HIV research has come a long way since the disease was discovered in the 1980’s. Triple therapy was a major milestone, and now biotech and pharma have shifted their focuses to finding an HIV cure. We’ve scanned the biotech industry and catalogued promising developments in the field.
In 2009, right here in Berlin, an HIV patient was cured of the disease for the first time anywhere in the world. The case of the ‘Berlin patient,’ Timothy Ray Brown, was first described in 2008 by Dr. Gero Hütter. He received a transplant of hematopoietic stem cells (HSCs) from a donor naturally resistant to HIV and has remained off antiretroviral therapy (ART) since the day of his transplant.
Twenty months after the procedure, HIV had disappeared completely from his tissue, and the medical world went nuts. After more than 30 years and countless lives destroyed, had we finally achieved an HIV cure?
While this result was incredibly encouraging, the answer remains, “not yet”. But not for lack of trying. Ten years after the HIV’s discovery, almost overnight by medical standards, a treatment was developed to manage the symptoms and prolong a patient’s life.
Since then, progress has slowed. A number of companies are further refining this therapy, while others are developing vaccines; but a functional HIV cure remains elusive, so giants like Gilead are pouring money into the effort find one. Gilead currently holds the largest market share of HIV therapies- 58%! – but GSK and ViiV Healthcare are threatening to seize some of it with its integrase inhibitor, Tivicay (dolutegravir).
But what are the major trends in the field? We reached out to leaders in the industry and finally sat down with Jean-Marc Steens, CMO of Abivax, to discuss its directions within Europe.
How are we currently addressing HIV?
The current standard of care is antiretroviral therapy (ART), first implemented in the mid-90’s as “triple therapy”. Such treatments stop the virus from replicating, but the virus DNA persists in reservoirs, cellular genomes into which it has integrated.
“These therapies pushed the virus below the level of detection, and they are now being tailored for tolerability, compliance, and smaller pill number and size,” says Jean-Marc. “The original ones were very toxic.”
Because ART’s only attack the circulating virus and don’t touch the reservoirs, it is unlikely they will be useful as cures. Moreover, they are expensive (on average €18K per year) and do not relieve the symptoms – they merely cease to progress.
If HIV is allowed to replicate, it rapidly becomes toxic; moreover, it could develop resistance to the cure. However, it is clear that the what is really needed is a therapy that also targets the reservoirs instead of the circulating virus in order to eradicate it completely and restore a patient’s health and independence from drugs. “We are cognisant of the problems with triple therapy, and we need to develop long-term solutions…we must get rid of the virus completely,” says Jean-Marc.
The Austrian Science Fund has been working to understand characteristics of HIV that make it so difficult to cure. In an article published in Nature, Regina Grillari and her group demonstrated how the virus is able to manipulate cells hosting reservoirs to be more durable and prolong the infection.
We were able to show that the HIV virus induces telomerase activity in macrophages. This was surprising to the extent that the enzyme’s known function was connected to cell division which in this case doesn’t even take place.” Regina Grillari, Professor of Biotechnology, University of Natural Resources and Life Sciences, Vienna
Insights like this could be leveraged as a target to develop and HIV cure. Further work from the group, published in a second article, analyses patterns of miRNA expression in HIV infections that could be exploited to resolve patients’ needs and personalize their treatments.
But while preclinical research is working on bringing these results to bear, how is the biotech industry doing? Jean-Marc went over the research trends towards a cure: he says that in particular, we should learn from developments in stem cell therapy and gene therapy.
Stem Cell Therapy: A New Hope from Berlin
Stem cell therapy for HIV is perhaps the oldest concept in treating the disease. It emerged around the time when the disease was first discovered in the late 1980’s: biotech startups were pursuing stem cell transplants as a means to introduce genetically modified cells to a patient’s body.
Certain genes have been identified as critical to HIV’s progression. CCR5 and CXCR4 for chemokine receptors, and without these, HIV cannot bind to a cell to enter it and launch an infection. If these genes are disrupted and the receptors destroyed in a patient, he or she would theoretically be immune.
Jean-Marc mentioned a modern method that capitalises on this theory: in HIV patients with leukemia, chemotherapy is administered to eliminate the patient’s bone marrow, which is responsible for leukemia, and at the same time wipe the HIV-infected cells. The patient then receives a transplant of compatible stem cells to replace the initial bone marrow.
Bone marrow transplants carry very high risks to the patient, including rejection of the graft and infections during bone marrow elimination; the procedure therefore has a high mortality rate. It remains a very interesting endeavour but unfortunately limited to leukemic HIV patients, for whom the benefits outweigh the elevated risk.
Given that genetics is at the core of these therapies, gene therapy is also worth exploring.
