IL2RG protein, encoded by tL2RG complementary DNA. (https://commons.wikimedia.org/wiki/File:Protein_IL2RG_PDB_2b5i.png)

As reported in the 18 April issue of the New England Journal of Medicine, researchers at the St. Jude Children’s Research Hospital (Memphis, TN) and their colleagues have used gene therapy to restore immune function to eight infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1).

SCID-X1 is sometimes called “bubble-boy disease”, because of the case of a boy born in 1971 with SCID-X1, who had to be isolated in a plastic bubble while awaiting a bone-marrow transplant.

SCID-X1 is a rare X-linked genetic disease caused by a mutation in the L2RG gene. This gene encodes the interleukin-2 receptor subunit gamma (IL-2RG), which is common to the receptor complexes for at least six different interleukin receptors, including IL-2 and IL-4. Individuals with SCID-X1 produce very few T and NK (natural killer) cells, and are thus severely immunodeficient. As a result, they are very susceptible to infections, and typically die before age 2 if not isolated or treated.

Although SCID-X1 is a rare disease, it is the most common form of severe combined immunodeficiency. It probably affects at least 1 in 50,000 to 100,000 newborns.

SCID-X1 can sometimes be cured by a bone-marrow transplant from a matched sibling donor. However, fewer than 20% of SCID-X1 patients have such an available donor.

A previous attempt to apply gene therapy to treatment of SCID-X1, in the early 2000s, utilized a Moloney murine leukemia virus (MoMuLV) gammaretrovirus as a vector. This resulted in a high level of leukemia induction, as discussed in a previous article on this blog. So this approach had to be abandoned. Instead, researchers have developed lentiviral vectors, which appear to have a lower risk of leukemogenesis than gammaretroviral vectors. We discussed the development and use of lentiviral vectors in our November 2015 book-length report, Gene Therapy: Moving Toward Commercialization, published by Cambridge Healthtech Institute.

The new experimental gene therapy for SCID-X1 utilized a lentiviral vector carrying IL2RG complementary DNA.  This was used to transfect patient-derived bone-marrow stem cells. The transfected stem cells were infused back into eight infants with newly diagnosed SCID-X1after low-exposure, targeted busulfan conditioning. (“Conditioning”, for example via a myelosuppressive chemotherapy like busulfan given prior to stem-cell transplantation, is designed to make room for transplanted blood stem cells to grow.

The eight infants were studied for a median of 16.4 months, and experienced no unexpected side effects. In seven of the infants, the numbers of T cells and NK cells normalized by 3 to 4 months after infusion. The vector was present in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors in these seven subjects. The eighth subject initially had an insufficient T-cell count. However, a boost of gene-corrected cells without busulfan conditioning resulted in T-cell normalization. Previous infections were cleared in all infants, and all continued to grow normally. The subjects also showed other signs of immune system normalization, including vaccine response in three of the infants.

The researchers concluded that the IL2RG-lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 showed low-grade acute toxic effects, and resulted in engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. Children treated with this gene therapy should therefore be protected against common ailments by their reconstituted immune systems. However, they will still need to be monitored long-term to determine if the treatment is durable and free of side effects over the long term.

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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.

Adeno-associated virus. Source: https://commons.wikimedia.org/wiki/File:Adeno-associated_virus_serotype_AAV2.jpg

In recent weeks, buyouts of gene therapy companies by Big Pharmas or Big Biotechs—as well as other major gene therapy deals—have been making the news. Specifically, on February 25, 2019, leading gene therapy company Spark Therapeutics (Philadelphia, PA) announced that it had entered into a merger agreement with Roche. Under this agreement, Roche will fully acquire Spark for $4.3 billion.

Roche will keep Spark as a independent entity, similar to Roche’s Genentech. This should enable the type of innovation that has been demonstrated by Spark since its founding in 2013.

Meanwhile, Biogen is buying gene therapy company Nightstar Therapeutics (London, UK) for $800 million in order to gain access to its suite of gene therapies for rare retinal diseases. According to “Endpoints News”, the Biogen/Nightstar deal is the result of a bidding war for Nighrstar by Biogen and three other (unnamed) companies.

