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.

Not so long ago, the once-promising field of RNA interference (RNAi)-based drugs was on the downswing. This was documented in our August 22, 2011 article on this blog, entitled “The Big Pharma Retreat From RNAi Therapeutics Continues”. That article discussed the retreat from RNAi drugs by such Big Pharma companies as Merck, Roche, and Pfizer. In our March 30, 2012 blog article, we also mentioned leading RNAi company Alnylam’s (Cambridge, MA) January 20, 2012 downsizing. This restructuring was made necessary by Alnylam’s inability to continue capturing major Big Phama licensing and R&D deals, as it had once done.

As we discussed in our August 22, 2011 article, the therapeutic RNAi (and microRNA) field represented an early-stage area of science and technology, which may well be technologically premature. This level of scientific prematurity was comparable to that of the monoclonal antibody (MAb) drug field in the 1980s. Big Pharmas did not have the patience to continue with the RNAi drug programs that they started.

In that article, we cited an editorial by oligonucleotide therapeutics leader Arthur Krieg, M.D. This editorial discussed the issues of therapeutic RNAi’s scientific prematurity, but predicted a rapid upswing of the field once the main bottleneck–oligonucleotide drug delivery–had been validated.

The January 2014 Alnylam-Genzyme/Sanofi deal

Now–as of January 2014–there is much evidence that the therapeutic RNAi field is indeed coming back. This is especially true for Alnylam. On January 13, 2014, it was announced that Genzyme (since 2011 the rare disease unit of Sanofi) invested $700 million in Alnylam’s stock. Alnylam called this deal “transformational” for both Alnylam and the RNAi therapeutics field.

Genzyme had previously been a partner in developing Alnylam’s lead product patisiran (ALN-TTR02) for the treatment of transthyretin-mediated amyloidosis (ATTR). [ATTR is a rare inherited, debilitating, and often fatal disease caused by mutations in the transthyretin (TTR) gene.] Under the new agreement, Genzyme will gain marketing rights to patisiran everywhere except North America and Western Europe upon its successful completion of clinical trials and approval by regulatory agencies. Genzyme will also codevelop ALN-TTRsc, a subcutaneously-delivered formulation of patisiran. Intravenously-delivered patisiran is now in Phase 3 trials for a form of ATTR known as familial amyloidotic polyneuropathy (FAP), and ALN-TTRsc is in Phase 2 trials for a form of ATTR known as familial amyloidotic cardiomyopathy (FAC).

The Alnylam/Genzyme deal will also cover any drugs in Alnylam’s pipeline that achieve proof-of-concept before the end of 2019. Genzyme will have the option to development and commercialize these drugs outside of North America and Western Europe.

On the same day as the announcement of the new Alnylam/Genzyme deal, Alnylam acquired Merck’s RNAi program, which consists of what is left of the former  Sirna Therapeutics, for an upfront payment of $175 million in cash and stock. (This compares to the $1.1 billion that Merck paid for Sirna in 2006.) Alnylam will receive Merck’s RNAi intellectual property, certain preclinical drug candidates, and rights to Sirna/Merck’s RNAi delivery platform. Depending on the progress of any of Sirna/Merck’s products in development, Alnylam may also pay Merck up to $105 million in milestone payments per product.

Alnylam’s Phase 1 clinical studies with its ALN-TTR RNAi drugs

In August 2013, Alnylam and its collaborators published the results of their Phase 1 clinical trials of ALN-TTR01 and ALN-TTR02 (patisiran) in the New England Journal of Medicine. At the same time, Alnylam published a press release on this paper.

ALN-TTR01 and ALN-TTR02 contain exactly the same oligonucleotide molecule, which is designed to inhibit expression of the gene for TTR via RNA interference. They differ in that ALN-TTR01 is encapsulated in the first-generation version of liponanoparticle (LNP) carriers, and ALN-TTR02 is encapsulated in second-generation LNP carriers. Both types of LNP carriers are based on technology that is owned by Tekmira Pharmaceuticals (Vancouver, British Columbia, Canada) and licensed to Alnylam.

