Biotech General Discussion

PDS Biotech (PDSB) has been the highest ASCO21 gainer to date, up more than 100% on its updated data from a combination immunotherapeutic regimen to treat advanced human papillomavirus (HPV)-associated cancers. The fairly complex immunotherapeutic regimen includes the following biologics: (1) a liposomal multipeptide therapeutic vaccine against HPV positive cancers (PDS0101) delivered subcutaneously, (2) Bintrafusp-alpha, a bifunctional fusion protein checkpoint inhibitor targeting PD-L1 and TGF beta (M7824) delivered intravenously, and (3) a tumor targeted (antibody-conjugated) immunocytokine (NHS-IL12) delivered subcutaneously (https://clinicaltrials.gov/ct2/show/NCT04287868). PDS0101 (Versamune-HPV), PDS Biotech’s lead candidate, is a liposomal formulation of PDSB’s Versamune® particles (positively charged nanoparticles about the size of a viral particle) and a proprietary mix of HPV16 E6/E7 peptide antigens (More Information). It is notable that although PDS0101 is being developed by PDSB, Bintrafusp alfa is being jointly developed by Merck KGaA and GlaxoSmithKline, and NHS-IL12 is being developed by Merck KGaA. This combination therapy is a good example of next-generation immunotherapeutic combinations that have made their way into clinical trials and ASCO21 presentations.

The trial for this therapeutic combination reported on in the ASCO21 abstract (ASCO abstract 199070), which will be the subject of an ASCO21 oral presentation on June 7, is sponsored by the National Cancer Institute (NCI). Data from the first 14 patients was reported on in the abstract. Treatfment with the therapeutic combination resulted in an 83% and 63% objective response rate (ORR) in relapsed/refractory HPV-16 positive advanced cancer patients who are either checkpoint inhibitor naïve or refractory, respectively. Furthermore, 90% of the responses are ongoing after a median of 5 months of follow-up. The therapy is aggressive with 4 of the 14 treated patients experiencing a grade 3 toxicity. However, these early results are impressive since only about 15-20% of HPV-associated malignancies respond to PD-(L)1 inhibitors and for the overwhelming majority of patients who progress on these immunotherapies there is no effective standard of care therapy (PDSB press release 5/20/21).

This Phase 1/2 trial is a basket-type trial for HPV associated malignancies, and is not limited to a certain cancer type. The patients in the NCI sponsored trial include cervical, anal, oropharyngeal vaginal/vulvar and a variety of other HPV-associated cancers. NCI reports that there are more than 630,000 cases of HPV-associated malignancies including cervical, oropharyngeal and anal cancer worldwide annually. HPV 16 is responsible for most of these cases. Thus, this appears to be a large market opportunity.

As shown in FIG. 1, although PDSB has several other candidates that are not yet in clinical trials, PDS0101 is PDSB's only clinical asset. The Phase 2 update at ASCO21 relates to 1 of 3 different cancer combinations in clinical trials for PDS0101. Of course based on PDS0101’s mechanism of action, all of the trials are related to HPV associated cancers. The other trials are also combination trials, either with Keytruda, Merck’s market-leading approved checkpoint inhibitor, or with chemotherapy and radiation therapy. It will be interesting to see how these other trials progress given the ASCO21 proof of concept data from the NCI-sponsored triple therapy trial.

FIG. 1

BPIQ.com Company pipeline page for PDSB

Competition for PDSB’s HPV vaccine will likely be fierce. For example, Merck has an approved HPV vaccine, Gardasil 9, which is approved for vaccination to protect individuals from developing many of the cancers in the Phase 2 NCI trial (https://www.gardasil9.com/). In fact, when we search clinicaltrials.gov we find a number of trials, including several actively recruiting clinical trials, testing Gardasil 9 (sometimes in combination with an anti-PD1 antibody) to treat cervical cancer or precursors thereof (See e.g. https://clinicaltrials.gov/ct2/show/NCT04096911).

