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Tuesday, June 4, 2019

Home exercise program reduces rate of falling in at-risk seniors

An in-home exercise program reduced subsequent falls in high-risk seniors by 36 per cent, according the results of a 12-month clinical trial published today in the Journal of the American Medical Association.
The study, conducted by UBC faculty of medicine researchers in partnership with the clinical team at the Falls Prevention Clinic at Vancouver General Hospital, found a reduction in fall rate and a small improvement in cognitive function in seniors who received strength and balance training through the clinical trial.
“When we think about falls we often think about loss of muscle strength and poor balance,” said Dr. Teresa Liu-Ambrose, principal investigator at the Vancouver Coastal Health Research Institute and professor in the department of physical therapy at the University of British Columbia. “However, the ability to remain upright and not fall is also dependent on cognitive abilities–calculating how far to lift your foot to get over a curb, making a decision as to when to cross the road, and paying attention to your physical environment while you are having a conversation.”
Falls increase risk of injury and loss of independence for older adults. Exercise is a widely recommended fall prevention strategy, but whether it can reduce subsequent falls in those who have previously fallen is not well established.
The study involved 344 adults aged 70 and older who had been referred to the Falls Prevention Clinic following a fall that had resulted in a visit to a medical facility, such as an emergency room. Participants had a history of falls, with an average of three prior falls per person, and generally had symptoms of frailty and limited mobility.
The study had participants perform a set of balance and resistance training exercises in the comfort of their homes, using simple equipment such as free weights, a minimum of three times per week. Over the course of six months, a physical therapist made five home visits to prescribe exercises and ensure that exercises were done properly. For those who completed the program, the results were notable. Participants were less likely to experience repeat falls, and as a secondary benefit, they improved in some markers of cognitive function.
Falls in older adults are the third-leading cause of chronic disability. According to the Public Health Agency of Canada, 20 to 30 per cent of Canadian seniors suffer falls each year, and falls are the leading cause of hospitalization for adults over age 65.
“It is well known that exercise benefits older people in general, but what was special about this study group was that they are at very high risk for losing their independence–they had both mobility and cognitive impairments and another fall may mean the inability to live in their own homes. Many already had difficulty navigating public spaces independently,” said Liu-Ambrose, who holds a Canada Research Chair in Physical Activity, Mobility, and Cognitive Neuroscience.
“Older adults who experience falls that require medical attention falls are medically complex and at high risk for both morbidity and mortality, and we demonstrated that exercise is a practical and cost-effective intervention that can improve older peoples’ outcomes after a significant fall,” she added.
Liu-Ambrose and her team at the Centre for Hip Health and Mobility are now looking at whether the exercise program resulted in reduced health care utilization and medical cost savings in this high-risk population.

Allena Announces Interim Results from Kidney Disorder Med Study

— Substantial Treatment Effect Observed in Patients with Enteric Hyperoxaluria, Including Robust Reductions in Both Urine and Plasma Oxalate 
— Reloxaliase Well-Tolerated Over 12 Weeks of Dosing 
— Detailed Results to be Presented at OHF International Hyperoxaluria Workshop in June 2019 —
Allena Pharmaceuticals, Inc. (NASDAQ: ALNA), a late-stage, biopharmaceutical company dedicated to developing and commercializing first-in-class, oral enzyme therapeutics to treat patients with rare and severe metabolic and kidney disorders, today announced interim data from Study 206, its Phase 2 basket clinical trial of reloxaliase, an orally-administered, recombinant oxalate-degrading enzyme. Study 206 includes adult and pediatric patients suffering from the progression of primary hyperoxaluria (PH) or enteric hyperoxaluria (EH) with advanced chronic kidney disease (CKD), both of which can lead to systemic oxalosis, a potentially life-threating condition. Consistent with Allena’s prior clinical experience, EH patients treated with reloxaliase in Study 206 demonstrated a substantial treatment effect.  This includes EH patients with advanced CKD, a patient population not previously treated with reloxaliase, who showed reductions in urine oxalate (UOx) and plasma oxalate (POx). Allena plans to present detailed results at the OHF International Hyperoxaluria Workshop, June 21-22, 2019 in Boston, MA.
“We are pleased to see a robust response to reloxaliase in EH patients suffering from advanced stages of the disease. We believe this reflects reloxaliase’s activity and novel mechanism of action of degrading oxalate within the GI tract, which is well-targeted to treat excess oxalate absorption driven by an underlying GI disorder. The potential to alleviate the high oxalate burden on these patients is very encouraging,” said Louis Brenner, M.D., President and Chief Executive Officer of Allena Pharmaceuticals. “To our knowledge, this is a first demonstration of a specific pharmacologic therapy leading to reduction in plasma oxalate and urinary oxalate levels in patients with EH and decreased kidney function, which represents a significant advancement for the field and especially for patients with systemic oxalosis. These results advance our efforts to develop reloxaliase as a potential first-in-class therapy for patients with enteric hyperoxaluria, and we look forward to additional data from Study 206, as well as topline data from our pivotal Phase 3 URIROX-1 trial, anticipated in the second half of the year.”

