Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

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.

CAR-T procedures
Source: National Cancer Institite

 

Late stage cellular immunotherapy products for treatment of hematologic tumors

In the field of commercialization of cellular immunotherapy for cancer, all eyes have been on two chimeric antigen receptor (CAR) T-cell therapies (from Novartis and Kite Pharma), which have been in preregistration with the FDA as of March 2017. We discussed the field of CAR-T cell therapies—as well as other cellular immunotherapies for cancer—in Chapter 6 of our recently published book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes

Both the Novartis therapy, CTL019 (tisagenlecleucel-T), and the Kite therapy, KTE-C19 (axicabtagene ciloleucel) target CD19, which is a cell surface protein that is expressed on all malignant and normal B-cells.

On July 13, 2017, Novartis announced  that FDA’s Oncologic Drugs Advisory Committee (ODAC) had unanimously recommended approval of CTL019 for the treatment of relapsed or refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL). The ODAC recommendation is based on review of Novartis’ CTL019 r/r B-cell ALL development program, including the ELIANA study (NCT02435849). ELIANA is the first pediatric global CAR-T cell therapy registration trial. Findings from other clinical trials in the U.S. also supported the recommendation and the Biologics License Application (BLA) for CTL019.

On August 30, 2017 the FDA approved Novartis’ CTL019—now known as Kymriah (tisagenlecleucel)—for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Novartis’ Kymriah is thus the first-ever commercially approved CAR-T cell therapy to reach the market. However, Kite’s KTE-C19 is close on Novartis’ heels.

On August 28, 2017, Kite and Gilead announced that the two companies have entered into a definitive agreement pursuant to which Gilead will acquire Kite for $11.9 billion. Via this acquisition, Gilead “instantly” becomes a leader in cellular immunotherapy for cancer, going head-to-head with Novartis.

Other CAR-T based immunotherapies for treatment of hematologic tumors

As discussed in our report, there is also a third company, Juno Therapeutics, that was in the race to develop CD19-targeting CAR-T-based cellular immunotherapies for regulatory approval in 2017. However, Juno’s lead product, JCAR015, suffered a series of toxicity-related setbacks. Juno thus abandoned both JCAR015 and the race for 2017 approval. It is now focusing on development of another CD19-targeting CAR-T product, JCAR017. This therapy is directed towards treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

JCAR017 demonstrated promising efficacy results in a Phase 1 trial known as TRANSCEND. Adverse results were generally mild, and could be resolved with treatment. [ The company presented the results of the TRANSCEND trial at the 2017 American Society for Clinical Oncology (ASCO) annual meeting in early June.]

Juno expects to begin a pivotal trial of JCAR017 this year in DLBCL. JCAR017 received a breakthrough therapy designation from the FDA for non-Hodgkin lymphoma in December 2016.

As we also discuss in our report, another CAR-T therapy directed against a hematologic malignancy, bluebird bio’s bb2121, is under development in collaboration with Celgene. bb2121 targets B-cell maturation antigen (BCMA), and is directed toward treatment of multiple myeloma (MM). bluebird and Celgene announced the results of an ongoing first-in-human open-label Phase 1 multicenter clinical study of bb2121 in 18 patients with relapsed/refractory MM at the 2017 ASCO Annual Meeting on June 5, 2017. bb2121 demonstrated promising efficacy results in this study, and no dose-limiting toxicities were observed. No patient in the active dose cohorts has had disease progression. The researchers thus plan on initiating the expansion phase of the study in the coming months of 2017.

Can researchers develop cellular immunotherapy for solid tumors?

As various companies work to move CAR T-cell therapies that target tumor antigens other than CD19 into the clinic, a particularly important question is whether CAR T-cell technology might be used to target solid tumors. Our report  discusses several clinical-stage products designed to target various types of solid tumors. These include products in three categories—tumor-infiltrating lymphocytes (TILs), CAR T-cells, and recombinant T-cell receptor (TCR) cells. Researchers developing such therapies (especially CAR T-cell therapies) recognize the special difficulty in targeting solid tumors, and are including studies attempting to determine the barriers that might prevent effective therapy of solid tumors with their experimental therapies. Some companies have also been producing therapies that are designed to overcome these barriers.