Furthermore, when we search our BPIQ database for other HPV cancer therapeutics, we find 6 other therapeutic candidates of smid-cap companies targeting HPV cancers in active clinical trials with data report outs in 2021 or early 2022. These include HB-201 and HB-202 from HOOKIPA Pharma, SQZ-PBMC-HPV from SQZ Biotechnologies, RTX-321 from Rubius Therapeutics, CUE-101 from Cue Biopharma, and Multikine from Cel-Sci Corporation. RTX-321, SQZ-PBMC-HPV, and HB201/HB2-202 are the subject of ASCO21 presentations. CUE-101 data is expected in mid 2021, and an additional combo trial from PDSB expects data in late 2021 or early 2022. Data from Cel-Sci is expected this year for the indication HNSCC, but the indications could be expanded to include HPV. SB206 from Novan has a planned Phase 3 trial, but there is currently no indication of initiation timing.

As far as PDSB’s cash runway, the company appears to be in good shape. The company had $25 million in cash as of Q1, 2021, with a burn rate of only around $3.0 million per quarter (See FIG. 2). We expect this burn rate to increase in the coming quarters, now that the company has this proof of concept data.

FIG. 2 BPIQ.com Company page header portion for PDSB

Thus, key questions for investors based on the exciting early findings in the NCI-sponsored Phase 2 trial that includes PDS0101, are 1) how much impact is PDS0101 having over the other components of the triple therapy being tested, and 2) how does PDSB’s HPV vaccine compare to other HPV vaccines. As to the first question, if the efficacy results of the triple combination hold at the 50% ORR mark, it would appear that PDS0101 is having an impact. As mentioned above, only about 15-20% of HPV-associated malignancies respond to PD-(L)1 inhibitors and for the overwhelming majority of patients who progress on these immunotherapies there is no effective standard of care therapy (PDSB press release 5/20/21). It seems unlikely that improved activity of the checkpoint inhibitor used in the NCI Phase 2 study, or enhancement of activity by the tumor-targeted cytokine, would result in such an increase over historical response rates. Of course, it will take a controlled clinical trial to make this determination with high confidence.

As far as how PDSB’s HPV vaccine compares to others in this context of treating cancer (not vaccinating to prevent cancer), as discussed above, a natural competitor would appear to be Merck’s HPV vaccine, GARDASIL 9, especially since Merck controls the other two components of the triple therapy in the NCI trial. Currently the GARDASIL 9 label expressly states that it is NOT for treatment of any cancer, and in particular those in the NCI Phase 2 trial (See label here). However, as discussed above, there are a number of investigator-sponsored trials directed at this. We don’t currently find a Merck-sponsored trial. Maybe the promising results from the NCI-sponsored study will prioritize such a trial for Merck.

A key question that will be answered later this year or early next, is whether PDS0101 appears to increase the efficacy of Keytruda or chemotherapy/radiation in its other ongoing clinical trials. If the data of these PDS0101 trials continues to be impressive, it seems that even without extensive cooperation by Merck, PDSB could find any number of other anti-PD1s or other checkpoint inhibitors to combine with PDS0101 that are not controlled by Merck. We have not analyzed any patents to confirm that Merck does not own some blocking patents in this area.

The key will be whether PDS0101’s liposomal nanoparticle formulation is superior to Merck (and NIH’s) virus-like particle technology (NIH Technology Licensed to Merck for HPV Vaccine | Office of Technology Transfer, NIH). And especially whether PDS0101’s delivery of HPV E6/E7 peptides from a single subtype (See our PDDS0101 IQ card), is superior to GARDASIL 9’s HPV capsid L1 proteins across 9 HPV types (HPV Vaccine | CDC). From an initial high-level perspective, E6 and E7 may be a better target for a cancer therapy since these proteins are involved in cancer formation (See Science Direct Page). This is consistent with the fact that GARDASIL 9 is designed to neutral viral infection by delivering a capsid protein-containing VLP (See NIH post here), not to help the immune system develop a response to treat an existing cancer likely caused at least in part, by expression of HPV genes by a patient’s cancer cells.

In summary, HPV cancers appear to be a hot area of clinical actively. PDSB is one of the players in the middle of this activity. It's very early days for PDSB, but there initial results look very promising not only for investors, but especially for patients with HPV cancers. At a current market cap and enterprise value under $300 million, PDSB is worth a closer look by smid-cap cancer biopharma investors.

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