March 26, 2020
PharmAbcine ("we") prepared these FAQs (Frequently Asked Questions) based on questions received recently from shareholders, investors and analysts. We plan to update FAQs on a regular basis.
1. Why did it take so long to start the Phase 2 clinical trial of olinvacimab for Avastin-nonresponding recurrent GBM (glioblastoma multifrorme) patients and how is the process?
The phase 2 clinical trial began in November 2019 after 12-month preparation following the IND (Investigational New Drug) approval by UDFDA in October 2018. Estimated enrollment of the trial is to recruit 36 participants and 7 patients have been recruited to the study as of March 2020.
We initially expected the preparation process to take about 5 months but it took 12 months. Our previous phase IIa trial for recurrent GBM patients conducted in Australia in 2017 took only 5 months for the whole processes between IND approval and first patient recruitment.
Unlike the previous trial, this trial is simultaneously running in two different countries, Australia and the US, and it required substantial efforts on our side to coordinate meetings and plans between hospitals and CROs (Contract Research Organizations). Some companies even can take much longer to submit an application to IRB (Institutional Review Board) because they have to go through rigorous internal review process before the submission and it takes more cautious review process before they sign a contract with CRO.
Dealing with these delays have allowed us to learn a valuable lesson. Since we now have a much better understanding of all the processes involved in global clinical trials, we expect to shorten a preparation period for next trials.
2. The progress of combination trials of olinvacimab with Merck’s Keytruda?
We have two on-going phase Ib combination trials of olinvacimab with Merck’s Keytruda in patients with mTNBC (metastatic triple negative breast cancer) and rGBM (recurrent glioblastoma multiforme) started in October 2018 in Australia. Patient recruitments have been completed for both trials, and patients are given 200mg of Keytruda in combination with 3 different dose levels of olinvacimb. We expect both Phase 1b studies to end by the end of 2020.
We will announce the interim results for the rGBM study at ASCO 2020 and the mTNBC results will be presented at 43rdAnnualSanAntonioBreastCancerSymposium(SABCS)2020inDecember.
3. When do we expect to have a partnership agreement or licensing opportunity with Merck or any other global pharmaceutical companies?
While several global pharmaceutical companies have shown interest in olinvacimab, it is hard to say when we will enter into a partnership agreement with a global pharmaceutical company, such as Merck. This is because we are still in progress to determine which indication is more feasible to substantiate strong potency/efficacy of olinvacimab and its optimal usage in such indications. Moreover, our statistically significant clinical data obtained from small numbers of patients are not large enough in numbers to determine a licensing opportunity. We believe that the chances of entering into a licensing agreement with a global partner will be higher after the phase II trial. As for combination therapies with Merck’s Keytruda, Merck will most likely wait until we have more clinical data from phase IIa studies.
Nonetheless, we believe that Merck’s interest in olinvacimab is genuinely strong. For the two ongoing combination trials, not only has Merck been providing and covering the cost of pembrolizumab, but also taking their responsibilities to perform IHC (Immunohistochemistry) study. We find this encouraging because it implies that Merck is endorsing our combination trials.
4. Why do we prefer Australia for our clinical trials?
Australia is a popular venue for clinical trials among global pharmaceutical companies because it creates tremendously great environment for clinical research studies. There are at least six reasons pharmaceutical companies might prefer Australia to conduct clinical trials. First, Australia has a diverse racial mix for patient recruitment that global pharmaceutical companies prefer and it is easy to recruit Caucasian patients. Second, Australia has excellent medical facilities. Third, the cost of clinical trials is relatively inexpensive. Fourth, the regulatory approval process for clinical trials is relatively fast. Fifth, since both Korea and Australia stay on similar time zones by 1hr difference, it is easy to oversee and manage studies. Lastly, USFDA acknowledges results of clinical trials performed in Australia.
5. When does the patent for olinvacimab expire?
The patent for olinvacimab expires in 2027 in most countries except the US. In the US, the patent expires in 2029. We are well aware of the patent weakness associated with olinvacimab and we are doing everything we can to overcome the weakness. We are carefully investigating all possibilities, including new formulations and new routes of administration, to file a new patent on olinvacimab.
Besides our own efforts, we are getting assistance from the Korean government. The Korean government runs a program to assist companies dealing with various patent issues. Earlier this year, the Korea Patent Strategy Development Institute, a subsidiary of the Korean Intellectual Property Office, decided to help us with the olinvacimab patent case and the government will help us carry out technical analysis and research ways to overcome the patent weakness.