Now comes a “Brief Report” (published in December 2016) in the New England Journal of Medicine that focuses on an experimental treatment for the brain cancer glioblastoma with CAR T-cells. The study was carried out by researchers at the City of Hope (Duarte, CA). In this study, the CAR T-cells used were designed to target the high-affinity interleukin-13 (IL-13) receptor IL13Rα2, which is overexpressed in a majority of glioblastomas. The researchers administered the therapy locally in the brain, by injecting it into the tumor site and/or via infusion in the brain’s ventricular system. This contrasts with the use of CAR T-cells for treatment of hematological malignancies, in which the CAR T-cells are administered systemically.

Treatment with the CAR T-cells induced a transient, complete response in a patient with recurrent multifocal glioblastoma. This included a dramatic improvement in quality of life, including the discontinuation of use of systemic glucocorticoids and a return to normal life activities. The remission was sustained for 7.5 months. Nevertheless, the patient eventually developed new tumors. The authors concluded that their study provides proof-of-principle data that confirm IL13Rα2 as a useful immunotherapeutic target in glioblastoma, and suggest that CAR T cells can mediate profound antitumor activity against a difficult-to-treat solid tumor.

Meanwhile, as discussed in our report, researchers at Kite Pharma and University of Pennsylvania/ Novartis have been studying treatment of glioblastoma with CAR T-cells that target the epidermal growth factor receptor variant III (EGFRvIII). Some 20-30% of glioblastomas express this variant. The two groups are running parallel early-stage clinical trials of two different EGFRvIII CAR agents. The researchers believe that these parallel studies may be informative for future development of CAR therapies for solid tumors. However, no dramatic results such as seen by the City of Hope group have yet been reported for these studies.

TIL therapies for solid tumor cancers

Currently, the most successful cellular immunotherapies for solid tumor cancers have involved treatment with TILs. Steven A. Rosenberg, M.D., Ph.D., of the National Cancer Institute pioneered the study of TIL therapy, and of cellular immunotherapy in general. Our 2017 report  includes extensive discussions of the studies of TIL therapy carried out by Dr. Rosenberg and his collaborators, from the 1980s to today. Unlike CAR T-cell and recombinant TCR-based therapies, TILs are normal T cells that have not been genetically engineered.

Most clinical studies with TIL therapy have been in advanced melanoma. However, more recent studies have included “proof of principle” studies in patients with epithelial cancers of the digestive system. In some cases, these have included studies with TILs that target cancers with the KRAS G12D mutation, a notorious “undruggable” driver mutation that is involved in causation of many human cancers. More recent work in Dr. Rosenberg’s group has included mechanistic studies designed to determine the neoantigens that are targeted by antitumor TILs. Some of these most recent studies are being applied to treatment of non-small cell lung cancer (NSCLC).

However, as discussed in our report and in another article on this blog , TIL therapies have been difficult to commercialize. Nevertheless, in recent years, a San Carlos, CA company called Lion Biotechnologies (which on June 27, 2017 changed its name to Iovance Biotherapeutics has been focusing on doing just that. Iovance has been working with Dr. Rosenberg and his colleagues at the NCI under a Cooperative Research and Development Agreement (CRADA) to develop and commercialize TIL therapies.

On June 5, 2017, Iovance announced a poster presentation  of a study of 16 patients enrolled in the first cohort of its ongoing Phase 2 study of LN-144 for the treatment of metastatic melanoma, at the ASCO Annual Meeting.   LN-144 is the company’s autologous TIL therapy for the treatment of patients with refractory metastatic melanoma. Iovance’s Phase 2 clinical trial of LN-144 (clinical trial number NCT02360579) is designed to assess the safety, efficacy, and feasibility of the autologous TIL therapy, followed by interleukin-2 (IL-2), in the treatment of this class of patients.

