On October 20, 2014, New Link Genetics Corporation (Ames, IA) announced that it had entered into an exclusive worldwide license agreement with Genentech/Roche for the development of NLG919, an IDO (indoleamine-pyrrole 2,3-dioxygenase) inhibitor under development by NewLink. The two companies also initiated a research collaboration for the discovery of next generation IDO/TDO (tryptophan-2,3-dioxygenase) inhibitors.

Under the terms of the agreement, NewLink will receive an upfront payment of $150 million, and may receive up to over $1 billion in milestone payments, as well as royalties on any sales of drugs developed under the agreement. Genentech will also provide research funding to NewLink in support of the collaboration. Other details of the agreement are outlined in NewLink’s October 20, 2014 press release.

The target of NewLink’s iDO/TDO program, and of its collaboration with Genentech, is cancer immunotherapy. As we discussed in our September 2014 report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies (published by Cambridge Healthtech Institute), Genentech is developing the PD-L1 inhibitor MPDL3280A, which is in Phase 2 trials in renal cell carcinoma and urothelial bladder cancer, and in Phase 1 trials in several other types of cancer. PD-L1 inhibitors such as MPDL3280A constitute an alternative means to PD-1 inhibitors of blocking The PD-1/PD-L1 immune checkpoint pathway.

Two PD-1 inhibitors, pembrolizumab (Merck’s Keytruda) and nivolumab (Medarex/Bristol-Myers Squibb’s Opdivo) are in a more advanced stage of development than MPDL3280A and other PD-L1 inhibitors. The FDA approved pembrolizumab for treatment of advanced melanoma in September 2014, and nivolumab was approved in Japan in July 2014, also for treatment of advanced melanoma.

MPDL3280A, pembrolizumab, and nivolumab are monoclonal antibody (MAb) drugs. Another MAb immune checkpoint inhibitor, ipilimumab (Medarex/BMS’s Yervoy) was approved for treatment of advanced melanoma in 2011. Ipilimumab, which was the first checkpoint inhibitor to gain regulatory approval, targets CTLA-4.

As summarized in the October 20, 2014 New Link press release, IDO pathway inhibitors constitute another class of immune checkpoint inhibitors. However, they are small-molecule drugs. The IDO pathway is active in many types of cancer both within tumor cells and within antigen presenting cells (APCs) in tumor draining lymph nodes. This pathway can suppress T-cell activation within tumors, and also promote peripheral tolerance to tumor associated antigens. Via both of these mechanisms, the IDO pathway may enable the survival, growth, invasion and metastasis of malignant cells by preventing their recognition and destruction by the immune system.

As also summarized in this press release, NewLink has several active IDO inhibitor discovery and development programs, and has also discovered novel tryptophan-2,3-dioxygenase (TDO) inhibitors. As with IDO, TDO is expressed in a significant proportion of human tumors, and also functions in immunosuppression. TDO inhibitors are thus potential anti-cancer compounds that might be used alone or in combination with IDO inhibitors.

The kynurenine pathway and its role in tumor immunity and in neurodegenerative diseases

IDO and TDO are enzymes that catalyze the first and rate-limiting step of tryptophan catabolism through the kynurenine pathway (KP). The resulting depletion of tryptophan, an essential amino acid, inhibits T-cell proliferation. Moreover, the tryptophan metabolite kynurenine can induce development of immunosuppressive regulatory T cells (Tregs), as well as causing apoptosis of effector T cells, especially Th1 cells.

A 2014 review by Joanne Lysaght Ph.D. and her colleagues on the role of metabolic pathways in tumor immunity, and the potential to target these pathways in cancer immunotherapy also highlights the role of IDO and kynurenine in upregulation of Tregs and in the phenomenon of T-cell exhaustion, in which T cells chronically exposed to antigen become inactivated or anergic.

In our cancer immunotherapy report, we discuss the role of Tregs and T-cell exhaustion in immune suppression in tumors, and the role of anti-PD-1 agents in overcoming these immune blockades. Targeting the IDO and TDO-mediated tryptophan degradation pathway may thus complement the use of anti-PD-1 (and/or anti-PD-L1) MAb drugs, and potentially lead to the development of combination therapies.

We have discussed the kynurenine pathway of tryptophan catabolism in another context in our July 11, 2011 article on this blog. This article discusses the potential role of kynurenine pathway metabolites in such neurodegenerative diseases as Alzheimer’s disease (AD) and Huntington’s disease (HD).

As discussed in that article, HD and AD patients have elevated levels of two metabolites in the KP–quinolinic acid (QUIN) and 3-hydroxykynurenine (3-HK)–in their blood and brains. Both of these metabolites have been implicated in pathophysiological processes in the brain. In contrast, kynurenic acid (KYNA), which is formed in a side arm of the KP by conversion of kynurenine by the enzyme kynurenine aminotransferase, appears to be neuroprotective.

Researchers have been targeting kynurenine 3-monooxygenase (KMO) in order to induce a more favorable ratio of KYNA to QUIN. As a result, they have discovered a drug candidate, JM6. They proposed to first conduct clinical trials in HD, since the cause of HD is much better understood than for AD, and disease progression in placebo controls is better characterized than for AD. Moreover, clinical trials in AD are notoriously long and expensive.

A 2014 review of targets for future clinical trials in HD lists JM6 as a “current priority preclinical therapeutic targets in Huntington’s disease”. It also contains an updated discussion of the mechanism of action of JM6.