Tekmira’s LNP technology was formerly known as stable nucleic acid-lipid particle (SNALP) technology. Alnylam and Tekmira have had a longstanding history of collaboration involving SNALP/LNP technology, as described in our 2010 book-length report, RNAi Therapeutics: Second-Generation Candidates Build Momentum, published by Cambridge Healthtech Institute. Although the ownership of the intellectual property relating to SNALP/LNP technology had been the subject of litigation between the two companies, these disputes were settled in an agreement dated November 12, 2012. On December 16, 2013, Alnylam made a milestone payment of $5 million to Tekmira upon initiation of Phase 3 clinical trials of patisiran.

LNP-encapsulated oligonucleotides accumulate in the liver, which is the site of expression, synthesis, and secretion of TTR. As we discussed both in our book-length RNAi report, and in an article on this blog, delivery of oligonucleotide drugs (including “naked” oligonucleotides and LNP-encapsulated ones) to the liver is easier than targeting most other internal organs and tissues. The is a major reason for the emphasis on liver-targeting drugs by Alnylam and other therapeutic oligonucleotide companies.

To summarize the published report, each of the two formulations was studied in a single-dose, placebo-controlled Phase 1 trial. Both formulations showed rapid, dose-dependent, and durable RNAi-mediated reduction in blood TTR levels. (Both mutant and wild-type TTR production was suppressed by these drugs.)

ALN-TTR02 was much more potent than ALN-TTR01. Specifically, ALN-TTR01 at a dose of 1.0 milligram per kilogram, gave a mean reduction in TTR at day 7 of 38%, as compared with placebo. ALN-TTR02 gave mean reductions at doses from 0.15 to 0.3 milligrams per kilogram ranging from 82.3% to 86.8% at 7 days, with reductions of 56.6 to 67.1% at 28 days. The main adverse effects seen in the study were mild-to-moderate acute infusion reactions. These were observed in 20.8% of subjects receiving ALN-TTR01 and in 7.7% (one patient) of subjects receiving ALN-TTR02. These adverse effects could be managed by slowing the infusion rate. There were no significant increases in liver function test parameters in these studies.

The results of these studies have established proof-of-concept in humans that Alnylam’s TTR RNAi therapies can successfully target messenger RNA (mRNA) transcribed from the disease-causing gene for TTR. Alnylam also said in its press release that these results constitute “the most robust proof of concept for RNAi therapy in man to date”, and that they demonstrate proof-of-concept not only for RNAi therapeutics that target TTR, but also for therapeutic RNAi targeting of liver-expressed genes in general. They also note that this represents the first time that clinical results with an RNAi therapeutic have been published in the New England Journal of Medicine.

Other recent RNAi therapeutics deals, and the resurgence of the therapeutic RNAi field

The January 2014 Alnylam/Genzyme/Sanofi agreement is not the only therapeutic RNAi deal that has been making the news in 2013 and 2014. On July 31, 2013, Dicerna Pharmaceuticals (Watertown, MA) secured $60 million in an oversubscribed Series C venture financing. These monies will be used to conduct Phase 1 clinical trials of Dicerna’s experimental RNAi therapies for hepatocellular carcinoma and for unspecified genetically-defined targets in the liver. So far, Dicerna has raised a total of $110 million in venture capital.

Dicerna’s RNAi therapeutics are based on its proprietary Dicer substrate siRNA technology, and its EnCore lipid nanoparticle delivery vehicles.

On January 9, 2014, Santaris Pharma A/S (Hørsholm, Denmark) announced that it had signed a worldwide strategic alliance with Roche to discover and develop novel RNA-targeted medicines in several disease areas, using Santaris’ proprietary Locked Nucleic Acid (LNA) technology platform. Santaris will receive an upfront cash payment of $10 million, and a potential $138M in milestone payments. On January 10, 2014, Santaris announced another agreement to develop RNA-targeted medicines, this time with GlaxoSmithKline. Financial details of the agreement were not disclosed.

As in the case of Alnylam, we discussed Dicerna’s and Santaris’ technology platforms in our 2010 book-length report, RNAi Therapeutics: Second-Generation Candidates Build Momentum.

