the modified intent to treat analysis.  And what we saw in the modified ITT is that Ensartinib showed a statistically significant superiority in terms of PFS over Crizotinib, and met the primary endpoint of the study.  At that time, you see they more than doubled the three years PFS rate, and this PFS was not reached at the interim analysis versus 12 months for Ensartinib for another ratio of 0.45.

Most importantly for explaining how different the drugs can be, Ensartinib showed a very good protection from brain metastasis.  In fact, the time to lung failure in the brain at 12 months was only 4% for Ensartinib, and five times more, 23% for Crizotinib.  This translated on your right side of the slide to a much longer PFS in those patients that did not have brain metastasis at diagnosis, when treated with Ensartinib.  So you see at three years, 61% of patients still disease free, compared to only 25% of Crizotinib, for PFS still not reached at the first interim analysis.  

The data were then updated and presented at the World Lung Cancer Conference in Singapore, still a virtual conference, in January 2021.  The conference was still called 2020 World Conference.  And our data card at the end of December, so seven months after the interim analysis, the PFS, by independent review, which is the primary point of the study, went over 30 months in the ITT population, and also reached 33 months by investigator in the mITT population, with a very important survival rate at two years of 78%. 

So how does that position Ensartinib into the global markets?  This is what three months ago was summarised by key opinion leaders in a conference dedicated to targeted therapies in lung cancer in Santa Monica, California.  And that was for the ALK, just a framework of how we look at this globally.  So again, like I said before, first generation TKIs, and then Ensartinib is part of the second generation, and Loriatinib as third generation.  So this is what the field accepts as a view. 

Now, this is also a different way of looking at the (17:26) described to you so far, in the top of the slides, went through first line approval by FDA.  Initially Crizotinib and Ceritinib were approved by being better than chemotherapy.  And then Alectinib was the first one to show superiority to Crizotinib.  Then Brigatinib, and then as recently as last year, a year ago, Loriatinib was approved, showing superiority to Crizotinib by FDA as a first line treatment, and next year, we expect an approval by FDA for Ensartinib. 

So this picture also needs to consider the fact that all these trials, they’re slightly different populations.  For example, the Brigatinib and Ensartinib study had prior chemotherapy allowed, and the percentage of brain metastases patients that are more difficult to treat are different across the study.  So something we have to consider when we try to position these drugs. 

As well, when you look at the other ratios in a composite way, you can see that some of these agents have similar other ratios, but there are differences based on how the data were reported in terms of looking at PFS, by investigator assessment, or by an independent review.  Loriatinib seems to be the most potent of the drugs so far available, but their data are the most immature, and they still need to report updated data, because their follow up is shorter. 

Now, what can we look forward, in order to position the drugs?  Again, we need to consider the fact that despite the great improvement over Crizotinib, there is still a fraction of the patients that you look at the first part of the Kaplan-Meier curve, they don’t derive any benefit over Crizotinib.  So what we call the bad ALK patients.  And at the other extreme of the curve, that is the good ALK patients.  That’s something we see in every trial. 

Why this is the case? because ALK is a very heterogeneous disease.  So at presentation, the ALK fusion is different from patient to patient.  You see at the bottom here, how these patients present with different variants of the fusion; the most common is variant 1, and then less common is variant 3, but they’re very structurally different, while the partner for the fusion to ALK is 95% of cases is always EML4. 

This brings implications, because you see that the potency of the drugs, based on the variant of the patients at the diagnosis. is different.  While variant 1 is very sensitive to almost all drugs, of course, less for Crizotinib, that is first generation.  In variant 3, you see that there is quite some resistance for Crizotinib, for Ceritinib, and also for Alectinib, while the newer drugs like Ensartinib, Brigatinib, and Loriatinib have more potency against variant 3.  And this is IC50 in vitro. 

But when you look in the clinic, also, for example, Alectinib reported, and you see the grey line, less efficacy in a retrospective analysis to variant 3.  So very short, much shorter PFS from comparing variant 1 and variant 3 when treated with Alectinib.  And one thing we didn’t see, for example, for Ensartinib, in a larger study conducted in China in over 150 patients, past Crizotinib, we don’t see this separation bivariate.  That makes us think that Ensartinib is a better candidate for patients at diagnosis that present with a variant 3. 

So we need to understand that this is a very dynamic field.  The patients at diagnosis are out ALK TKI naive, and then they start developing resistance based on an ALK dependent mechanism.  And then they need to be treated progressively with different ALK inhibitors, or they are independent of ALK in terms of resistance, and then they could use combinations or chemotherapy.  And that, again, in my view, contributes to the different positioning of the drugs. 

So now, after all these that I explain to you, at the same conference that we were attending in Santa Monica, the view is changing.  It is changing instead of looking at drugs by generation, so by how old they were in development, or how new they are, we’re looking at drugs based on their functional activity.  So how effective they are in the brain, or, for example, how they are active against different mutations, that could be a single mutation or the double mutant.  And there is a few agents that are here in development in pipeline from other companies.  So you see how the field is switching how they look and how they position the drugs. 

So in conclusion, I hope I could make a point of how Ensartinib could have a global role.  It was developed in a Phase 3 study versus Crizotinib, like the other ALK inhibitors, and by virtue of this global trial that was conducted by Xcovery in many different countries in the world, but with a very strong footprint in China, with half the patients, the drug got approved in 2022, this year, a couple of months ago, in China for first line indication, and will be managed and commercialised by Betta.

Also there, Ensartinib as it shows the PFS that is similar to Alectinib, and superior to Brigatinib, and the best in class so far, because an independent read was showing a PFS over 32 months.  The different kinase profile that I showed you before, makes also contribution for the safety profile.  Ensartinib is more selective on ALK, and therefore the safety profile is favourable compared to the other ALK inhibitors.  And as part of the differentiation, we need to consider also the patient compliance, so the once a day formulation versus for example, electing twice a day.  And like I told you a few moments ago, the differential efficacy on the variants.  So there are, for example for variant 3, 40% of our patients at diagnosis. 

Again, based on resistant profiles, different potency of the drugs, we need to conclude that we must come with a good and preferred sequence of drugs in order to choose your most preferred agent in first line to start with, and allowing for the other agents to be still effective after, for example, Ensartinib, and that’s what is a potential way of going forward.  Versus after Loriatinib, there seems to be a resistant profile that will not allow us to use other ALK inhibitors. 

So in my view, I hope I convinced you that Ensartinib has the potential to have a global positioning.  It’s approved in China, and will have a collocation utilisation in subsets, and preferred potentially first agent of choice in the rest of the world, for the ALK space in 2022 and beyond.  Thank you.

Dr Chen: Thank you.  Thank you, Dr Selvaggi, for your wonderful presentation to share with us your data, and also global view on your Ensartinib.  We are looking forward to hearing more at the panel discussion. 

Now, let me introduce our second speaker, Dr Michael Molyneaux, and he is the Chief Medical Officer from the Sirnaomics.  Please, Dr Molyneaux?

Dr Molyneaux: Thank you. Thank you, Dr Chen. Can you see my screen? 

Dr Chen: Yes.

Dr Molyneaux: Hi, good evening, to the folks in the US, and good morning to the folks in China and Asia.  My name is Mike Molyneaux, I’m the Chief Medical Officer for Sirnaomics.  I’d like to thank the organisers of this event as well as the sponsors for allowing me to come here and speak about the company.  And I’d also like to thank the Chairman, Dr Wu, and our moderator, Dr Chen. 

This is the disclaimer, because we are a public company.  This tells you that we’re compliant in terms of this presentation.  And it’s a bit of a formality, but I have to at least show that slide and discuss it. 

Sirnaomics is a global company, and we’re an RNA company specialising in platform technologies.  We have innovation in both sRNA therapeutics and also mRNA therapeutics.  We have a very strong footprint in two of the largest healthcare markets in the world, the United States and China.  As you can see, we’ve got offices in Beijing, which encompass our clinical operations and regulatory; Suzhou, which is our non-clinical; Guangzhou is our manufacturing; and Hong Kong is our finance base.  And then we also are headquartered in Gaithersburg, Maryland, and we also have offices in Boston, and then on the west coast, as well.

sRNA and other RNA therapeutics have taken a very significant rise over the past number of years, particularly with Alnylam and their approved drugs.  And then also we saw recently the success of mRNA products with the vaccine therapies as well.  So it’s a very exciting time to be in this space.  And Sirnaomics has an advantage of having this global footprint, compared to other sRNA or RNA companies.