And Johnson & Johnson has signed a deal with MeiraGTX (London and New York) for rights to its experimental gene therapies for rare retinal diseases. The two companies also will collaborate on improving gene therapy manufacturing. J&J paid Meira $100 million in cash upfront, and Meira could get up to $340 million in additional downstream payments plus royalties on sales if its products reach the market. J&J will be paying for clinical development of the therapies.

Our previous discussions of Spark and Nightstar

We discussed Spark and Nightstar and their gene therapy programs in our 2015 book-length report, Gene Therapy: Moving Toward Commercialization. We also updated our discussion of Spark’s lead ophthalmological gene therapy product Luxturna (voretigene neparvovec-rzyl) (formerly known as SPK-RPE65), in our December 21, 2017 article on this blog.

As we discussed in these publications, Spark’s 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. It consists of a version of the human RPE65 gene delivered via an adeno-associated virus 2 (AAV2) viral vector, and is administered via subretinal injection. Luxturna is the first FDA-approved gene therapy for a genetic disease, the first FDA-approved pharmacologic treatment for an IRD, and the first AAV-vector gene therapy approved in the USA.

Nightstar is clinical stage company whose initial focus is treatment of the IRD choroideremia (CHM). CHM is an X-linked genetic disease caused by mutations in the X-CHM gene. These mutations interfere with the production of Rab escort protein-1 (REP1). REP1 is involved in intracellular protein trafficking, and the elimination of waste products from retinal cells.

Nightstar’s lead product is NSR-REP1 (formerly known as AAV2-REP1). This gene therapy consists of an AAV2 vector containing recombinant human complementary DNA, (cDNA), that is designed to produce REP1 inside the eye. NSR-REP1 is currently in a Phase 3 registrational clinical trial, known as the STAR trial. It is thus the most clinically advanced candidate for choroideremia in the world.

In addition to discussing gene therapies under development (including the above-mentioned Spark and Nightstar programs, as well as many others), our 2015 gene therapy report also discusses development and use of gene therapy vectors, especially AAV. It thus continues to be a valuable reference for understanding the gene therapy field.

MeiraGTX

MeiraGTX focuses on AAV-based gene therapies. Its five programs in clinical development include three ophthalmological therapies, as well as gene therapies for a salivary gland condition, and for Parkinson’s disease. The company’s most advanced programs are in Phase 1/2 clinical development, and include treatments for achromatopsia and X-linked retinitis pigmentosa.

Spark is also developing gene therapies for hemophilia

As discussed in a February 23, 2019 “Endpoints News” article on the Roche/Spark merger, Roche’s interest in Spark is not only because of its leadership position in ophthalmological gene therapies, but also because of its broad product portfolio. Notably, among Spark’s product candidates is SPK-8011, one of the leading clinical-stage gene therapies for hemophilia A. SPK-8011 is a novel AAV vector containing a codon-optimized human factor VIII gene under the control of a liver-specific promoter. As the result of promising Phase 2 data, SPK-8011 is now in a lead-in study (NCT03876301) for phase 3 clinical trials. Also in a lead-in study for Phase 3 trials (sponsored by Spark’s partner for this therapy, Pfizer) is Spark’s hemophilia B candidate, fidanacogene elaparvovec (SPK-9001).

The hemophilia gene therapy field is highly competitive. Other companies with clinical-stage hemophilia gene therapies include BioMarin, uniQure, and Sangamo/Pfizer.

Roche’s acquisition of Spark’s SPK-8001 may enable Roche/Genentech to strengthen its leading competitive position in the hemophilia A market. Roche received FDA approval for its blockbuster prophylactic Hemlibra for hemophilia A without factor VIII inhibitors in October 2018.

Pfizer enters the gene-therapy buyout arena

In late-breaking (March 20, 2019) news, Pfizer has taken an exclusive option to acquire Vivet Therapeutics (Paris, France).