6. Why did the company raise W100b via CB issuance in 2019? Many could see it as lack of confidence?
Issuance of convertible bonds (CBs) in May 2019 was a preemptive move to secure funding needed for planned clinical trials for olinvacimab as well as other new molecules in the pipeline. The costs of clinical trials can only go up as ongoing clinical trials proceed to later phases. We also expect to initiate other clinical studies for PMC-309 and PMC-402 in 2020 given that both have shown excellent anti-cancer effects in non-clinical studies. Note that there will be substantial costs for R&D, GMP manufacturing, and IND enabling studies and various assays.
Recently many biotech companies in Korea find it difficult to secure financing for their projects. The fact that we can finance our projects makes us ahead of the curve in this rough time.
7. Merck entered into a partnership agreement with Eisai to develop a lenvatinib-pembrolizumab combination therapy. Both lenvatinib (Lenvima) and olinvacimab have the same target, i.e., VGFR. How does this deal affect PharmAbcine’s chance of entering into a partnership agreement with Merck for olinvacimab-pembrolizumab combo?
We do not think the Merck-Eisai deal will meaningfully affect our pursuit of a partnership agreement with Merck.
The number of ongoing combination studies probably provides the best answer for this question. As of March 19, 2020, there were 1,235 clinical studies of combination treatment with Keytruda (pembrolizumab). Of these studies, about 50 combination trials involved angiogenesis inhibitors, including olinvacimab and Lenvima. We have not heard of a single company that has discontinued their combination studies after the deal was announced in 2018. The reason is that treating cancer is not simple and patients’ responses to a particular drug are different.
Another good example that could answer this question is Roche’s Avastin. After the USFDA approval on Avastin in 2004, none of companies have stopped developing their angiogenesis inhibitors. In fact, more companies have been investing in R&Ds for new anti-angiogenesis molecules with new mechanisms.
Olinvacimab distinguishes itself from other anti-angiogenesis molecules in safety. For Lenvima, 71% of patients experience adverse events such as high blood pressure, renal failure, and proteinuria. Even Avastin and Cyramza cause adverse events such as gastric/lung/vaginal perforation, intestinal bleeding, and proteinuria. Olinvaciamb has not shown these adverse events.
In TNBC (triple negative breast cancer), safety is considered as important as efficacy. Previously, anti-angiogenic drugs failed to procure approval on their therapeutic usage in HER2-negative breast cancer due to adverse events following the treatment. In contrast, the combination treatment trial of olinvacimab and permbrolizumab in mTNBC will be more likely to bring great news to mTNBC patients, demonstrating its great efficacy and safety
8. What kind of drug is PMC-402?
PMC-402 is an antibody drug that could normalize leaky blood vessels typically formed around tumors. Leaky blood vessels prevent delivery of anti-cancer drugs and immune cell infiltration to the site, but allow cancer cells to spread (metastasis). PMC-402 can not only enhance the drug delivery/immune cell infiltration to TME (tumor microenvironment) but also ameliorate a hypoxic condition through normalizing blood vessels in TME. Thus it can manage the growth of tumor and slow down the spread of cancer cells (metastasis). We plan to release the mechanism and animal (in-vivo study) results in AACR2020 this year.
In addition to tumorigenesis, pathological vasculature is responsible for the development of ophthalmic diseases such as wet age-related macular degeneration (wAMD) and diabetic retinopathy (DR). Attributable to its vessel normalization characteristics, PMC-402 can be a promising treatment option for these diseases.
We signed a CDO contact for the development and manufacturing of PMC-402 and planning to conduct IND enabling studies by the end of this year and start a phase I clinical trial by 2021.
9. What kind of drug is PMC-309?
PMC-309 is an immune checkpoint suppressor. It interferes with the activity of VISTA (V-domain Ig Suppressor of T cell Activation) and allows immune cells, especially T cells, to have anticancer effects. VISTA is an immune checkpoint protein primarily expressed on immune suppressive cells, including MDSCs (myeloid-derived suppressor cells), and it regulates and impairs the anti-tumor activity of TILs (tumor-infiltrating lymphocytes), namely T cells. PMC-309 can improve the antitumor effects of T cells through precluding the action of VISTA.
Our plan is to develop mono- and combination therapies. We are planning to initiate IND enabling studies this year and launch a phase 1 clinical study in 2021