Biopharmconsortium Blog

21 December 2017

FDA approves Spark Therapeutics’ retinal disease gene therapy Luxturna, a month ahead of schedule

By |2018-09-12T21:33:46+00:00December 21, 2017|Drug Development, Eye Diseases, Gene Therapy, Haberman Associates, Personalized Medicine, Rare Diseases, Recent News|

Interface of retinal pigment epithelium and photoreceptor cells. Source: NIH Open-i

 

As we discussed in our December 17, 2015 article on this blog, Spark Therapeutics’ (Philadelphia, PA) SPK-RPE65 had achieved positive Phase 3 results at that time. It was expected to reach the U.S. market in 2017.

As announced by Spark in a press release, SPK-RPE65, now known as Luxturna (voretigene neparvovec-rzyl), was approved by the FDA on Dec. 19, 2017. This was ahead of the FDA’s PDUFA date for the therapy (i.e., the deadline for action by the FDA) in mid-January 2018.

Luxturna is a one-time gene therapy designed to treat patients with an inherited retinal disease (IRD) caused by mutations in both copies of the RPE65 (retinal pigment epithelium-specific 65 kDa protein) gene who have sufficient viable retinal cells as determined by their treating physicians. Luxturna consists of a version of the human RPE65 gene delivered via an adeno-associated virus 2 (AAV2) viral vector. It is administered via subretinal injection.

As outlined in the Spark December 19, 2017 press release, Luxturna is first FDA-approved gene therapy for a genetic disease, the first FDA-approved pharmacologic treatment for an inherited retinal disease (IRD), and first adeno-associated virus (AAV) vector gene therapy approved in the United States. However, two gene therapies, uniQure/Chiesi’s Glybera (alipogene tiparvovec) (an expensive money-losing therapy that has only been used once) and GlaxoSmithKline’s Strimvelis, were approved in Europe prior to the FDA approval of Luxturna. Moreover, the CAR-T (chimeric antigen receptor  T-cell) cellular immunotherapies Kymriah (tisagenlecleucel) (Novartis) and Yescarta (axicabtagene ciloleucel) (Gilead/Kite), which are ex vivo gene therapies, were approved in 2017—prior to the approval of Luxturna. Thus although Luxturna is a pioneering gene therapy that represents a number of “firsts”, it is only one of several of the first gene therapies that have reached regulatory approval in recent years.

Pricing and patient access issues with Luxturna

On January 3, 2018, Spark announced that it has set an $850,000 wholesale acquisition cost for Luxturna — $425,000 per eye affected by an RPE65 gene mutation. This makes Luxturna—which is intended as a one-time treatment—the highest priced therapy in the U.S. to date. Some 2,000 patients (fewer than 20 new patients per year) may be eligible for treatment with Luxturna, provided that Spark can persuade payers to cover the treatment.

Also on January 3, 2018, Spark announced a set of three payer programs designed to enable patient access to treatment with Luxturna. These include “an outcomes-based rebate arrangement with a long-term durability measure, an innovative contracting model and a proposal to CMS [The Centers for Medicare & Medicaid Services] under which payments for Luxturna would be made over time.” Spark has reached agreement in principle with Harvard Pilgrim Health Care to make Luxturna available under the outcomes-based rebate program, and under the contracting model that is designed to reduce risk and financial burden for payers and treatment centers. Spark has also reached an agreement in principle with affiliates of Express Scripts to adopt the innovative contracting model.

Spark’s proposal to CMS is based on enabling the company to offer payers the option to spread payment over multiple years, as well as greater rebates tied to clinical outcomes.

As pointed out by John Carroll of Endpoints News, pricing and payer programs that become established for Luxturna may have a wide impact on the whole gene therapy field, in particular gene therapies for hemophilia. As we discussed in our February 2, 2016 blog article, several companies—including Spark—are developing one-time gene therapies for hemophilias A and B. Hemophilia could prove to be the most competitive area of gene therapy in the near future.

