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Cell vaccines; AFFiRiS´ PCSK9 and PD vaccines; Pfizer´s smoking cessation vaccine

This time I will scan selected vaccines against chronic and non-infectious diseases as appeared in my report (available also via this link). There should have been available results from about 20 Phase III to Phase I vaccine trials in 2016. And some interesting clinical trials started in 2016. Again, my selection is very subjective, not pretending to be comprehensive or representative. Just my selection. For more details you can go to my original report or to some of the posts published on my website.

Let´s have a look on 3 vaccine with 2016 milestones. I believe that success of infectious disease vaccines and saving of millions of lives can be translated also into vaccines for non-infectious indications and chronic diseases. In parallel to very complicated underlying basis of chronic diseases (in comparison to infectious diseases), it will be also a technology employed which matters in development of successful vaccines against chronic diseases. So far we have seen a lot of failures in this field. There are however also some optimistic news and still many vaccines in development in biotech, universities and pharma companies.

Algenpantucel-L vaccine against pancreatic cancer
Algenpantucel-L was an advanced cell vaccine in Phase III for treatment of pancreatic cancer in development at the company New Link Genetics. In May 2016 the company announced failure of the vaccine in the Phase III commercialization trial and shortly after that stopped all vaccine developments based on the same technology. They had also other candidates of the same technology in late development- Tergenpumatucel -L/Hyperacute® Lung for treatment of non-small-cell lung cancer (Phase II/III), HyperAcute® Prostate for treatment of prostate cancer (Phase I/II) and the combination vaccine Tergenpumatucel-L+indoximod (checkpoint inhibitor) for non-small cell lung cancer (Phase IB/II).

Algenpantucel-L consisted of 2 modified pancreatic cancer cell lines (HAPa-1 and HAPa-2) that have been modified to express a molecule α-gal. After immunization, pre-existing antibodies in humans against α-gal (which are thought to be a consequence from chronic immunological stimulation) immediately opsonized mouse pancreatic cells. α -gal epitopes are the major target of the hyperacute rejection response. This response occurs when organs are transplanted from lower animal donor species into primates and results in a rapid destruction of transplanted tissue and an augmented response against transplant antigens, including antigens not related to the α-gal epitopes. Such destroyed allogeneic pancreatic cancer cells are then processed by immune cells. Because cancer-specific antigens within the algenpantucel-L are shared by cancer cells in the patient, patient cancer cells were believed to be targeted by the immune system.

New Link Genetics is focused now on their other technology- inhibitors of the indoleamine 2,3-dioxygenase (IDO) pathway with two candidates. One candidate is licensed to Genentech. IDO pathway inhibitors belong to so called checkpoint inhibitors (like PD-1 or PD-L1). PD-1 checkpoint inhibitors Keytruda (Merck) and Opdivo (BMS) are both approved medicines in USA and in EU for more cancer indications.

AFFiRiS´PCSK9 and Parkinson´s disease vaccines
I cannot of course forget the peptide vaccines from my former employer AFFiRiS. Two PCSK9 vaccines AT04A and AT06A have different mode of action on the PCSK9 molecule.

Inhibition of PCSK9 was shown to decrease the “bad” LDL cholesterol (LDLc) which is involved in development of atherosclerosis and cardiovascular diseases (CVD). Two monoclonal antibodies against PCSK9 were approved by FDA and EC in 2015, however the trials to definitely confirm that decrease of LDLc by targeting PCSK9 is accompanied by an improved CVD rate, are still running.

Nevertheless, AFFiRiS PCSK9 vaccines, if they succeed, will have at least two big advantages over the expensive monoclonal antibodies treatment- a much lower price allowing also a preventive approach in a high proportion of population and an easy possibility to combine- e.g with vaccines against other “CVD” targets.

AT04A and AT06A are peptide vaccines consisting of a few amino acids sequences mimicking the original sequences of PCSK9 coupled to the carrier KLH and mixed with the adjuvant Alum. Both vaccines are B-cell vaccines, so the main mode of action is to induce, like normal infectious disease vaccines, antibodies in a body.

Despite the AT04A and AT06A trial should have been already finished in middle of 2016, AFFiRiS has so far not announced any results from this trial. It seems that the company is collecting data also from a “boost” study to provide more solid dataset, especially in the light of the promising results from their PD01A vaccine boost study (AFF008A) for treatment of Parkinson´s disease.

In the PD01A Phase I clinical trial, supported financially also by Michael J. Fox Foundation, “Immune Response was seen in 86% of patients, resulting in an increase of responder rate after boost immunization” and “PD01A-induced Antibodies Preferentially Bind to Fibrilic Alpha-Synuclein (aSyn)” as announced by the company in September 2016.

Pfizer´s vaccine(s) on smoking cessation
The Phase I trial on the PF-05402536 (NIC7-001) and PF-06413367 (NIC7-003) vaccines was already as of January 2016 marked as completed. Preclinical results from these vaccines on mice and primates were published in 2015 and also in 2016. The vaccines had been in the Pfizer´s pipeline still in August 2016 and then in the newest update, they are, or at least the PF-05402536, discontinued.

The PF-05402536/NIC7-001 vaccine was consisting of the NIC7 (peptide) coupled to the carrier molecule CRM197 and mixed with adjuvants Alum (AL(OH)3) and CpG (TLR9 agonist).

There are so far no results available from the Phase I study with the smoking cessation vaccines PF-05402536 and PF-06413367. Pfizer however published in 2016 very interesting results on how “Prior exposure to CRM or Qb-VLP significantly reduced subsequent responses to the conjugated antigen having the homologous carrier”. Qb-VLP is another carrier/adjuvant which is used, similarly as the CRM197, to induce an immune response by short molecules (haptens) which are normally not immunogenic. Such results showing the big negative effect of the “helping” carrier molecule on immune response against the antigen (which is THE target) can have very pronounced consequences and can be behind certain failures observed in this field.

Pfizer has been one of the few pharmaceutical companies which have vaccines inducing antibodies for treatment of chronic diseases in pipeline. Now, after discontinuing of PF-05402536, the only vaccine of such kind in their official pipeline is the PF-06753512/PrCa VBIR treatment which is a combination of multi-antigen vaccines, monoclonal antibody and a small molecule for treatment of prostate cancer. At least one vaccine in this regimen is a DNA vaccine since an electroporation device is also tested in this trial. Phase I trial is still recruiting patients and results are not expected before 2019. Fate of the Pfizer´s preclinical PCSK9 vaccine is not known to me.