NewLink’s IDO inhibitor development program

NewLink presented progress posters on its IDO inhibitor development program at the American Society for Clinical Oncology (ASCO) 2014 annual meeting. These described trials in progress, which did not yet have any results. As described in these presentations, NewLink’s most advanced IDO inhibitor, indoximod is in:

• a Phase 1/2 clinical trial in combination with ipilimumab in advanced melanoma
• a Phase 1/2 study in combination with the alkylating agent temozolomide (Merck’s Temodar) in primary malignant brain tumors
• a Phase 2 study in combination with the antimitotic agent docetaxel (Sanofi’s Taxotere) in metastatic breast cancer
• a Phase 2 study in which indoximod is given subsequent to the anticancer vaccine sipuleucel-T (Dendreon’s Provenge) in metastatic castration-resistant prostate cancer.

The company also presented a progress poster on a first-in-humans Phase 1 study of NLG919, in solid tumors. NLG919, the focus of NewLink’s alliance with Genentech, is the second product candidate from NewLink’s IDO pathway inhibitor technology platform.

The major theme of NewLink’s ASCO meeting presentations is thus the development of the company’s IDO inhibitors as elements of combination immuno-oncology therapies with MAb immune checkpoint inhibitors, cancer vaccines, and cytotoxic chemotherapies.

In this connection, NewLink also hosted a panel discussion on combination therapies entitled “Points to Consider in Future Cancer Treatment: Chemotherapy, Checkpoint Inhibitors and Novel Synergistic Combinations” at the ASCO meeting. The collaboration of NewLink with Genentech will provide the opportunity for the two companies to test combinations of IDO inhibitors with Genentech’s PD-L1 inhibitor MPDL3280A.

Might targeting T-cell metabolism be used to enhance cancer immunotherapy?

In their 2014 review, Dr. Lysaght and her colleagues outline changes in metabolism as T-cells become activated, and differences in metabolism between various T-cell subsets (e.g., effector T cells, Tregs, exhausted or anergic T cells, and memory T cells). These researchers propose devising means to modulate T-cell metabolism in order to enhance anti-tumor immunity. However more research needs to be done in order to make such approaches a reality. In the meantime, development of IDO and TDO inhibitors is already in the clinic, providing the possibility of a metabolic approach to cancer immunotherapy.

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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 an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

As we said in our September 10, 2014 article, we intended to post updates on companies that we had been following on our blog, and that have achieved significant progress in recent months. So far, we have covered Agios and Zafgen. Both of these companies were featured in Boston-area meetings in October—Zafgen in Xconomy Xchange: Boston’s Life Science Disruptors on October 8, and Agios in the New Approaches to Cancer Drug Discovery symposium at Harvard Medical School on October 14.

Now we turn to the small-molecule cystic fibrosis (CF) therapeutics program at Vertex Pharmaceuticals (Boston, MA).

We covered Vertex’ CF program in our articles of January 24, 2013 and February 15, 2013. As a result of the publication of these articles, I was interviewed for and quoted in an article in the March 11, 2013 issue of Elsevier Business Intelligence’s The Pink Sheet entitled “Cystic Fibrosis Market Snapshot: Disease-Modifying Drugs Elusive 24 Years After Discovery Of Root Cause”. (A subscription is required to view the full text of this article.)

To summarize our discussions of CF in these earlier articles, CF causes a suite of symptoms that affect the skin, the lungs and sinuses, and the digestive, endocrine, and reproductive systems. The most important results of CF is that patients accumulate thick, sticky mucus in the lungs. This results in clogging of the airways with mucus. This leads to inflammation and bacterial infections. Lung transplantation is often necessary as the disease worsens. With proper management, patients can live into their late 30s or 40s.

The gene that is affected in cystic fibrosis encodes the cystic fibrosis transmembrane conductance regulator (CFTR).  CFTR is an ion channel that regulates the movement of chloride and sodium ions across epithelial membranes, including the epithelia of lung alveoli. CF is an autosomal recessive disease, which is most common in Caucasians. The most common mutation that causes CF, ΔF508, is a deletion of three nucleotides that causes the loss of the amino acid phenylalanine at position 508 of the CFTR protein. The ΔF508 mutation accounts for approximately two-thirds of CF cases worldwide and 90% of cases in the United States. However, there are over 1500 other mutations that can cause CF.

Ion channels constitute an important class of drug targets, which are targeted by numerous currently marketed drugs. These compounds were developed empirically by traditional pharmacology before knowing anything about the molecular nature of their targets. However, discovery of novel ion channel modulators via modern molecular methods has proven to be challenging.

The ΔF508 mutation results in defective cellular processing, and the mutant CTFR protein is retained in the endoplasmic reticulum. Some other mutations in CTFR (which affect a small percentage of CF patients) result in mutant proteins that reach the cell membrane, but are ineffective in chloride-channel function.

After a long discovery and development program (which we outlined in our February 15, 2013 article), Vertex identified two types of candidate small-molecule CF therapeutics:

• CFTR potentiators, which potentiate the chloride channel activity of mutant CFTR molecules at the cell surface;
• CFTR correctors, which partially correct the folding and/or trafficking defect of such mutant CFTRs as ΔF508, thus enabling a portion of these mutant proteins to exit from the endoplasmic reticulum and to deposit in the cell membrane.