As I mentioned before, one of the advantages is that we’re a platform company.  We have two different distinct platform technologies.  One is the PNP platform, which is histidine, lysine polypeptide.  And then we also have GalNAc platforms, which target more liver specific diseases, and specifically the hepatocyte.  We’re in the clinic now with the PNP platform, and we’re predominantly focused on fibrosis and oncology.  With the GalNAc platform, we’ll be in the clinic in the first half of 2023, focusing on cardio metabolic disease, anticoagulation, and complement mediated diseases. 

This is our pipeline currently, and as you can see, I mentioned we focus on oncology and fibrosis with the PNP asset.  We’ve also got antiviral therapeutics that are in nonclinical development, and also medical aesthetics, we will come to the clinic with a medical aesthetics product within the Q2 of 2022.  And then on the bottom you see those GalNAc assets that are currently in nonclinical phase.  The closest one to clinic is the STP122, and we will be in clinic with that first half of 2023. 

This is the oncology pipeline.  It’s predominantly based on our lead asset which is STP705 and 707.  Those target TGF-β1 and COX-2 genes.  The 705 asset is used for local delivery in various indications that you can see on screen.  707, we’re studying it now in a solid tumour study, and we plan to extend that out once we receive the data on dose escalation.  And then we’ve got some other assets on the oncology side that are currently in nonclinical development and coming to IND enabling phase.  We expect to have 355 and 369 in the clinic as well, sometime first half of 2023, mid-2023. 

What I’m going to talk to you about today are the results of our completed non-melanoma skin cancer study.  Non-melanoma skin cancer is obviously a disease with a high unmet need, particularly in the west.  It’s a large market, with approximately 3.5 million people diagnosed yearly in the United States.  And there’s two subtypes; basal cell carcinoma predominates, with about 80% of the cancers being basal cell; and then squamous cell carcinoma is about 16% of the cancers.  Overall, they make up the two most common cancer types of any cancer, particularly skin cancers as well. 

Approximately 15,000 people die of metastatic squamous cell carcinoma each year, and more than twice as many of those people die of melanoma.  90% of these are caused by ultraviolet light exposure.  And the current treatment options are predominantly surgical.  So we feel that there’s a high unmet need for non-surgical therapy, particularly with low risk lesions, and lesions in the face.  The most common surgical procedures are what’s called electro-desiccation curettage.  There’s also a Mohs surgical procedure, and then standard surgical incision.  Some of the disadvantages are prolonged healing time, scar development and then risk of infection.  And they’re not great treatment options for immunocompromised patients, or patients with multiple comorbidities, or patients that are hard to heal. 

Some non-surgical options approved for BCC include a topicals such as 5-FU and Imiquimod, and then radiation therapy is used sometimes for local disease treatment in patients that are not candidates for surgery.  Chemotherapy is reserved for patients with locally advanced lesions.  So with our product, we would not be targeting advanced lesions, but rather what we would consider low risk lesions, such as squamous cell carcinoma in situ, or basal cell carcinoma. 

This is the lead asset that we studied in the non-melanoma skin cancer trial.  It’s called STP705.  As I mentioned, we target TGF-β1 and COX-2.  It’s a dual targeting asset, and we feel that that’s a distinct advantage.  And that’s also an advantage of the HKP platform; it allows you to target more than one gene. 

In terms of a commercial standpoint, the product has a very long shelf life; 36 months stability that we have now a lyophilised state, and this is at normal refrigeration.  We’ve completed multi-species tox, both subcutaneous and IV tox, 28 days, and we recently completed long term 13 week tox.  And so far we’ve seen very good safety profile with the drug, administered both subcutaneously and intravenously.

The study that we completed for which we now have data, was squamous cell carcinoma in situ.  It was an open label study, we did dose escalation, dose range finding, and we looked at evaluating obviously safety, but also efficacy.  For the efficacy endpoint, we wanted to see the proportion of subjects that had complete histological clearance, which is the gold standard for treating skin cancer.  We also looked at adverse events.  And then the other component that we thought was a key, was the incident severity of local skin response.  This will give you some insight into the aesthetic appearance of the skin after treatment.  Obviously, with surgical therapy, there’s going to be scarring.  So we feel that the differentiator for this product could be the fact that we see a better cosmetic result at the end of treatment.

We looked at five different doses ranging from 10 micrograms per injection once a week, up to 120 micrograms per injection once a week, and they were injected up to six weeks consecutive, and the product was injected directly into the lesion.  So the lesion is on the skin, and we injected directly into the lesion.  And subjects had to have biopsy confirmation of squamous cell carcinoma in situ prior to study entry. 

This is the results of the study.  And obviously overall, we saw 76% achieve complete histological clearance.  Of the two dosing groups that we’re moving forward with in the Phase 2B study which is now ongoing, 30 and 60 microgram dosing groups, we achieved a 90% histological clearance.  There was no treatment related adverse events, and no treatment related serious adverse events. 

And another important thing that we found is improved cosmetic result with the study.  So the local skin response scores improved in the 10, 20, 30, and the 60 microgram dosing group.  And if you look in that lower left, that’s the appearance of the skin post treatment.  So it really was a very good cosmetic result.  And if you compare that to surgery or electro desiccation curettage, it invariably comes with a scarring. 

The other thing that we looked at for this particular study was the histology.  So we wanted to see biological effects.  So we saw efficacy, we saw safety.  Another important readout that we wanted to determine was, are we seeing biological mechanism of action?  One of the most important things obviously in sRNA therapy is gene target engagement.  So when we looked at all (35:38) tissue pre and post treatment, we saw significant gene target reduction in TGF-β1, and we also saw a significant gene target reduction in COX-2. 

We also saw, this we feel is one of the benefits of these targets, they’re both upstream targets, but they have implications in both fibrosis and oncology.  So we looked at pan-oncogenic biomarkers as well, such as Ki67, NF-κB and β-catenin.  And we saw significant reduction in those downstream oncogenic biomarkers.  We feel that this could have applicability to obviously other tumour types. 

In summary, we saw 76% achieve complete histological clearance, with 90% achieving clearance in the Phase 2B study dosing cohort that we’re moving forward, the 30 and the 60.  We didn’t see any cutaneous skin reactions, and actually the skin response scores improved.  And we saw no treatment related adverse events.  We saw significant gene knockdown as mentioned, and suppression of pan-oncogenic biomarkers.  Another aspect of the mechanism of action that we feel is important is the activation of T-cells and T-cell infiltration in the tumour tissues.  There’s a lot of studies that suggest upregulation of TGF-β1 occurs in that tumour environment, particularly solid tumours.  And if you can down-regulate that TGF-β1, you may enhance T-cell response or the innate immune response.  We did see a trend towards T-cell infiltration in the tumour tissues that had residual tumour.  It was a small number, it was six subjects.  But this is something that we’ve demonstrated in animal models as well. 

This is the Phase 2B study that’s ongoing now.  This is a randomised placebo control dose escalation.  We’re looking at 30 and the 60 microgram dosing group, as we mentioned previously, and we’ve added a third dosing group of 90 micrograms.  We’re following the same pattern of treating directly into the tumour, once a week injection for up to six weeks, and we’re comparing it to placebo.  We plan to do that 40 subject run in, and then we’ll look at the data and determine the best two doses to move forward with the second half of the study.  We’ll also plan to meet with the FDA or the regulatory agencies around the time of that data readout.  And that should give us a clear signal in terms of the approvability, the endpoints that the regulatory agencies will be looking for, and how we can position the drug. 

The second half of the study, as I mentioned, we’ll do 60 subjects, the two best doses from the 40 subject cohort and placebo.  We’re getting close to 40 subjects now.  So we anticipate having that read out probably in Q4, 2022.