Our gene therapy report

Our book-length report, Gene Therapy: Moving Toward Commercialization, contains extensive information on the development of improved gene therapy vectors (especially including AAV vectors). It also contains detailed information on SPK-RPE65/Luxturna and its mechanism of action, as well as on other gene therapies in clinical development (such as those for hemophilia). In addition, it contains information on leading gene therapy companies including Spark. It is an invaluable resource for understanding clinical development of gene therapies, and the academic groups and companies that are carrying out this development.

To order our report, Gene Therapy: Moving Toward Commercialization, please go to the Insight Pharma Reports website.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

7 December 2017

”Improving Candidate Selection: Translating Molecules into Medicines.”

By |2018-09-12T21:41:42+00:00December 7, 2017|Cancer, Drug Development, Drug Discovery, Gene Therapy, Haberman Associates, Immunology, Monoclonal Antibodies, Oligonucleotide Therapeutics, Recent News, RNAi, Strategy and Consulting|

Bromodomain. A chromatin “reader” that is a target of PPI drug development. Source: WillowW at the English language Wikipedia.

 

Allan B. Haberman, Ph.D. was one of about 25 experts from pharmaceutical, biotechnology, and consulting firms who attended Aptuit’s  one-day think-tank event, ”Improving Candidate Selection: Translating Molecules into Medicines”. This was the third and final such networking and discussion symposium, which was held in downtown Boston, on December 4, 2017. The previous two events in this series had been held in San Francisco (18th & 19th Sept 2017) and in Hertfordshire, UK (22nd & 23rd Oct 2017). The Boston discussion session was preceded by a relaxed networking dinner on the evening of the 3rd.

Attendees and presenters at the Boston meeting were from Shire, Celgene, Forma Therapeutics, Roche, Amgen, Novartis, the Broad Institute, Warp Drive Bio, Mass General Hospital, EnBiotix, Yumanity, and Ra Pharma—among others—as well as from Aptuit and its parent company Evotec.

The focus of the meeting was on improving drug candidate selection in order to improve development success. Only about 10% of drug candidates make their way from first-in-humans trials to regulatory approval. The greatest amount of attrition occurs in Phase 2. Approximately half of candidates fail at that stage, mainly due to lack of efficacy.

One of the key issues discussed in the symposium was the role of the Lipinski Rule of Five—a set of physico-chemical properties that determine the “drug-likeness” of a clinical candidate; i.e., whether a compound is likely to be an orally active drug in humans. Some participants stated that these guidelines had been interpreted too rigidly, and have excluded many potentially good drugs from further development. They stated that the Lipinski rules are only guidelines, and do not replace thinking. (For a similar point of view, see Paul Leeson’s 2012 News and Views article in Nature.) For example, researchers should measure physical properties empirically, rather than inferring them.

The Lipinski rules also exclude whole classes of drug candidates—such as natural products and macrocyclic compounds—from consideration. Before the era of combinatorial chemistry and high-throughput screening, natural products were the mainstay of drug discovery and development.

The Haberman Associates website contains reports, articles, and links to reports that are useful in understanding the issues discussed in the Aptuit symposia. Links to most of these publications can be found on our Publications page. Notably, there is a 2009 report entitled Approaches to Reducing Phase II Attrition, which is available from Insight Pharma Reports. There is also a 2009 article (available on our website at no cost) based on that report, entitled “Overcoming Phase II Attrition Problem.”

Drug attrition numbers have not changed since our 2009 publications. However even back in 2009, pharmaceutical company researchers attributed high attrition rates due to lack of efficacy to companies’ addressing more complex diseases, with the need to discover and develop drugs that have novel mechanisms of action and/or address unprecedented targets. At the December 4 Aptiut symposium, participants similarly attributed high attrition rates to researchers’ tackling new classes of drugs. These included drug classes whose development involves working with premature technologies—e.g., protein-protein interactions (PPIs), gene therapy, RNAi, CAR-T therapies, cancer vaccines, , and combination immuno-oncology therapies.

Working on development of drugs based on premature technologies involves development of enabling technologies that will allow researchers to “move up the technology development curve” and thus to achieve increasing success in drug development. R&D in some of these fields—notably development of checkpoint inhibitors for use in immuno-oncology—has been moving up the technology curve, resulting in notable successes.