Vertex’ CTFR potentiator ivacaftor (Kalydeco, formerly known as VX-770) was approved by the FDA in January 2012, and approved in Europe in July 2012. At that time, ivacaftor was only indicated for treatment of CF patients age 6 and over carrying the CFTR G551D mutation (Gly551Asp). Although the G551D mutation only affects approximately 4% of CF patients, it is the most common CFTR gating mutation (i.e., a mutation that affects transport of sodium and chloride ions across epithelial membranes).

New indications for ivacaftor (Kalydeco)

On July 31, 2014, Vertex announced that the European Commission had approved ivacaftor for treatment of CF patients age 6 and over who have one of eight non-G551D gating mutations in the CFTR gene. The eight additional gating mutations included in the new approval affect approximately 250 people ages 6 and older in the European Union.

The approval was based on data from a Phase 3 randomized, double-blind, placebo-controlled study of 39 people with CF ages 6 and older who have a non-G551D gating mutation.

The European approval followed the February 21, 2014 announcement that the FDA had approved ivacaftor for treatment of CF patients 6 and older who have one of the same additional eight mutations in the CFTR gene. In the U.S., approximately 150 people ages 6 and older have one of the additional eight mutations.

On October 21, 2014, the FDA’s Pulmonary Allergy Drugs Advisory Committee (PADAC) voted 13-2 to recommend approval of ivacaftor in CF patients age 6 and older who have the R117H mutation in the CTFR gene. This new indication is now under review by the FDA.

Thus Vertex has been pursuing a strategy of testing and seeking approval of ivacaftor for treatment of CF patients with gating mutations in the CTFR gene other than the G551D mutation, in a systematic, step-by-step fashion. As a result of this strategy, ivacaftor is currently approved to treat over 2,600 people ages 6 and older in North America, Europe and Australia.

Vertex’ development of the CFTR correctors lumacaftor (VX-809) and VX-661

Meanwhile, Vertex has also been pursuing approval for its CFTR correctors lumacaftor (VX-809) and VX-661. We have discussed these agents in our February 15, 2013 blog article.

As we discussed in that article, as of February 2013 Vertex had completed Phase 2 studies of a combination of ivacaftor and lumacaftor in CF patients who were homozygous for the CFTR ΔF508 mutation. They then planned pivotal phase 3 trials of the combination therapy in this patient population. The rationale for the combination treatment was that VX-809 potentates the deposition of CFTR ΔF508 in the cell membrane, and invacaftor potentiates the function of cell-surface CFTR ΔF508.

As of February 2013, Vertex was also conducting Phase 2 trials of another CTFR corrector, VX-661, alone and in combination with ivacaftor in CF patients homozygous for CFTR ΔF508.

On June 24, 2014, Vertex announced that results from two Phase 3 studies of lumacaftor in combination with ivacaftor showed statistically significant improvements in lung function in people ages 12 and older with cystic fibrosis (CF) who were homozygous for CFTR ΔF508. All four 24-week combination treatment arms in the studies, known as TRAFFIC and TRANSPORT, met their primary endpoint of mean absolute improvement in lung function from baseline compared to placebo at the end of treatment. The combination treatments were also generally well tolerated.

Data from a pre-specified pooled analysis also showed improvements in multiple key secondary endpoints, including lowering pulmonary exacerbations.

On October 9, 2014, Vertex announced updates of the results of the TRAFFIC and TRANSPORT studies, in conjunction with the company’ presentations at the 28th Annual North American Cystic Fibrosis Conference (NACFC). Patients who completed 24 weeks of treatment in TRAFFIC or TRANSPORT were eligible to enter a Phase 3 rollover study to receive a combination regimen of lumacaftor and ivacaftor. The first interim data from the rollover study (presented at NACFC) showed that the improvements in lung function observed in the 24-week TRAFFIC and TRANSPORT studies were sustained through 48 weeks of treatment with the combination treatment. At the time of the interim analysis, safety and tolerability results were also consistent with those observed in the initial Phase 3 TRAFFIC and TRANSPORT studies.

In the October 9, 2014 press release, Vertex also announced the submission of an NDA in the U.S. and an MAA in Europe for the approval of ivacaftor in children with CF ages 2 to 5 with one of the same 9 CTFR gene mutations for which the drug is approved in patients 6 or older. These line extension submissions are based on further Phase 3 studies, which were also presented at the NACFC.

On November 5, 2014, the company announced that it had submitted an NDA to the FDA and an MAA to the European Medicines Agency (EMA) for a fully co-formulated combination of lumacaftor and ivacaftor for CF patients age 12 and older who are homozygous for CFTR ΔF508. There are approximately 22,000 people with CF ages 12 and older who are homozygous for CFTR ΔF508 in North America, Europe and Australia. This includes approximately 8,500 people in the United States and 12,000 people in Europe. These new submissions are based on data from TRAFFIC and TRANSPORT, and on the first interim data from the subsequent rollover study.

Meanwhile, as also announced on October 9, 2014, clinical studies of VX-661 are continuing. Vertex presented data from Phase 2 studies of VX-661 in combination with ivacaftor at the 2014 NACFC. In the October 9 press release, Vertex announced that it plans to initiate a pivotal Phase 3 development program for VX-661 in combination with ivacaftor in CF patients who have one or two copies of the CFTR ΔF508 mutation, including patients with a second CFTR mutation that causes a defect in the gating of the CFTR protein. The initiation of this study is pending regulatory discussions and data from a fully enrolled 12-week Phase 2b study of VX-661 in combination with ivacaftor in patients who are homozygous for CFTR ΔF508.

