BioNTech: Clinical Hold Removal Pushes ADC Development Program Forward

Summary:

• Partial clinical hold of BioNTech SE’s BNT326/YL202 for the treatment of patients with solid tumors in phase 1 study was lifted by the FDA.
• The primary endpoint of ORR of BNT111 in combination with Libtayo, for the treatment of patients with anti-PD-1/anti-PD-L1 relapsed/refractory or unresectable stage III or IV melanoma, met with statistical significance.
• Positive results obtained from an open-label phase 2 study, using BNT311 + Keytruda for the treatment of patients with relapsed/refractory metastatic non-small cell lung cancer; 12-month overall-survival [OS] rate of 69%.
• Updated data from the open-label phase 2 study, using BNT311 in combination with Keytruda for patients with relapsed/refractory metastatic non-small cell lung cancer, to be presented at the 2024 World Conference September 7th — 10th.

BioNTech SE (NASDAQ:BNTX) has been able to achieve several key milestones regarding its pipeline recently. Most notably, it and its partner MedLink Therapeutics [MedLink] had the lifting of the partial clinical hold by the FDA for the antibody drug conjugate [ADC] being developed for the treatment of patients with different types of solid tumors. This candidate is known as BNT326/YL202, which is being advanced in a phase 1 study. With the removal of this partial clinical hold, this allows the company to mitigate risk for patients and still move forward with the 3.0 mg/kg dose of BNT326.

Why should investors care about this program? That’s because the data released from this study was quite promising, especially when you consider that these patients had already undergone two other prior Standard of care [SOC] therapies.

I will be going over this data below, but the key thing to note is that this program can now move forward towards the targeting of solid tumor types. Another highly promising program would be the development of BNT111, which is being explored in a phase 2 study targeting patients with unresectable stage III or IV melanoma whose disease had progressed following an anti-PD-[L]1 containing therapy. It was noted that the trial met the primary endpoint of achieving a statistically significant objective response rate [ORR] compared to historical control. Investors should look towards this program because updated data are expected to be released at an upcoming medical conference in 2024. Not only that, but it is expected that this data will be made available to the public in a peer-reviewed medical journal. BNT111 is taking advantage of the FixVAC platform using mRNA-based therapies.

However, this biotech is also in the process of developing protein-based therapeutics. Having said that, one candidate being developed with Roche (OTCQX:RHHBY) is known as BNT311 [acasunlimab]. This drug in combination with a PD-1 inhibitor was shown to do well for patients with previously treated metastatic non-small cell lung cancer [NSCLC]. Updated data from this study will be presented at the 2024 World Conference on Lung Cancer [WCLC], which is taking place September 7th — 10th of 2024. With the removal of the clinical hold of BNT326/YL202 for the treatment of patients with solid tumors, plus recent advancements made in several parts of its oncology pipeline, I believe that investors could benefit with any potential gains made.

BNT326 Program For Advanced Solid Tumors Moves Forward With Partial Clinical Hold being Lifted

I believe that the most notable recent event for BioNTech, would be that it was able to get the FDA to lift the partial clinical hold. This was placed on BNT326/YL202 for the treatment of patients with advanced solid tumors. It all started back on June 17th of 2024, where the FDA had placed a partial clinical hold of this HE3-targeting antibody drug conjugate [ADC] for BioNTech and its partner MedLink Therapeutics.

Why was this partial hold placed in the first place? That’s because it was noted by the FDA that higher doses had unreasonable risk in place, and thus it had to place this partial hold. With this happening, its partner MedLink had placed a pause on further enrollment into this phase 1 study. This was terrible news for this program, especially for these patients with advanced or metastatic disease who have already been previously treated with a few other treatments.

That’s the bad news.

However, it is keen to note that this hold has been lifted. It was announced that the partial clinical hold on BNT326 was lifted by the FDA. The reason was four risk mitigation measures put in place, which are as follows:

• Data analysis in place
• Updated investigator brochure
• Informed consent for patients
• Amended clinical trial protocol.

The last one being the most important because the trial protocol had to be amended to include lower doses. Having said that, this trial is moving forward with no higher dose above 3 mg/kg of BNT326 to treat these patients with advanced solid tumors. Why investors should care about this program is because some encouraging clinical activity was observed. As of February 4th, 2024, a total of 52 patients were enrolled in this phase 1 study. Out of these patients, 46 patients were evaluable for efficacy. It was noted that the patients treated from between dose level 3 to dose level 5 had achieved an objective response rate [ORR] of 41%. The trial will continue on with the 3 mg/kg dose of BNT326 noted above.