The data presented at the ASCO meeting showed that Iovance can manufacture TILs at its central GMP facilities to treat patients at multiple clinical sites. According to the company, the initial data show clinically-meaningful outcomes, as assessed both by objective response rate (ORR) and disease control rate (DCR), in a heavily pre-treated patient group, all of whom had received prior anti-PD-1 (e.g., pembrolizumab or nivolumab) and over 80% with prior anti-CTLA-4 (e.g., ipilimumab) checkpoint inhibitors.

In the ASCO poster presentation, the company’s academic collaborators presented updated data from 16 patients who were infused as of April 24, 2017. These advanced metastatic melanoma patients were a median age of 55 and were highly refractory to multiple prior lines of therapy with significant tumor burden at baseline. Of the evaluable patients, a 29% ORR was reported, including one complete response (CR) continuing beyond 15 months post-administration of a single TIL treatment. 77% percent of patients had reduction in target tumor size. The mean time to first response was 1.6 months, with the CR developing at 6 months.

Responses were observed in patients with wild type tumors and with tumors carrying BRAF  mutations. The protocol for this study was amended to increase the sample size for the study, as well as to further define the patient population to patients with unresectable or metastatic melanoma who have progressed after immune checkpoint inhibition therapy, and if BRAF mutation-positive, after BRAF targeted therapy.

In addition to the melanoma study, Iovance plans to initiate Phase 2 TIL therapy studies in cervical and head-and-neck cancers during 2017. The TIL populations to be used for these studies, LN-145, will be selected for reactivity to human papillomavirus (HPV) proteins E6 and E7. The selection and use of such TIL populations was developed by researchers in Dr. Rosenberg’s group. Iovance is currently enrolling patients in its Phase 2 melanoma and cervical and head-and-neck cancer studies.

Recent review on treating solid tumors with CAR-T cell therapies

Now comes a review by Irene Scarfò, Ph.D. and Marcela V. Maus, MD, Ph.D. published in March 2017 in the Journal for ImmunoTherapy of Cancer. This review focuses on factors that may limit the efficacy of CAR-T cell therapies in solid tumors, and how these factors might be overcome.

Some of the factors discussed in this review include:

  • Hypoxia, nutrient starvation, and resulting changes in T-cell metabolism (many human solid tumors contain high percentages of hypoxic tissue)
  • Interactions between CAR T-cells and tumor stroma that may inhibit the ability of CAR T-cells to penetrate tumors
  • Targeting cytokine networks, for example by inducing the local release of cytokines that promote anti-tumor immune responses. For example, interleukin-12 (IL-12) is a key inflammatory cytokine, which is able to induce several pathways that promote such a response. (We discussed IL-12-based therapeutics for use in immuno-oncology, as well as therapeutics based on such cytokines as IL-2, IL-10 and IL-15, in Chapter 1 of our report.) Starting from these considerations, several groups are investigating so-called “fourth generation” CAR T-cells, which are CAR-T cells that are designed to secrete IL-12.

The immunosuppressive environment of the interior of solid tumors results in the upregulation of surface inhibitory receptors, especially programmed death-1 (PD-1) on CAR T-cells. PD-1 inhibits the antitumor activity of the CAR T-cells. Researchers are therefore developing therapies in which they treat solid tumors with a combination of CAR T-cells directed to an appropriate tumor antigen and an immune checkpoint inhibitor such as pembrolizumab or nivolumab. Alternatively, researchers may use a genetic engineering strategy to block PD-1.

Currently, researchers are testing approaches based on these factors in animal models, and may soon be advancing into human clinical trials. As with other approaches classified as “immuno-oncology 2.0”, these trials will involve the use of combination therapies. The goal of early clinical trials in this area will be to determine the safest and most effective combinations for treatment of patients with solid tumors.