Continued Peanut Allergy Therapy Spurs Greater Tolerance, Data Shows

As Aimmune Therapeutics awaits potential regulatory approval of its peanut allergy treatment, the company released additional data that showed an extension of daily therapy with its experimental AR101 asset significantly improved tolerability to peanut allergies.
Aimmune announced results from ARC004, an open-label, rollover study of the landmark Phase III PALISADE trial that showed an extension of daily therapy with AR101 by an additional 28 weeks improved tolerability with lower numbers of adverse events compared to the PALISADE therapeutic dosing period. Initial Phase III data showed treatment with the AR101 peanut allergy therapy was effective in more than 67% of juvenile patients. At the time the trial data was released, Aimmune said the patients administered AR101 in the PALISADE trial could tolerate exposure of at least a 600-mg dose of peanut protein in the exit food challenge. Only 4% of patients on the placebo could tolerate that amount, the company said when the late-stage data was released.
The latest data though, presented at the European Academy of Allergy and Clinical Immunology Congress 2019 in Lisbon, shows that longer treatment with AR101 provides even greater protection. The study showed that 79.8% of patients who continued taking AR101, an oral biologic desensitization therapy that is sprinkled over food before eating, could tolerate doses of at least 1,000 mg of peanut protein. Nearly half, 49%, of the patients, tolerated the highest 2,000 mg dose during the exit food challenge. Patients enrolled in the study continued to see meaningful immunological changes, reinforcing the potential benefits of continued daily AR101 dosing after one year, Aimmune said.

“These findings demonstrate that AR101 treatment extended into the second year reduces adverse events, increases ability the ability to tolerate even high levels of exposure to peanut protein over time, and further modulates the immune response to peanut in most patients,” said Daniel Adelman, Aimmune’s chief medical officer, said in a statement.
Adelman added that the results of the extended study should provide some peace of mind to patients with peanut allergy and their families.
Approximately 2.5% of all children in the U.S. may be allergic to peanuts. It is one of the most common food allergies. According to the American College of Allergy, Asthma and Immunology, the incidence of peanut allergies in children in the U.S. has risen about 21% since 2010.
A U.S. Food and Drug Administration advisory committee is expected to weigh in on Aimmune’s peanut allergy treatment in September. The FDA accepted the BLA for AR101 in March 2019 and previously informed Aimmune that completion of its review would be targeted by late January 2020. AR101 was granted Fast Track designation from the FDA.
Last year, in anticipation of the likely approval of AR101, Nestlé increased its stake in the company. The nearly $100 million investment gave the conglomerate a 19% ownership of Aimmune. Nestlé first pumped $145 million into the company in 2016 and then another $30 million as part of its initial public offering last year.