Gene Therapy: The Empire Strikes Back at HIV
Before the advent of CRISPR, zinc-finger nucleases were used to target CCR5, since most HIV strains rely on this gene instead of CXCR4. Any kind of ‘molecular scissors’ can be used to modify cells extracted from the body by disrupting these genes, and these can then be readministered using methods like lentiviral vectors, adenoviral vectors and plasmid DNA nucleofection.
Theravectys, a spin-off of Pasteur, completed the first Phase I/II trial of a lentivector-based vaccine that could be turned into a cure. Instead of chemokine receptors, however, it targets immunogenic regions of HIV proteins. The treatment aims to induce a response from a patient’s own T-cells CD8 and CD4 against these HIV proteins, and it proved to be safe and tolerable in the first clinical trial.
The drawback of these gene-based treatments is that HIV mutates quickly, making it difficult to develop targeted gene therapies. However, you might have noticed that these two avenues to a cure rely pretty heavily on the immune system. Could this be another therapeutic mine?
Immunotherapy: The Return of the T Cells
Since HIV is characterized by the shutdown of the immune system, some companies are focusing their efforts on bringing it back to life and to bear against the HIV infection, usually via T cells.
Mologen targets the gene for TLR9, a toll-like receptor that is critical to innate immunity. By activating this gene, the company hopes to activate the immune system to respond to HIV. It has already made it to the clinic: Mologen began recruiting patients late last year and recently opted to extend the study.
Immunocore is a leader in this area. The company published breakthrough results earlier this year on its application of TCR to cure HIV. Its TCR candidate for infectious disease, ImmTAV, was able to re-direct the immune system to kill HIV-infected cells, even those ‘laying low’ like CD4+ T-cells.
Oslo-based Bionor is another remarkable company whose HIV vaccine performed superbly in Phase I earlier this year. The company intends to combine its therapy with others to make a ‘functional HIV cure’ in what it calls a ‘shock and kill strategy’: its vaccine, Vacc-4x, ‘kills’ HIV by inducing CD4+ and CD8+ T-cell responses, after the virus is ‘shocked’ from latency with Celgene’s Istodax (romidepsin).
A third company working on an HIV cure with these T cells is InnaViraVax. The company’s lead candidate, VAC-3S, is administered through the company’s vaccine platform, which generates human polyclonal antibodies against 3S, a subunit of the HIV. With the aid of 3S, the virus binds to a certain entity of CD4+ T cells and eventually initiates their apoptosis.
While these companies are focused on T cells, Genmab focuses on bispecific antibodies, and its program has attracted big fish interested in a variety of diseases. Most notably, Genmab recently licensed its technology out to Gilead for its effort to develop an HIV cure.
Curevac is attempting to elicit an immune response with mRNA. ‘The RNA People’ at Curevac focus on leveraging mRNA to develop vaccines for common viruses, including HIV, and for their work, they earned the EU prize for Vaccines and hefty financial support from the Bill & Melinda Gates Foundation. We interviewed the Chief Corporate Officer, Franz-Werner Haas, for a closer look at their work.
Figure 6. A 3D rendering of HIV
And now for something completely different
For its part, Abivax has made exciting progress via a unique pathway: it is developing a first-in-class orally available small molecule, ABX-464, that inhibits HIV replication by blocking the biogenesis of viral RNA without interfering in other RNA processes. It has passed Phases Ia and Ib in the clinic, and its success has made Abivax the only company with a functional HIV cure to make it as far as Phase II.
ABX-464 is already demonstrating itself to be an effective monotherapy in a short-term Phase IIa trial with treatment-naive patients! More will be conducted to see how well it works in combination with other therapies.
So what can we hope for?
While a cure has yet to emerge from all of this research, we may see a cure as soon as 2020. For all the cynics out there, we asked if bringing a cure was really in the financial interests of big pharma and biotech. His answer? “Of course! It’s a huge market!”
Indeed, in 2015, 36.7M people were living with HIV, 2.1M of them had been infected that year, and 1.1M died of an AIDS-related cause. Jean-Marc pointed to the example of Gilead, a company hardly known as a paragon of patient-minded business that recently brought a cure for Hepatitis C to market.
Since only 46% of people with HIV were enrolled in a treatment program, it is clear that the number of patients will continue to outweigh those that can be successfully treated. While research has not brought any new treatments to bear since triple therapy, we have gained a much deeper understanding that is essential to developing an HIV cure.
Progress in gene therapy is a great cause for optimism. When gene therapy was first discovered in the 1990’s, it was estimated that it wouldn’t hit the clinic for another 30 years. But the first product hit the market way earlier!
“Of course, progress depends on the disease and the challenge, but as we gain a much deeper understanding, it will go more quickly,” says Jean-Marc. With companies like Abivax leaving no stone unturned in their research and already bringing a therapy to the clinic, we may see an HIV cure on the market within the next 10 years.