A January 15, 2014 FierceBiotech article reported that RNAi therapeutic deals were a hot topic at the 2014 J.P. Morgan Healthcare Conference in San Francisco, CA. This is a sign of the comeback of the therapeutic RNAi field, and of the return of interest by Big Pharma and by venture capitalists in RNAi drug development.

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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.

In a news release on September 23, 2013, Agios Pharmaceuticals (Cambridge, MA) announced that it had initiated its first clinical study. The company further discussed its early clinical and preclinical programs in its press release on its Third Quarter financial report, dated November 7, 2013.

Specifically, the company initiated a Phase 1 muticenter clinical trial of AG-221 in patients with advanced hematologic malignancies bearing an isocitrate dehydrogenase 2 (IDH2) mutation. The study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics and efficacy of orally-administered AG-221 in this patient population. The first stage of the Phase 1 study is a dose-escalation phase, which is designed  to determine the maximum tolerated dose and/or the recommended dose to be used in Phase 2 studies. After the completion of this phase, several cohorts of patients will receive AG-221 to further evaluate the safety, tolerability and clinical activity of the maximum tolerated dose.

We discussed AG-221 in our June 17, 2013 article on this blog. AG-221 is an orally available, selective, potent inhibitor of the mutated IDH2 protein. It is thus a targeted (and personalized) therapy for patients with cancers with an IDH2 mutation.

As we summarized in our June 17, 2013 article, wild-type IDH1 and IDH2 catalyze the NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate. Mutant forms of IDH1 and IDH2, which are found in certain human cancers, no longer catalyze this reaction, but instead catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2-HG). Agios researchers hypothesized that 2HG is an oncometabolite. They further hypothesized that developing mutant-specific small molecule inhibitors of IDH1 and IDH2 might inhibit the growth or reverse the oncogenic phenotype of cancer cells that carry the mutant enzymes.

As we further discussed in our article, Agios researchers published two articles in the journal Science in May 2013 that support these hypotheses. The researchers showed that drugs that inhibit the mutant forms of IDH1 and IDH2 can reverse the oncogenic effects of the mutant enzymes in patient-derived tumor samples. These results constitute preclinical support for the hypothesis that the two mutant enzymes are driving disease, and that drugs that target the mutant forms of the enzymes can reverse their oncogenic effects.

In the results reported in one of these research articles, Agios researchers tested a mutant-IDH2 inhibitor in hematologic malignancies (including one model leukemia and one patient-derived leukemia), and showed that treatment with the inhibitor caused differentiation of the leukemic cells to normal blood cells. This preclinical study thus supports the initiation of Agios’ new Phase 1 study of AG-221 in patients with mutant-IDH2 bearing hematologic malignancies.

Additional pipeline news in Agios’ Third Quarter 2013 Report

In addition to the report of the initiation of Phase 1 studies of AG-221, Agios reported  that it had advanced AG-120, a mutant-IDH1 inhibitor, toward Investigational New Drug (IND) filing. The company plans to initiate Phase 1 clinical trials of AG-120 in early 2014, in  patients with advanced solid and hematological malignancies that carry an IDH1 mutation.

Agios also reported in their Third Quarter 2013 Report that the company had advanced AG-348 into IND-enabling studies. AG-348 is an activator of pyruvate kinase R (PKR). Germline mutation of PKR can result in pyruvate kinase deficiency (PK deficiency), a form of familial hemolytic anemia. Agios’ in vitro studies indicate that PKR activators can enhance the activity of most common PKR mutations, and suggest that these compounds may be potential treatments for PK deficiency.

Agios’ AG-348 program is part of its R&D aimed at development of treatments for inborn errors of metabolism (IEM). We discussed this program in our November 30, 2011 article on this blog.

Agios to present preclinical research at the ASH meeting in December 2013

In a second November 7, 2013 press release, Agios announced that it would present the results of the preclinical studies of its lead programs in cancer metabolism and in IEM at the 2013 American Society of Hematology (ASH) Annual Meeting, December 7-10, 2013 in New Orleans, LA.