Vivet focuses on the development of gene therapies for inherited liver diseases with high unmet medical need. Under the new agreement, Pfizer has acquired 15% of Vivet’s equity, and an exclusive option to acquire all outstanding shares. Initially, the two companies will collaborate on the development of Vivet’s VTX-801, a preclinical-stage gene therapy for Wilson disease.

Wilson disease is a rare and potentially life-threatening liver disorder involving impaired copper transport, resulting in severe copper poisoning. The Wilson’s disease mutation disables the excretion pathway for copper via the bile. This results in excess copper accumulation in the liver and other organs, including the central nervous system. Untreated, Wilson disease results in severe copper toxicity, which can be fatal. It can only be cured by liver transplantation. Existing therapies for Wilson disease are of low efficacy and/or result in significant side effects.

VTX-801, like other therapies discussed in this article, is an AAV-based gene therapy. It is Vivet’s first gene therapy, and the most advanced in development.

Under the terms of the agreement, Pfizer paid approximately €45 million (US$51 million) upon signing and may pay up to €560 million (US$635.8 million) in milestone payments. Pfizer also has an option to acquire 100% of Vivet, based on the results of a Phase 1/2 clinical trial for VTX-801. Pfizer senior executive Monika Vnuk, M.D., Vice President, Worldwide Business Development, is also joining Vivet’s Board of Directors.

Vivet’s earlier-stage preclinical liver-directed gene therapies include a program for progressive familial intrahepatic cholestasis (PFIC) for bile excretion defects and in citrullinemia for defects in the urea cycle.

The Pfizer/Vivet agreement is yet another example of the recent Large Pharma/Biotech enthusiasm for buying up small gene-therapy companies.

Concerns about cost and patient selection for “one and done” gene therapies

As we discussed in our December 21, 2017 article on this blog, Luxturna, as the first FDA-approved gene therapy for an inherited disease, is expected to be a one-time (“one and done”) therapy for its targeted condition. It is expensive, priced at $850,000 ($425,000 per eye affected by an RPE65 gene mutation). This made Luxturna the highest priced therapy in the U.S. to date. Other “one and done” gene therapies are also expected to be expensive. Pricing and related issues with “one and done” gene therapies thus affect the prospects for gene therapy companies and for larger companies that are planning to acquire or partner with them.

In our December 21, 2017 article, we discussed payer programs designed to enable patient access to treatment with Luxturna. These include an outcomes-based rebate plan with a long-term durability measure, and a proposal under which payments for Luxturna would be made over time. Such programs are designed to reduce risk and financial burden for payers and treatment centers. As we discussed, pricing and payer programs that become established for Luxturna may have a wide impact on the entire gene therapy field.

A March 5, 2019 article on gene therapy by Jeremy Schafer, PharmD, MBA of Precision for Value was published in Clinical Leader. This article focused on designing gene therapy clinical trials to meet the concerns of payers and health systems.

At the recent annual meeting of the Academy of Managed Care Pharmacy, the results of a survey that included the perceptions of gene therapy among health plans and health system stakeholders were presented. Among these respondents, 35% stated that their primary concern with gene therapy was “selecting appropriate patients.” Another 30% named “the potential need for retreatment” as their main concern. The major concern of 5% of respondents was that patients treated with gene therapy would still need conventional treatment for their condition. A total of 88 percent of respondents felt that information on appropriate patient selection as well as durability of response would be extremely valuable. Another 60 percent would like to have an economic model on the long-term value of the gene therapy.

Dr. Schafer’s article discussed how clinical trial design might help address these concerns. For example, gene therapy clinical trials might include a long-term follow-up plan to capture data on an ongoing basis. This might help address the question as to whether a gene therapy is truly “one and done”. Ongoing data from these trials might be shared in peer-reviewed publications. The long-term data might be used in economic models by health plans.

In terms of identifying appropriate patients for gene therapies, clinical trial design might include clearly-defined inclusion and exclusion criteria, based on good scientific rationales. Preplanned subgroup analyses might show which groups respond well or not so well to a gene therapy. Clinical trials could also be designed to determine whether and to what extent gene-therapy patients will still need ongoing therapy with conventional drugs.