We’re also looking at this in a solid tumour study.  So the 705 asset has an HKP histidine and lysine, polypeptide nanoparticle.  In 707 we added the HKP plus an extra histidine.  We found that in our work, that is a much better asset to use with the intravenous administration.  In the 707 study, it’s a dose escalation, open label, looking at solid tumours.  We’ve completed dosing in the first cohort, we’ve now completely enrolled the second cohort, and we’ll have safety meeting on that to determine whether or not we’ll move to the third cohort.  But so far things are looking positive in that study. 

We’re looking at max tolerated dose, and established the dose recommendations for dose expansion.  So we look at this as a dose escalation.  So it’s a bit of an adaptive design, and then we’ll roll directly into dose expansion.  At that time, the plan would be to look at this as a monotherapy, but also to add other agents which could be used in combination with this drug. 

I’d like to acknowledge Professor Jim Mixson, who is the scientific founder of the technology, particularly the HKP Technology.  Professor Daniel Van Hoff is the head of our Scientific Advisory Board for Oncology.  Professor Brian Berman and also Professor Mark Nestor are both heads of the Scientific Advisory Board for the DERM Oncology Division.  And thank you very much for your attention and time.

Dr Wu: Thank you, Dr Mike Molyneaux, and RNA treatment, obviously, it’s one of the most exciting area, and congratulations, and looking for harder to hearing more on the exciting data. 

So let me introduce the third speaker, Dr Patricia Keegan.  She’s from on TopAlliance Bioscience, and she’s also the Chief Medical Officer.  And Dr Patricia Keegan, please.

Dr Keegan: Thank you.  One moment.  Is my slide up there?  Hello.  Hello, and I want to thank you, the organisers, for my invitation to present at this exciting conference, and to be able to share my thoughts.  I don’t have a disclaimer slide, because to be honest, most of this is basically public domain information, and not proprietary information on any particular product. 

But just my thoughts and considerations, having been a long time FDA employee, and now working in the industry, it really is true that you have to walk a mile in somebody else’s shoes before you see how things are very different from the other side.  And so I wanted to give some perspectives that I’ve noted over the last couple of years, in terms of the changing environment and evolving US regulatory requirements for diversity and clinical trials, particularly clinical trials of cancer, and how they I believe will be impacting our approaches towards drug development going forward.

Dr Wu: Patricia, sorry, I just remind – we couldn’t see your slides, I’m not sure if you are sharing your sides (41:43) present.

Dr Keegan: Hang on one moment, it looked like they were being shared.  Oh.  Okay, one second. 

Dr Wu: Yes, great. 

Dr Keegan: Very good.  Thank you.  Thank you for interrupting me too.  So as I said, no disclaimer, but I’m going to move on to a little bit of the overview of what I wanted to cover.  Partly just to put us on the same page, a little bit of the historical context for evidentiary standards for approval in the US, some of the more recent diversity initiatives, and how it appears that some of these new initiatives are impacting the evidentiary standards and clinical trial designs, and how I think this is going to address new challenges for the industry in moving forward with clinical trial development. 

So to start, legislation of drugs in the United States goes back to the 1800s with the establishment of the US Pharmacopoeia in 1820.  In the early 1900s, there was a Biologics Control Act and the Food & Drugs Act of 1906.  But it really wasn’t until 1962 that the Food and Drug Administration established efficacy requirements for the approval of new drugs to be marketed in the United States.  And this was primarily based on the public outcry for stronger drug regulation, following the terrible tragic birth defects seen in patients in pregnant women taking thalidomide in a sleeping pill at that time, under evaluation. 

And so this really was part of the driving force leading to what is called the Kefauver-Harris amendments to the Food, Drug & Cosmetic Act in 1962.  That mandated that all drugs approved in the US must – that the Food and Drug Administration must conclude in order to approve those drugs, that they’re both safe and effective.  And it also spelled out what that evidentiary standard is.  And that is a demonstration of substantial evidence of effectiveness, which had really three prongs.  The first is that there be adequate and well-controlled investigations.  The second is that those trials be conducted by experts who are qualified to be able to actually interpret the data, and understand and evaluate the effectiveness of the drug.  And then the last, being that the results of the trial were actually interpretable, and the data showed that the drug showed the treatment effects that it was purported to have.  So kind of an end of the era of snake oil salesmen, but that the claims were credible. 

Let’s see.  Too many slides.  Okay, one more.  Yes.  Okay, so sorry about that.  So there wasn’t much happening on this horizon until the Food & Drug Modernization Act, or FDAMA, that was passed in 1977, which required the Food and Drug Administration to publish some guidances with additional clarification on what was meant by the term ‘substantial evidence of effectiveness’.  And the major change in this legislation grew out of the observation that the FDA was already approving drugs based on a single trial, a well-controlled clinical trial, with additional information.  And therefore, the law mandated that the FDA put out guidance to clarify what that criteria could be.  So it was stated as a single trial with confirmatory evidence, which could include trials in related populations or indication, or convincing evidence of a drugs mechanism of action.  And that guidance discussed what that confirmatory evidence could be, both within the trial and external to the trial.

In 2019, the Agency decided to publish an additional guidance, further clarifying FADAMA, and expanding on provisions allowing flexibility and demonstration of substantial evidence, discuss the characteristics of trial designs and surrogate endpoints and statistical methodology.  And in addition, it talked a bit about the use of mechanistic data, pharmacologic data and nonclinical evidence as confirmatory evidence for a single trial.  So further expanding that level of flexibility.

Then, the last part of background on evidentiary standards was information regarding FDA’s acceptance of foreign data as part of a data package to support approval of a new drug.  And this was actually a fairly old part of FDA’s regulation, dating back to about 1985, which said that FDA would in fact accept data supporting a marketing application, and even would accept data as the sole basis for the marketing application, if that data was deemed to be applicable to the US population and US medical practice; that the studies were performed by clinical investigators of recognised competence; the data may be considered valid without the need for onsite inspection, or if an onsite inspection was needed, that FDA would be able to come in and perform that onsite inspection.  Further, the regulation note strongly encourages applicants to meet with the Agency prior to submission of the data, but doesn’t require that. 

And I would now like to switch a little bit to information regarding diversity initiatives by the Agency.  I would like to quickly cover the 2018 publication of the ICH E17 general principles for planning and design of multiregional trials.  The stated purpose of this guidance was to increase the efficiency of trial conduct and completion, in a manner that would obtain data acceptable to all ICH participating regions.  And so to allow and facilitate the simultaneous submission of applications in different regions, based on the same trial. 

It would also allow for earlier identification or confirmation of important intrinsic and extrinsic factors that might affect response to a drug, if such factors are present, and it did not presume that such factors would always be present.  In fact, the guidance document references ICAG5, which notes that there are settings of low risk for intrinsic and extrinsic factors affecting drug pharmacology. 

The guidance stipulates there should be an agreement across regulatory agencies, on key endpoints and aspects of the clinical trial design, and that the guidance also acknowledges that there are settings where single region trials may be appropriate, perhaps based on differences in disease prevalence across these regions.  In addition, FDA has issued a number of guidances on increasing diversity and clinical trials.  The majority of these guidances really focus on broadening eligibility criteria in cancer clinical trials after the completion of initial safety studies.  And then in early April 2022, FDA released a guidance for consideration of trial design and trial conduct, that would enhance enrolment of racially and ethnically diverse populations. 

So why did the Agency feel the need to do this?  Well, it had been clear to the Agency for some time that there was multiregional enrolment of clinical trials in data submitted to the Agency, as a result of the regulation that allowed this.  And in 2010, an Office of the Inspector General for Health and Human Services, or DHHS for people who like acronyms, took note of the increasing use of foreign clinical data and studies submitted to FDA.  Specifically in 2008, they noted that 80% of marketing applications submitted to the US FDA contained foreign data, and more than 50% of clinical trial subjects or clinical sites were located outside the US. 