The high cost of Kalydeco causes controversy

Kalydeco (ivacaftor) costs nearly $300,000 a year. These costs are usually borne by insurers and governments, and Vertex has pledged to provide the drug free to any U.S. patient who is uninsured or whose insurance won’t cover it.

However, the high cost of this drug—and the anticipated higher cost of combination therapies for treatment of CF—has generated controversy in some circles. This issue has been discussed, for example, in 2013 articles in the M.I.T. Technology Review and in MedPage Today. (MedPage Today is a peer-reviewed online medical news service for clinicians, which provides breaking medical news, professional medical analysis and continuing medical education (CME) credits to its physician readers.)

According to the Technology Review article, by Barry Werth, doctors and patients enthusiastically welcomed Kalydeco because it offers life-saving health benefits and there is no other treatment. Insurers and governments readily paid the cost. However, commentators quoted in the MedPage Today article said that the price of Kalydeco is exorbitant, and the increasing numbers of high-priced life-saving drugs to treat rare diseases (although nor usually borne directly by patients themselves) is unsustainable. Vertex—as quoted in the MedPage Today article—said that the price of Kalydeco reflects its high degree of efficacy, the time and cost [and risk] it took to develop the drug, and the company’s commitment to reinvest in continued development of newer drugs to help other CF patients.

The discussions of the high cost of Kalydeco echoes the discussions of the cost of novel drugs for life-threatening cancers, as mentioned in our October 2, 2014 article, “Late-breaking cancer immunotherapy news”, on this blog.

With respect to the development of Kalydeco and other small-molecule CF drugs, the publicly-funded—and successful—research to determine the molecular cause of CF was of little help in enabling researchers to develop disease-modifying drugs. (See our January 24, 2013 blog article, “Determining the molecular cause of a disease does not necessarily enable researchers to develop disease-modifying drugs”.) As outlined in our February 15, 2013 blog article, Vertex’ own drug discovery and development program (partially funded by the nonprofit Cystic Fibrosis Foundation, which now receives royalties on sales of Kalydeco) was long (beginning in 1998), expensive, risky, and involved considerable ingenuity.

Given the high barrier between the knowledge of the molecular biology of CF and its use in discovering and developing safe and efficacious small-molecule drugs, the development of such agents as ivacaftor, lumacaftor, and VX-661 is almost miraculous. Vertex’ arguments that justify the high cost of the drug thus have considerable merit. However, discussions in the medical community and beyond on how the costs of novel life-saving drugs for rare diseases and cancer may be sustained will and should continue.

Conclusions

The goal of Vertex’ CF program as a whole is the development, approval and marketing of multiple combinations of small-molecule therapeutics that will have disease-modifying efficacy in the great majority of CF patients. Especially with the recent progress with clinical studies of the ivacaftor/lumacaftor combination in patients with CFTR ΔF508 mutations, and with line extensions of ivacaftor, Vertex appears to be well on its way to accomplishing this, pending regulatory approvals.

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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 an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

In our September 16, 2014 article on this blog, we announced the publication by Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports of a new book-length report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, by Allan B. Haberman, Ph.D.

As we said in that blog article, “cancer immunotherapy is a ‘hot’, fast-moving field”. Thus—inevitably—in the short time since the publication of our report, a great deal of late-breaking news has come in.

This article is a discussion of several key late-breaking news items, which were not published in the report.

Pricing of checkpoint inhibitor agents

As discussed in the report, two PD-1 inhibitors have been recently approved. Bristol-Myers Squibb (BMS)/Ono’s nivolumab was approved in Japan (where it is know by the brand name Opdivo) in July 2014 for treatment of unresectable melanoma. Pembrolizumab (Merck’s Keytruda) was approved in the U.S. for treatment of advanced melanoma on September 5, 2014. The very first checkpoint inhibitor to reach the market, the CTLA-4 inhibitor ipilimumab (Medarex/BMS’s Yervoy), was approved in the U.S. in 2011.

At the same time as the news of the approval of the PD-1 inhibitors nivolumab and pembrolizumab came out, information on the pricing of these agents also became available. However, because of the need to complete the report for publication, there was no time to discuss the issue of pricing adequately.

As discussed in a September 4, 2014 article in FiercePharma, the cost of nivolumab in Japan (according to the Wall Street Journal) is $143,000. According to the FierceBiotech article, this was greater than the introductory price for any other cancer drug, especially in Japan, where prices tend to be somewhat lower than in the U.S.

Meanwhile, as reported in a September 4, 2014 article in FierceBiotech, the cost of pembrolizumab in the U.S. will be $12,500 a month, or $150,000 a year.

For comparison, the launch price of BMS’ ipilimumab was $120,000. As we discussed in the report, the PD-1 inhibitors nivolumab and pembrolizumab—as seen in early clinical trials—appear to be more efficacious and have fewer adverse effects in treatment of melanoma.

As discussed in our report, checkpoint inhibitors such as ipilimumab, nivolumab and pembrolizumab are eventually likely to be used in combination with other drugs, including other immuno-oncology drugs, targeted therapies, and others. The price per month or per year of these potentially life-saving and at least in some cases curative combination therapies may thus be expected to go still higher. However, if cancers are pushed into long-term remission or even cure, then it might be possible to discontinue treatment with these expensive drug combinations. In such cases, the cost of treatment may even be less than current therapeutic regimens.