All these issues in structuring payer programs and in clinical trials designed to meet the concerns of payers and health plans (and of partner and acquiring companies) may enable the development and acceptance of gene therapies as this field moves beyond the release of the first few products.

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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.

NIH Clinical Center

On December 7, 2017 we published an article on this blog entitled ”Improving Candidate Selection: Translating Molecules into Medicines”. This article was based on a December 4, 2017 symposium sponsored by Aptuit entitled “Improving Candidate Selection: Translating Molecules into Medicines”. The focus of the meeting was on improving drug candidate selection in order to improve development success.

Our article stated that “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.” As we also stated in that article, drug attrition numbers have not changed since our 2009 publications, “Approaches to Reducing Phase II Attrition” and “Overcoming Phase II Attrition Problem”.

However, especially since the year 2000, drug developers have been working with increasingly newer classes of drugs. They attribute continuing high attrition rates to difficulties in working with ever-changing classes of drugs designed to treat complex diseases. Attrition thus continues to be a moving target.

Several more recent estimates of clinical trial success are comparable to those cited by participants in the Aptuit symposium, and in our own 2009 publications. For example, as pointed out by Endpoints News, BIO (the Biotechnology Innovation Organization) in a recent publication analyzing clinical development success rate from 2006 to 2015, determined that the overall likelihood of approval from Phase 1 for all drug candidates was 9.6%, and 11.9% for all indications other than cancer. (The likelihood of approval for oncology candidates was 5.1%; this is about the same as the figure for oncology success cited in our 2009 report.) Meanwhile, AstraZeneca cited a 5% success rate for its own candidates in a January 2018 analysis.

Now comes a January 2018 study by Andrew W Lo, Ph.D. and his colleagues at MIT that concludes that 13.8% of all drug development programs eventually lead to approval. This study was discussed in a February 1, 2018 article in Endpoints News by John Carroll. Dr. Lo is the Director of the MIT Laboratory for Financial Engineering.

As with earlier studies, the success rates depend on the particular indication. For example, infectious disease vaccines have the highest rate of success, 33.4%. Oncology drugs—as in most such studies—have the lowest rate of success—3.4%.

Dr. Lo’s study represents a Big Data approach to determining drug development success rates.The MIT group analyzed a large dataset of over 40,000 entries from nearly 186,000 clinical trials of over 21,000 compounds. To analyze this dataset, the researchers developed automated algorithms designed to trace each drug development path and compute probability of success (POS) statistics in a matter of hours. If generating POS estimates had been done by traditional manual methods, it would have taken months or years.

Despite the intense focus of the biopharmaceutical industry, investors, and the general public on cancer, the POS for oncology drugs has been consistently abysmal for years—as shown by our 2009 report, the 2016 BIO report, and the Lo et al. 2018 MIT study. However, according to the MIT study, although the POS for oncology drugs had the lowest overall approval rate of 3.4% in 2013, it rose to 8.3% in 2015. Both Dr. Lo’s group and John Carroll of Endpoint News attribute this sharp rise to the advent of immuno-oncology drugs.

As we discussed in our February 22, 2018 blog article, “JP Morgan 2018 (JPM18) panel optimistic for new breakthrough immuno-oncology therapies despite a crowded field”, leading researchers in academia and industry believe that because of the strong emergence of immuno-oncology therapies, now is probably the best time for progress in oncology in several decades. This is consistent with the findings of Dr. Lo’s group. However, as we stated in our previous blog article (based on the conclusions of the JPM18 panel), “This historic opportunity would be maximally capitalized if people from academia, industry, regulatory agencies, and nonprofit organizations work together, especially in adopting novel collaborative study design, aimed at bringing the promise of cancer immunotherapies to patients, sooner rather than later.”