Although attrition rates have not changed since 2009, drug developers have been working with increasingly newer classes of drugs. Attrition thus continues to be a moving target.

Among the publications available on our website is our 2012 report—Advances in the Discovery of Protein-Protein Interaction Modulators. As the result of corporate restructuring, this report has not be available anywhere in recent years. However, with the permission of the publisher, Datamonitor Healthcare (a division of Informa), we are now hosting it on our website.

Aptuit’s “Translating molecules into medicines” symposia and improving drug discovery and development

The purpose of Aptuit’s symposia was “to discuss and learn from the experiences of those involved in working at the interface of discovery and development. These meetings were designed to give attendees the chance to build meaningful relationships, challenge their understanding of certain subjects and learn from leading members of their peer group in a non-commercialized setting.”

The organizers of the symposia ask whether “having the flexibility to think beyond established rules and adopting more collaborative development strategies will be just as important as the innovative science and technologies for drug discovery and development.” We at Haberman Associates look forward to assisting you in your efforts to move your drug discovery and development programs forward.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

21 November 2017

Our 2017 Cancer Immunotherapy 2.0 report featured in Drug Development & Delivery

By |2018-09-12T21:30:40+00:00November 21, 2017|Cancer, Drug Development, Haberman Associates, Immunology|

 

Drug Development and Delivery published an article based on our 2017 report on Cancer Immunotherapy 2.0 in its November/December 2017 issue.

To see the article, please go to http://www.drug-dev.com/Main/Back-Issues/CANCER-IMMUNOTHERAPY-Building-on-Initial-Successes-1402.aspx

To order our report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, please see the CHI Insight Pharma Reports website.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

 

19 October 2017

Can immunotherapy 2.0 strategies save the cancer vaccine field?

By |2018-09-12T21:30:39+00:00October 19, 2017|Cancer, Drug Development, Drug Discovery, Haberman Associates, Immunology, Monoclonal Antibodies, Personalized Medicine, Recent News, Strategy and Consulting, Translational Medicine|

CTLs attacking cancer cells.

 

On September 15, 2017, Bavarian Nordic’s Phase 3 trial of its cancer vaccine Prostvac ended in failure. Prostvac failed to improve overall survival in patients with metastatic castration-resistant prostate cancer, as determined by the clinical trial.

We had listed Prostvac in Chapter 5 and in Table 5-2 of our 2017 report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, as a cancer vaccine that was in Phase 3 clinical trials. However, as we stated in that chapter, “It is possible that one or more of the experimental agents listed in Table 5-2 may [also] experience late-stage failure.” That is because the cancer vaccine field has been subject to a high rate of clinical failure, including several late-stage failures in 2016.

Despite the high rate of failure in the cancer vaccine field, there are now two FDA approved cancer vaccines— sipuleucel-T (Dendreon/Valeant’s Provenge) and talimogene laherparepvec (Amgen’s Imlygic/T-Vec), the latter of which is an oncolytic virus, rather than a true cancer vaccine. However, both of these agents are rather marginal therapies. Sipuleucel-T has an apparently minimal effect and is very expensive and difficult to manufacture. T-Vec must be injected directly into a tumor, and as a monotherapy, there is no evidence for improvement of overall survival or effects on distant metastases. However, researchers have hypothesized that as a directly-injected agent, T-Vec might produce an inflammatory tumor microenvironment that will provide an ideal target for checkpoint inhibitors. Thus, researchers have had expectations that combination therapies of T-Vec with checkpoint inhibitors which are now in progress may yield much better results.

Indeed, on October 6, 2017, a peer-reviewed Phase 2 published study indicates that a combination of Imlygic and Bristol-Myers Squibb’s (BMS’) CTLA4 checkpoint inhibitor Ipilimumab (Yervoy) doubles response rates in advanced melanoma as compared to Yervoy alone. The published trial results show that the objective response rate for the combination was 39%, compared to 18% for Yervoy alone. With respect to complete responses, the combination gave13% as compared to 7% for Yervoy alone. Responses occurred in patients with and without visceral disease and in uninjected lesions after combination treatment, according to the study.