There are no analyses of the costs of specific immunotherapy drugs or cellular therapies in our report. However, we do discuss the issue of drug costs in the survey and interviews that are part of the report.

The issue of the costs of expensive drugs for life-threatening cancers is under discussion in the cancer community. For example, the American Society of Clinical Oncology (ASCO) has initiated an effort to rate oncology drugs not only on their efficacy and adverse effects, but also on their prices. ASCO’s concern is that pricing be related to the therapeutic value of drugs. And commentators such as Peter Bach, MD, MAPP (the Director of the Memorial Sloan Kettering Cancer Center’s Center for Health Policy and Outcomes) have been weighing in with their analyses. As additional immunotherapy drugs and cellular therapies reach the market, these discussions will certainly continue.

The Bristol-Myers Squibb-Merck lawsuit over PD-1 inhibitors

Another late-breaking news item that came out at the time of the publication of our report is the lawsuit between BMS and Merck over PD-1 inhibitors. Specifically, as soon as Merck gained FDA approval for pembrolizumab, BMS and its Japanese partner Ono sued Merck for patent infringement.

The patent in question is U.S. patent number 8,728,474. It was filed on December 2, 2010, granted to Ono on May 20, 2014, and licensed to BMS. The patent covers the use of anti-PD-1 antibodies to treat cancer. According to BMS and Ono’s claims, Merck started developing pembrolizumab after BMS and Ono had already filed their patent and were putting it into practice by developing their own PD-1 inhibitor, nivolumab.

The lawsuit asks for damages, and for a ruling that Merck is infringing the BMS/Ono PD-1 patent. Such a ruling may mean that BMS and Ono are owed royalties on sales of all rival PD-1 drugs, not just Merck’s. BMS/Ono and Merck are involved in parallel litigation in Europe.

Merck acknowledges Ono’s method patent, but says that it is invalid. Merck also said the lawsuit will not interfere with the U.S. launch of pembrolizumab.

We shall have to watch the proceedings in the U.S. District Court for the District of Delaware to see the outcome of this case. Although this lawsuit was not discussed in our report, the report does include a discussion of the fierce race between PD-1 inhibitor developers Merck and BMS to be the first to market, and to gain the largest market share. The lawsuit is clearly one element in this race.

Merck Serono discontinues development of the cancer vaccine tecemotide

On September 18, 2014, Merck KGaA (Darmstadt, Germany; also known as Merck Serono and EMD Serono) announced that it has discontinued development of the cancer vaccine tecemotide. Tecemotide is a peptide vaccine that was formerly known as Stimuvax. It was originally developed by Oncothyreon (Seattle, WA) and licensed to Merck Serono in 2007.

We covered tecemotide in our report, both as an example of a cancer vaccine that had failed in Phase 3 clinical trials, and as an example of a vaccine that was nevertheless still under development. As discussed in our report, in a Phase 3 trial known as START in non-small cell lung cancer (NSCLC) patients, researchers found no significant difference in overall survival between administration of tecemotide or placebo. However, a subsequent analysis suggested that there was a statistically significant survival advantage for tecemotide compared with placebo in a pre-defined subset of patients. Based on these results, Merck Serono began a second Phase 3 trial in that subset.

However, as the result of a failure in a Phase 3 trial in Japan sponsored by Oncothyreon (reported on August 19, 2014), Merck Serono decided to discontinue development.

As stated by Merck Serono’s Executive Vice President and Global Head of R&D Luciano Rossetti, “While the data from the exploratory subgroup analysis in the START trial generated a reasonable hypothesis to warrant additional study, the results of the recent trial in Japanese patients decreased the probability of current studies to reach their goals.”

As we discussed in our report, the cancer vaccine field has been rife with clinical failures—from its beginnings in the 1990s to the present day. This has especially included late-stage failures, not only that of Merck Serono’s tecemotide, but also, for example, GlaxoSmithKline’s (GSKs) MAGE-A3 vaccine. Only one anticancer vaccine—sipuleucel-T (Dendreon’s Provenge) for treatment of metastatic castration-resistant prostate cancer—has ever reached the market, and its therapeutic effects appear to be minimal.

Despite these poor results, researchers and companies persist in their efforts to develop cancer vaccines. Our report discusses why cancer vaccine R&D continues despite the overwhelming history of failure, the hypothesized reasons for these failures, and what researchers and companies can do and are doing to attempt to obtain better results.

Conclusions

As a fast-moving, important field, cancer immunotherapy will continue to generate scientific, medical, and market news. There will continue to be periodic meetings, such as the 2014 European Society for Medical Oncology (EMSO) meeting (September 26-30, Madrid, Spain), in which positive results of small, early-stage trials of several checkpoint inhibitors were presented. Our report—an in-depth discussion of cancer immunotherapy—can enable you to understand such future developments, as well as current ones. It is also designed to inform the decisions of leaders in companies and in academia that are involved in cancer R&D and treatment.

For more information on Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, or to order it, see the Insight Pharma Reports website.

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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.

The Biopharmconsortium Blog has over the years included numerous articles about obesity, and the attempts of researchers and companies to develop treatments for this disease.