Another issue discussed by Dr. Lo and his colleagues in their study is role of biomarkers in the success of clinical trials. The researchers compared POS estimates for trials that stratified patients using biomarkers to those that did not use biomarkers. They found that trials that utilized biomarkers tended to be more successful (by nearly a factor of 2) than those that did not. However, biomarker-stratified trials studied by the MIT group were nearly all in oncology. Therefore, it was not possible for the MIT researchers to obtain valid conclusions on the role of biomarkers for therapeutic areas outside of oncology.

Nevertheless, with the continuing development of oncology biomarkers, coupled with breakthrough R&D results in immuno-oncology, the MIT researchers expect that the rates of approval of cancer drugs will continue to improve.

Conclusions

Dr. Lo’s group intends to provide continuing information on the success rates of clinical trials, beyond this initial study. The goal is to provide greater risk transparency to drug developers, investors, policymakers, physicians, and patients, order to assist them in their decisions.

Moreover, our book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes can help you understand the role of advances in immuno-oncology in the current and expected increases in drug development success in the cancer field.

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.

On January 12, 2018, Endpoints News sponsored a breakfast panel at the 2018 JP Morgan Healthcare Conference (JPM18) in San Francisco, CA. The focus of this panel was the current state of clinical cancer immunotherapy development. The full panel is recorded as a video on YouTube. The panel is also discussed in a special Web article on Endpoint News.

The impetus for this panel was a published research report (dated 1 January 2018) by Aiman Shalabi and his colleagues at The Anna-Maria Kellen Clinical Accelerator, Cancer Research Institute (CRI), New York, NY USA. A slide presentation based on this report [including the role of the CRI in immuno-oncology (IO) innovation] is also included at the bottom the Endpoint News special article.

The panelists in the Endpoint News program (which was entitled “How many PD-1/L1 drugs do we need? Where is immunotherapy headed?”) were Jay Bradner (Novartis Institutes for BioMedical Research) Hervé Hoppenot (Incyte), Ellen Sigal ( Friends of Cancer Research), David Berman (AstraZeneca), Gideon Blumenthal (FDA Office of Hematology and Oncology Products), and Aiman Shalabi. The moderator of the panel was John Carroll, the Co-founder and Editor of Endpoints News.

The major conclusion of the published research report and of the panel discussion was that anti-PD-1/PD-L1 studies (including studies of combinations of anti-PD-1/PD-L1 therapies with other agents) will continue to deliver many breakthroughs, with the strong potential to change the standard of care for many types of cancer. However, there is an urgent need for efficiencies. Specifically, a large number of companies and academic groups are testing the same combinations, often using inefficient trial designs. In particular, there has been a great increase in the number of small, investigator-initiated studies.

The CRI team discussed some initiatives aimed at addressing these challenges. In particular, there is the need to move toward novel, collaborative trial designs that allow more questions to be answered more efficiently in a single multicenter trial. Many biotechnology and pharmaceutical companies are adopting these types of study designs. (For example, see Merck’s KEYNOTE-001 adaptive trial of pembolizumab/Keytruda, which led to accelerated approval for metastatic melanoma and NSCLC, as well as a companion diagnostic.) However, such clinical studies sponsored by a single company tend to include drugs only from their own portfolio.

The nonprofit and public sectors, however, can facilitate and conduct these innovative trials across multiple companies and research centers. There are now several examples of nonprofit organizations leading such novel study designs. One example, which was discussed in the Endpoint News panel, is the LUNG-MAP study for lung cancer. LUNG-MAP is a collaboration between Friends of Cancer Research, Foundation for NIH, National Cancer Institute, the Southwest Oncology group, and various biopharmaceutical and diagnostic companies. (Panelist Ellen Sigal of Friends of Cancer Research was especially active in discussing LUNG-MAP.) The study is now open with multiple arms at hundreds of sites.

Dr. Shalabi and his colleagues conclude that now—with the strong emergence of IO therapies—is probably the best time for progress in oncology in several decades. This historic opportunity would be maximally capitalized if people from academia, industry, regulatory agencies, and nonprofit organizations work together, especially in adopting novel collaborative study design, aimed at bringing the promise of cancer immunotherapies to patients, sooner rather than later.