Asco 2019 – Macrogenics builds a case for margetuximab

Demonstrating an overall survival benefit remains crucial for Macrogenics’ anti-Her2 antibody margetuximab, for regulatory approval and any partnering deals alike.
It is still far from clear whether Macrogenics will be able to win approval for margetuximab in Her2-positive breast cancer – not least because the pivotal Sophia trial has yet to demonstrate a survival benefit. Full presentation of the results at Asco today, showing a benefit in patients with a particular genotype, could well raise some hopes.
New gastric cancer data, to be detailed by the company today at an investor event, might also help bolster opinions about margetuximab: an impressive 17-month survival benefit has been generated in a second-line setting, and a first-line study will start later this year, the group’s chief executive, Scott Koenig, told Vantage this morning.
“We are seeing tremendous responses – the overall survival we have seen not only beats standard of care in second line, but in first line as well,” he said.
Progress in gastric cancer, another Her2-driven tumour type, is comfort of sorts for investors as the next survival analysis approaches for the Sophia breast cancer trial, due in the second half of the year. Margetuximab, an engineered antibody, has been designed to be a “better Herceptin”, and trials in both of these settings are crucial tests of the project
Asco presention
Today’s presentation at Asco provided full details of the first interim analysis of Sophia, which was already known to have hit on progression-free survival (Surprise! Macrogenics could have a commercially viable drug, February 6, 2019).
Sophia recruited a heavily pretreated population – subjects had to have received at least two prior anti-Her2 therapies, and went on to receive chemo plus either Herceptin or margetuximab. Progression-free survival and overall survival were sequential primary endpoints; these data were outlined in a press release a couple of weeks ago.
On PFS margetuximab beat Herceptin by just under one month, a result that was statistically significant but whose clinical relevance looks doubtful. In a subset of patients carrying a particular gene – called the CD16A/158F allele – the benefit was slightly more marked: PFS improved to 6.9 months versus 5.1 months for Herceptin, with a hazard ratio of 0.76.
86% of the Sophia patients were carriers of CD16A/158F, a figure that probably reflects the real world distribution. It has long been suspected that patients with this genotype have a poor response to Herceptin.
An interim look at overall survival appears to confirm this: OS underwhelmed in the total trial population, but thanks to a late separation in the survival curves it was improved at the median in CD16A/158F patients.
Still, shares in the company dropped 13% after the Asco presentation, presumably on the first look at the OS curves.
Macrogenics Asco 2019 Sophia study presentation
An important point here is that, although stratification by this genotype was prespecified, the findings can only be considered exploratory because no statistical power was attributed to these analyses.
What the regulators make of this remains to be seen, and in any case Mr Koenig said Macrogenics would file on the totality of the data, rather than actively seeking a label in CD16A/158F patients.
“They can decide to restrict it – and we wouldn’t be unhappy if they did restrict it to the 85% of the population… but I would be surprised based on the small numbers [of patients who do not carry the CD16A/158F allele],” he said.
He added that when investigators analysed the patients who did not carry CD16A/158F they found a disparity in terms of elderly and later-line patients, which could also explain the different responses seen.
Macrogenics intends to file when it has the next interim OS data in house, which will happen when 270 deaths have occurred. The final analysis will be triggered after 385 deaths, and Mr Koenig played down the possibility of seeing a survival benefit before then.
“At 270 events it is more likely we won’t hit statistical significance – if we do that would be wonderful,” he said, adding that the FDA had not discouraged the company from filing early. “The guidance to us is if we hit PFS, and there is perceived clinical benefit, that could be the basis of an approval.”
Of course the basis for approval and the basis for commercial success can be entirely different, as previous companies that have shown only marginal efficacy have discovered. Much depends here on regulators’ and ultimately clinicians’ views of the rigour of this exploratory subgroup; Mr Koenig added that nothing in discussions with the FDA had suggested that a request for a confirmatory trial might emerge.
The company is also in talks with “a number” potential partners with regional and worldwide footprints, though no firm decisions have been made about the way forward here, he said. A demonstrable survival benefit would obviously be a huge benefit during such negotiations, adding more pressure on that final survival readout.

After raising $40M, Celgene partner Inhibrx eyes nearly $75M IPO

Celgene-partnered biotech Inhibrx has had a busy 2019 so far. The La Jolla, California-based company kicked off an early-stage oncology study, partnered with Bluebird bio, signed a pact with Italy’s Chiesi Group and secured a $40 million venture capital injection. On Monday, it laid the groundwork for a roughly $75 million IPO.
Inhibrx is developing a plethora of biologics — it has three oncology programs in human clinical trials, a rare disease program, for which it expects to initiate a human study in the third quarter of 2019, as well as two preclinical drugs.
Its lead experimental drug targets death receptor 5, or DR5, and is designed to treat multiple tumor types, including difficult-to-treat gastrointestinal tumors and mesothelioma both as a monotherapy and in combination with chemotherapy. It is currently being investigated in an early stage trial in patients with solid tumors including sarcomas, and the readout of that study is expected in the second half of this year.
Global rights to Inhibrx’s drug, INBRX-103, that targets CD47 — which protects tumor cells from being engulfed by macrophages — have been licensed to Celgene $CELG. Meanwhile, it has entered into an option agreement with Chiesi for development and commercialization rights outside of North America for INBRX-101 — which is being developed for the rare respiratory disease Alpha-1 antitrypsin (AAT) deficiency.
Now, Inhibrx is looking to list on the Nasdaq under the symbol “$INBX” and raise $74.75 million in the IPO. In a separate private placement concurrent with the offering, Chiesi is buying $10 million worth of Inhibrx shares, according to Inhibrx’s filing.
Last month, Inhibrx raised $40 million from Viking Global Investors — altogether the company has so far raised $205 million since its inception. Other investors in the biotech include RA Capital, Lilly Asia Ventures, ArrowMark Partners, WuXi Biologics and Alexandria.