Amgen’s head of R&D, Sean E. Harper MD says that the trial provides an important proof-of-concept for combining the complementary mechanisms of an oncolytic viral immunotherapy and a checkpoint inhibitor to enhance antitumor effects, adding that the company intends to test Imlygic in combination other checkpoint inhibitors in “a variety of tumor types”.

Imlygic—in combination with another checkpoint inhibitor, pembrolizumab (Merck’s PD-1 inhibitor Keytruda)—is in a Phase 3 trial (KEYNOTE-034, clinical trial number NCT02263508) in advanced melanoma. This trial is expected to yield preliminary results in 2018. In 2014, the Phase 1b/2 MASTERKEY-256 trial of the Imlygic/Keytruda combination in advanced melanoma showed an overall response rate (ORR) of around 56%.

These data indicate that the immunotherapy 2.0 strategy of using Imlygic to generate an inflammatory tumor microenvironment may produce a synergistic clinical effect and enhanced anti-tumor immune response in patients with metastatic melanoma who are also treated with a checkpoint inhibitor.

As we discuss in Chapter 5 of our 2017 Cancer Immunotherapy report, several cancer vaccine developers are pursuing a similar strategy—use cancer vaccines to render tumors inflamed [i.e. especially with cytotoxic tumor-infiltrating lymphocytes (TILs)], and use checkpoint inhibitors to induce regression of the inflamed tumors. In some cases, cancer vaccines are being tested in combination with checkpoint inhibitors in Phase 1 or Phase 2 clinical trials, rather than the “traditional” approach of first getting a vaccine approved and then conducting trials of the vaccine in combination with other agents. The hope is that testing a vaccine in combination with a checkpoint inhibitor in early stage clinical trials might prevent clinical failure of a potentially useful cancer vaccine. However, whether this strategy will work for any particular vaccine remains to be seen.

Neoantigen cancer vaccines

Another novel immunotherapy 2.0 strategy for cancer vaccine discovery and development discussed in our report involves neoantigen science. Recent studies exploring mechanisms by which TILs and other components of the immune system recognize tumor cells and differentiate them from noncancer cells have focused on “neoantigens”—i.e. antigens that are specific for cancer cells as opposed to normal, noncancer cells. These neoantigens are associated with somatic mutations that arise in the evolution of tumor cells. Neoantigen-specific TILs appear to mediate tumor regression, and this antitumor activity may be enhanced by checkpoint inhibitor therapy. Such studies have led researchers to hypothesize that personalized neoantigen-based vaccines may be more effective than earlier types of cancer vaccines. Some researchers have therefore been attempting to develop technology platforms for vaccine design based on determination of neoantigens in tumors.

In particular, neoantigen researchers at the Dana-Farber Cancer Institute, the Broad Institute, Massachusetts General Hospital, and Brigham and Women’s Hospital recently founded a company, Neon Therapeutics (Cambridge, MA). Neon focuses on neoantigen science and technology for the development of neoantigen-based therapeutic vaccines and T-cell therapies to treat cancer.

These researchers published a report in the 13 July issue of Nature describing their Phase 1 study in patients with previously untreated high-risk melanoma of a personalized neoantigen vaccine designated NEO-PV-01 by Neon Therapeutics and in Chapter 5 of our report.

As discussed in our report, Neon’s lead clinical program, NEO-PV-01, builds upon initial clinical trials developed collaboratively by the Broad Institute and the Dana-Farber. NEO-PV-01 is a personalized vaccine that is custom-designed and manufactured to include targets for the immune system [i.e. naturally-processed, major histocompatibility complex (MHC)-binding, neoantigen peptide epitopes] that are unique to an individual’s cancer. The 13 July Nature report focuses on results of the ongoing Phase 1 clinical trial designated NCT01970358 of the combination of poly-ICLC [poly-inosinic acid/poly-cytidylic acid/poly-lysine, an adjuvant] and multiple neoantigen peptide epitopes in melanoma.