Agios researchers will give one presentation on a study of AG-221 treatment in a primary human IDH2 mutant bearing acute myeloid leukemia (AML) xenograft model. They will also present two posters–one on a mutant-IDH1 inhibitor in combination with Ara-C (arabinofuranosyl cytidine) in a primary human IDH1 mutant bearing AML xenograft model, and another on the effects of a small molecule activation of pyruvate kinase on metabolic activity in red cells from patients with pyruvate kinase deficiency-associated hemolytic anemia.

Can Agios Pharmaceuticals become a new Genentech?

On October 13, 2013, XConomy published an article on Agios’ CEO, David Schenkein. The article is entitled “David Schenkein, Cancer Doc Turned CEO, Aims to Build New Genentech”.

As many industry experts point out, the business environment is much different from that in which Genentech (and Amgen, Genzyme and Biogen) were founded, and grew to become major companies. As one illustration of the difference between the two eras, neither Genentech nor Genzyme are independent companies today. Biogen exists as a merged company, Biogen Idec, which between 2007 and 2011 had to fend off attacks by shareholder activist Carl Icahn.

Moreover, this has been the era of the “virtual biotech company”. These are lean companies with only a very few employees that outsource most of their functions, and that are designed to be acquired by a Big Pharma or large biotech company. The virtual company strategy has been designed to deal with the inability of most young biotech companies to go public in the current financial environment. (However, there has been a surge in biotech IPOs in the past year, including Agios’ own IPO on June 11, 2013. So it is possible that the environment for young biotech companies going public is changing.)

Nevertheless, the XConomy article states that when Dr. Schenkein was in discussions with venture capitalist Third Rock on becoming the CEO of one of their portfolio companies, he stated that he wanted “a company with a vision, and investor support, to be a long-term, independent company”. As we have discussed in this blog, and also in an interview for Chemical & Engineering News (C&EN), Agios’ strategy is to build a company that can endure as an independent firm over a long period of time, and that can also demonstrate sustained performance. This strategy has been characterized (especially in the 1990s and early 2000s) as “Built to Last”, a term that I used in the interview.

Later, Agios posted a reprint of the C&EN article on its website, which it retitled “Built to Last”. This illustrates Agios’ commitment to “Built to Last”, as is more importantly shown by the company’s financial and R&D strategy.

Even if Agios cannot become the next Genentech, it–as well as a few other young platform companies mentioned in the CE&N article–might become an important biotech or pharmaceutical company like Vertex. However, all depends on the success of Agios’ products in the clinic and at regulatory agencies like the FDA, as well as the future shape of the corporate, financial and health care environment.

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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.

On August 20, 2013, Novartis announced in a press release that the FDA had granted breakthrough therapy designation to its experimental agent BYM338 (bimagrumab) for treatment of the rare muscle wasting disease sporadic inclusion body myositis (sIBM).

sIBM is a rare–but increasingly prevalent–disease. It is the most common cause of inflammatory myopathy in people over 50. sIBM has a yearly incidence of 2 to 5 per million adults with a peak at ages 50 to 70, with male predominance. Muscle wasting caused by sIBM is superimposed upon the sarcopenia (degenerative loss of muscle mass) that typically occurs with aging.

sIBM is characterized by a slowly progressive asymmetric atrophy and weakness of muscles. Typically, patients become wheelchair bound within 10 to 15 years of onset. Death may occur due to falls, respiratory infection, or malnutrition.

The causes of sIBM are not well-understood. In sIBM, an autoimmune process and a degenerative process appear to occur in muscle cells in parallel. In the autoimmune process, T cells that appear to be driven by specific antigens invade muscle fibers. In the degenerative process, holes appear in muscle cell vacuoles, and inclusion bodies containing abnormal proteins are deposited in muscle cells.

Despite the lack of understanding of the causes of sIBM, in recent years researchers have developed potential therapeutic approaches to this disease. These therapeutic strategies are based on the hypothesis that enhancing muscle regeneration can be beneficial in treating muscle-wasting diseases regardless of their cause. Researchers have thus been working on several approaches, principally 1. developing drugs that stimulate myofiber regeneration, and 2. cell-mediated therapies to replace damaged myofibers (e.g., autologous stem cell therapy). It is the first approach that led to the discovery of Novartis’ bimagrumab.