Obesity, which has historically been considered the result of “lack of willpower” or other behavioral issues, was recognized as a disease by the American Medical Association in June 2013. This followed many years of genetic, molecular biology, and physiological studies that revealed the pathobiological basis of obesity. Nevertheless, many people—including many doctors, patients, and nutritionists—persist in the believing the older view of obesity. This continues to fuel an extremely lucrative diet industry, even thought most—if not all—attempts at dieting eventually fail.

However, researchers and companies have continued in their efforts to develop approved therapies for obesity. We have followed the results of companies that had come close to obtaining FDA approval for three central nervous system (CNS)-acting antiobesity agents in 2010—only to encounter opposition due to safety concerns. However, two of their agents were approved in 2012. Now the third one was approved in September 2014.

Orexigen/Takeda’s Contrave approved by the FDA

On September 11, 2014, Orexigen Therapeutics (La Jolla, CA) and its partner, Takeda, announced that the FDA had approved their antiobesity agent, Contrave (naltrexone HCI and bupropion HCI) extended-release tablets as an adjunct to diet and exercise for chronic weight management in obese adults [body mass index (BMI) of 30 kg/m2 or greater], and in overweight adults (BMI of 27 kg/m2 or greater) who have at least one weight-related comorbid condition (e.g, high cholesterol, Type 2 diabetes, or hypertension).

However, the FDA requires Contrave’s label to carry a boxed warning of increased risk of suicidal thoughts and other psychiatric issues. The label also warns that “The effect of Contrave on cardiovascular morbidity and mortality has not been established.” Orexigen is also required to conduct several post-marketing studies, including studies in pediatric patients, and assessment of the effects of long-term treatment with Contrave on the incidence of major adverse cardiovascular (CV) events in overweight and obese subjects with CV disease or multiple CV risk factors.

The September 2014 approval of Contrave followed the February 2011 issuance by the FDA of a Complete Response Letter requiring extensive clinical studies before Contrave could be approved. In 2010 the FDA had also rejected the applications of two other preregistration antiobesity drugs—Vivus’ Qnexa and Arena Therapeutics’ lorcaserin (Lorqess). Also in 2010, the then-marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request.

Concern about long-term safety was the major consideration in all of these cases.

Nevertheless, lorcaserin (rebranded as Belviq) was approved in June 2012, and Qsymia (formerly known as Qnexa) was approved in July 2012.

Thus there are now three CNS-targeting weight-loss drugs on the U.S. market—all of which are “adjuncts to diet and exercise”, all of which work by suppressing appetite, and all of which have safety concerns that require post-marketing studies. Moreover, at least two of these drugs have levels of efficacy less than might be desired. For example, in one trial of Contrave, significant weight loss — defined as the loss of at least 5% of body weight — was achieved by 42% of Contrave-treated subjects, and 17% of subjects in the placebo group. The FDA says that patients taking Contrave should be evaluated after 12 weeks of treatment. Those who have failed to lose at least 5% of their body weight should discontinue Contrave.

Lorcaserin is the least efficacious of these drugs. Qsymia is the most efficacious, with 66.7% of patients on high-dose Qsymia losing at least 5% of body weight, as compared to 17.3% for placebo. The average weight loss in that trial was 10.9% of body weight with high-dose Qsymia and 1.2% with placebo.

A drop in weight of as little as 5% can have positive effects on risk of obesity’s comorbidities (e.g., insulin resistance, diabetes, high blood pressure, dyslipidemia, cardiovascular disease). Nevertheless, all three of these drugs are aids in management of obesity, rather than effective treatments. Moreover, their potential adverse effects are significant. It must be remembered that it was adverse effects that resulted in the withdrawal from the market of several antiobesity drugs (including sibutramine), and prevented the approval of any obesity drugs at all in 2010.

The FDA’s approval of these three drugs indicates that the agency is more willing to make antiobesity drugs available to patients than it has been previously, even in the face of continuing concerns about long-term safety. Rather than rejecting these drugs, the FDA is handling its concerns about safety via post-marketing studies, and restricted distribution of the drugs.

Liraglutide for treatment of obesity?

Meanwhile, Novo Nordisk is awaiting the FDA’s decision on the approval of its high-dose formulation of liraglutide (Saxenda) for treatment of obesity. An FDA advisory board recommended approval of the agent on September 11, 2014. The drug has an October 20 PDUFA date. The advisory board vote was based on Phase 3 results, which indicated that liraglutide produced an average 8% weight loss in obese subjects, when combined with diet and exercise. 69% of prediabetic obese individuals who were treated with liraglutide also showed no signs of prediabetes after 56 weeks, as compared to 33% for the placebo group.

We have discussed the potential use of liraglutide in treatment of obesity on this blog. A lower-dose formulation of this agent, under the trade name of Victoza, is already approved for treatment of type 2 diabetes. Liraglutide is a recombinant protein drug. It is a member of a class of drugs called incretin mimetics. An incretin is a gastrointestinal hormone that triggers an increase in insulin secretion by the pancreas, and also reduces gastric emptying. The latter effect slows nutrient release into the bloodstream and appears to increase satiety and thus reduce food intake. The major physiological incretin is glucagon-like peptide 1 (GLP-1), and incretin-mimetic drugs are peptides with homology to GLP-1 that have a longer half-life in the bloodstream than does GLP-1.