As discussed in that Nature paper, neoantigens were long envisioned as optimal targets for anti-tumor immune responses. However, the systematic identification of neoantigens in a particular patient’s tumors only became feasible with the availability of massively parallel sequencing for detection of coding mutations, and of machine learning technology to reliably predict those naturally-processed mutated peptides that bind with high affinity to autologous major histocompatibility (MHC) molecules. (The term “naturally-processed” refers to antigenic peptide epitopes that are processed intracellularly and which bind with high affinity to autologous class I or class II MHC molecules. The MHC/peptide complexes are then recognized by T cells.)

In the study described in the 13 July Nature paper, the researchers demonstrated the feasibility, safety, and immunogenicity of a vaccine (designated NEO-PV-01 as discussed earlier), which targets up to 20 predicted personal tumor neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of 97 unique neoantigens across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumor. Of six vaccinated patients, four had no recurrence as of 25 months post-vaccination. Two other patients who had recurrent disease were subsequently treated with the anti-PD-1 antibody pembrolizumab (Merck’s Keytruda). These two patients experienced complete tumor regression, with expansion of the repertoire of neoantigen-specific T cells.

These results strongly support further development of the researchers’ neoantigen vaccine approach, both alone and in combination with checkpoint inhibitors or other immunotherapies. Neon Therapeutics is currently sponsoring an open-label Phase 1b clinical study of NEO-PV-01 plus adjuvant in combination with nivolumab (BMS’ Opdivo) in patients with melanoma, smoking-associated non-small cell lung carcinoma (NSCLC) or transitional cell bladder carcinoma (clinical trial number NCT02897765). Neon entered into a collaboration with BMS to perform this clinical trial in late 2015.

Neon is also developing NEO-PTC-01, a personal neoantigen autologous T cell therapy, which is now in the research and process development stage. As discussed in Chapter 6 of our 2017 cancer immunotherapy report, neoantigen science is also a factor in adoptive cellular immunotherapy for cancer, especially in Steven A. Rosenberg MD, PhD’s recent studies of TIL therapy.

Other neoantigen cancer vaccine companies

In addition to Neon, other young companies that specialize in development of neoantigen-based cancer vaccines include BioNTech AG (Mainz, Germany), Gritstone Oncology (Emeryville, CA and Cambridge, MA), ISA Pharmaceuticals (Leiden, The Netherlands), Agenus (Lexington, MA), and Caperna (Cambridge, MA). Of these companies, BioNTech and Caperna [which is a Moderna (Cambridge, MA) venture company] are developing RNA-based personalized neoantigen vaccines. The other companies are developing peptide neoantigen vaccines based on their proprietary technologies.

Conclusions

As discussed in this article, and in our 2017 report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, researchers and developers are applying several immunotherapy 2.0 approaches to attempt to reverse the high rate of failure in the cancer vaccine field.

Moreover, neoantigen science has a potentially wide field of application, ranging from improving clinical outcomes of treatments with checkpoint inhibitors to development of more effective cancer vaccines and of novel cellular immunotherapies.

Our report contains materials designed to enable readers to understand complex issues in neoantigen science, and especially to understand applications of neoantigen science in research reports, clinical trials, corporate news, and product development.

For more information on our report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, or to order it, see the CHI Insight Pharma Reports website.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

20 September 2017

How immunotherapy 2.0 has been shaping corporate acquisition strategy: the Merck-Rigontec deal

By |2018-09-12T21:30:36+00:00September 20, 2017|Business, Cancer, Drug Development, Drug Discovery, Haberman Associates, Immunology, Personalized Medicine, Recent News, Strategy and Consulting, Translational Medicine|

PD-1 extracellular domain

 

As noted in our 2017 Insight Pharma Report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes” the most successful class of immunotherapeutics continues to be that of the checkpoint inhibitors (discussed in Chapter 2 of our report).