Survival benefit in melanoma for Novartis Tafinlar + Mekinist

  • Five-year Tafinlar + Mekinist survival data presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting and published simultaneously in The New England Journal of Medicine
  • Results are from the largest dataset and longest follow-up of more than 500 patients with BRAF-mutated metastatic melanoma, a genetic mutation common for this aggressive skin cancer
  • Additional Novartis melanoma research presented at ASCO includes efficacy and safety data investigating the immunotherapy spartalizumab (PDR001) combined with Tafinlar + Mekinist
Novartis announced today results from the landmark COMBI-d and COMBI-v clinical trials, concluding that first-line treatment with Tafinlar (dabrafenib) and Mekinist (trametinib) offers both overall and progression-free long-term survival benefits to patients with unresectable or metastatic BRAF-mutation positive melanoma. Researchers reported that 34% (95% CI: 30-38%) of all patients in the pooled analysis who were treated with Tafinlar + Mekinist survived at five years[1]. Study authors also reported on prolongation in progression-free survival (PFS), with 19% (95% CI: 15-22%) of patients showing no sign of disease progression or death at five years. Five-year overall survival and PFS were similar in the pooled patient population[1],[4].
The results, from a pooled analysis of 563 patients from the COMBI-d and COMBI-v trials, represented the largest collection of data and longest follow-up among patients with advanced melanoma with BRAF V600-mutated unresectable or metastatic melanoma who were treated with Tafinlar + Mekinist. These data were presented at the 2019 ASCO Annual Meeting (Abstract #9507) and published simultaneously in The New England Journal of Medicine[1],[4].
“Our analysis demonstrates that first-line therapy with Tafinlar + Mekinist leads to five-year disease control in about one-fifth of the patients and five-year survival in about one-third of those treated,” said Caroline Robert, MD, Ph.D., Head of the Dermatology Unit at the Institut Gustave Roussy in Paris. “While metastatic melanoma has historically had a very poor prognosis for patients, there are many reasons to be encouraged today. Our analysis demonstrates a clinically meaningful and positive impact on patient survival. These results show that targeted therapies may provide long-term survival and offer durable outcomes.”

Celgene Announces Data from Ongoing Blood Cancer Studies

Celgene Corporation (NASDAQ: CELG) today announced that data from the TRANSCEND CLL 004 and TRANSCEND NHL 001 trials studying the investigational anti-CD19 chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel; JCAR017) in patients with B-cell blood cancers were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
Updated results from the ongoing, open-label multicenter phase 1/2 TRANSCEND CLL 004 study (Abstract #7501) of liso-cel in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) were presented in an oral presentation today. The data included safety and efficacy findings from 23 patients who received liso-cel infusion at one of two dose levels: 50 × 106 or 100 × 106 total CAR-positive T cells following lymphodepleting chemotherapy. All patients had been previously treated with ibrutinib, and more than half had received prior venetoclax. The median number of lines of prior therapy was five and 83% of patients had high-risk cytogenetic features.
In the study, 22 of 23 patients were evaluable for response. The best overall response rate was 82% (18/22), with 46% (10/22) of patients achieving complete remission with or without complete blood count recovery (CR/CRi). Of 20 patients evaluable for minimal residual disease (MRD), 75% (15/20) achieved undetectable MRD (uMRD) by blood measures (sensitivity, 10-4) and 65% (13/20) achieved uMRD by bone marrow measures (sensitivity, 10-4). Responses have been durable, with 83% of patients (5/6) who were in CR/CRi at six months post liso-cel infusion showing ongoing response.
“For patients who have failed the current standard of care treatments for CLL, such as ibrutinib and venetoclax, there is a need for additional treatment options,” said lead study investigator Tanya Siddiqi, M.D., City of Hope National Medical Center. “I am highly encouraged by this early data showing manageable toxicity and promising clinical activity in a heavily pretreated patient population with high-risk CLL. In this preliminary analysis, clinical responses are rapid, deep and durable when assessed by clinical and MRD criteria. We look forward to further investigation of liso-cel in CLL patients who have relapsed from or have become refractory to currently available treatment options.”