Since that time, this trend has continued, as evidenced in this graph actually taken from the Lancet article published by Dr [Pasradol], the perspective piece, showing that there’s been a continuous trend for not only real world data – I’m sorry, multiregional data submitted to FDA, but that there’s an increasing amount of patient and participation by both China, which is the purple line at the bottom, the purple colour, and the rest of Asia, which is the somewhat orange colour at the bottom.  And likely a bit less participation by the US and the rest of the world in clinical trials.  So this is a persistent and continuing observation across the entire decade from 2010 to 2021. 

This observation is not limited to certain diseases other than oncology, but in fact, is equally well observed in oncology.  The diversity of this slide here presents snapshots from clinical trials leading to the approval of new molecular entities – that’s what NME is at the top of the slide – that are approved by FDA in the years 2018, 2019 and 2020.  And as you can see, the amount of patients enrolled and the number of drug approvals vary somewhat; it ranges from 11 drugs to 18 drugs over those three years, and from 3,500 patients to nearly 5,000 patients, depending upon the year.  There’s a range in the proportion of patients by various demographic characteristics.  But the consistent finding in the lowest row is that less than 50% of patients enrolled in these clinical trials supporting drug approval for cancer drugs in the US, less than 50% of those patients were enrolled in clinical study sites in the US.

This is a quick overview of the cancer clinical trials leading to new drug approval, which had the lowest enrolment between 2018 and 2020.  And I want to point out here, that while some of these are either rare tumours, or subsets of common tumours, making them much rarer, this is not the case for all such trials.  So there is a range of different diseases and different prevalence across the globe.  And yet all of them had the consistent issue of having relatively low US enrolment. 

So based on these observations that the FDA had not been particularly good at increasing other US enrolment in clinical trials, nor in obtaining increasing diversity, despite the guidances and multiple workshops from 2015 on, the FDA has appeared to take a somewhat stronger approach, in attempting to increase the amount of patients enrolled in clinical trials in cancer, and the diversity of such populations.  And the discussion, or the public statements regarding this, have not been in the form of guidance, but rather, these concerns had been predominantly expressed in public statements, either during the Oncologic Drugs Advisory Committee, or in editorials to major peer reviewed journals, on the lack of diversity and that this is problematic for the FDA.

Based on their position, so based on these public statements, the position of the Agency currently seems to be that there’s a substantial shift from previous statements, even those made just recently in 2019.  Specifically, it appears that the FDA finds that multiregional clinical trials are the recommended study design, except in some rare circumstances that I will comment on in the next slide.  I will note that the FDA appears to be less willing to consider external data, real world information, as a basis for extrapolation of information to the US population and US medical practice, and would like to see that sort of information obtained primarily through the participation of US clinical sites, in clinical studies. 

In particular, the other relatively new component of the FDA’s public advice is that multiregional trials are essential, and that they should be designed to show comparative efficacy to US approved drugs in the same class.  This practice would limit all but the first approval of a drug in a class for a specific indication to clinical studies that would essentially be non-inferiority trials.  So I think this is a rather dramatic change in the FDA stance on clinical studies, and how and what kinds of studies are needed to provide that substantial evidence of effectiveness. 

Because this is a dramatic change, I do believe that the FDA needs to provide greater guidance on determining when and how to achieve the diverse enrolment that is necessary.  In particular, I think FDA must provide clear guidance on those limited situations when a trial in a single region, for example, the Asia Pacific region, is acceptable.  The current criterion remain that based on what’s been stated in op-ed pieces, and prospective pieces, it remains unclear whether both of the conditions that I’ve listed here, that the diseases must occur predominantly in Asia, such as nasal pharyngeal carcinoma, where US enrolment in a trial would be expected to be low, and whether western companies have neglected drug development, are both criteria that need to be met, in order to find that a single region trial is an acceptable clinical trial to support marketing approval.

I think it would be good to have a better understanding on what thresholds the FDA has in mind for the US and for Asia, when they’d say that a disease occurs predominantly in Asia.  And it would be good to understand, if this is a required factor, what neglected drug development means in their thinking, and it would also be helpful to know why this should be considered a relevant factor.

I believe that guidance is needed regarding expectations for adequate regional representation across the globe, as well as a diversity assessment within any region.  So I know that frequently both the FDA and companies will think in terms of a fraction.  Can we do 10%, 20%, X number of patients in the US?  But I think that’s not really the appropriate approach.  I think what we really need to do is consider what is the recommended number needed to conduct meaningful subgroup assessments, so that if a trial has 100 people, and another trial as 1,000 people, we’re not talking the same fraction.  We really need to understand what’s a valid and reasonable subgroup assessment, which should be driven more, I believe, by statistical principles than any magic number. 

Should efforts to ensure racial and ethnic diversity be contingent on risk, that these are important factors in predicting differential treatment effects, and if so, what factors should be considered?  For example, as noted in ICH E5, there are drugs that are ethnically sensitive to different metabolic factors, and result in different pharmacokinetics.  And there are other drugs that are really not particularly sensitive to metabolic factors.  And therefore, there is no expectation, and to be frank, in multiple trials it has been demonstrated that there is no significant differences in pharmacokinetics.  And so, to what extent should that be weighing into this? 

I also think that we need to understand a little bit about when there are differences in natural history of the disease.  What is it actually driven by, in the sense that this may not be driven by race alone, but for instance, in the United States, differences in socio economics and in healthcare access.  And I point to the recent article in the Journal of the American Medical Association, which noted that the differences in cancer outcomes for black patients as compared to those who are white in the US, are decreasing, they’re coming closer together.  But where they remain, the authors actually attributed these differences more to socio economic parameters and lack of access to healthcare.  So that I think we may be focusing on a surrogate for the real problem, rather than the problem itself.  And I think that those are issues that should be considered, if you really want to look at things like socio economics or other things, that that should be the marker that you want to look at, rather than using race as a surrogate. 

And then, I think the part of this that is most concerning to me is, and I know that one of the speakers might have mentioned it before, was the challenges in implementation of multiregional clinical trials, where those trials might require a non-inferiority trial design.  And I think that there are many issues here.  One is that there’s differences in time to approval of new drugs and new indications.  So there may be different standards of care in different regions.  Some drugs may simply not be available to run that; does that mean we exclude that region for that reason?  I don’t know.  But recent recommendations (62:22) that there should be comparisons to the US approved new drugs, regardless of the availability in other regions. 

Such non-inferiority trials, I think, would be very challenging to design.  First, many of them would be based on treatment effects from a single clinical trial experience.  And that type of experience is likely to yield results, which are uncertain, perhaps I should – uncertain might be too harsh a term.  But ones that are not fully reliable to clearly characterise the treatment effect.  It might be along the continuum, but the point estimate that was observed may not be the most reliable indicator of the of the treatment effect. 

The other is if we have a single study that was performed, and it wasn’t performed across many regions, do we know that the treatment effects will be the same in new regions that we haven’t studied the drug in?  So there’s another level of uncertainty.  The last I think, is one that that we don’t talk about very much, which is the feasibility of conducting non-inferiority trials.  There are large sample sizes involved, the study durations are often long.  And I think these things tend to blunt investigator interests, they tend to drag on a long time, these trials, and therefore, is this the model we should use for everything?  Or should we be a little bit more selective in determining when such trials are necessary?

I will note the drug approvals based on non-inferiority trials in oncology in the US are very uncommon.  And it has been much more difficult to satisfy this requirement of demonstration of non-inferiority in the oncology arena than, say, cardiovascular, infectious disease trials.  And I think we should look into what aspects of this disease versus other diseases make it a bigger challenge to conduct non-inferiority trials. 

And the next slide kind of goes over two of these issues.  But even when you have agreement that the drugs are all approved, they’re available, there still are often regional differences in standard of care for control arms, and for comparator arms, based on either different trials were done in different regions, or differential acceptance of the risk benefit.  And if we can’t agree on the standard of care, or if we can agree on the appropriate control, it’s going to affect, it’s going to make it very challenging to identify a single clinical trial endpoint, or a single sample size for these clinical trials. 