Conclusions

The field of cellular immunotherapy for cancer is an increasingly exciting and fast-moving area. Most of the focus is on breakthrough treatments of CD19+ hematologic tumors, with late-stage CAR T-cell therapies such as Novartis’ CTL019 (tisagenlecleucel-T), and Kite’s KTE-C19 (axicabtagene ciloleucel), which are rapidly approaching the market. However, there are also new indications that researchers and companies might be able to develop cellular immunotherapy-based treatments for certain types of solid tumors in the next several years. All in all, cellular immunotherapy will be an increasing area of focus for researchers, companies, and analysts over the remainder of this decade and beyond.

For more information on our recent 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.

 

 

CAR T cells attacking a cancer cell. (Source: National Cancer Institute)

On May 3, 2017 Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports announced the publication of a new book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, by Allan B. Haberman, Ph.D.

The new 2017 report includes an updated discussion of approved and clinical stage agents in immuno-oncology. It also addresses the means by which researchers and companies are attempting to build on prior achievements in immuno-oncology to achieve improved outcomes for more patients. This approach is often referred to as “immuno-oncology 2.0.” The American Society of Clinical Oncology (ASCO) named “immunotherapy 2.0” as its “Advance of the Year” for 2017.

As discussed in the report, researchers have found that checkpoint inhibitors such as pembrolizumab (Merck’s Keytruda) and nivolumab (Bristol-Myers Squibb’s Opdivo) produce tumor responses by reactivating TILs (tumor infiltrating lymphocytes). As a result, they have been developing biomarkers that distinguish inflamed (i.e. TIL-containing) tumors—which are susceptible to checkpoint inhibitor therapy—from “cold” tumors, which are not. They have also been working to develop means to render “cold” tumors inflamed, via treatment with various conventional therapies and/or development of novel agents. These studies constitute the major theme of immuno-oncology 2.0.

Meanwhile, cellular immunotherapy has also been advancing, with two chimeric antigen receptor (CAR) T-cell therapies (from Novartis and Kite Pharma) in preregistration with the FDA as of March 2017.

These and other areas of current cancer immunotherapy R&D are discussed in the new report.

The first wave of immuno-oncology 2.0 treatments has begun to achieve regulatory approval:

  • On May 12, 2017, Merck gained FDA approval to market a combination of pembrolizumab with chemotherapy (specifically, carboplatin plus pemetrexed) for first-line treatment of non-small cell lung cancer (NSCLC). This is based on a Phase 2 clinical study that showed that the chemo/pembrolizumab combination resulted in a much higher statistically-significant overall response than chemo alone — 55% vs. 29%. As we discuss in our report, certain types of chemotherapy can induce immune responses that convert “cold” tumors into inflamed tumors, thus making them susceptible to checkpoint inhibitor treatment.
  • On May 23, 2017, the FDA awarded accelerated approval to Merck’s pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that exhibit high microsatellite instability (MSI-H) or are mismatch repair deficient (dMMR). This indication includes patients with solid tumors that have progressed following prior treatment, and who have no satisfactory alternative treatment options. It also includes patients with colorectal cancer that has progressed following treatment with chemotherapy. This is the first approval of an anticancer agent based on a tumor’s biomarker, regardless of where the tumor originated in the body. As we discuss in our report, mismatch-repair deficiency results in a large somatic mutation load. This supports a large and diverse population of TILs, which are specific for mutation-associated neoantigens. Treatment with checkpoint inhibitors may reactivate these TILs, resulting in effective antitumor immune responses.

Our report is designed to enable readers to understand current and future developments in immuno-oncology, especially including new developments in immunotherapy 2.0. It is also designed to inform the decisions of leaders in companies and in academic groups that are working in areas that relate to cancer R&D and treatment.

For more information on the report, 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.

Adenosine Deaminase

Adenosine Deaminase

Our recent book-length report, Gene Therapy: Moving Toward Commercialization was published by Cambridge Healthtech Institute in November 2015. As indicated by its title, the report focuses on clinical-stage gene therapy programs that are aimed at commercialization, and the companies that are carrying out these programs.