However, it is critical to note that it remains to be seen what the next set of data will look like. Now that several safety measures have been implemented, plus a lower dose level of 3 mg/kg of drug has been placed, there is no guarantee that the ORR will remain similar to what has been achieved thus far.

BNT111 For The Treatment Of Patients With Advanced Or Metastatic Melanoma Meets Primary Endpoint

The other candidate to go over in the pipeline would be the use of BNT111, which is being developed in a phase 2 study for the treatment of patients with anti-PD-1/anti-PD-L1 refractory/relapsed, unresectable stage III or IV melanoma. It is important to note that this trial is being done in collaboration with Regeneron Pharmaceuticals (REGN). The thing is that this clinical candidate uses BioNTech’s FixVac platform, which makes use of off the-shelf uridine messenger RNA [uRNA]-lipoplex. This cancer vaccine was specifically designed to encode several shared melanoma associated antigens that could possibly boost efficacy. FixVac stands for Fix Combination Vaccine, and this is responsible for finding several tumor associated antigens it could utilize. Other parts of this tech I noted from above can be classified as follows:

• uridine messenger RNA [uRNA] — increased immunostimulatory effect and enhances pharmacological activity
• Lipolex [LPX] — used for improved delivery technology to penetrate cells.

The thing to note is that BNT111 is not being developed alone as a monotherapy for the treatment of these advanced or metastatic PD-1/PD-L1 relapsed/refractory advanced melanoma patients. Instead, this uRNA therapy is being combined with Regeneron’s Libtayo [cemiplimab] for the treatment of this patient population.

The final result was that this combination therapy of BNT111 was statistically significant compared to historical controls observed for this patient population. While the ORR data was noted to be significant compared to historical controls, there is another reason why investors should keep an eye on this program. It is because this phase 2 trial is pressing on, exploring several other efficacy measures. At the time of the meeting of the primary endpoint measure, no other endpoints were mature. Thus, it remains to be seen if other efficacy measures like progression-free survival [PFS], overall-survival [OS], plus many others turn out to be statistically significant.

All of this remains to be seen, but there are two key catalysts relating to this program for investors to look forward to. The first is that both BioNTech and Regeneron expect to present this data at a medical conference in 2024. Secondly, the goal is for the companies to submit these data for publication in a peer-reviewed medical journal, which may also be released at some point in 2024.

BNT311 Is Another Promising Oncology Product But As a Protein Therapeutic

The two products I went over above are shots on goal in targeting solid tumors using an ADC [BNT326] and uRNA [BNT111]. However, BioNTech has another part of its pipeline which is using protein-based therapeutics to treat cancer. Having said that, it, along with its partner Genmab [Subsidiary of Roche], are developing a candidate known as BNT311 or acasunlimab. What makes this candidate to special is that it is a bispecific antibody candidate which incorporates the targeting of PD-L1 and the 4-1BB co-stimulatory domain. The thing is that this drug targets both aspects as follows:

• 4-1BB domain — enhancing the effect of T-cells and natural killer cells by having them survive and targeting tumors far more effectively
• PD-L1 Checkpoint blockade — the PD-L1 portion of a tumor cell is responsible for blocking the binding of a T-cell to it and thus evade the immune system — Thus a PD-1 inhibitor put in place could counter this brake of the immune system and cause cancer killing to occur.

Speaking of the PD-L1 that BNT311 already takes care of, there is even further synergy possible. How so? Well, this drug can further be enhanced with another PD-L1 checkpoint blockade effect. That is, BNT311 is being combined with PD-1 inhibitor Keytruda to treat relapsed/refractory metastatic non-small cell lung cancer [mNSCLC] whose tumors have a PD-L1 expression of tumor proportion score [TPS] of ≥1.

Has the synergistic effect of BNT311 and Keytruda for the treatment of this patient population proven? This actually had been shown and was done so in the open-label phase 2 study. When the data was released, it was revealed that there was a manageable safety profile. Plus, that there was a 12-month overall-survival [OS] rate of 69% as well. Along with a median overall-survival [mOS] of 17.5 months and a 30% ORR [confirmed 17%]. These results are encouraging because these were not 1st-line patients who were treated. Instead, these were NSCLC patients who had already been treated with and failed on prior PD-1 therapies. That is, they failed to respond to previous standard of care [SOC] treatments. A catalyst opportunity exists for this program as well. That is, it is expected that updated data from this ongoing open-label phase 2 trial will be presented at the upcoming 2024 World Conference [WCLC] held on September 7th — 10th. All the candidates are important to consider when looking at this company, but I believe this program to be solid for one reason. Why is that? That’s because it is the one being pushed forward towards late-stage clinical testing. That is, it is expected that a phase 3 study using BNT311 + a checkpoint inhibitor like Keytruda for the treatment of PD-L[1]-positive metastatic NSCLC, could be initiated by the end of 2024.