Although liraglutide does not act in the CNS, its major mechanisms of action in treatment of obesity appears to be—like CNS drugs—appetite control. Moreover, clinical trial results indicate that liraglutide is more of an aid in management of obesity than an effective treatment. Nevertheless, liraglutide’s antidiabetic effects and lack of CNS adverse effects constitute potential advantages over CNS-acting antiobesity drugs.

Sales of approved antiobesity drugs have been struggling

Despite the excitement over the approval of antiobesity drugs after so many roadblocks, sales of these drugs have fallen short of estimates. Estimates for Qsymia sales have fallen to $141 million in 2016 from the $1.2 billion projection for 2016 when the drug was approved in 2012. Eisai estimates that Belviq will generate $118 million in sales. Producers and marketers of these two drugs hope that the approval of Contrave will drive patient acceptance of all three CNS-targeting antiobesity drugs. At least one analyst projects that Contrave may achieve $740 million in sales in 2018.

If it is approved, Saxenda may have a sales advantage over the CNS-targeting drugs, since the low-dose formulation, Victoza for type 2 diabetes, is an established drug, with relationships with doctors and insurers already in place. Analysts project that liraglutide (branded as Saxenda) will generate $556 million in weight-loss sales in 2018, in addition to $3.2 billion for the antidiabetic low-dose formulation, Victoza.

A big factor in the level of sales of antiobesity drugs has been insurance reimbursement. It is estimated that some 50 percent of people with private insurance receive at least some coverage for diet drugs. However, insurers tend to classify Qsymia and Belviq as third-tier medications, requiring large patient co-payments. Moreover, Medicare and Medicaid do not pay for the drugs. Analysts hope that the approval of Contrave will result in expanded insurer coverage.

Obesity specialist company Zafgen continues to make progress

The vast majority of efforts to develop antiobesity drugs—over several decades—have been aimed at targeting the CNS. However, obesity is a complex metabolic disease that involves communication between numerous organs and tissues, notably adipose tissue (white, brown, and beige fat), skeletal muscle, the liver, the pancreas, the brain (especially the hypothalamus), the digestive system, and the endocrine system. The pathophysiology of obesity is also related to that of other major metabolic diseases, especially type 2 diabetes.

The mechanistic basis of obesity is not well understood, even though breakthroughs in understanding aspects of this disease have occurred in recent years. Thus there is great need for continuing basic research, and for novel programs aimed at development of breakthrough treatments for obesity based on non-CNS pathways.

One company that has been active in this area is Zafgen (Cambridge, MA), which we have been following on this blog. On June 24, 2014, Zafgen announced the closing of its Initial Public Offering. Zafgen is thus a young company pursuing an alternative approach to antiobesity drug discovery and development that has been able to go public.

In our May 23, 2012 article on this blog, we discussed Zafgen’s lead drug candidate, beloranib (ZGN-433). Beloranib is a methionine aminopeptidase 2 (MetAP2) inhibitor, which exerts an antiobesity effect by downregulating signal transduction pathways in the liver that are involved in the biosynthesis of fat. Animals or humans treated with beloranib oxidize fat to form ketone bodies, which can be used as energy or are excreted from the body. The result is breakdown of fat cells and weight loss. Obese individuals do not usually have the ability to form ketone bodies.

On June 22, 2013, Zafgen announced the interim results of an ongoing double blind placebo-controlled Phase 2 study of beloranib in a group of obese men and women. These results were presented in a poster session at the American Diabetes Association’s 73rd Scientific Sessions in Chicago on June 23, 2013.

Subjects had a mean age of 40.3 years, a mean weight of 101.2 kg (223.1 lbs.), and a mean BMI of 37.9 kg/m2 at the beginning of the study. 38 subjects receiving 12 weeks of treatment in the full trial were randomized to one of three doses of subcutaneous beloranib vs. placebo. The subjects were counseled not to change their usual diet and exercise patterns—this protocol thus differed from trials of the agents discussed earlier in this article. The interim analysis was of results from the first 19 subjects who completed 12 weeks of treatment.

Beloranib appeared safe and showed dose responsive weight loss. After 12 weeks, subjects on 0.6 mg, 1.2 mg, or 2.4 mg of beloranib lost an average of 3.8, 6.1 and 9.9 kg, respectively (8.4, 13.4, and 21.8 lbs.), versus 1.8 kg (4.0 lbs.) for placebo; these results were statistically significant. In addition, beloranib treated subjects showed improvements versus placebo in CV risk factors including levels of triglycerides, LDL cholesterol and C-reactive protein. Sensation of hunger also was reduced significantly.

Subcutaneous beloranib treatment over 12 weeks was generally well-tolerated. There were no major adverse events or deaths.

If later clinical trials confirm these interim Phase 2 clinical results, beloranib may have significant advantages over the three approved CNS-targeting drugs and over Saxenda, because of beloranib’s apparent benign adverse-effect profile, and major effects on weight and fat loss, even in the absence of diet and exercise advice. However, beloranib is years away from reaching the market for treatment of severe obesity with no known genetic causation.

Zafgen is attempting to develop beloranib not only as a superior alternative to “diet drugs”, but also as an alternative to bariatric surgery. In order to obtain approval for that indication, beloranib must (in late-stage, long-term clinical trials) demonstrate both the degree of weight loss and the positive metabolic effects seen in severely obese patients treated via bariatric surgery.