Until recently, gene therapy was thought of as a scientifically-premature field with little prospect of near-term commercialization. However, as outlined in our report, numerous companies have been pursuing clinical programs aimed at regulatory approval and commercialization. These efforts have attracted the interest of investors and of large pharma and biotech companies. As a result, several gene therapy specialty companies have gone public, and some companies in this sector have attracted large pharma or biotech partnerships.

A key question addressed in our report is whether any gene therapies might be expected to reach the U.S. and/or European markets in the near term. In the last chapter (Chapter 9) of the report, we included a table (Table 9.1) of eight gene therapy products that we deemed to be likely to reach the market before 2020.

One of these products, uniQure/Chiesi’s Glybera (alipogene tiparvovec), a treatment for the ultra-rare condition lipoprotein lipase deficiency (LPLD), was approved in Europe in 2012. It is thus the “first commercially available gene therapy” in a regulated market. However, uniQure has dropped plans to seek FDA approval for Glybera.

As we discussed in our December 17, 2015 article on this blog, another product listed in Table 9.1, Spark Therapeutics’ SPK-RPE65, is expected to reach the U.S. market by 2017. SPK-RPE65 is a gene therapy for the rare retinal diseases Leber congenital amaurosis and retinitis pigmentosa type 20. As of March 9, 2016, Spark is preparing to file a Biologics License Application (BLA) for SPK-RPE65 in the second half of 2016. SPK-RPE65 may be the first gene therapy approved in the U.S. Spark also plans to file a marketing authorization application (MAA) in Europe in early 2017.

Now comes an announcement of the impending European marketing of a third product listed in Table 9.1, GlaxoSmithKline/San Raffaele Telethon Institute for Gene Therapy (TIGET)’s GSK2696273, now called Strimvelis. On April 1, 2016, the The European Medicines Agency (EMA) recommended the approval of Strimvelis in Europe, for the treatment of children with ADA severe combined immune deficiency (ADA-SCID) for whom no matching bone marrow donor is available. ADA-SCID is a type of SCID caused by mutations in the gene for adenosine deaminase (ADA).

Approximately 15 children per year are born in Europe with ADA-SCID, which leaves them unable to make certain white blood cell that are involved in the immune system. ADA-SCID is an autosomal recessive condition that accounts for about 15% of cases of SCID. ADA deficiency results in the intracellular buildup of toxic metabolites that are especially deleterious to the highly metabolically active T and B cells. These cells thus fail to mature, resulting in life-threatening immune deficiency. Children with ADA-SCID rarely survive beyond two years unless their immune function is rescued via bone marrow transplant from a compatible donor. Thus Strimvelis is indicated for children for whom no compatible donor is available.

As we discussed in our report, the development of therapies for ADA-SCID goes back to the earliest days of gene therapy, in 1990. Interestingly, Strimvelis (GSK2696273) is based on a Moloney murine leukemia virus (MoMuLV) gammaretrovirus vector carrying a functional gene for ADA. In other applications (for example, gene therapy for another type of SCID called SCID-X1), the use of MoMuLV vectors resulted in a high level of leukemia induction. As a result, researchers have developed other types of retroviral vectors (such as those based on  lentiviruses) that do not have this issue. Nevertheless, Strimvelis Mo-MuLV-ADA gene therapy has been show to be safe over 13 years of clinical testing, with no leukemia induction. As discussed in our report, researchers hypothesize that ADA deficiency may create an unfavorable environment for leukemogenesis.

Delivery of Strimvelis requires the isolation of hematopoietic stem cells (HSCs) from each patient, followed by ex vivo infection of the cells with the MoMuLV-ADA construct. The transformed cells are then infused into the patient, resulting in restoration of a functional immune system.

With the EMA recommendation of approval for Strimvelis, it is expected that the therapy will be approved by the European Commission approval in July 2016.

Strimvelis is the result of a 2010 partnership between GSK and Italy’s San Raffaele Telethon Institute for Gene Therapy (TIGET), and the biotechnology company MolMed, which is based at TIGET in Milan. MolMed is currently the only approved site in the world for production of and ex vivo therapy with Strimvelis. However, GSK is looking into ways of expanding the numbers of sites that will be capable of and approved for administration of the therapy. GSK’s plans will include seeking FDA approval for expansion into the U.S. market.