Immune checkpoints refer to a large number of inhibitory pathways in the immune system, especially those that block the response of T cells to antigens. Marketed checkpoint inhibitors are all monoclonal antibodies (mAbs). The two leading checkpoint inhibitors, both of which target PD-1, are pembrolizumab (Merck’s Keytruda), and nivolumab, (Bristol-Myers Squibb’s Opdivo), both approved by the FDA in 2014. Of these two, Keytruda has become the market leader during 2016/2017, after a long process of competition with BMS’ Opdivo..

On July 26, 2017, Forbes published a long article by David Shaywitz MD, PhD, entitled “The Startling History Behind Merck’s New Cancer Blockbuster”. This article is a complete history of Keytruda, from discovery through commercialization. As discussed in this article, Roger Perlmutter MD PhD (who became head of Merck Research Labs during the process of development of Keytruda) redirected virtually all work at Merck towards the Keytruda program. He determined that Keytruda was more valuable than the entire rest of Merck’s portfolio put together. Dr. Perlmutter essentially bet both his own career and Merck’s enterprise on the Keytruda program.

Merck has been engaging in an aggressive R&D and commercialization program for Keytruda. In the second quarter of 2017, Keytruda achieved three accelerated approvals and one full approval in the U.S., a recommendation in the EU, and a 180% increase in sales. As of September 2017, Merck has over 550 clinical trials evaluating Keytruda in more than 30 tumor types.

As expected for such an aggressive program, not all of Merck’s efforts have been successful. Three of the company’s combination trials of Keytruda, with Celgene’s Revlimid (lenalidomide) or Pomalyst (pomalidomide) plus dexamethasone in multiple myeloma, have been on hold because of an excess number of deaths in the treatment arm. Merck also had a missed endpoint in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-040 trial. Despite this, Keytruda has held onto its accelerated approval for this indication, and other HNSCC trials are ongoing.

Merck’s acquisition of Rigontec

Keytuda has become as much a platform as a product for Merck. This is illustrated by the recent acquisition by Merck of the German company Rigontec for $150 million in cash and another $453 million in milestones payments. According to John Carroll’s Endpoints News, this is an example of how Merck’s Perlmutter likes to augment the work being done around Keytruda with the occasional add-on.

Mr. Carroll refers to the Rigontec deal as a “bolt-on” acquisition. In a “bolt-on” acquisition, a platform company (such as Merck) with the management capabilities, infrastructure and systems that allows for organic or acquisition growth will look for acquisition of smaller companies “that provide complementary services, technology or geographic footprint diversification and can be quickly integrated into the existing management infrastructure.”

Rigontec’s technology platform is based on developing agents that mimic viral infections. Specifically, double-stranded viral RNA is recognized by pattern recognition receptors called RIG-I-like helicases (RLH) that are present in the cytoplasm. Synthetic RLH ligands (such as those being developed by Rigontec) working via RLH initiate a signaling cascade that leads to an antiviral response program, characterized by the production of type I interferon (IFN) and other innate immune response genes. RLH signaling also induces apoptosis in tumor cells. Finally, exposure of CD8alpha+ dendritic cells (DCs) to RLH-activated apoptotic tumor cells induces DC maturation, efficient antigen uptake and cross-presentation of tumor-associated antigens to naive CD8+ T cells.

The exploitation of the RLH system thus constitutes a potential means to activate tumor-specific CD8+ T cells. As discussed in our 2017 Insight Pharma report, checkpoint inhibitors work by reactivating intratumoral T-cells, especially CD8+ cytotoxic T cells. Rigontec’s agents may work to render “cold” tumors inflamed (specifically, with DCs and CD8+ T cells), thus making them more susceptible to the antitumor action of checkpoint inhibitors such as Keytruda. This type of strategy, as discussed in our report, is a major theme of “second wave” immuno-oncology, or “immuno-oncology 2.0.”