The myostatin pathway

Myostatin is a regulator of muscle growth in mammals and other vertebrates. It is a secreted protein that is a member of the transforming growth factor beta (TGF-β) family. It is secreted in an inactive form, and must be activated via cleavage by a metalloproteinase. The activated myostatin then binds to its receptor, activin receptor type IIB (ActRIIB). The binding of myostatin to ActRIIB on myoblasts initiates an intracellular signaling cascade, which (as with other members of the TGF-β family), includes activation of transcription factors of the SMAD family. The SMADs (SMAD2 and SMAD3) in the myostatin pathway go on to induce myostatin-specific gene regulation, which inhibits the proliferation of myoblasts and their differentiation into mature muscle fibers.

Bimagrumab, the myostatin pathway, and muscle-wasting diseases

Bimagrumab is a novel, fully human monoclonal antibody (MAb), which was developed by the Novartis Institutes for Biomedical Research (NIBR), in collaboration with the human MAb specialist company MorphoSys (Martinsried, Germany). MorphoSys’ HuCAL (Human Combinatorial Antibody Library) technology was used to identify bimagrumab.

Bimagrumab binds with high affinity to the ActRIIB receptor, thus blocking myostatin binding. The researchers working on development of bimagrumab hypothesized that treatment with the drug would have the same physiological result as myostatin deficiency. For example, myostatin knockout mice have a two-fold to three-fold increase in muscle mass, without other abnormalities. Humans with a loss-of-function mutation in myostatin exhibit marked increase in muscle mass, as well as increased strength. These findings suggest that a myostatin receptor antagonist such as bimagrumab would be a potent stimulator of muscle growth.

According to Novartis’ press release, this hypothesis has been borne out in human studies. The FDA granted breakthrough status for bimagrumab based on the results of a Phase 2 proof-of-concept (POC) study that showed that the drug substantially benefited patients with sIBM compared to placebo. The results of this study will be presented at the American Neurological Association meeting on October 14, 2013. Novartis also expects to published the results of the study in a major medical journal later in 2013.

In addition to sIBM, Novartis is developing bimagrumab for the common muscle-wasting disease of aging sarcopenia, as well as for cachexia in cancer and in chronic obstructive pulmonary disease (COPD) patients, and for muscle wasting in mechanically ventilated patients. In particular, the company is sponsoring a Phase 2 POC study (Clinical Trial Number NCT01601600) of bimagrumab in older adults with sarcopenia and mobility limitations. The study is designed to determine the effects of the drug on skeletal muscle volume, mass, and strength and patient function (gait speed). It will also generate data on the safety, tolerability, and pharmacokinetics of bimagrumab in older adults, as well as (via an extended study duration) the stability of drug-induced changes in skeletal muscle and patient function.

As we discussed in the Conclusions section of our August 15, 2013 blog article on aging, aging-related sarcopenia is a major causes of disability and death. We also said in that section that sarcopenia is not normally a target for drug development. At that time, we did not know about Novartis’ development of bimagrumab. We are happy to be proven wrong about drug development for sarcopenia.

Another approach to myostatin pathway-based drug development

A fully-human anti-myostatin MAb, Regeneron/Sanofi’s REGN1033 (SAR391786), is in Phase 1 clinical development for treatment of sarcopenia. Unlike bimagrumab, which binds to the myostatin receptor ActRIIB, REGN1033 binds directly to myostatin. REGN1033 thus represents an alternative approach to treatment of sarcopenia and other muscle-wasting conditions via the myostatin pathway.

Attempts to address the causes of muscle degeneration in sIBM directly

Despite the evidence from early clinical trials that therapies that enhance muscle regeneration may be effective in treating sIBM, some researchers believe that it will be necessary to identify the causes of muscle degeneration in sIBM and to address them. For example, there is evidence that in some patients, autoantibodies may recognize antigens that are enriched in regenerating muscle fibers. Some researchers therefore hypothesize that treating such patients with therapies that enhance muscle regeneration without addressing the autoimmune pathology may be counterproductive. Therefore, continuing research on the causes of muscle degeneration in sIBM and on potential therapies to slow this degeneration may still be important, despite the apparent progress of clinical trials of such drugs as bimagrumab.