Moreover, as discussed in our report, under the GSK/TIGET agreement,  GSK has exclusive options to develop six further applications of ex vivo stem cell therapy, using gene transfer technology developed at TIGET. GSK has already exercised its option to develop two further programs in two other rare diseases. Both are currently in clinical trials. Because of the issue of leukemogenesis with most gammaretrovirus-based gene therapies, these other gene therapy products are based on the use of lentiviral vectors.

Given the tiny size of the market for each of these therapies, pricing is an important—and tricky—issue. For example, treatment with UniQure’s Glybera, as of 2014, cost $1 million. As of now, GSK is not putting a price on Stremvelis, but reportedly the therapy will cost “very significantly less than $1 million” if and when it is approved.

Conclusions

The success of researchers and companies in moving three of the eight gene therapies listed in Table 9.1 toward regulatory approval suggests that gene therapy will attain at least some degree of near term commercial success. However, Glybera and Strimvelis are for ultra-rare diseases, and are thus not expected to command large markets.

However, as discussed in our previous blog article, SPK-RPE65 may achieve peak sales ranging from $350 million to $900 million. And as discussed in our report, some of the remaining therapies listed in Table 9.1, especially those involved in treatment of blood diseases or cancer, may achieve sales in the billions of dollars. Thus, depending on the timing and success of clinical trials and regulatory submissions of these therapies, gene therapy may demonstrate a degree of near-term commercial success that few thought was possible just five years ago.

Meanwhile, even therapies that address rare or ultra-rare diseases will be expected to save the lives or the sight of patients who receive these products.

_________________________________________________________________________________________

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.

photo of Tsarevich Alexei of Russia

Tsarevich Alexei of Russia

The boy pictured above is Tsarevich Alexei Nikolaevich of Russia, who lived between 1904 and 1918, and was the heir to the throne of Imperial Russia. He is arguably the most famous hemophiliac in history.

Alexei suffered from hemophilia B, a form of hemophilia that was passed from Queen Victoria of Britain through two of her five daughters to the royal families of Spain, Germany, and Russia. He inherited the disease—which is X-linked and recessive—from his mother, the Empress Alexandra Feodorovna, a granddaughter of Queen Victoria.

During Alexei’s lifetime, there was no good treatment for hemophilia. So Empress Alexandra turned to the charlatan Grigori Rasputin, a supposed “holy man” whom she thought had the power to heal the boy. The relationship between the Empress and Rasputin, and the disastrous rule by the two during September 1915—February 1917, led to the fall of the Romanov dynasty and the eventual rise of Bolshevism. In July 1918, the Bolsheviks murdered Tsar Nicholas II and his entire family, including Tsarevich Alexei, who was one month shy of his 14th birthday.

Current treatments for hemophilia

In 2016, there are much better approved therapies for hemophilia than in Alexei’s day. Hemophilias include hemophilia A and B. Both are X-linked recessive disorders, which thus affect mainly males. Hemophilia A involves a deficiency in factor VIII (FVIII),  and hemophilia B involves a deficiency in factor IX (FIX). Both of these are clotting factors made in the liver. Hemophilia occurs in approximately one in 5,000 live births, and hemophilia A is four times as common as hemophilia B.

Management of hemophilia—from the early 1990s to today—is based on the use of recombinant FVIII or recombinant FIX, for the treatment of hemophilia A and B, respectively. Examples of these products include Baxalta’s Advate and Pfizer’s Xyntha (both recombinant FVIII products), and Pfizer’s BeneFix and Biogen’s Alprolix (both recombinant FIX products). (Baxalta was spun off from Baxter International in July 2015, and then acquired by Shire in January 2016.)

To avoid joint damage and other complications, patients with severe hemophilia need regular infusions, lasting 30 minutes or more, of relatively short-acting and expensive recombinant clotting factors. The cost of these products per patient could total more than $300,000 in 2014.