Are there enough patients for IO clinical trials in 2018?

One factor that is often cited as severely limiting the ability of researchers to conduct all the clinical trials in progress and planned for IO agents and combinations is a shortage of patients. The panelists cited a number of 52,000 patients now in trials, with many more needed. However, the panelists estimated that there are 2 million patients per year that are dying of cancer. The best chance for these patients’ survival is for them to be enrolled in a clinical trial, often an IO trial. However, most cancer patients are treated in community settings, and are not even offered clinical trials—let alone the clinical trials that would be the most appropriate for each patient’s disease. From the point of view of patients, their caregivers, and of the research community, these patients need access to clinical trials.

Several panelists (notably Jay Bradner of Novartis) cited the need to move toward patient-driven IO clinical research, and to enlist the patient as a collaborator in clinical trials (for example, via conducting on-treatment tumor biopsies). In support of moving towards patient-driven IO clinical research, the CRI website includes a “Patients” page, that links to a “clinical trial finder”. In our own Biopharmconsortium Blog, the January 12, 2015 article included a section entitled “Implications for patients with terminal cancers”. That section featured links to CRI web pages on immunotherapy trials for pancreatic cancer and glioblastoma, which we used as examples of deadly cancers that have become the subject of IO clinical trials. Now—in 2018—it is even more imperative that IO trials become patient-driven.

Why so many IO combination clinical trials?

Many of the IO trials currently in progress are combination trials with a checkpoint inhibitor and a second agent. The rationale for these trials is that there is a significant unmet need in IO, since (depending on the type of cancer) some 80% of patients do not respond to checkpoint inhibitors. As we discussed at length in our 2017 book-length report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes”, and more briefly in our September 20, 2017 article on this blog, checkpoint inhibitors work by reactivating intratumoral T cells, especially CD8+ cytotoxic T cells. Checkpoint inhibitors are therefore ineffective in treating “cold” tumors (which lack T cell infiltration), and immunosuppressed tumors that inhibit infiltrating T cells. Researchers and companies are therefore attempting to develop agents that render cold or immunosuppressed tumors “hot”. When such agents are given in combination with checkpoint inhibitors, they may improve their effectiveness, thus resulting in tumor shrinkage. This type of strategy, as discussed in our report, is a major theme of “second wave” immuno-oncology, or “immuno-oncology 2.0.” Many of these agents are discussed in our 2017 report.

Many of these complementary “immunotherapy 2.0” agents are being developed by small or medium-sized biotechnology companies. (One such medium-sized company, Incyte, was represented on the JPM18 panel.) Large pharmaceutical companies that have been developing checkpoint inhibitors are thus seeking to collaborate with or acquire smaller companies that are developing “immunotherapy 2.0” agents. Interestingly, Jay Bradner of Novartis stated that he was more concerned about competition from the “500 biotechs within a 20 mile radius around Novartis Institutes for BioMedical Research (NIBR)-Cambridge” than from another Big Pharma in IO. However, in terms of conducting clinical trials, Novartis has a big advantage over small biotechs because of its global reach—it can expand a clinical trial by opening up sites in Europe. Nevertheless, NIBR-Cambridge is actively recruiting the participation of biotech companies in IO combination studies, and wishes to become the “partner of choice” for such collaborative studies.

The JPM18 panel is optimistic for the prospects of IO therapies

The JPM18 panel was very optimistic that IO clinical studies will result in breakthrough therapies that will change the practice of treatment of important types of cancer, and that such breakthroughs should start to emerge within the next two years.

This is in contrast to the pessimism of many people in the biotech/pharma industry, and in parts of the venture capital community. For example, a January 4, 2018 article in Forbes by venture capitalist Bruce Booth suggests that the crowding of the IO field is making it difficult for small biotechs to compete with the clinical and post-marketing programs of the larger companies, and that starting new IO companies is difficult. Researchers, entrepreneurs and funders would be better off focusing on areas like neuroscience, according to this article.