However, so far the potential use of Rigontec’s RLH ligands in cancer therapy is based on studies in preclinical tumor models for melanoma, ovarian cancer and pancreatic cancer. Currently, Rigontec has been sponsoring a first-in-humans Phase 1/2 trial of its lead RIG-1 agonist, RGT100, in solid tumors and lymphoma (clinical trial number NCT03065023). This study is designed to assess “safety, tolerability and pharmacokinetics of RGT100 in patients with injectable solid tumor lesions”. In the absence of evidence for clinical efficacy in human cancer patients, the Merck acquisition of Rigontec is a speculative deal. However, upfront Merck’s investment in Rigontec is small, and it gives Merck access to a new mechanism of action, which is complementary to the larger company’s strategy and current pipeline.

Other immunotherapy 2.0 approaches designed to enhance the effectiveness of checkpoint inhibitors

As noted in our 2017 Insight Pharma Report, although checkpoint inhibitors such as Keytruda have achieved spectacular success in treating some patients, they do not work for the majority of patients. Even in the case of melanoma, where checkpoint inhibitors have shown the greatest degree of efficacy, these agents only cure 20% of patients. Therefore, numerous researchers and companies are working to discover and develop complementary “immunotherapy 2.0” treatments to enhance the efficacy of checkpoint inhibitors in various classes of cancer patients. Rigontec’s technology represents only one such approach.

In a recent article published (Sep 7, 2017) in FierceBiotech, writer Arlene Weintraub discussed two companion treatments that might potentially enhance the effectiveness of checkpoint inhibitors. One of these treatments, discovered by scientists at Columbia University Medical Center, is a drug that’s already on the market: pentoxifylline, which is used to increase blood flow in patients with poor circulation. Pentoxifylline’s activity in cancer immunology is based on its inhibition of NF-kB c-Rel.  This results in the inhibition of regulatory T cells (Tregs) in the tumor mcroenvironment. In mouse models, inhibition of c-Rel function by pentoxifylline delayed melanoma growth by impairing Treg-mediated immunosuppression, and thus and potentiated the effects of anti-PD-1 immunotherapy. Adverse effects, such as the induction of autoimmunity that would be expected if the treatment caused global inhibition of Tregs, were not seen. Once again, these studies in mice await confirmation via human clinical trials; such human trials are currently planned.

The other experimental immunotherapy 2.0 approach discussed in Ms. Weintraub’s article involves combining an oncoloytic virus [the modified vaccinia virus Ankara (MVA)] with a checkpoint inhibitor. Once again, the example discussed in this article was in mouse models. As in other immunotherapy 2.0 approaches, the goal is to enable the immune system to recognize the tumor as foreign by injecting the oncolytic virus into it, thus prompting a CD8+ T-cell response. Checkpoint inhibitors might then reactivate the intratumoral T cells, inducing an antitumor response. These studies were also carried out in mouse models, and human trials are planned.

Our report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes”, also includes discussions of the use of oncolytic viruses to boost the anticancer efficacy of checkpoint inhibitors. Some of these approaches (such as studies of combinations of Amgen’s Imlygic (talimogene laherparepvec), an FDA-approved modified oncolytic virus therapy, with checkpoint inhibitors), are already in human studies.

Also in our report is a discussion of treatments being developed by NewLink Genetics designed to modulate the IDO (indoleamine-pyrrole 2,3-dioxygenase) pathway. Such compounds are designed to reverse IDO-mediated immune suppression. IDO pathway inhibitors may complement the use of anti- PD-1and/or anti-PD-L1 checkpoint inhibitors. The same Endpoints News article that discusses the Merck/Rigontec acquisition  also mentions an earlier Merck bolt-on deal—the 2016 acquisition of IOmet. IOmet also works on IDO pathway inhibitors.

More generally, our 2017 Insight Pharma Report contains a wealth of potential immunotherapy 2.0 approaches. Importantly, this includes an “immunotherapy 2.0” approach to cancer vaccine development, which emphasizes combinations of cancer vaccines with checkpoint inhibitors. This may both enhance the efficacy of checkpoint inhibitors, and reverse the high rate of failure of cancer vaccines. Other immunotherapy 2.0 strategies discussed in our report may well make the news over the next several years, in terms of corporate deals and product approvals. Our report is thus well worth reading for those who are interested in the further devlelopment of immuno-oncology.

For more information on our report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, or to order it, see the CHI Insight Pharma Reports website.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.