In recent decades, clotting factor replacement therapy has reduced the morbidity and mortality of hemophilia. However, compared with individuals with normal coagulation, deaths still occur at higher rates due to bleeding episodes. Prophylactic therapy via regular intravenous infusions of factor two to three times per week is now the standard of care for children and increasingly for adults, especially for patients with severe hemophilia. With the expense of current therapies, and the need for frequent infusions, compliance is difficult. Moreover, convenient access to peripheral veins is often a problem. Many children require use of central venous access devices, with the risks of infection and thrombosis.

As a result, pharmaceutical and biotechnology companies have been attempting to develop longer-acting recombinant clotting factor products, with some success. Example of recently-developed products include Biogen/Swedish Orphan Biovitrum’s Alprolix (recombinant factor IX Fc fusion protein, approved by the FDA in March 2014 for treatment of hemophilia B) and Biogen/Swedish Orphan Biovitrum’s Eloctate (recombinant factor VIII Fc fusion protein, approved by the FDA in June 2014 for treatment of hemophilia A). Both of these products are fusion proteins between recombinant clotting factors and Fc immunoglobulin domains. The use of Fc domains is designed to prolong the half-life of the recombinant fusion proteins in the circulation. Other companies that have been active in developing longer-acting recombinant FIX and FVIIII products include Bayer and Novo Nordisk.

The new longer-acting recombinant clotting factors can reduce the frequency of infusion needed for control of a patient’s hemophilia. However, some patients, especially children under 12, may require higher doses or more frequent infusions than most adults.

Gene therapies for hemophilia under development

The ideal therapies for hemophilia A and/or B would be gene therapies. Gene therapies would potentially eliminate the need for lifelong, frequent infusions of clotting factors, with improved quality of life and reduced risk of death due to bleeding episodes.

As discussed in our recently published book-length report, Gene Therapy: Moving Toward Commercialization (published by Cambridge Healthtech Institute), hemophilia A and B have been extensive researched as candidates for gene therapy. This research has included development and use of animal models, development of coagulation assays that can be used in quantitating the results of treatment, and development of actual candidate gene therapies, especially in the case of hemophilia B.

Development of gene therapies for hemophilia B (the disease that afflicted Tsarevich Alexei and other European royals) enjoys the advantage of the relatively small size of the coding region of the gene for FIX. It is approximately 1.4 kB of cDNA (complementary DNA) coding sequence. This allows researchers to insert this coding element into many different gene transfer vectors, especially adeno-associated virus (AAV) vectors. (AAV is the most commonly used vector in gene therapy today.) The small size of the FIX coding region also allows for the addition of transcriptional regulatory elements to modulate the expression of an FIX transgene into small vectors such as those based on AAV.

In contrast, FVIII cDNA is over 8kB in size. Thus, it is not as readily accommodated in small gene transfer vectors such as AAV.  Researchers and companies have been employing several strategies to overcome this difficulty. Although R&D efforts aimed at making gene therapy for hemophilia A possible are underway, commercial development of gene therapy for hemophilia B is far ahead of that for hemophilia A.

As discussed in our report, an important factor that favors the use of gene therapy in treatment of hemophilias is that there is a relatively low threshold for success. In a hemophilia patient, If long-term expression of 2-3% of wild-type (or normal) levels of a functional clotting factor (FIX for hemophilia B or FVIII for hemophilia A) could be achieved, then a substantial reduction in the clinical manifestations of the disease could be attained. Expression of over 30 percent of the wild-type level of the clotting factor could restore a patient to phenotypic normality, although higher levels may be required in the case of hemostatic challenge.

Preliminary results of uniQure’s clinical trial of its hemophilia B gene therapy, AMT-060

In our report, we discuss four programs for development of hemophilia B gene therapies that have reached the clinic. All are based on AAV vectors. One of these four therapies, AMT-060, is being developed by uniQure (Amsterdam, The Netherlands). uniQure has the distinction of having developed the first, and currently (as of January 2016) the only, gene therapy product that has received regulatory approval in a regulated market. This is Glybera (alipogene tiparvovec), a treatment for the ultra-rare genetic disease lipoprotein lipase deficiency (LPLD). uniQure’s hemophilia B gene therapy candidate, AMT-060, is being developed in Europe in collaboration with Chiesi (Parma, Italy).