In addition to developing beloranib for severe obesity, Zafgen is developing this drug for treatment of the rare genetic disease Prader-Willi syndrome (PWS). Patients with PWS exhibit such symptoms as low muscle mass, short stature, incomplete sexual development, cognitive disabilities, and a chronic feeling of hunger that can result in life-threatening obesity. PWS is the most common genetic cause of life-threatening obesity. Many children with PWS become morbidly obese before age 5.

In January 2013, the FDA granted Zafgen orphan designation to treat PWS with beloranib. On July 10, 2014, the European Commission also granted orphan drug designation for beloranib for this indication. These regulatory actions were based on the initial results of Zafgen’s Phase 2a clinical trial of beloranib in PWS. This trial showed improvements in hunger-related behaviors and body composition, including reductions in body fat and preservation of lean body mass.

On October 1, 2014, Zafgen announced that it had begun a randomized, double-blind, placebo-controlled Phase 3 clinical trial of beloranib in obese adolescents and adults with PWS (clinical trial number NCT02179151). The company is also testing beloranib in Phase 2 trials in obesity due to hypothalamic injury, and is in preclinical studies with a second-generation MetAP2 inhibitor for treatment of general obesity.

Energesis Pharmaceuticals

The Biopharmconsortium Blog has also been following an earlier-stage company, Energesis Pharmaceuticals (Cambridge, MA), whose approach to developing antiobesity therapeutics is based on targeting brown fat. On June 19, 2014, FierceBiotech and Energesis announced that Janssen Pharmaceuticals and Johnson & Johnson Innovation had entered into a collaboration with Energesis, aimed at identifying agents that stimulate the formation of new brown fat in order to treat metabolic diseases.

Conclusions

The antiobesity drug field, which in 2010 was the domain of a “pall of gloom”, is now populated by three approved CNS-targeting drugs, perhaps to be soon joined by Saxenda. These drugs promise to give patients and physicians a new set of tools to aid in the management of obesity. However, the history of the CNS-targeting obesity drug field is littered with tales of the withdrawal of drug after drug due to unacceptable adverse effects. Moreover, the market—and especially payers—have not yet fully accepted the new antiobesity agents.

As readers of this blog well know, we favor approaches to treatment of obesity and its comorbidities based on targeting somatic physiological pathways that appear to be at the heart of the causation of obesity, not just the CNS. The progress of Zafgen in addressing a set of these pathways is very encouraging. However, these results must be confirmed by Phase 3 clinical trials.

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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.

On September 9, 2014, Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports announced the publication of a new book-length report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, by Allan B. Haberman, Ph.D.

As attested by the torrent of recent news, cancer immunotherapy is a “hot”, fast-moving field. For example:

• On September 5, 2014, the FDA granted accelerated approval to the PD-1 inhibitor pembrolizumab (Merck’s Keytruda, also known as MK-3475) for treatment of advanced melanoma. This approval was granted nearly two months ahead of the agency’s own deadline. Pembrolizumab is the first PD-1 inhibitor to reach the U.S. market.

• On July 4, 2014, Bristol-Myers Squibb’s rival PD-1 inhibitor nivolumab was approved for treatment of advanced melanoma in Japan, where it will be marketed as Opdivo by Ono Pharmaceuticals. Nivolumab is the first PD-1 inhibitor to reach the Asian market.

• On May 8, 2014, the New York Times published an article about a woman in her 40’s who was treated with adoptive immunotherapy with autologous T cells to treat her cancer, metastatic cholangiocarcinoma (bile-duct cancer). This deadly cancer typically kills the patient in a matter of months. However, as a result of this treatment, the patient lived for over 2 years, with good quality of life, and is still alive today.

These and other recent news articles and scientific publications attest to the rapid progress of cancer immunotherapy, a field that only a few years ago was considered to be impracticable.

Our report focuses on the three principal types of therapeutics that have become the major focuses of research and development in immuno-oncology in recent years:

• Checkpoint inhibitors
• Therapeutic anticancer vaccines
• Adoptive cellular immunotherapy

The discussions of these three types of therapeutics are coupled with an in-depth introduction and history as well as data for market outlook.

Also featured in this report are exclusive interviews with the following leaders in cancer immunotherapy:

• Adil Daud, MD, Clinical Professor, Department of Medicine (Hematology/Oncology), University of California at San Francisco (UCSF); Director, Melanoma Clinical Research, UCSF Helen Diller Family Comprehensive Cancer Center.

• Matthew Lehman, Chief Executive Officer, Prima BioMed (a therapeutic cancer vaccine company with headquarters in Sydney, Australia).

• Marcela Maus, MD, PhD, Director of Translational Medicine and Early Clinical Development, Translational Research Program, Abramson Cancer Center, University of Pennsylvania in Philadelphia.

The report also includes the results and an analysis of a survey of individuals working in immuno-oncology R&D, conducted by Insight Pharma Reports in conjunction with this report. The survey focuses on market outlook, and portrays industry opinions and perspectives.

Our report is an in-depth discussion of cancer immunotherapy, an important new modality of cancer treatment that may be used to treat as many as 60% of cases of advanced cancer by the late 2010s/early 2020s. It includes updated information from the 2014 ASCO (American Society of Clinical Oncology) and AACR (American Association for Cancer Research) meetings. The report is designed to enable you to understand current and future developments in immuno-oncology. 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 Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, or to order it, see the Insight Pharma Reports website.

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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.