Nevertheless:

1. Potentially important IO deals between small and large companies are being done. For example, on February 14, 2018 Nektar Therapeutics (San Francisco, CA) and Bristol-Myers Squibb (BMS) announced that they had concluded a $3.6 billion collaboration deal for a minority share of Nektar’s early-stage T-cell modulator NKTR-214, a CD122 agonist. The collaboration will study combinations of NKTR-214 with BMS’ checkpoint inhibitors Opdivo and Yervoy, in 20 indications involving 9 types of tumors. We covered NKTR-214 in the chapter on immune agonists in our 2017 Cancer Immunotherapy report.The Opdivo/NKTR-214 combination has been evaluated in Phase 1/2 studies. Nektar and BMS now are initiating clinical trials with the potential for registration data that could start coming in in about 18 to 24 months.

2. New IO companies are being started and funded. Tmunity Therapeutics, a CAR-T based cellular immunotherapy company, was founded by Carl H. June, MD and his collaborators at Penn Medicine in January 2016. On January 23, 2018, Tmunity announced that it was raising $100 million from a group of investors including Gilead Sciences, the Parker Institute for Cancer Immunotherapy, Ping An Ventures, and Be The Match, a patient advocacy group. The company will use the funding in part to finance two clinical trials that will attempt to use genetically modified T-cells to treat solid tumors. As we discussed in our 2017 Cancer Immunotherapy report, using CAR-T and related types of T cells to treat solid tumors has proven to be more difficult than treating blood cancers. Tmumity researchers are attempting to overcome these difficulties.

Meanwhile, CAR-T company Juno Therapeutics (Summit, NJ) is being acquired by Celgene for approximately $9 billion.

3. Researchers continue to make discoveries with the potential to improve the efficacy and safety of IO therapies for increasing numbers of patients. For example, the February 2018 issue of Nature Biotechnology reported on two such discoveries: a model to determine which tumor neoepitopes (or neoantigens) are likely to result in tumor response to checkpoint inhibitor therapy, and studies on the effects of gut bacteria on patent response to IO treatments. The tumor neoepitope research was originally published in the 22 November 2017 issue of Nature . We discussed neoantigen modeling and other aspects of neoantigen science in three types of IO therapies (checkpoint inhibitor, cancer vaccine, and cellular immunotherapy) in our 2017 Cancer Immunotherapy report.

The gut bacteria/tumor IO research was originally published in the 2 November 2017 issue of Science, and was reviewed in a News article in Nature.

A third recent discovery concerns the role of TGF-beta in resistance to checkpoint inhibitor therapy. In mouse models, a TGF-beta inhibitor enables T cells to get into IO resistant tumors. Checkpoint inhibitor therapy (given together with the checkpoint inhibitor) then becomes more effective in shrinking the tumor. Several TGF-beta inhibitor/checkpoint inhibitor combinations are now in clinical studies. However, to date, TGF-beta inhibitors have been suffering from various safety and/or efficacy issues.Therefore, some researchers have suggested the need for developing improved TGF-beta pathway inhibitors for use in combination with checkpoint inhibitors.

As research on IO continues, some of these discoveries will make their way into improved therapies with increased patient benefit.

Our report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes”

Our 2017 Cancer Immunotherapy report can help you achieve a deep understanding of the IO field. This especially applies to immuno-oncology 2.0, which is the basis for IO combination trials. Our report covers the three major areas of IO R&D—checkpoint inhibitor therapy (including combination therapies), cancer vaccines, and cellular immunotherapies. Immunotherapy 2.0 strategies, agents, and companies discussed in our report may well make the news over the next several years, in terms of corporate deals and product approvals. This has already been happening, as illustrated by the BMS/Nektar collaboration discussed earlier, the emergence of strategies and clinical trials aimed at developing CAR-T therapies for solid tumors at Tmunity, and the continuing development of neoantigen science aimed at improved IO therapies. Our report is thus well worth purchasing and reading for those who are interested in the further development of IO.

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.

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.