On January 7, 2016 uniQure announced preliminary results from the low-dose cohort of an ongoing Phase 1/2 clinical trial (clinical trial number NCT02396342) being conducted in adult hemophilia B patients treated with uniQure’s novel AAV5-FIX gene therapy, AMT-060. At the time of their enrollment in the trial, all five patients in the low-dose cohort had FIX levels of less than 1-2% of normal levels, and required chronic treatment with prophylactic recombinant FIX (rFIX) therapy.

The first two patients out of the five have completed 20 and 12 weeks of follow-up and had FIX expression levels of 5.5% and 4.5% of normal, respectively, as of the cutoff date of December 16th, 2015. The three other patients have been dosed, but had not achieved the full 12 weeks of follow-up at the cutoff date. However, as of January 6, 2016, four of the five patients, including the first two patients enrolled in the study, have been able to fully discontinue prophylactic rFIX. The first patient in the low-dose cohort experienced a mild, transient and asymptomatic elevation of liver transaminase levels in serum at 10 weeks after treatment; this was easily resolved by treatment with prednisolone. No elevated transaminase levels have been observed in the other four patients so far.

As outlined in our report, AMT-060 consists of an AAV5 vector carrying a gene cassette encoding a codon-optimized (i.e., using codons most frequently found in highly expressed eukaryotic genes) wild-type human FIX (hFIX), under the control of a liver-specific promoter. The gene cassette has been exclusively licensed by uniQure from St. Jude Children’s Research Hospital (Memphis, Tenn.). It is the same gene cassette that has been successfully tested in published Phase 1 trials. AMT-060 is manufactured using uniQure’s proprietary insect cell based technology. The therapy is administered, without the use of immunosuppressants, through a peripheral vein in one treatment session for approximately 30 minutes. The study includes a low-dose and a high-dose cohort. So far, there have been no issues with pre-existing neutralizing antibodies against AAV5 or with development of inhibitory FIX antibodies.

This early data suggests that AMT-060 is well-tolerated, and is able to successfully transduce the liver, and thus to produce clinically meaningful levels of serum FIX.

uniQure and its collaborators are continuing the study. The investigators intend to present a more complete analysis of the data from the low-dose cohort at a scientific conference in the second quarter of 2016. uniQure also anticipates initiating enrollment of the high-dose cohort in the first quarter of 2016.

The hemophilia gene therapy field will be competitive

Among the clinical-stage hemophilia B programs covered in our report, Spark Therapeutics expects to report initial efficacy data in mid-2016 for its Phase 1/2 clinical trial of SPK-FIX, which it is developing in collaboration with Pfizer. As discussed in our report, only Baxalta has reported early clinical trials for its therapy, AskBio009/BAX335. These results were reported in July 2015. As in many early studies of hemophilia gene therapies, there were issues with neutralizing antibodies that led to decreased FIX expression. Baxalta continues to work to address the observed immune responses, while maintaining target levels of FIX expression. As uniQure continues with its clinical trial of AMT-060 and treats more patients with higher doses, it remains to be seen to what extent immune reactions might affect results with its hemophilia B gene therapy.

The other hemophilia B program discussed in our report is at Dimension Therapeutics. At the time of our report’s publication, Dimension’s first clinical trial was to commence in the second half of 2015. As reported by Dimension, the Phase 1/2 study for its AAVrh10-FIX product DTX101 was actually initiated on January 7, 2016.

Other companies that are entering the hemophilia B or A gene therapy field include Biogen, Sangamo in collaboration with Shire, and Biomarin. Biomarin’s program is in hemophilia A, and all the companies mentioned in this article and in our report that have hemophilia B programs also are developing hemophilia A gene therapies. At least some commentators believe that “hemophilia could prove to be the most competitive gene therapy race to date.”

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