Financials

According to the 6-K SEC Filing, BioNTech had cash and cash equivalents, current security investments and non-current security investments of $20.5 million as of June 30th of 2024. The truth is that vaccine revenues with COMIRNATY have been dropping. Thus, this is not one avenue that will be sustainable for the long term, but will still provide it with some revenues going forward. For instance, for the 3-months ending June 30th of 2024, Covid-19 vaccine revenues were $79.9 million. This, compared to the 3-months ending June 30th of 2023, where Covid-19 revenues were $175.8 million. The cash burn is about $1.2 billion per quarter, therefore with the total cash on hand it has, I don’t believe that there is any near term risk of dilution.

Risks To Business

There are several risks that investors should be aware of before investing in BioNTech. The first risk to consider would be regarding the treatment of patients with metastatic or advanced solid tumors using BNT326 in the ongoing phase 1 study. First, even though the partial clinical hold was lifted by the FDA for this ADC, there is no assurance that another similar partial hold or full clinical hold won’t be placed on it at a later time. Secondly, the 41% ORR observed beforehand utilized higher doses. Thus, there is no assurance that the doses of 3 mg/kg or lower of BNT326 will be enough to yield a similar ORR.

The second risk to consider would be in terms of the development of BNT111 in combination with Libtayo for the treatment of patients with anti-PD-1/Anti-PD-L1 refractory/relapsed metastatic melanoma in the ongoing phase 2 study. The primary endpoint was statistically significant compared to historical controls. However, there is no assurance that the other efficacy measures not yet revealed will turn out to be positive. Nor, that this mid-stage is going to turn out to be positive.

The third risk to consider would be regarding the development of BNT311 or acasunlimab for the treatment of patients with relapsed/refractory metastatic non-small cell lung cancer [mNSCLC] whose tumors have a PD-L1 expression of tumor proportion score [TPS] of ≥1. The data revealed was highly positive, showing that there was a 12-month overall-survival [OS] rate of 69% for the patients who took BNT311 in combination with Keytruda. Updated data from this open-label phase 2 study will be presented at the upcoming 2024 World Conference in September. There is no assurance that the updated data from this mid-stage trial will turn out to be positive. Nor, that the data to be released will result in the stock market reacting accordingly.

The fourth and final risk to consider would be in terms of the ongoing lawsuits that had been placed against it and Pfizer for COMIRNATY due to patents. For instance, Arbutus Biopharma (ABUS) and Genevant filed its patent lawsuit back in April 2023. Plus, GlaxoSmithKline (GSK) later filed a patent infringement claim against BioNTech and Pfizer as well, back in April 2024. The thing is that patents and patent courts are sporadic and thus, the outcome is not known. BioNTech and Pfizer believe they have defenses against such patent claims, but this remains to be seen. The risk here is that if somehow the company and its partner Pfizer end up losing in patent court, then they would have to give up a lot of cash. Plus, the stock prices could trade lower as a result

Conclusion

BioNTech has done well to advance several of its oncology products in its pipeline. It had ridden the way of Covid-19 vaccine sales with COMIRNATY, but that has quickly subsided, as I have shown above. While the loss in sales is going to hurt in the short-term, it could be in a good place if it can deliver in the long term on its FixVac and iNEST technology platforms. Specifically, it is advancing towards late-stage development for a few programs. Thus, there is a chance to do well. For instance, I think one of the promising programs for solid tumor treatment, I noted above, would be BNT311.

The reason is, I believe it is nice that there is a synergistic effect when you have a bispecific monoclonal antibody like this targeting PD-L1 and 4-1BB co-stimulatory domain together with another drug targeting PD-L1. This has been proven with the 12-month OS rate of 69%. Plus, the fact that this data is going to help this company to be in a position to initiate a phase 3 study by the end of 2024. In my opinion, I believe that it can recover with its oncology pipeline, despite COMIRNATY sales not going well.

Editor’s Note: This article discusses one or more securities that do not trade on a major U.S. exchange. Please be aware of the risks associated with these stocks.

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