And so I picked just one of the one of the things that seems to be dragging on forever, which is the three versus six months of adjuvant therapy in stage three colorectal cancer, and is it XELOX or FOLFOX, or CAPEOX, whichever you like to do.  I mean, looking at the achieved trial that was conducted in agents, it looked like everybody was happy, primarily pretty happy with shortening the duration of therapy from six to three months.  And that CAPEOX was a reasonable standard, whereas the NCCN guidelines are all over the place, they go on for multiple bullet points; should we use this?  Should we use that? Should we use FOLFOX for six months, but CAPEOX for three months, but only CAPEOX in certain patients with certain characteristics of stage three disease?  It’s a very messy, complicated recommendation from the National Comprehensive Cancer Network.  And I don’t know that this will play well across all regions.  So if I was somebody was trying to do a clinical trial in stage three colorectal cancer, an adjuvant trial, I would be very concerned about reaching international agreement on what the appropriate standard of care was.

Dr Chen: Dr Keegan, sorry, in the interests of time, just to sorry to push, maybe a little bit.  Thank you.

Dr Keegan: Okay, I’ve just got two more.  So I think the last two points are really very short, and I can make them, which is this is not only a US issue, and even if we have US FDA comment on these things, I think what we need is more detailed advice from regional authorities across the globe, whether they share the same approach as US FDA, or whether they have different thoughts on this.  And we also would have to then develop a better mechanism for obtaining parallel scientific advice across multiple authorities at the same time. 

And then the last is that I think there are some potential issues with unintended consequences for this approach.  Whether this might have a chilling effect on new drug approvals in the US, or fewer treatment options; if yes, is this good for patients?  And how we might want to consider the impact of this stance on the acceptability of US-only studies by other regions.  Thank you.

Dr Chen: Well, thank you, Dr Patricia Keegan.  I’m really sorry to push you

Dr Keegan: No, it’s all right.

Dr Chen: But your talk is very, very insightful.  Actually, you ask, you raise a lot of legitimate question for panel discussion, (67:49). 

So with this, I would like to thank you all, the speakers, for your excellent presentation, and allow me to welcome Dr Wu back to the stage to moderate the panel discussion.  And in the meantime, I want to introduce two more panellists to join us here, who is Dr Lily Li.  She’s the VP of the Strategic Collaboration Betta Pharmaceuticals.  The other one is Dr Dewan Zeng.  She is Vice President, the head of the Search and Evaluation from BeiGene, USA.  So Dr Wu.

Dr Wu: Hi, thank you Dr Chen.  And also I appreciate the talks from the three speakers, they talk about the new, the ALK inhibitor, the therapy, and the regulatory in the US.  So I think this is very exciting, the talk. 

So now we are move to discussion.  Today the topic is the regulatory the China and the US.  As you know, in China, we, or the company or the biotech or bio family, that will to go the global.  So called the (69:13) global, I think the US is a great wall, and the mountain.  Everybody needs to go to the US, and then we could say “Oh, this is the (69:26).” 

But in (69:27) we have the (69:30) story, one story about the two months ago, in (69:34) first approved the drug in the US, but I think this is a failure, because the FDA say this is not the adapter for the US, the people.  The second way (69:50) and the (69:53) also approved as well in the US, but also some that difficult.  The last one about the (70:02) that happened.  They also the one.  But in these three stories, I have, I think that we have the three, the different story.  So now all the same is the FDA approved the (70:21) the region.  We need the population, multiple region clinical trial, and then maybe could prove in FDA. 

So this is more or less the thinking about five years ago in China.  The China FDA, the China NAPA, the China should also send the reason or the drug in US or the EU, if then one to China approval, also another clinical trial in China.  I think this may be the centre story.  And also the slide from Dr Keegan, that the EMA maybe sum the situation.  So the first question I ask all the panellists; do you think this is the global trend, or only the in the US?  Yeah.  So I first invite (71:34).  So you give the option?

Dr Zeng: Wow, that’s a very tough question.  I was hoping that question would go to Dr Keegan.  I mean, I think she highlighted all the challenges in the current regulatory environment.  I was just reflecting on her last point, it’s very, very critical to align the different health authority, right.  And your question pointed to that.  I don’t know, I think US is probably at the forefront of requesting more representative, or patient population represent US.  I think it’s probably because US is, financially, is probably the largest pharmaceutical market.  I don’t know how to answer that question.  It’s very challenging.  I would defer to Dr Keegan.

Dr Wu: Yeah, I think this is because you need, the company needs to go to the global, I think you need to answer this question. 

Dr Zeng: Yeah.

Dr Wu: Yeah, Dr Li, what’s your opinion about this? 

Dr Li: Well, I’d like to take this from a different angle, Dr Wu.  If you look at why big pharma became so successful in China, because they bring something that they didn’t have, back in 1995, or 2015, the 20 years.  So they brought in truly innovative drugs that when the Chinese market was full of generics, and they bring a lot of – they provided a very excellent training ground.  So most of us, if you look at the panellists, we work at big pharmas.  And what you just mentioned at your opening talk, you said there’s a biotech booming in the past 10 years in China, all based on these talents. 

So I think the root cause for FDA recently raising the bar is for Chinese pharmaceutical company, you cannot – the only answer that we can have to bring for the US market is more affordable price, if you look at the innovative interaction with FDA.  So the FDA openly remarked, they said “We are not talking about prices, we’re talking about MRCP”.  So I think that’s the key challenges for all Chinese companies.  If you have to ask yourself, if there’s any unmet needs from the US, or from the rest of the market, and you ask for EMA, that what Chinese company can bring, this unmet needs not necessarily medical needs, but you have to really to find what they are looking for before knocking at their door.  And if you can find that need, I think this raising bar, what you’re asking if you need to run separate trials, that will be resolved.  So that’s just my personal take.  Not from a clinical perspective, but from a more, if you look at context, what even the government needs, the market needs.

Dr Wu: Yes, thank you.  That’s a good point.  Dr Keegan, also you’re more express, you’re more the (75:01) on this, how to overcome the different bar from the different countries?

Dr Keegan: Right.  I think it’s challenging to – I think part of the challenge with multiregional trials, because I do think we’re going to be moving that way regardless, I think that, as Dr Li said, you may have started with, we have to address the unmet needs in China, but now that you’ve done that, and you’ve moved on, and you have a lot more therapy available as you move into the regional market, you need to, you probably need to offer something globally, that’s true.

But you also, in order to do the trials, I think what we need is a better system for more rapidly gaining agreement across regions.  What do they want to see?  Are they all on the same page?  I think it’s going to be challenging for certain diseases where there are regional differences in the approach, and how to overcome that.  Or whether they’re actually as important as we think they are.  I think that we spend a lot of time looking at things that are different.  But we don’t always know if those differences are meaningful.  And we don’t always know if those differences are the true – as I said, are they a surrogate for something else, or are they true differences, that identify a unique patient population?  And where you might want to further investigate your drug. 

I think the other possibility is, even when there’s a drug that’s already approved, if there’s a drug that’s not entirely neglected, let’s say, or a disease (76:43), might there be a different niche in that area, a different stage of disease, a different subset population, a different area where you could provide value?

Dr Molyneaux: Yeah, I think, sorry, I can give some perspective.  I think as we move towards more precision therapeutics, and we’re linking diseases more to specific, let’s say, gene expression, or some type of surrogate biomarker, we are going to have to study it in more diverse populations.  I think the days of studying a drug in a uniform population and getting an approval, I think those days are probably gone. 

And I think there’s still some utility for some of these generics and a cholesterol drug and various things like that.  But again, as we get into more precision medicine, there are certain genetic differences that make people predisposed.  So glandular carcinoma in Southeast Asia is a completely different disease than glandular carcinoma in North America.  So if you have a glandular carcinoma drug that a western population response to it doesn’t necessarily mean an Asian population will respond to the same drug. 

So I think this is going to become more the norm.  And as Dr Keegan said, I think it’s going to be a lot of stops and starts and a little bit of a difficult path forward until we figure this out.  But again, I think it’s going to become the norm rather than the exception.

Dr Wu: Thank you.  So I think you just talked about – Mike, the question for you is why do you choose the (78:22) therapy (78:24) in China and in the US, but not in the EU?  Yeah.  (78:30).