For example, some researchers hypothesize that sIBM is a primary degenerative disease, like Alzheimer’s and Parkinson’s disease. As with these neurodegenerative diseases, some researchers have found evidence that misfolded proteins may be involved in the pathogenesis of sIBM. This avenue of research has led to the hypothesis that agents that enhance correct protein folding may slow muscle degeneration in sIBM patients. One such agent, CytRx’ arimoclomol has been in clinical trials in sIBM patients. [Arimoclomol is also in clinical trials in patients with amyotrophic lateral sclerosis (ALS)].  Arimoclomol appears to act as a coinducer of chaperone proteins such as heat shock protein 70 (Hsp70). Chaperone proteins promote the correct folding of intercellular proteins.

In a small POC Phase 2a clinical trial in Europe, arimoclomol showed early signs of efficacy, in addition to being well tolerated. There was a trend toward slower degeneration in physical function, muscle strength, and right-hand grip muscle strength in arimoclomol-treated patients as compared to placebo over an 8-month period.

Other researchers are attempting to address the inflammatory aspects of sIBM. For example, there are early clinical trials in progress of  the-anti-lymphocyte agent alemtuzumab (Genzyme’s Campath/Lemtrada) and the anti-tumor necrosis factor agent etanercept (Amgen/Pfizer’s Enbrel).

Meanwhile, additional basic research on the causation of sIBM continues. Some of these approaches may eventually lead to additional drug discovery strategies for this disease.

However, whether or not muscle-enhancing therapies such as bimagrumab might provide adequate treatment for at least some classes of sIBM patients (without addressing the autoimmune and/or degenerative aspects of the causation of the disease) will depend on the results of late-stage clinical trials now in the planning stage.

Conclusions

The development of bimagrumab represents an example of Novartis’ pathway-based rare disease strategy. We discussed this strategy in our July 20, 2009 Biopharmconsortium Blog article. Novartis researchers note that in many cases rare diseases are caused by disruptions of pathways that are also involved in other rare diseases and/or in more common diseases. The researchers therefore develop drugs that target these pathways, and obtain POC for these drugs by first testing them in small populations of patients with a specific rare disease. Drugs that have achieved POC in this rare disease may later be tested in other indications (especially including more common diseases) that involve the same pathway.

As we discussed in our July 20, 2009 article, the first drug that Novartis developed by using this strategy is the interleukin-1β inhibitory MAb drug Ilaris (canakinumab). The company conducted its first clinical trials in patients with cryopyrin-associated periodic syndromes, (CAPS), a group of rare inherited auto-inflammatory conditions that are characterized by overproduction of IL-1β. In 2009, the FDA and the European Medicines Agency approved Ilaris for treatment of CAPS. Since that time, Novartis has been conducing clinical trials of canakinumab in such conditions as systemic juvenile idiopathic arthritis (SJIA), gout, acute gouty arthritis, type 2 diabetes, and several others. Canakinumab had also been tested in rheumatoid arthritis, but these trials have been discontinued.

In the case of bimagrumab, Novartis researchers are targeting the myostatin pathway. The strategy is to first target the rare disease sIBM, and to obtain POC in human studies in that disease. Novartis claims (and the FDA concurs with them) that they have obtained POC in sIBM, and the company plans to present the results of its POC clinical trial later this year, both in a scientific meeting and in a publication. Novartis then plans to complete development of bimagrumab for sIBM, while also developing the drug for other muscle-wasting conditions, especially the more common aging-related condition sarcopenia, which is becoming a major public health problem.

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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 reported in Nature News on 27 February 2013 ophthalmologist Masayo Takahashi M.D., Ph.D. and her colleagues at the RIKEN Center for Developmental Biology (Kobe, Japan), plan to submit an application to the Japanese health ministry for a clinical study of induced pluripotent stem cell (iPS)-derived cells. The researchers planned to submit their application in March 2013; if approved, they could begin recruiting patients as early as September.

The author of the Nature News article is Nature‘s Asian-Pacific Correspondent, David Cyranoski, who is based in Tokyo.

The researchers plan to treat approximately six people with severe age-related macular degeneration (AMD). Specifically, the researchers are targeting “wet” AMD, in which angiogenic blood vessels invade the retina, destroying the retinal pigment epithelium (RPE) that supports the light-sensitive photoreceptors.

AMD is a common cause of blindness that affects at least 1% of adults over 50. Wet AMD can be treated with anti-vascular endothelial growth factor (anti-VEGF) agents such as ranibizumab (Genentech/Novartis’ Lucentis), pegaptanib (Gilead/OSI/Pfizer’s Macugen), aflibercept (Sanofi/Regeneron’s Eylea), and–off-label–small doses of the anticancer agent bevacizumab (Genentech/Roche’s Avastin). However, the use of these agents requires that they be injected repeatedly into the eye.

According to the Nature News article, Dr. Takahashi and her colleagues will take an upper arm skin sample the size of a peppercorn, and transform the cells from this sample into iPS cells by using specific proteins. They will then add other factors that will induce differentiation of the iPS cells into retinal cells. Then a small sheet of these retinal cells will be placed under the damaged area of the retina, where they are expected to grow and repair the damaged RPE.

Although the researchers would like to demonstrate efficacy of this treatment in ameliorating the disease, the main focus of these studies will be on safety. Safety concerns include immunogenicity of the transplanted cells, and formation of tumors if the transplanted cells multiply uncontrollably. Another concern is that the transplanted cells might fail to engraft, and to integrate with the host tissue. It is also possible that the RPE identity of the transplanted and differentiated cells might not be stable over time.

With respect to these concerns, studies published by Japanese researchers in 2013 (Araki et al.) and reviewed in a recent Nature News article contradicted the original mouse studies that suggested that syngeneic or autologous iPS cells might be immunogenic.

With respect to tumor formation, Dr. Takahashi’s proposed studies will involve using only a few iPS cells, thus reducing the probability of forming tumors. Moreover, since the eye is relatively accessible, any tumors would be relatively easy to remove.

In addition, Dr, Takahashi has presented preclinical studies at conferences, which indicate that her iPS cells do not form tumors in mice and are safe in non-human primates. (Dr. Takahashi’s preclinical studies have also been submitted for publication.) The studies have provided reassurance of the cells’ safety to at least some leading researchers, such as Martin Pera (University of Melbourne, Australia) and George Daley (Harvard Medical School, Boston MA).

However, other researchers believe that to take iPS cell-derived tissue into the clinic at this time is premature. Robert Lanza, M.D., the chief scientific officer at Advanced Cell Technology (ACT) (Santa Monica CA) says that he cannot imagine regulatory agencies permitting studies such as Dr. Takahashi’s without years of preclinical testing.

As mentioned in the Nature News article, ACT has a program involving human embryonic stem cell (hES cell) and iPS-derived platelets for transfusion. This program is in the preclinical stage. Since platelets lack a nucleus and cannot form tumors, it is inherently less risky that clinical programs of stem-cell (and especially iPS cell) derived differentiated cells that have nuclei.

Dr. Takahashi’s proposed study of her therapy in humans is considered a “clinical study”, not a clinical trial. In Japan’s regulatory system, clinical studies are less tightly regulated than clinical trials. However, a clinical study cannot by itself lead to approval of a potential therapeutic for clinical use as a treatment. If Dr. Takahashi’s clinical study data is positive, that might attract investors or help her to get approval for a formal clinical trial. As in the U.S. or Europe, successful clinical trials will be required if Dr. Takahashi’s cellular therapy is ever to be used to treat patients.

Dr. Takahashi’s clinical study was approved by institutional review boards at both the natural sciences institute RIKEN in Wako and the Institute of Biomedical Research and Innovation in Kobe, where the surgical procedures will be carried out. Final approval will depend on the action of a committee of the Japanese Ministry of Health, Labour and Welfare. If Dr. Takahashi wins approval by September 2013 as expected, it will take another eight months to produce the tissue implants needed for her clinical study.

Other retinal repair programs involving human embryonic stem cell-derived RPE cells

Dr. Takahashi’s research does not represent the only RPE cell-based retinal repair program now being developed. There are at least two others, both of which are based on hES cells, not iPS cells.