Dr Molyneaux: Yeah, the EU is definitely a market for us.  But I think for us, we’re still in Phase 1, Phase 2.  So I think after we get early, let’s say Phase 2A data, we would then look for scientific advice in EU or EMEA, and then look at tailoring our late stage strategies so that something is more acceptable to the EU or the EMEA, so that we know that we’re on track for approval there with pivotal studies. 

So I think, for example, we look at China because some of the disease indications that we target are orphan diseases in the United States as a hepatocellular carcinoma, but it’s a very common, it’s a common cancer in China.  So I think having that footprint in both countries enables us to promote or augment our recruitment efforts, for example, building our KOL networks in China as well as the US.  But I think in general, it’s something that we want to leverage both sides of the pond, and look at both populations, and co-develop.  And then EMEA is definitely on our radar, but it will come once we have data and once we go for scientific advice and later stage trials.

Dr Wu: Thank you.  So Dr Giovanni, you talk about the (79:50), and also we are now the uncertainness, the (79:56) that studies, so the different from the (80:01) is another because this is (80:04) high, involving the US and another region.  But actually, in these clinical trials, the patient from the US also, the [deaths] then, another reason.  So based on this data, do you see something the program (80:27) too difficult to apply that in the US?

Dr Selvaggi: I think that’s a good question.  But I think the solution to this is the interaction that we had from the beginning with FDA.  And so we follow the recommendations of the Agency when it came to study design, statistical plan, and propose population.  So I guess the FDA would like to see a study that is representative of the US population, because of course, they act on behalf of the American citizens, so they need to protect them. 

But yes, I guess it’s a matter of agreement with the Agency, or what is representative in your study of the US population.  And I think Dr Keegan explained that there is some guidance there.  And sometimes it’s not about the fix percentage.  And some diseases are exactly the same in Asia as in US; for example EGFR is 40% of cancers in China, versus 16, 20% in US.  But for ALK it’s the same percentage of patients with lung cancer in China and in US, so there is no difference there.  For the response to PD1 and PD1 inhibitors, there is absolutely no difference between Chinese population and western populations.  So I think this here, there is no problem.  So it depends.  I think the secret is agreement with the Agency when you conduct your study, so that makes a better way of working together.

Dr Wu: Thank you.  So when the drug Ensartinib, approved in the US? 

Dr Selvaggi: That’s (82:27), you’ll have to ask FDA, not me.

Dr Wu: But you, you are the medical director. 

Dr Selvaggi: Right, but that does not depend on me, it depends on FDA.  So I think next year.

Dr Wu: Next year, okay, I (82:47).  So I think there’s the interest about the so-called multiple clinical trials.  But another point is I know the FDA also raised another point; how to choose the standard, so-called the standard of care?  Because in the US, so many new drugs approved first, and then the standard of care does so quickly change.  But in other countries, the (83:25), they are based on the older data, not based on the US now.  But if they go to US, the FDA also approve.  (83:35) the standard of care changed.  So how to overcome this issue?  I would ask everybody.  First Dewan Zeng.

Dr Zeng: That’s another excellent question.  I think what we’re what I’ve seen, observed, right, is, as Dr Keegan pointed out, the first in class enjoy easier comparison to the standard of care.  And then you give a second class, you want to make sure you started your pivotal study before the first in class get approved, right?  So the challenge is really, if the first in class already approved, and then you have to do non-inferiority study, I just couldn’t imagine that.  I think it’s just very, very challenging.  And if you’re talking about standard care in a different reason, it’s so different.  And then the question Dr Keegan asked, then do we have to do each country with a different protocol?  And then how do we pool the end result?  Those are all questions we are facing right now. 

So I was just reflecting on her talk, was that is it safety is more important?  Because in the good old days, we’re saying do no harm first, right?  And so is the safety is more important than the efficacy?  I mean, if we can, for example, she used examples, and it that’s another (85:12), right.  Even the study that was approved, it was only 8%, which you said, they are on your slide, I didn’t know where that number coming from.  But we have a huge safety database in other indications.  So if FDA move forward with this, you have to have a representative from US, is the safety, enough safety data from US patient could satisfy their first approval?  I think that may be an angle we could all think about, because we could definitely supplement each indication with safety data from other patient population.

Dr Wu: Yeah, I agree with you, the safety data is the most important.  But I want to the example for the PD1 or PD1, or the target design in China, (86:15) aren’t always the chemotherapy in the first line setting.  But the EU and the US, the first line now, the chemotherapy plus the IO.  So if you are one to the PD1, PD1 in the global, I think you need to compare the with the IO, the treatment, not the chemotherapy.  And also in (86:42), that is a first generation.  Now we have so many, many, the so-called the second, even the third generation (86:54).  So how to choose the comparator, I think these are very important issue.  As the company I want to know, you are all the medical director, what do you think about this? Lily, please?

Dr Li: (87:12) having the BD, but I can give you an example, and then Giovanni, maybe you can add more.  So you talk about PD1.  I think we have an excellent example.  So we licence Agenus’ PD1 and PD1 CTLA-4, to monoclonal antibody.  So at that time, they were doing cervical cancer, second line, and they are using their PD1, and they got the accelerated pass from FDA.  So they got the nod. 

So they’re running the trial.  And then suddenly they approve Keytruda for the second line.  So they had to withdraw their PLA application, because changing their SOC.  So my statement is not a huge challenge only for Chinese company, it’s also a huge challenge even for Us biotechs.  So that’s a typical example.  And in China, we are still running the second line PD1 monotherapy.  So we are carefully monitor the status for even, not only for Keytruda, but other competitors, because we will mostly losing that very narrow window of opportunity to get a single arm approval.  So this is the very typical example that you just mentioned, the SOC, the status of recent approval completely changed the landscape and the SOC.

Dr Wu: Yeah, so you mean the indication is the most important?  Yeah?

Dr Li: Yes.

Dr Wu: Yes, good.

Dr Selvaggi: And that’s the same that happened to Ensartinib, because Ensartinib in China was approved first in second line, with an accelerated approval, and then confirmed in first line.  In US, FDA never allowed Ensartinib to go for second line accelerated approval, because they said that we would not qualify for a breakthrough designation, because there was already regarding even Alectinib approved.  So they were not considering our data supportive of accelerated approval.  So in US, we had to finish the study, and we are still waiting for the first line filing.  While in China, the drug was approved the first time already, I think in ’20, Lily, correct me if I’m wrong, end of 2020, or beginning of 2021 in second line.  So to your point of different standard of care, it’s the availability of different drugs in different countries.

Dr Chen: For this question, if I may, just a bit on this.  So the dynamic is, for the SOC, is accelerating rapidly, and I mean, specialist oncology and across the region.  So what would be your strategic consideration from the company perspective?  You need to start even earlier, much earlier, to plan this, or you just needed to be more adaptive along the way.  Obviously, it’s very difficult to keep changing your strategy.  So I would like to hear from you.

Dr Wu: Okay, thank you.  So I think Dr Keegan, do you think about that, especially for the NPC (90:40) in the US (90:44).

Dr Chen: Yeah, that’s the typical (90:44).

Dr Keegan: Right.  Well, I mean, it was a great position to be in, because it fell within the parameters that FDA identified as both neglected and predominantly in Asia.  But I think one of the things, and I think it was Dr Selvaggi said it, it does appear to me that close contact with the Agency throughout the development period, and obviously, I think EMA will probably feel the same way, EMA will feel the same way.  But to consult them and to work through these issues, is probably better than to go down your path and not have that conversation. I think it’s probably better to seek that advice, and to raise these issues, the what-ifs.

It is a little bit different in that there didn’t used to be such a hard line of the day one drug is approved, the other drug is, you have to change your whole development plan.  And usually, if your trial was ongoing, that was not an issue.  I think that maybe – I don’t know where this is going.  But I think being close to the Agency and being able to call them up and say, “Okay now that this has happened, are their concerns, do we need to be concerned?”, I don’t know that will result in FDA giving you different advice than they would otherwise.  But at least you would get that information much more quickly than if you go down the road, and just hope that it’s not going to be a problem.  So but yeah, I think that the only relief I can think is more closer contact with the Agency.