As was not mentioned in the Nature News article, ACT has Phase 1 trials underway in its own RPE retinal repair program. ACT’s RPE cells are derived from human embryonic stem cells (hES cells). The company’s Phase 1 safety studies are in Stargardt’s Macular Dystrophy (SMD) and in dry AMD (which results from atrophy of the RPE layer, and causes vision loss through loss of photoreceptors in the central part of the eye. Dry AMD does not involve angiogenesis.). SMG is a rare inherited juvenile macular degeneration.

In February 2012, Dr. Lanza and his academic collaborators at the University of California at Los Angeles published a preliminary report of their clinical studies in dry AMD and SMG. In this study, one patient with each of the two conditions was treated with hES cell-derived RPE cells. The hES cell-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. Neither patient showed loss of vision, and there were signs of improvement of vision. As a result of this very preliminary study, the researchers decided in the design of future clinical studies to treat patients earlier in the disease processes, potentially increasing the likelihood of improvement of vision.

The other RPE-based retinal repair program is a collaborative effort between Neusentis (A Cambridge U.K. and Durham NC-based Pfizer research unit) and “The London Project” which was formed by Professor Pete Coffey [Institute of Ophthalmology, University College London (UCL)] and his collaborator Lyndon da Cruz (Moorfields Eye Hospital) to develop cellular therapies for all types of AMD. The London Project began collaborating with Pfizer in 2008; this collaboration was brought under the aegis of Neusentis when it was formed in 2011. Research is based on RPE cells derived from hES cells.

The Neusentis/London Project group claims to have developed a deep understanding of the biology of hEC cell-derived RPE cells, and to have worked out methods of producing enough RPE cells under GMP conditions to support clinical studies. They also claim to have developed a clear approach to establishing the safety of the therapy via preclinical studies. The collaborative group is now moving towards clinical studies of their therapies, which they “hope to achieve in the not too distant future”.

As we discussed in our February 15, 2011 article on this blog, Pfizer–as of February 1, 2011–closed its Memorial Drive laboratory in Cambridge, MA. This laboratory housed most of Pfizer’s regenerative medicine research, as well as the company’s RNAi therapeutics research group. However, as we said in this article, Pfizer was folding its Cambridge, UK regenerative medicine group–“which had been focusing on development of preclinical embryonic stem (ES) cell-based ophthalmology therapies, in collaboration with the University of London”–into a “new pain and sensory disorder research unit”. According to its website, Neusentis, which was formed in 2011, has “a particular focus on pain and sensory disorders”.

Japanese government backing for iPS cell research and commercialization

Japan has been a hotbed of iPS cell research, since these cells were first produced by Shinya Yamanaka, M.D. Ph.D. (Kyoto University) in 2006. He received The Nobel Prize in Physiology or Medicine in 2012 for his work on iPS cells. The co-recipient of the Prize, Sir John B. Gurdon, successfully cloned a frog using intact nuclei from the somatic cells of a Xenopus tadpole back in 1958. The two scientists received the 2012 Prize “for the discovery that mature cells can be reprogrammed to become pluripotent”. Since their discovery, iPS cells have been employed in such areas as basic research, disease modeling, and drug screening. (Follow this link for a recently-published example of the potential use of iPS cells in designing personalized treatments for Alzheimer’s disease.)

In 2013, as part of its stimulus package, the Japanese government has been providing generous funding for iPS research. This funding includes ¥700 million for a cell-processing centre at the Foundation for Biomedical Research and Innovation in Kobe, mainly to support Dr. Takahashi’s regenerative medicine research. In general, the iPS funding under the stimulus is aimed at moving university research on iPS cells into commercial and medical applications.

Moreover, according to Mr. Cyranoski’s 27 February 2013 Nature News article, the Japanese parliament is expected to rule by late June 2013 on a provision of a revised drug law, which would fast-track iPS-based therapies that appear to be effective in phase 2 or phase 3 trials. However, the success of the Japanese government’s efforts to accelerate commercialization of iPS-based therapies may depend in part on the success of Dr. Takahashi’s clinical research.

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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.