Dr Molyneaux: I think too, you should – we kind of need to acknowledge that somebody has to pay for this as well.  And in the US, the payers are becoming much more rigorous.  So for example, in the Keytruda example, it could be to the point where Keytruda is the only one that would eventually get reimbursement for that particular indication in the United States.  So apart from being shut out from a regulatory standpoint, sometimes companies pass the gate on the regulatory side, but they don’t on the payment side.  And that’s a whole other mountain to climb in the United States. 

I think in other countries where there’s socialised medicine, it’s a little bit different, and it’s a little bit, there’s less choice, obviously, in the therapeutics, but at the same time, they’re very price sensitive, as Dr Li kind of mentioned earlier, on pricing.  So reimbursement is almost as difficult as FDA approval when you get into this landscape with multiple therapeutics and the same indication.

Dr Wu: Yeah, okay.  Thank you.  So I think we, every company, also, all the clinical oncology also face the same (93:40).  And so now I think, everybody, I asked the panellists, so how to be better in your company, for this new situation?  Your company, how to be better based on this situation?  Dewan Zeng, first.  You’re first one.

Dr Zeng: Actually, I reflect on Beijing’s clinical development strategy, and almost all of our in-house developed [molecule] the first in-patient study were done in Australia, because historically, it’s much faster to get CDA in Australia, than getting the IND approved in China.  So I think that’s critical.  As soon as we can open the China side and get in China data, the first step is to compare whether there’s ethnic difference, right, in terms of safety and in terms of PK.  I think if the companies start to consider that, implement as many regional in Phase 1 as possible, that will give you an early signal, are you, I mean, beyond the disease differences, is your drug, any difference?  Your PKR safety is different from different region.  And then you can choose wisely.  If you observe regional difference, even in Phase 1 that just showed the challenge of moving to late stage development is higher.  I guess that would be the one of the de-risk strategy.  I’d like to hear the other panellists if they have other strategy.

Dr Wu: So (95:24), the molecule or the nuclear compound, the first choice is the global, not only then in China?

Dr Zeng: I think it’s that you may not have to include a lot of different country, but at least US and Asian country, or European country, Asian country.  So you have some different ethnic participation in your Phase 1, so you could gather early evidence.  It doesn’t have to be like 40 countries, like we run Phase 3 studies.  Yeah.

Dr Wu: But I think the (96:04) is a lot of money, you could do everything.  Oh, so now I’m with the Betta company.  So Giovanni, (96:15) how to (96:18) the global strategy of your company.

Dr Li: So I’ll start, Gio, you can add on.  So I think, Dr Wu, different company may have different strategies.  So if you look at BeiGene, you just said, I checked their website, more than half of their senior management team come from outside of China, so they’re not Chinese.  So just a more simple, natural process for them to go global.  And you know Betta really well.  So the whole company grew out of one domestic drug, Icotinib.  And we have very strong commercial capabilities in China.  So it makes more sense for us just to maximise our potential in the Chinese market, rather than go global.  So you’ll see that our step is just much slower, if I may say, comparing to Beijing, or some of the new biotechs. 

So Gio just gave us the story of Ensartinib, and it just an evolving process for Betta.  So first, we en-licence their China rights, when we got to know this drug back in 2014, ASCO, it just made more sense.  We just got the China rights.  And then we are running a global Phase 3 trial, and then Xcovery faced some financial challenges.  And Betta began with the loan.  So we lend some money to Xcovery, just to make sure the Phase 2 trial will go smoothly.  And then we, gradually we became, finally became the major stockholder for Xcovery.  So for Betta it’s just an evolving process.  And we’re still trying to figure out what’s the best global development strategy for Betta. 

So recently, we just started another trial.  So Betta has more than 10 INDs, so we have 15 now, or 20 clinical programs in China.  So we carefully choose two or three programs that we will started trials in the US.  So there are several criteria.  So relatively new MOA, which you just said, and then some clear differentiation points for this, if you (98:29) Betta programs.  So has potential, best in class potential.  And the market size in the US, or yield in the west and Caucasian people, we have to have a fairly good market size.  So we are not going that fast, comparing with BeiGene or some other companies.  So we’re really watching very, very step by step, because from Ensartinib we learn it’s just a very expensive risk that you take, so we spend a lot of money on starting the Phase 3 global trial.  Gio?  That’s my perspective.

Dr Selvaggi: A beautiful way of framing it, but I can only add that by virtue of this very interesting collaboration we set up between Xcovery and Betta, now what Lily said, the plan is to run two or three INDs at the same time in US and in China.  So our Phase 1s will be, if you want to duplicate it, one in China, one in US.  We can help each other on PKs, those levels, safety and integrated to programs.  So yes, at the beginning is going to be slower, but we have two shots, and we may actually be more efficient in later phases of the studies.  So the choice for now is to develop the Phase 1s, one in China, one in US, and so that probably offsets some risks, at the expense of some speed, but probably better quality of the understanding of the how the drug work.

Dr Wu: Okay.  Okay, how about the TopAlliance, Dr Keegan?

Dr Keegan: TopAlliance – and I have only been there two years, so I can say that the original mission was really to develop drugs for the Chinese population.  So most of the original studies were in China, China-centric, to cover that population and their needs.  But I don’t know, recently, more recently, and before I joined, even before I joined the company, there was an effort made to specifically look also into the US and to have, again, INDs in the US and in China.  Although we too have begun to look a little bit at initiation studies in Australia.  Each of the countries offers something different.  Obviously, start-up times are really quick in Australia.  And in the US, that you can often pose much more innovated Phase 1, 2 strategies, so that you can do a lot more seamless designs, and basket trials, all kinds of things that you could do a little bit differently, maybe, not that other countries and regions don’t use that.  But there’s generally a pretty good acceptance of that kind of somewhat unique trial designs. 

And then obviously, no one can compete with the ability and the accrual of Chinese studies.  There’s just no competition there at all.  So I think for the early studies, sometimes outside of China is good to get some preliminary information.  And I do agree that relying on both safety, but even more importantly, the pharmacokinetics.  And we have primarily predominantly biologic products, which are not particularly sensitive, but I think when you’re into the small molecule world, it’s really important to have that handle on understanding the metabolism, to be able to determine where – it’s going to affect your dosing all the way down the line.  So having a good handle on that, and whether there are differences that are ethnically or racially driven, is really important.  So there I would try and probably look at one of them as diverse as you could get.

Dr Wu: Thank you.  So I think the (102:30) lung cancer of water cancer treatment, or the [nils], I think.  So I want to heard about the IND (102:39), how to develop the IND treatment, the global strategies.

Dr Molyneaux: Yes, so our strategy is a little bit different than obviously like a BeiGene.  We’re obviously a much smaller company with more limited resources.  And RNA therapeutics, you tend to see the history of it, they target rare diseases initially.  And then one of the benefits of having the footprint in China is some rare diseases in the US, which we’re able to get into the clinic quickly, are more common diseases in China, hepatocellular carcinoma, for example.  So we tend to target, obviously, diseases with high unmet need, like all the panellists, but we also look to China to see what is the population there.  We can obviously get quicker into the clinic in the US under US FDA, and then we run a parallel path in China. 

So a lot of times we’ll do our Phase 1, let’s say, dose escalation in the US, while we’re working on the China regulatory, and then if we do a dose expansion or a Phase 2A, we will then include various China sites.  As an indication, for example, looking at a Factor XI product, or let’s say APOC3, there are familial or rare diseases within that APOC3 space where we can show very good proof of concept with small populations of people.  So we don’t need to study thousands of people to show triglyceride reduction in the general population.  Studying that rare disease population allows you to get very good proof of concept with 50 to 75 subjects.  And then after that point, you can look at out-licensing or partnering the technology, or deciding whether you get the funding to develop it in larger populations.  So being a little bit smaller company, our strategy is a little bit different, we have to be a little bit more nimble with our resources.

Dr Wu: So do you have the plan that (104:24) in the lung cancer?

Dr Molyneaux: After the solid tumour 707, which is ongoing, once we do dose escalation, that’s a basket study, as Dr Keegan mentioned, those are pretty easy to do in the US.  We’re looking at multiple different solid tumour types with the single asset 707 targeting TGF-β1 and COX-2.  After dose escalation, the plan would be to move to dose expansion and look at this potentially in non-small cell lung cancer.

Dr Wu: Thank you. I hope that you could do the lung cancer, this is the matter interesting (104:59).  Yeah, thank you.  (105:03) how to better your global trial, strategies?

Dr Chen: Thank you Dr Wu.  I want to take this opportunity to thank you to steer and moderate this very, very exciting and live discussion.  Well, I mean, my personal thinking, and I agree with some of the panellists’ discussion; go global is very, very important.  It’s essential to prove capability from China of the innovation.  But it’s not a simple answer, there is no one simple strategy applicable for every country.  So it depends on what is your innovation, what is MOA, and also the funding situation, and also the area you’re working on.  I think in the end it should be the ultimate goal to go global, if your innovation, you believe your innovation is not only for Chinese patients, but also the global patients.  Yeah, I believe so, that’s the way.

Dr Wu: So I think that in China, I think most of the company, now the drug, the strategies are [faster follow], or know the new, the target, and the new innovation.  So I think this is the big problem, how to debate the new, the target, (106:43).  First, this is the issue.  Only the first of (106:49), although I think this is very difficult to go to the Global.  This my point.

Dr Chen: Fully agree, yeah. 

Dr Wu: Yeah.  So BeiGene, how to (107:01) a new target?  I talked about the (107:05) everybody in there, also, we have the (107:08) of the [compounder].  How to do better, the new, the target?

Dr Zeng: Yeah, I think, in our R&D day, Dr Li Wong, head of R&D at BeiGene, had actually presented our R&D strategy, in our current pipeline, that we do have fairly number of first in class potential.  Obviously, until you get approved, you don’t know if you’re first in class.  But yeah, I think it’s invest, BeiGene invest heavily in the research to, as you said, developing novel class of agent, or leveraging novel platform, are critical.  So I think that that’s the inspiration for companies that reside in China, how do we bring the first in class molecule to the global stage?  Yeah.  If you want to know the detail, I would recommend you listen to the R&D day.  It was over in an hour, so I can’t really repeat everything Dr Li Wong has said in that presentation.

Dr Wu: Good.  So the Betta family?

Dr Li: Well, Dr Wu, you raise a very good question.  So doing first in class, or you said, truly innovative MOA, I think it’s probably very challenging for our Chinese pharmaceutical company right now.  Because most of the compounds come from screening, if you look at small molecules, right?  And for big pharmas, they have 100, 200 years of history, so they have thousands, millions of compounds bank, that’s why they can use them for screening the new MOA.  And Chinese pharmaceutical companies don’t have that. 

So the truly innovation mostly come, also come from institution, or from basic research.  So which I think (109:17) raised the question that China has much more publications, but we don’t have, we are not there yet, for translational science, that this publication truly transfer to new drugs in the pharmaceutical industry. 

And my second point, if you look at big pharmas, which you’re familiar with, so most of their drugs are also, to me, better drugs.  If you look at Atorvastatin, right?  The (109:48) cancer drug, or if you look at HCV drug, (109:53).  If I look at the structure from what Mark is doing, or what BMS doing, they basically have the same scaffold, so they’re running the same route.  For them, doing the first in class is not easy, either. 

But I agree with you, it’s truly rewarding to come up with a first in class drug.  If you look at AstraZeneca, it’s third generation EGFR, [Ostutinib].  The sales is significantly much higher.  So I agree with you, the ultimate goal is to develop first in class.  But again, I have to say it’s an evolving process, what Chinese we say that you can’t build Rome from the ground in one day, you just have to give it some patience, some time.  Because for pharmaceutical industry, it takes us 15 years to come up with one drug.  And our Chinese pharmaceutical industry is only, say, 20 years old, right?

Dr Wu: Yeah, I think, but maybe the (110:55) industrial molecule, the first in class.  But I think another point, another, such as the ADC, such as a product, maybe we have the (111:06) new, the compound, the first in class.  Dr Keegan, so your point?

Dr Keegan: Well, I think I agree with what’s been said.  It’s really nice if you can identify, and if you’re good at identifying a new compound, a first in class compound, I think there might be something to be said for bio-better, though, as well, that if one can improve, in many – and sometimes those improvements don’t even have to be major.  Sometimes they’re dosing improvements, or [MOS] safety improvements.  There are many ways to be better.  I think it’s a little bit harder to be a ‘me too’, particularly as a pharmaceutical, and make a go with that.  But I think for the others, I agree, that I think it would be lovely – it’s a little bit difficult to do that, and sometimes the better strategy for a lot of companies, I think, would be to look at something and make it, and engineer it better, better engineer it, or come up with a different strategy that will make it either safer, or easier to give, something like that.

Dr Wu: Thank you.  Dr Molyneaux, you are almost a first in class.  What do you think about this?

Dr Molyneaux: Yeah, so I think for sRNA and RNA therapeutics, it’s a little bit different, because you have that possibility of hitting what would be previously considered undruggable targets for small molecule.  But then we see now as some RNA therapeutics are being very effective, that they’re coming up with antibiotic antibody drugs that match the same target, for example.  So the liver itself, there’s thousands of targets that just come from hepatocyte alone.  So there’s still a number of untapped targets within the liver, and within the hepatocyte for sRNA therapeutics. Same as messenger RNA therapeutics, and something like editing RNA, where you can add in functional RNA to somebody who’s deficient in a particular gene or protein. 

So the nonclinical team that we have obviously works a lot on the target selection.  There’s a lot of research done previously, that we try to dovetail off.  But that’s kind of the magic, holy grail, if we could all come up with novel new targets every day, we’d all be very, very successful.  But it’s a very difficult process.  And as Dr Li says, it takes about 10 to 15 years to get a drug to market, after 2,000 drugs go into the funnel and one comes out.  2,000 targets or assets, for example, go into the funnel, the nonclinical, and one comes out 10 or 15 years later.  So it’s a difficult game.

Dr Wu: Yeah, thank you so much.  I think that we have this very, very good discussion, because the time is close, I will close this panellists’ discussion.  I think important that we now, (114:14) though we are one to go to global for the Chinese company, the first I think, we need much more the first in class, the drug at the one point.  The second point, we need the (114:28), the international [rule], regular [rule] or the clinical trial [rule] or the ICH [rule].  We need to follow this [rule], then we could go to (114:38) interglobal.  The third, we need to consider each of the company (114:44) based on your point, and then the better new international strategies.  So thank you so much for your attention.  I will invite Xiaoxiang Chen, please.

Dr Chen: Thank you.  Thank you Dr Wu for this, to chair this wonderful, wonderful and very live discussion.  I think myself and also all the audience will really enjoy the discussion, and also very much insightful, very informative comments from every panellist.  Thank you everyone for the presentation, and also the panellists discussion. 

So here, I would like, again, to thank our sponsor, Novotech, for the great support to this webinar, to make it happen.  And so for the people, if you couldn’t join, I hope you could, if you couldn’t join, the ASCO onsite at Chicago, eChinaHealth actually will help you to provide the daily brief for all five days, and to keep you updated with what’s going on over there.  So please keep eyes on it. 

Next one.  So I just wanted to tell you, our next webinar will be chaired by Dr Shun Lu, talking about as China NSCLC latest progress, on May 28.  And also for this one, if you could go to Chicago for ASCO meetings this year, eChinaHealth, we organise a China dinner, as a 50 years, I believe, 50 years.  So welcome everyone to join the dinner.  I’m sure for the one like Dr Wu who cannot go there personal, I hope we are enjoying the virtual dinner together.

Dr Wu: Virtual dinner, yeah, I hope, yeah.

Dr Chen: Okay, so thanks again, everyone, and also for Betta Pharmaceutical, Sirnaomics, TopAlliance, and Novotech for everyone, for this wonderful webinar.  Thanks again, Dr Wu, I really enjoying this wonderful webinar and also wonderful panel discussion.  If you wanted to watch the making records, you can follow the eChinaHealth WeChat for the instruction.  So all our meetings will be recorded.  We’ll be sharing with you.  So thank you, and good night, and good morning.  Good day.


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